Continuing Education Activity

The white dot syndromes constitute a group of inflammatory chorioretinopathies. The common defining clinical feature is the presence of multiple, discrete, white lesions located at the deeper levels of the retina and choroid. Though several white dot syndromes are associated with a viral prodrome, an etiology is lacking for these conditions. Typically seen in young, otherwise healthy adults, the white dot syndromes most often present with symptoms of photopsia, floaters, decreased night vision, blurred vision, and visual field loss. These conditions are acute in onset, and many, though not all, are transient without long-term visual consequences. Though the white dot syndromes share similar clinical features, including the tell-tale chorioretinal lesions, several distinct clinical features, and diagnostic testing findings allow for additional characterization. This activity outlines the white dot syndromes and includes a discussion of etiologies, epidemiology, pertinent history, examination findings, options for evaluation, and the interprofessional healthcare team's role in managing patients with these conditions.

Objectives:

• Identify the typical clinical features of the white dot syndromes.
• Outline the appropriate evaluation of a patient with a presumptive white dot syndrome.
• Differentiate the management options available for white dot syndromes.
• Summarize interprofessional team strategies for improving care coordination and communication to advance the management of white dot syndromes and improve outcomes.

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Introduction

The white dot syndromes constitute a group of inflammatory chorioretinopathies. The common, defining clinical feature is the presence of multiple, discrete, white lesions located at the deeper levels of the retina choroid.[1] Several white dot syndromes are associated with a viral prodrome; an etiology is lacking for these conditions. Typically seen in young, otherwise healthy adults, the white dot syndromes most often present with symptoms of photopsia, floaters, decreased night vision, blurred vision, and visual field loss.[2] These conditions can be acute in onset or transient without long-term visual consequence. White dot syndromes share similar clinical features, including the "tell-tale" chorioretinal lesions, several distinct clinical features, and diagnostic testing findings that allow for additional characterization. Commonly recognized white dot syndromes include Multiple evanescent white dot syndrome (MEWDS), acute retinal pigment epitheliopathy (ARPE), acute posterior multifocal placoid pigment epitheliopathy (APMPPE), multifocal choroiditis and panuveitis (MCP), acute zonal occult outer retinopathy (AZOOR), birdshot chorioretinopathy, serpiginous choroidopathy, and punctate inner choroidopathy (PIC).[1] These conditions are conventionally recognized as distinct identities, and some suggest that they represent a spectrum of chorioretinal diseases.[3] 

Etiology

The etiology of the white dot syndromes remains unknown. Several entities are associated with a viral prodrome, suggesting a potential viral or infectious etiology. Like most autoimmune conditions, an unknown trigger is thought to precipitate an inflammatory or autoimmune process in the posterior eye.[4] The white dot syndromes represent a primary ocular process and are not associated with systemic inflammatory or autoimmune disease. An increased prevalence of such conditions has been demonstrated in several subgroups of patients with white dot syndrome (ie, AZOOR).[5] Birdshot chorioretinopathy is highly associated with the presence of the HLA-A29 haplotype.[6] This correlation is so prominent that the absence of this haplotype, even within typical clinical features, should prompt consideration of an alternative diagnosis.

Epidemiology

With a few exceptions (birdshot chorioretinopathy, serpiginous choroiditis), white dot syndromes are present in young, otherwise healthy adults below 50.[1] Gender differences allow further characterization of these entities, with a female predominance recognized in birdshot chorioretinopathy, MCP, PIC, AZOOR, and MEWDS.[2] The incidence of white dot syndromes in a community-based population was 0.45 per 100,000 per year, consistent with their description as rare disease entities.[7]

History and Physical

Historical features most consistent with a white dot syndrome include the relatively acute onset of visual symptoms, including visual field loss or scotoma, flashes of light or photopsia, blurred vision, and floaters.[2] Consistent with a potential viral or infectious etiology, patients may report symptoms of a viral prodrome. The primary feature involves developing characteristic white or cream-colored chorioretinal lesions, the morphology and distribution of which aid in distinguishing white dot syndrome from others. White dot syndromes may differ in the laterality of involvement, with some conditions typically presenting in a unilateral fashion (MEWDS); others are bilateral (APMPPE, birdshot chorioretinopathy, MCP).[1] The presence of anterior chamber cells or inflammation is rare, except for MCP. Vitritis may be seen in several white dot syndromes, most consistently in birdshot chorioretinopathy.[8]

Evaluation

Laboratory testing in patients with white dot syndrome is generally most useful in excluding alternative etiologies on the differential diagnosis.[9][10][11] Serologic testing for syphilis is recommended in all patients, with screening for tuberculosis conducted in those patients with known exposure or risks. Poor screening tests and angiotensin-converting enzyme levels are often obtained in conjunction with chest X-ray imaging to evaluate for evidence of underlying sarcoidosis.[12] Ocular diagnostic testing may assist in the differentiation of specific white dot syndromes with suggestive features often evident in fluorescein angiography, optical coherence tomography, visual field testing, indocyanine green angiography, fundus autofluorescence, and electroretinography studies.[13][14][15][16]  

Treatment / Management

Many white dot syndromes are benign and self-limited, negating the need for treatment. A few white dot syndromes are persistent and progressive, with significant visual consequences if untreated (MCP, serpiginous choroiditis, and birdshot chorioretinopathy). Treatment in these conditions initially involves using local or systemic corticosteroids with a transition to steroid-sparing systemic immunotherapy.[17][18] Typical agents would include traditional immunotherapies such as methotrexate, mycophenolate mofetil, azathioprine,and cyclosporine, as well as biological agents, including anti-TNF medications: adalimumab and infliximab.[19] The cytotoxic agents cyclophosphamide and chlorambucil have been utilized in vision-threatening conditions such as serpiginous choroiditis.[20] Management of associated ocular complications such as cystoid macular edema (CME) and choroidal neovascularization (CNV) may involve immunosuppression or localized ocular therapies, including anti-vascular endothelial growth factor agents, laser photocoagulation therapy, or photodynamic therapy.[21][22][23] 

Differential Diagnosis

Infectious and noninfectious entities are included in the differential diagnosis of the white dot syndromes. The noninfectious processes include sarcoidosis, Vogt-Koyanagi-Harada syndrome, sympathetic ophthalmia, and intraocular lymphoma.[11] Syphilis, primary ocular histoplasmosis syndrome, tuberculosis, and diffuse unilateral subacute neuroretinitis are infectious entities that should be considered in the differential diagnosis of white dot syndrome.[24]

Prognosis

The prognosis for most white dot syndromes (ARPE, MEWDS, APMPPE, AZOOR) is good, with most patients experiencing a benign and self-limited course with an eventual return to or near baseline vision.[25][26][27][26] The persistence of various visual phenomena, such as scotoma and photopsia, may occur in a small percentage of such patients.[26] Several white dot syndromes (MCP, birdshot chorioretinopathy, serpiginous choroiditis) demonstrate a more persistent and progressive clinical course and may result in moderate to severe visual decrement.[28][29][30][28] Therefore, early identification and management of these conditions are paramount.

Complications

Extraocular complications of white dot syndromes are rare. Patients may present with a viral prodrome that is typically self-limiting. In patients with APMPPE, symptoms of a viral prodrome may include meningeal features.[31] A few white dot syndromes are associated with autoimmune disease, so carefully evaluate for symptoms or signs that might suggest such a condition.[4] Potential complications related to the use of systemic immunotherapy require monitoring by a specialist trained in the use of such agents.[19] Associated ocular complications include those inherent to chorioretinopathy, such as CME and CNV. The development of choroidal neovascular membranes is a prominent complication seen in patients with PIC, with estimates of 40% to 75% in some cases series.[32] Ocular complications related to topical, periocular, and intravitreal corticosteroids would include premature cataract formation, increased intraocular pressure, and procedural or surgical management.[33][34]

Deterrence and Patient Education

As stated previously, most white dot syndromes are self-limiting; therefore, no treatment is generally necessary. The clinician may want to closely monitor the condition for a month using dilated funduscopic examinations.

Pearls and Other Issues

A detailed review of individual white dot syndromes is beyond the scope of this topic. The following pearls highlight several key distinguishing clinical features of several white dot syndromes.[1][2]

• MEWDS: young patients (age 20 to 50 years), women > men, often viral prodrome, typically unilateral, good visual prognosis, small white dots in the outer retina, “wreath-like” pattern of hyperfluorescence on FA [27][35]
• ARPE: young patients (age 10 to 30 years), women = men, most often unilateral, small hyperpigmented lesions, excellent visual prognosis [25]
• APMPPE: young patients (age 20 to 30 years), women = men, typically bilateral, flat gray or white placoid lesions at the level of the retinal pigment epithelium (RPE) and inner choroid, good visual prognosis [26]
• AZOOR: young patients, often myopic, women > men, typically bilateral (though asymmetric), initially normal-appearing fundus followed by zonal RPE atrophy and pigmentary changes, no clear benefit from treatment, good visual prognosis, though may progress or recur [36]
• MCP: young to middle-aged patients (age 20 to 60 years), women > men, bilateral, presence of anterior chamber and vitreous inflammation along with multiple yellow-white chorioretinal lesions with subsequent atrophy and scarring, complicated by CME and CNV, poor visual prognosis, treatment generally required [37]
• Birdshot chorioretinopathy: middle-aged patients (age 40 to 60 years), women > men, bilateral, difficulty with night vision, multiple cream-colored lesions in a birdshot style, radiating pattern nasally predominant, associated vitritis, CME, and retinal vasculitis, highly correlated with the presence of HLA-A29, “quenching” on FA, guarded visual prognosis, treatment generally required [30]
• Serpiginous choroiditis: middle-aged patients (age 30 to 60 years), men > women, bilateral (asymmetric), the geographic pattern of chorioretinal scarring, guarded to poor prognosis, treatment may require alkylating agents [29] 
• PIC: young patients (under 40 years of age), women > men, bilateral, small punctate gray or yellow lesions in the posterior pole evolve to atrophic scars, absence of vitritis, associated with CNV, good visual prognosis though more guarded with the development of CNV [32]

Enhancing Healthcare Team Outcomes

Thankfully, many white dot syndromes are self-limited and do not require treatment. Still, exceptions exist, and treatment often involves systemic immunosuppressive therapy in these circumstances. Coordination of care between an ophthalmologist specializing in chorioretinal disease and a rheumatologist is often needed for optimal care. Consideration should be given to case conferences or joint clinics to facilitate such coordination.[38] An interprofessional healthcare team coordinating between the patient's family clinician, ophthalmology specialists, and nursing staff leads to optimal results through accurate diagnosis, patient education, and, in some instances, active intervention based on the particular variant.

The views expressed are those of the author and do not reflect the official policy of the Department of the Army, the Department of Defense, or the U.S. Government.

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Disclosure: George Mount declares no relevant financial relationships with ineligible companies.

Disclosure: Evan Kaufman declares no relevant financial relationships with ineligible companies.