Continuing Education Activity

The white dot syndromes constitute a group of inflammatory chorioretinopathies in which 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 of the 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. In general, these conditions are acute in onset, and many, though not all, are transient without long-term visual consequence. Though the white dot syndromes share many 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 to include a discussion of etiologies, epidemiology, pertinent history and examination findings, options for evaluation, and the interprofessional healthcare team's role in managing patients with these conditions.

Objectives:

• Describe the typical clinical features of the white dot syndromes.
• Outline the appropriate evaluation of a patient with a presumptive white dot syndrome.
• Review 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.

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 of the white dot syndromes are associated with a viral prodrome, and 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 many 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 disease.[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. Similar to 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 (i.e., 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 the presence of typical clinical features, should prompt consideration of an alternative diagnosis.

Epidemiology

With a few exceptions (birdshot chorioretinopathy, serpiginous choroiditis), white dot syndromes present in young, otherwise healthy, adults below the age of 50.[1] Gender differences allow for 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 cell or inflammation is rare, except for MCP. Vitritis may be seen in several white dot syndromes; it is most consistently seen in birdshot chorioretinopathy.[8]

Evaluation

Laboratory testing in patients with a 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. A poor screening test, angiotensin-converting enzyme (ACE) 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 on fluorescein angiography (FA), optical coherence tomography (OCT), visual field testing, indocyanine green (ICG) angiography, fundus autofluorescence, and electroretinography (ERG) studies.[13][14][15][16]  

Treatment / Management

Many of the 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, cyclosporine, as well as biological agents, including anti-TNF medications: adalimumab and infliximab.[19] In vision-threatening conditions such as serpiginous choroiditis, the cytotoxic agents cyclophosphamide and chlorambucil have been utilized.[20] Management of associated ocular complications such as cystoid macular edema (CME) and choroidal neovascularization (CNV) may involve immunosuppression or localized ocular therapies to include anti-vascular endothelial growth factor (VEGF) agents, laser photocoagulation therapy, or photodynamic therapy.[21][22][23] 

Differential Diagnosis

Both infectious and noninfectious entities are included in the differential diagnosis of the white dot syndromes. The noninfectious processes include sarcoidosis, Vogt-Koyanagi-Harada (VKH) syndrome, sympathetic ophthalmia, and intraocular lymphoma.[11] Syphilis, primary ocular histoplasmosis syndrome (POHS), tuberculosis, and diffuse unilateral subacute neuroretinitis (DUSN) 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] Early identification and management of these conditions are, therefore, of paramount importance.

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 of the 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 cystoid macular edema (CME) and choroidal neovascularization (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 the use of topical, periocular, and intravitreal corticosteroids would include premature cataract formation and increased intraocular pressure, as well as those related to procedural or surgical management.[33][34]

Deterrence and Patient Education

As stated previously, most white dot syndromes are self-limiting, and 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 article. The following pearls highlight several key distinguishing clinical features of several of the white dot syndromes.[1][2]

• Multiple evanescent white dot syndrome (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]
• Acute retinal pigment epitheliitis (ARPE): young patients (age 10 to 30 years), women = men, most often unilateral, small hyperpigmented lesions, excellent visual prognosis[25]
• Acute posterior multifocal placoid pigment epitheliopathy (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]
• Acute zonal occult outer retinopathy (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]
• Multifocal choroiditis and panuveitis (MCP): young to middle-age 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] 
• Punctate inner choroidopathy (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, in these circumstances, treatment often involves the use of systemic immunosuppressive therapy. 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 will lead to optimal results through accurate diagnosis, patient education, and in some instances, based on the particular variant, active intervention. [Level 5]

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.