Grand Rounds at the New England Eye Center

Woman referred for blurry vision, flashes of light and floaters

Fundoscopic exam revealed deep retinal circular yellowish-white lesions in the left eye.

A 26-year-old Caucasian woman with a 3-day history of blurry vision, flashes of light and floaters in her left eye was referred by an outside comprehensive ophthalmologist for a retina evaluation. She had a medical history significant for hypothyroidism managed with a low dose of levothyroxine. Her ocular history was remarkable for one episode of unilateral iritis 3 years ago. She was a non-smoker, denied intravenous drug use and was in a monogamous relationship with her boyfriend. Her family history was non-contributory. On review of systems, she denied shortness of breath, joint pain, rash, headache, oral or genital ulcers, recent upper respiratory symptoms or other viral illness.

Examination

On examination, the patient’s uncorrected visual acuity was 20/20 in the right eye and 20/70 in the left eye, which did not improve with pinhole. She had a mild relative afferent pupillary defect in the left eye. IOPs were within normal limits in both eyes. Extraocular muscles were full and orthophoric in both eyes. Confrontation to visual fields was full in both eyes. Anterior segment exam was unremarkable in each eye.

Figure 1. Color fundus photography of the right eye and left eye.

Images: Wright EC, Reichel E

Dilated fundoscopic exam revealed a normal fundus in the right eye. Left eye fundoscopy demonstrated trace vitreous cell, mild hyperemia of the optic nerve head with blunting of the disc margins, an orange-yellow foveal granularity and numerous deep retinal circular yellowish-white lesions distributed throughout the posterior pole but sparing the central fovea. These spots were approximately one-eighth to one-quarter disc diameter, had mildly ill-defined margins and were more prevalent in the area of the superior arcade and just nasal to the optic nerve head. The vessels were of normal course and caliber without any sheathing (Figure 1).

What is your diagnosis?

See answer on next page.

Yellowish-white retinal lesions

The differential diagnosis of unilateral yellowish-white deep retinal or choroidal lesions in the setting of photopsias and floaters includes inflammatory, infectious and neoplastic etiologies. Included on the list of possible inflammatory etiologies are multiple evanescent white dot syndrome (MEWDS), acute retinal pigment epitheliitis, sarcoidosis, acute posterior multifocal placoid pigment epitheliopathy (APMPPE), multifocal choroiditis and panuveitis/punctate inner choroidopathy (MCP/PIC), and birdshot chorioretinopathy. APMPPE typically presents with larger, more confluent, plaque-like lesions. MCP/PIC and birdshot chorioretinopathy are less likely as they typically present bilaterally. Infectious etiologies that must be considered in the setting of this patient’s fundoscopic appearance include syphilis, tuberculosis and diffuse unilateral subacute neuroretinitis. Lastly, although low on the differential, primary and metastatic neoplastic etiologies should be considered.

With the combination of this patient’s history, exam findings and fundoscopic appearance, multimodal chorioretinal imaging should be done to provide further insight into the diagnosis. As such, OCT, fundus autofluorescence (FAF), fluorescein angiography (FA) and indocyanine green angiography (ICGA) were obtained for this patient. OCT of the patient’s left eye revealed subfoveal photoreceptor inner and outer segment as well as ellipsoid zone disruption and mild mottling of the subfoveal retinal pigment epithelium (RPE). The left eye also had a mild epiretinal membrane evident on OCT. OCT of the right eye was grossly unremarkable (Figure 2). OCT of the retinal nerve fiber layer revealed mild thickening or edema of the left optic nerve head relative to the right (Figure 3). FAF of the left eye demonstrated diffuse hyper-autofluorescence around the optic nerve and throughout the macula that corresponded to the deep retinal spots seen on fundoscopic exam and color fundus photography. Subtle perifoveal hypo-autofluorescence is also seen in the left eye. FAF of the right eye was unremarkable (Figure 4).

FA was performed and revealed faint punctate hyper-fluorescent white spots in the posterior pole in the early frames and marked hyper-fluorescence consistent with leakage throughout the posterior pole in the late frames. Late staining of the optic nerve was also seen (Figure 5). The late leakage in the pattern of a wreath-like configuration is classic for MEWDS. FA of the right eye was unremarkable. ICGA of the left eye showed late hypo-cyanescent lesions throughout posterior pole, more numerous than the deep retinal yellowish-white lesions seen on fundoscopy and color fundus photography (Figure 6). ICGA of the right eye was normal.

Figure 2. OCT of the macula of the right eye and left eye.
Figure 3. OCT retinal nerve fiber layer of both eyes.
Fundus autofluorescence photography
Figure 4. Fundus autofluorescence photography of the right eye and left eye.
Figure 5. Fluorescein angiography of the left eye.
Figure 6. Indocyanine green angiography of the left eye.
Figure 7. OCT of the left eye at 3- and 5-week follow-up visits.

The combination of the patient’s presenting symptoms, exam findings and multimodal chorioretinal imaging points toward a diagnosis of MEWDS. There are case reports of infectious and neoplastic etiologies; hence, a basic infectious and hematologic workup was obtained and results were non-reactive or within normal limits. Given the working diagnosis of MEWDS, the patient was observed with close follow-up. At follow-up examinations 3 weeks and 5 weeks from initial presentation, the patient’s left eye visual acuity improved to 20/50 and 20/30, respectively. Fundus exam demonstrated steady resolution of the yellowish-white retinal spots, and OCT showed gradual reconstitution of the photoreceptor layer (Figure 7). The patient’s steady improvement with observation further confirmed the diagnosis of MEWDS.

Discussion

Multiple evanescent white dot syndrome is one disease entity of the group termed “white dot syndromes.” Many have suggested that “white dot syndromes” is perhaps a poorly named epithet given that it is a relatively vague descriptor of numerous unrelated disease entities. MEWDS typically presents unilaterally, although there are rare reports of bilaterality. Patients classically present with sudden onset blurred vision, shimmering photopsias, dyschromatopsia, and paracentral and often temporal scotomas. Visual acuity may range from 20/20 to 20/400, there is often a relative afferent pupillary defect and mild vitreous cell (normal anterior segment), and the optic nerve may be hyperemic. The fundoscopic exam is characterized by multiple ill-defined white spots at the level of the RPE or outer retina in the peri-macula and mid-periphery. Foveal orange-yellow granularity is nearly pathognomonic and may persist even after inflammation has subsided.

Epidemiologically, MEWDS is characterized by a 5:1 female predilection and typically presents between the ages of 20 years and 45 years. There is no known racial or hereditary association. It often occurs in patients with moderate myopia, and approximately half of the patients have a viral prodrome.

As seen with this case, multimodal imaging offers further clarity in making a definitive diagnosis. OCT characteristically demonstrates an accumulation of hyper-reflective material that extends anteriorly from the RPE through the interdigitation zone, ellipsoid zone and outer nuclear layer. FAF photography typically demonstrates areas of hyper-autofluorescence in the acute phase of disease in the regions that correspond to the white dots seen on color fundus photography. Pinpoint hypo-autofluorescence corresponding to foveal granularity may also be seen. FA classically reveals punctate hyperfluorescent lesions (early and late) in a classic “wreathlike” configuration in the mid-peripheral retina; late staining of the optic disc is also often seen. ICGA reveals early and mid-phase round hypo-cyanescent spots in posterior and mid-peripheral fundus that are often more numerous than seen on FA. Other testing may be done, including visual field, electroretinogram (ERG) and electrooculogram (EOG) testing. Patients with MEWDS may have an enlarged blind spot and occasional temporal or paracentral scotomas on formal visual field testing. ERG testing will show a reduction in the a-wave amplitude indicative of pathology to the RPE and photoreceptor layers. EOG testing may be abnormal.

The precise etiology of MEWDS is unknown, but a viral etiology has been strongly suggested. Patients’ visual acuity is typically restored within 7 to 10 weeks without treatment, and recurrences are uncommon. Rare recurrent cases have been treated effectively with cyclosporine. Visual field deficits (enlarged blind spot), dyschromatopsia and photopsias may persist. Concomitant choroidal neovascular membranes are infrequent, and when they have occurred, they have reportedly been treated successfully with intravitreal anti-VEGF injections.

Debate continues around whether the primary pathology of MEWDS is localized to the choriocapillaris or the outer retina. Early ICGA analysis led to speculation by Thomas and colleagues that late hypofluorescent lesions might be caused by defects in choriocapillaris flow. Agoyagi and colleagues showed that subfoveal choroidal thickness is increased in the acute phase of MEWDS in both affected and unaffected eyes, which suggests that inflammation may occur in the choroidal stroma and choriocapillaris. In favor of localization to the outer retina, however, it has been hypothesized that the late hypo-cyanescent lesions may be due to a blocking effect of space-occupying lesions. Furthermore, spectral-domain OCT localizes the pathology to the photoreceptor layer of the outer retina. Pichi and colleagues studied 29 eyes with acute MEWDS that underwent OCT angiography imaging and demonstrated that the superficial and deep retinal capillary networks as well as the choroidal vasculature were comparable to normal healthy controls. As a result of these findings, it was suggested that MEWDS may be a result of primary inflammation of the outer photoreceptor layer, or a “photoreceptoritis.” Further OCTA studies should be done to confirm these findings.

A 26-year-old Caucasian woman with a 3-day history of blurry vision, flashes of light and floaters in her left eye was referred by an outside comprehensive ophthalmologist for a retina evaluation. She had a medical history significant for hypothyroidism managed with a low dose of levothyroxine. Her ocular history was remarkable for one episode of unilateral iritis 3 years ago. She was a non-smoker, denied intravenous drug use and was in a monogamous relationship with her boyfriend. Her family history was non-contributory. On review of systems, she denied shortness of breath, joint pain, rash, headache, oral or genital ulcers, recent upper respiratory symptoms or other viral illness.

Examination

On examination, the patient’s uncorrected visual acuity was 20/20 in the right eye and 20/70 in the left eye, which did not improve with pinhole. She had a mild relative afferent pupillary defect in the left eye. IOPs were within normal limits in both eyes. Extraocular muscles were full and orthophoric in both eyes. Confrontation to visual fields was full in both eyes. Anterior segment exam was unremarkable in each eye.

Figure 1. Color fundus photography of the right eye and left eye.

Images: Wright EC, Reichel E

Dilated fundoscopic exam revealed a normal fundus in the right eye. Left eye fundoscopy demonstrated trace vitreous cell, mild hyperemia of the optic nerve head with blunting of the disc margins, an orange-yellow foveal granularity and numerous deep retinal circular yellowish-white lesions distributed throughout the posterior pole but sparing the central fovea. These spots were approximately one-eighth to one-quarter disc diameter, had mildly ill-defined margins and were more prevalent in the area of the superior arcade and just nasal to the optic nerve head. The vessels were of normal course and caliber without any sheathing (Figure 1).

What is your diagnosis?

See answer on next page.

PAGE BREAK

Yellowish-white retinal lesions

The differential diagnosis of unilateral yellowish-white deep retinal or choroidal lesions in the setting of photopsias and floaters includes inflammatory, infectious and neoplastic etiologies. Included on the list of possible inflammatory etiologies are multiple evanescent white dot syndrome (MEWDS), acute retinal pigment epitheliitis, sarcoidosis, acute posterior multifocal placoid pigment epitheliopathy (APMPPE), multifocal choroiditis and panuveitis/punctate inner choroidopathy (MCP/PIC), and birdshot chorioretinopathy. APMPPE typically presents with larger, more confluent, plaque-like lesions. MCP/PIC and birdshot chorioretinopathy are less likely as they typically present bilaterally. Infectious etiologies that must be considered in the setting of this patient’s fundoscopic appearance include syphilis, tuberculosis and diffuse unilateral subacute neuroretinitis. Lastly, although low on the differential, primary and metastatic neoplastic etiologies should be considered.

With the combination of this patient’s history, exam findings and fundoscopic appearance, multimodal chorioretinal imaging should be done to provide further insight into the diagnosis. As such, OCT, fundus autofluorescence (FAF), fluorescein angiography (FA) and indocyanine green angiography (ICGA) were obtained for this patient. OCT of the patient’s left eye revealed subfoveal photoreceptor inner and outer segment as well as ellipsoid zone disruption and mild mottling of the subfoveal retinal pigment epithelium (RPE). The left eye also had a mild epiretinal membrane evident on OCT. OCT of the right eye was grossly unremarkable (Figure 2). OCT of the retinal nerve fiber layer revealed mild thickening or edema of the left optic nerve head relative to the right (Figure 3). FAF of the left eye demonstrated diffuse hyper-autofluorescence around the optic nerve and throughout the macula that corresponded to the deep retinal spots seen on fundoscopic exam and color fundus photography. Subtle perifoveal hypo-autofluorescence is also seen in the left eye. FAF of the right eye was unremarkable (Figure 4).

FA was performed and revealed faint punctate hyper-fluorescent white spots in the posterior pole in the early frames and marked hyper-fluorescence consistent with leakage throughout the posterior pole in the late frames. Late staining of the optic nerve was also seen (Figure 5). The late leakage in the pattern of a wreath-like configuration is classic for MEWDS. FA of the right eye was unremarkable. ICGA of the left eye showed late hypo-cyanescent lesions throughout posterior pole, more numerous than the deep retinal yellowish-white lesions seen on fundoscopy and color fundus photography (Figure 6). ICGA of the right eye was normal.

Figure 2. OCT of the macula of the right eye and left eye.
Figure 3. OCT retinal nerve fiber layer of both eyes.
Fundus autofluorescence photography
Figure 4. Fundus autofluorescence photography of the right eye and left eye.
Figure 5. Fluorescein angiography of the left eye.
Figure 6. Indocyanine green angiography of the left eye.
Figure 7. OCT of the left eye at 3- and 5-week follow-up visits.

The combination of the patient’s presenting symptoms, exam findings and multimodal chorioretinal imaging points toward a diagnosis of MEWDS. There are case reports of infectious and neoplastic etiologies; hence, a basic infectious and hematologic workup was obtained and results were non-reactive or within normal limits. Given the working diagnosis of MEWDS, the patient was observed with close follow-up. At follow-up examinations 3 weeks and 5 weeks from initial presentation, the patient’s left eye visual acuity improved to 20/50 and 20/30, respectively. Fundus exam demonstrated steady resolution of the yellowish-white retinal spots, and OCT showed gradual reconstitution of the photoreceptor layer (Figure 7). The patient’s steady improvement with observation further confirmed the diagnosis of MEWDS.

Discussion

Multiple evanescent white dot syndrome is one disease entity of the group termed “white dot syndromes.” Many have suggested that “white dot syndromes” is perhaps a poorly named epithet given that it is a relatively vague descriptor of numerous unrelated disease entities. MEWDS typically presents unilaterally, although there are rare reports of bilaterality. Patients classically present with sudden onset blurred vision, shimmering photopsias, dyschromatopsia, and paracentral and often temporal scotomas. Visual acuity may range from 20/20 to 20/400, there is often a relative afferent pupillary defect and mild vitreous cell (normal anterior segment), and the optic nerve may be hyperemic. The fundoscopic exam is characterized by multiple ill-defined white spots at the level of the RPE or outer retina in the peri-macula and mid-periphery. Foveal orange-yellow granularity is nearly pathognomonic and may persist even after inflammation has subsided.

Epidemiologically, MEWDS is characterized by a 5:1 female predilection and typically presents between the ages of 20 years and 45 years. There is no known racial or hereditary association. It often occurs in patients with moderate myopia, and approximately half of the patients have a viral prodrome.

As seen with this case, multimodal imaging offers further clarity in making a definitive diagnosis. OCT characteristically demonstrates an accumulation of hyper-reflective material that extends anteriorly from the RPE through the interdigitation zone, ellipsoid zone and outer nuclear layer. FAF photography typically demonstrates areas of hyper-autofluorescence in the acute phase of disease in the regions that correspond to the white dots seen on color fundus photography. Pinpoint hypo-autofluorescence corresponding to foveal granularity may also be seen. FA classically reveals punctate hyperfluorescent lesions (early and late) in a classic “wreathlike” configuration in the mid-peripheral retina; late staining of the optic disc is also often seen. ICGA reveals early and mid-phase round hypo-cyanescent spots in posterior and mid-peripheral fundus that are often more numerous than seen on FA. Other testing may be done, including visual field, electroretinogram (ERG) and electrooculogram (EOG) testing. Patients with MEWDS may have an enlarged blind spot and occasional temporal or paracentral scotomas on formal visual field testing. ERG testing will show a reduction in the a-wave amplitude indicative of pathology to the RPE and photoreceptor layers. EOG testing may be abnormal.

The precise etiology of MEWDS is unknown, but a viral etiology has been strongly suggested. Patients’ visual acuity is typically restored within 7 to 10 weeks without treatment, and recurrences are uncommon. Rare recurrent cases have been treated effectively with cyclosporine. Visual field deficits (enlarged blind spot), dyschromatopsia and photopsias may persist. Concomitant choroidal neovascular membranes are infrequent, and when they have occurred, they have reportedly been treated successfully with intravitreal anti-VEGF injections.

PAGE BREAK

Debate continues around whether the primary pathology of MEWDS is localized to the choriocapillaris or the outer retina. Early ICGA analysis led to speculation by Thomas and colleagues that late hypofluorescent lesions might be caused by defects in choriocapillaris flow. Agoyagi and colleagues showed that subfoveal choroidal thickness is increased in the acute phase of MEWDS in both affected and unaffected eyes, which suggests that inflammation may occur in the choroidal stroma and choriocapillaris. In favor of localization to the outer retina, however, it has been hypothesized that the late hypo-cyanescent lesions may be due to a blocking effect of space-occupying lesions. Furthermore, spectral-domain OCT localizes the pathology to the photoreceptor layer of the outer retina. Pichi and colleagues studied 29 eyes with acute MEWDS that underwent OCT angiography imaging and demonstrated that the superficial and deep retinal capillary networks as well as the choroidal vasculature were comparable to normal healthy controls. As a result of these findings, it was suggested that MEWDS may be a result of primary inflammation of the outer photoreceptor layer, or a “photoreceptoritis.” Further OCTA studies should be done to confirm these findings.