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QUESTION
HOW DO I DIFFERENTIATE ALL OF THOSE WHITE DOT SYNDROMES?
Arthi Venkat, MD
Sunil K. Srivastava, MD
Although seeing a patient with a white dot syndrome can be intimidating at first, once you examine the patient and review his or her history in a systematic manner, the differential diagnosis can be markedly narrowed.
Once our suspicion of white dot syndrome in a patient has increased, the history needs to be reviewed thoroughly. Specifically, we are interested in characterizing the symptoms further. Is he or she having visual disturbances? These include decreased vision, photopsias, nyctalopia, dyschromatopsia, floaters, or metamorphopsia. Does he or she describe any symptoms of eye redness, light sensitivity, or ocular/periocular pain? Next, a complete review of systems is needed, including systemic symptoms such as any preceding viral illnesses, headaches, other neurological findings, fevers, chills, night sweats, wasting, joint pain or swelling, rashes, or temperature intolerance.
Some white dot syndromes typically have a preceding viral illness. We always are interested in symptoms that may allude to a respiratory condition, such as shortness of breath, coughing, hemoptysis, asthma, or chest pain. Such symptoms could lead toward conditions like sarcoidosis or tuberculosis, both of which can cause a white dot syndrome. Infectious diseases may sometimes masquerade as a white dot syndrome and should be on the differential. Inquiry into sexual history, including history of sexually transmitted infections or unprotected sexual activity, is crucial to evaluating risk for syphilis and HIV.
We make sure to ask about other ophthalmic history, specifically a history of myopia either currently or prior to previous refractive or cataract surgery, as this is a part of certain white dot syndromes. Finally, we inquire about demographics, including age, gender, and race, and ask about where the patient is currently living and where they have lived in the past, any history of travel to other countries, and any pets or animals he or she may have been around.
“Why so many questions?” you may ask. Well, many of the white dot syndromes can look similar, and a detailed history will help us determine if this disease is a local ocular process or part of a systemic inflammatory disease. Also, asking these questions can help assess whether further work-up is needed. It also ensures that potential infectious masquerades are not missed, particularly tuberculosis and syphilis.
Armed with this information, a complete examination is needed to determine the location, severity, and chronicity of inflammation. We quantitate the severity of inflammatory cell and flare and look for signs of previous inflammation, such as posterior synechiae, keratic precipitates, and pigment on the lens. Nodules on the iris and/or conjunctiva can point to diseases such as sarcoidosis, tuberculosis, or even lymphoma.
When examining the posterior segment, we quantify the amount of vitreous inflammation and look at the size, color, and characteristics of the white dots. Are they small (less than the caliber of the central retinal artery), large (bigger than the optic nerve), or in between? Are they round or irregular? Are the borders sharp or ill-defined? Are the dots white or yellow, atrophic-appearing or pigmented (this helps to determine the level of activity)? Is there any associated hemorrhage or vascular sheathing? Finally, we look for any changes around the optic nerve, such as edema, peripapillary atrophy, or tilting.
Imaging is vital in this disease category, as it will unmask the location of lesions and assist in determining disease activity. Once we determine which imaging test reveals the disease activity particularly well, we then use that imaging test to follow the patient. Ultra-widefield fluorescein angiography and widefield indocyanine green angiography assist in identifying the location of choroidal and retina lesions, especially in the periphery. Additionally, angiography can differentiate between inactive and active areas. Usually, active areas will block early and hyperfluoresce late and have indistinct borders, while inactive borders tend to either hypofluoresce or stain and have sharp borders. Indocyanine green angiography can assist in identifying choroidal lesions that are not readily seen.
Optical coherence tomography (OCT) is important as it provides crucial cross-sectional information. Imaging of the macula and of suspicious lesions outside the macula should be obtained. OCT assists in determining the location of inflammation, the level of activity based on the disruption of the outer retinal structures. Furthermore, OCT can identify cystoid macular edema, intra- or subretinal fluid, the latter raising concern for secondary choroidal neovascularization (CNV). OCT is also useful in visualizing choroidal structures.
Additional imaging tests, such as fundus autofluorescence and OCT angiography (OCT-A), are obtained in certain situations. Fundus autofluorescence can be useful in identifying active lesions which typically hyperautofluoresce. OCT-A is useful in identifying CNV and assessing vascular perfusion, as well as identifying flow voids or abnormalities corresponding to choroidal lesions.
Armed with the information from the history, examination, and imaging, it is now time to develop a differential. It is important to remember that many of these diseases are idiopathic in origin and have overlapping features. It is vital not to miss an infectious etiology and crucial to identify features that may imply a systemic disease or masquerade. We first determine the location, chronicity, and severity of inflammation. In patients with panuveitis, we begin with diseases such as multifocal choroiditis, sarcoidosis, syphilis, tuberculosis, and rarely lymphoma. We use the imaging findings to help us further. Choroidal involvement implies sarcoidosis and tuberculosis, while broad, plaque-like changes in the outer retina is suspicious for syphilis. Large subretinal lesions would be concerning for lymphoma.
In those diseases with posterior involvement, we use the size of the lesions and imaging findings to further categorize them. Smaller dots are suspicious for diseases such as multiple evanescent white dot syndrome, punctate inner choroidopathy (PIC), and multifocal choroiditis (MFC). PIC and MFC lesions tend to be punched out when inactive and have gray/white borders when active. Multiple evanescent white dot syndrome lesions are typically very small and are often missed, but identified on imaging. Syphilis, sarcoidosis, and tuberculosis can masquerade as any of these smaller lesion diseases. Diseases such as birdshot choroidopathy and lymphoma can also mimic the appearance of some of these smaller dots, especially with MFC involvement.
More confluent, larger, or placoid lesions point toward conditions like acute posterior multifocal placoid pigment epitheliopathy or serpiginous chorioretinitis. When active, these diseases have characteristic fluorescein angiographic features, including blocking early and hyperfluorescing late. Still, syphilis, sarcoidosis, and tuberculosis are often included in the differential for these larger lesion diseases.
Ultimately, some of these may be difficult to distinguish definitively at the first visit, but we try to develop a strong suspicion for infectious vs inflammatory conditions. At the initial visit, we will test for infectious diseases, such as syphilis and tuberculosis, and based on the findings and differential, inflammatory diseases, such as sarcoidosis. Once we have ruled out infectious etiologies, corticosteroids can be used to treat active inflammation, especially in those with vision threatening diseases such as MFC, serpiginous, and PIC. Although controversial, we will often treat acute posterior multifocal placoid pigment epitheliopathy patients with systemic corticosteroids to speed recovery and limit permanent damage. Imaging is used to follow these patients to monitor response to therapy. In those with more chronic disease, systemic immune suppression is needed to control the disease. Secondary complications, such as CNV, are treated with local anti-vascular endothelial growth factor therapy.
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