What's Your Diagnosis?

Elderly man has central vision loss, lipofuscin accumulation

Fundus photography showing the distinct yellow intraretinal lesions in the fovea.
Source: Shaleen Ragha, OD

A 74-year-old Caucasian man presented with a chief complaint of bilateral and symmetric progressive decrease in central vision over the last 2 years. His self-reported ocular history was relevant for phacoemulsification with intraocular lens implantation in both eyes 4 years ago. He denied use of any ocular medications.

His systemic history was positive for hypertension, hypercholesterolemia, prostate cancer and a recent diagnosis of progressive supranuclear palsy with cognitive decline. Daily systemic medications included: 10 mg lisinopril, atorvastatin 30 mg, carbidopa 25 mg, donepezil 10 mg and memantine 10 mg. The patient had no known drug allergies and had discontinued smoking 20 years ago.

SD-OCT demonstrates hyper-reflective material between the RPE basal lamina/Bruch’s membrane band and photoreceptor integrity line. Retinal layers appear intact despite displacement secondary to the lesion. Focal subretinal hyper-reflective elevations underlie the intraretinal lesions in both eyes.

Best-corrected Snellen visual acuity was 20/70 OD and 20/70 OS at distance and near, with a prescription of +0.75 D -0.50 D x 135 OD and +0.50 D OS with a +3.00 D add at 30 cm. Acuity testing showed limited visual dynamics, as the patient was able to read only the first and last letters of each line. Pinhole testing yielded no improvement. Extraocular motilities, confrontation visual fields and pupil testing were unremarkable. Amsler grid testing revealed central relative scotomas in both eyes. Slit lamp examination was unremarkable. Intraocular pressures by Goldmann applanation tonometry measured 15 mm Hg OD and 13 mm Hg OS.

Fundus autofluorescence imaging demonstrating properties of hyperautofluorescence in both eyes, consistent with lipofuscin accumulation.

Dilated fundus examination of the optic nerve heads, vasculature and peripheral retina were unremarkable in each eye. The maculae revealed bilateral, well-demarcated, yellowish foveal lesions with a darker hue beneath the lesion upon direct illumination. Proximal illumination of the areas better delineated the focal, elevated areas internal to the broader lesions. Both lesions were approximately one-half to one-third disc diameter in size. A few faint yellow deposits were visible surrounding the central lesions.

Cross-sectional evaluation of the fovea by spectral domain optical coherence tomography showed depositions isolated between the photoreceptor integrity line and the retinal pigment epithelium (RPE) in both eyes. Focal elevation of the RPE below the deposits was also noted. Fundus autofluorescence of both eyes exhibited focal, well delineated areas of hyperautofluorescence confined to the fovea, with a patchier pattern in the right eye.

What’s your diagnosis?
See answer on the next page.

Given the clinical findings, the differential diagnoses are limited. Findings appeared most consistent with adult-onset foveomacular vitelliform dystrophy (AOFVD).

Controversy exists over whether AOFVD is its own separate entity or a variant of age-related macular degeneration, Best’s disease or even a type of pattern dystrophy. AMD is characterized by drusen, late age of onset and sometimes a choroidal neovascularization (CNV) or geographic atrophy. These features exist in some variants of AOFVD. This overlap can lead to AOFVD being misdiagnosed as AMD. CNV is more common in AMD, and parafoveal superficial retinal vessel density is increased in patients with AOFVD compared to AMD eyes.

Best’s disease, caused by mutations in the BEST1 gene, is the most common form of autosomal dominant macular dystrophy. The BEST1 gene has also been linked in a limited number of AOFVD cases. However, Best’s disease presents with an earlier age of onset, larger lesion size, an abnormal electro-oculogram and poorer visual prognosis.

Shaleen Ragha

Butterfly-shaped pigment dystrophy is a pattern dystrophy of autosomal dominant inheritance appearing as a spoke-like pigment pattern with a yellowish subretinal lesion with branches. Additionally, it presents after the seventh decade of life along with poorer visual acuity and has also been linked to PRPH2 mutations. The clinical course and location of lesions in butterfly-shaped pigment dystrophy are similar to those in AOFVD, leading to debate as to whether the two are manifestations of the same anomaly or two distinct conditions.

Acquired vitelliform lesions have also been seen in cases of central serous retinopathy, angioid streaks in pseudoxanthum elasticum, mitochondrial retinal dystrophy, Kearns-Sayre syndrome, and toxic and paraneoplastic conditions.

Pattern dystrophy

AOFVD is a rare, late-onset subset of a pattern dystrophy. Most studies indicate manifestation of the disease after the sixth decade of life. Ophthalmoscopy will commonly reveal bilateral, solitary, subfoveal yellowish deposits approximately one-third of the optic disc area in size. The appearance of the lesion can vary from a subtle, dull yellow to an egg-yolk yellow. The lesion may have a central pigmented spot that becomes more apparent as the yellowish lesion fades over time due to RPE atrophy. A subset of patients may have the concurrent presence of drusen or multifocal vitelliform lesions rather than a solitary one. The yellowish lesion initially expands then resorbs over many years, followed by outer retinal and RPE atrophy. This progression is similar to that of Best’s disease staging, which is as follows: pre-vitelliform, vitelliform, pseudohypopyon, vitelliruptive, atrophic and cicatricial.

Common visual complaints include central blur, central scotoma or metamorphopsia and/or disturbances of central vision. Vision is normal or mildly reduced in early stages of the disease despite the presence of the vitelliform lesion. Preservation of vision correlates with the integrity of the outer nuclear layer and ellipsoid zone. Commonly, retinal atrophy and, infrequently, CNV can then lead to worsening visual acuity as the vitelliform lesion fades. Balaratnasingam and colleagues showed that CNV development occurs in 2.1% of eyes.

Histology and electron microscopy indicate that photoreceptors are likely the first cells damaged during disruption secondary to rapid shedding or inefficient processing of abnormal outer segments. Subsequent impaired RPE uptake leads to accumulation of vitelliform material, comprising photoreceptor outer segment debris, lipofuscin, melanin, melanolipofuscin-loaded macrophages and RPE cells. As the disease progresses, the vitelliform material is resorbed, theorized to be the RPE’s recuperated ability to phagocytize the vitelliform material once fewer photoreceptor outer segments are produced. Resolution of most vitelliform lesions leads to progressive thinning of the outer retinal layers. Some cases exhibit migrated pigment clumps in the outer retina, assumed to be RPE’s stress response to insult.

The term dystrophy is typically reserved for genetically inherited conditions. The majority of AOFVD cases are not associated with genetic mutations, thus, it may be more appropriately identified as a degeneration, given the gradual loss of tissue and function in older individuals. Some cases of AOFVD have been linked to a mutation in genes PRPH2, BEST1, IMPG1 and IMPG2, as well as a single nucleotide polymorphism in the HTRA1 gene. No clear inheritance pattern has been identified, as most patients have a negative family history. Alternatively, patients’ family members may be asymptomatic or unaware of their disease. An indefinite inheritance pattern could be attributable to variable expression or decreased penetrance.

Diagnostic testing

Eyes with AOFVD will commonly present with a hyperautofluorescent lesion. A study by Parodi and colleagues observed that a patchy pattern correlated with worse fixation stability and worse visual acuity. Outer retinal and RPE loss will generally be hypoautofluorescent. In addition, central hypoautofluorescence can also be seen in the vitelliform stage corresponding with the pigmented spot.

Andrew Rixon

A dome-shaped hyper-reflective lesion will be located between the photoreceptor layer and RPE in the vitelliform stage. This subretinal material has been shown to be heterogeneously hyper-reflective more often than homogenously hyper-reflective. In the pseudohypopyon stage, there will be an optically empty zone above or adjacent to the vitelliform lesion. In the vitelliruptive stage, there is collapse of the lesion along with hyper-reflective clumps of pigment migrating to the inner retina. Resolution of most vitelliform lesions leads to progressive thinning of the outer retina. In the atrophic stage, disruption of the photoreceptor inner segment/outer segment (IS/OS) junction and external limiting membrane are correlated with the extent of vision loss. Areas of outer retinal, RPE and choriocapillaris degeneration can be seen.

Hypo-reflective subretinal fluid is sometimes seen between the RPE and the vitelliform material, presumably due to inefficient RPE fluid pumping. On the other hand, presence of fluid may indicate an active CNV when seen as well-circumscribed hypo-reflective spaces that distort surrounding retinal layers or RPE. A CNV can also present with RPE detachments or tears, fibrovascular or disciform scarring, or vitreous hemorrhaging. OCT can help determine if the CNV is type 1, where vessels are confined under the RPE, or type 2, where vessels proliferate into the subretinal space.

Treatment

Currently, no validated therapy has been shown to prevent retinal atrophy and subsequent loss of vision. Verteporfin photodynamic therapy was unsuccessful, leading to RPE atrophy and visual decline in eyes. The literature does not justify the use of anti-VEGF injections in patients without CNV, as visual acuity improvement in studies has been temporary (Gallego-Pinazo et al., Montero JA et al., Kandula et al.) Gene therapy may show potential in treating monogenic forms of AOFVD (Conley et al., Guziewicz et al.). Anti-VEGF has shown regression of the neovascular network in eyes with CNV, but multiple studies indicated many eyes still had poor visual prognosis secondary to progression of the lesion and outer retinal atrophy (Mimoun et al., Tiosano et al., Prieto-Calvo et al.). Without the presence of a CNV, our patient did not require additional treatment.

Vision rehabilitation

For visual disability, a consultation with a low vision specialist may be appropriate to improve quality of life due to loss of independence, risk for falls and accidents, and psychological cost. Individuals who experience difficulty performing daily tasks can be referred for optical device evaluations, counseling and additional resources.

The consultation should include a comprehensive review of the patient’s understanding of the condition and history, a clinical evaluation of visual function, a review of their daily routine and environment, and potential visual goals.

This patient’s management

Our patient was referred internally for the low vision consultation. He noted difficulty reading books and the newspaper and viewing his cellphone. As for mobility, he had an electric wheelchair and support cane to use when needed. His wife provided assistance for most daily needs.

Evaluation of devices included a +16 DS (4X) handheld LED magnifier, a +20 DS (5X) stand magnifier, high-powered reading glasses and 3X Galilean binoculars. He appreciated improvement in contrast with yellow filter shields and better lighting. A bold felt tip pen and bold lined paper were issued to the patient along with instructions to write slower and larger. Several large-print books were also ordered for him.

After thorough instruction of device usage and recommendations to minimize risks to health and safety, the patient was advised to follow up as needed.

Disclosures: Ragha, Rixon and Semes reported no relevant financial disclosures.

Fundus photography showing the distinct yellow intraretinal lesions in the fovea.
Source: Shaleen Ragha, OD

A 74-year-old Caucasian man presented with a chief complaint of bilateral and symmetric progressive decrease in central vision over the last 2 years. His self-reported ocular history was relevant for phacoemulsification with intraocular lens implantation in both eyes 4 years ago. He denied use of any ocular medications.

His systemic history was positive for hypertension, hypercholesterolemia, prostate cancer and a recent diagnosis of progressive supranuclear palsy with cognitive decline. Daily systemic medications included: 10 mg lisinopril, atorvastatin 30 mg, carbidopa 25 mg, donepezil 10 mg and memantine 10 mg. The patient had no known drug allergies and had discontinued smoking 20 years ago.

SD-OCT demonstrates hyper-reflective material between the RPE basal lamina/Bruch’s membrane band and photoreceptor integrity line. Retinal layers appear intact despite displacement secondary to the lesion. Focal subretinal hyper-reflective elevations underlie the intraretinal lesions in both eyes.

Best-corrected Snellen visual acuity was 20/70 OD and 20/70 OS at distance and near, with a prescription of +0.75 D -0.50 D x 135 OD and +0.50 D OS with a +3.00 D add at 30 cm. Acuity testing showed limited visual dynamics, as the patient was able to read only the first and last letters of each line. Pinhole testing yielded no improvement. Extraocular motilities, confrontation visual fields and pupil testing were unremarkable. Amsler grid testing revealed central relative scotomas in both eyes. Slit lamp examination was unremarkable. Intraocular pressures by Goldmann applanation tonometry measured 15 mm Hg OD and 13 mm Hg OS.

Fundus autofluorescence imaging demonstrating properties of hyperautofluorescence in both eyes, consistent with lipofuscin accumulation.

Dilated fundus examination of the optic nerve heads, vasculature and peripheral retina were unremarkable in each eye. The maculae revealed bilateral, well-demarcated, yellowish foveal lesions with a darker hue beneath the lesion upon direct illumination. Proximal illumination of the areas better delineated the focal, elevated areas internal to the broader lesions. Both lesions were approximately one-half to one-third disc diameter in size. A few faint yellow deposits were visible surrounding the central lesions.

Cross-sectional evaluation of the fovea by spectral domain optical coherence tomography showed depositions isolated between the photoreceptor integrity line and the retinal pigment epithelium (RPE) in both eyes. Focal elevation of the RPE below the deposits was also noted. Fundus autofluorescence of both eyes exhibited focal, well delineated areas of hyperautofluorescence confined to the fovea, with a patchier pattern in the right eye.

What’s your diagnosis?
See answer on the next page.

PAGE BREAK

Given the clinical findings, the differential diagnoses are limited. Findings appeared most consistent with adult-onset foveomacular vitelliform dystrophy (AOFVD).

Controversy exists over whether AOFVD is its own separate entity or a variant of age-related macular degeneration, Best’s disease or even a type of pattern dystrophy. AMD is characterized by drusen, late age of onset and sometimes a choroidal neovascularization (CNV) or geographic atrophy. These features exist in some variants of AOFVD. This overlap can lead to AOFVD being misdiagnosed as AMD. CNV is more common in AMD, and parafoveal superficial retinal vessel density is increased in patients with AOFVD compared to AMD eyes.

Best’s disease, caused by mutations in the BEST1 gene, is the most common form of autosomal dominant macular dystrophy. The BEST1 gene has also been linked in a limited number of AOFVD cases. However, Best’s disease presents with an earlier age of onset, larger lesion size, an abnormal electro-oculogram and poorer visual prognosis.

Shaleen Ragha

Butterfly-shaped pigment dystrophy is a pattern dystrophy of autosomal dominant inheritance appearing as a spoke-like pigment pattern with a yellowish subretinal lesion with branches. Additionally, it presents after the seventh decade of life along with poorer visual acuity and has also been linked to PRPH2 mutations. The clinical course and location of lesions in butterfly-shaped pigment dystrophy are similar to those in AOFVD, leading to debate as to whether the two are manifestations of the same anomaly or two distinct conditions.

Acquired vitelliform lesions have also been seen in cases of central serous retinopathy, angioid streaks in pseudoxanthum elasticum, mitochondrial retinal dystrophy, Kearns-Sayre syndrome, and toxic and paraneoplastic conditions.

Pattern dystrophy

AOFVD is a rare, late-onset subset of a pattern dystrophy. Most studies indicate manifestation of the disease after the sixth decade of life. Ophthalmoscopy will commonly reveal bilateral, solitary, subfoveal yellowish deposits approximately one-third of the optic disc area in size. The appearance of the lesion can vary from a subtle, dull yellow to an egg-yolk yellow. The lesion may have a central pigmented spot that becomes more apparent as the yellowish lesion fades over time due to RPE atrophy. A subset of patients may have the concurrent presence of drusen or multifocal vitelliform lesions rather than a solitary one. The yellowish lesion initially expands then resorbs over many years, followed by outer retinal and RPE atrophy. This progression is similar to that of Best’s disease staging, which is as follows: pre-vitelliform, vitelliform, pseudohypopyon, vitelliruptive, atrophic and cicatricial.

Common visual complaints include central blur, central scotoma or metamorphopsia and/or disturbances of central vision. Vision is normal or mildly reduced in early stages of the disease despite the presence of the vitelliform lesion. Preservation of vision correlates with the integrity of the outer nuclear layer and ellipsoid zone. Commonly, retinal atrophy and, infrequently, CNV can then lead to worsening visual acuity as the vitelliform lesion fades. Balaratnasingam and colleagues showed that CNV development occurs in 2.1% of eyes.

Histology and electron microscopy indicate that photoreceptors are likely the first cells damaged during disruption secondary to rapid shedding or inefficient processing of abnormal outer segments. Subsequent impaired RPE uptake leads to accumulation of vitelliform material, comprising photoreceptor outer segment debris, lipofuscin, melanin, melanolipofuscin-loaded macrophages and RPE cells. As the disease progresses, the vitelliform material is resorbed, theorized to be the RPE’s recuperated ability to phagocytize the vitelliform material once fewer photoreceptor outer segments are produced. Resolution of most vitelliform lesions leads to progressive thinning of the outer retinal layers. Some cases exhibit migrated pigment clumps in the outer retina, assumed to be RPE’s stress response to insult.

PAGE BREAK

The term dystrophy is typically reserved for genetically inherited conditions. The majority of AOFVD cases are not associated with genetic mutations, thus, it may be more appropriately identified as a degeneration, given the gradual loss of tissue and function in older individuals. Some cases of AOFVD have been linked to a mutation in genes PRPH2, BEST1, IMPG1 and IMPG2, as well as a single nucleotide polymorphism in the HTRA1 gene. No clear inheritance pattern has been identified, as most patients have a negative family history. Alternatively, patients’ family members may be asymptomatic or unaware of their disease. An indefinite inheritance pattern could be attributable to variable expression or decreased penetrance.

Diagnostic testing

Eyes with AOFVD will commonly present with a hyperautofluorescent lesion. A study by Parodi and colleagues observed that a patchy pattern correlated with worse fixation stability and worse visual acuity. Outer retinal and RPE loss will generally be hypoautofluorescent. In addition, central hypoautofluorescence can also be seen in the vitelliform stage corresponding with the pigmented spot.

Andrew Rixon

A dome-shaped hyper-reflective lesion will be located between the photoreceptor layer and RPE in the vitelliform stage. This subretinal material has been shown to be heterogeneously hyper-reflective more often than homogenously hyper-reflective. In the pseudohypopyon stage, there will be an optically empty zone above or adjacent to the vitelliform lesion. In the vitelliruptive stage, there is collapse of the lesion along with hyper-reflective clumps of pigment migrating to the inner retina. Resolution of most vitelliform lesions leads to progressive thinning of the outer retina. In the atrophic stage, disruption of the photoreceptor inner segment/outer segment (IS/OS) junction and external limiting membrane are correlated with the extent of vision loss. Areas of outer retinal, RPE and choriocapillaris degeneration can be seen.

Hypo-reflective subretinal fluid is sometimes seen between the RPE and the vitelliform material, presumably due to inefficient RPE fluid pumping. On the other hand, presence of fluid may indicate an active CNV when seen as well-circumscribed hypo-reflective spaces that distort surrounding retinal layers or RPE. A CNV can also present with RPE detachments or tears, fibrovascular or disciform scarring, or vitreous hemorrhaging. OCT can help determine if the CNV is type 1, where vessels are confined under the RPE, or type 2, where vessels proliferate into the subretinal space.

Treatment

Currently, no validated therapy has been shown to prevent retinal atrophy and subsequent loss of vision. Verteporfin photodynamic therapy was unsuccessful, leading to RPE atrophy and visual decline in eyes. The literature does not justify the use of anti-VEGF injections in patients without CNV, as visual acuity improvement in studies has been temporary (Gallego-Pinazo et al., Montero JA et al., Kandula et al.) Gene therapy may show potential in treating monogenic forms of AOFVD (Conley et al., Guziewicz et al.). Anti-VEGF has shown regression of the neovascular network in eyes with CNV, but multiple studies indicated many eyes still had poor visual prognosis secondary to progression of the lesion and outer retinal atrophy (Mimoun et al., Tiosano et al., Prieto-Calvo et al.). Without the presence of a CNV, our patient did not require additional treatment.

Vision rehabilitation

For visual disability, a consultation with a low vision specialist may be appropriate to improve quality of life due to loss of independence, risk for falls and accidents, and psychological cost. Individuals who experience difficulty performing daily tasks can be referred for optical device evaluations, counseling and additional resources.

PAGE BREAK

The consultation should include a comprehensive review of the patient’s understanding of the condition and history, a clinical evaluation of visual function, a review of their daily routine and environment, and potential visual goals.

This patient’s management

Our patient was referred internally for the low vision consultation. He noted difficulty reading books and the newspaper and viewing his cellphone. As for mobility, he had an electric wheelchair and support cane to use when needed. His wife provided assistance for most daily needs.

Evaluation of devices included a +16 DS (4X) handheld LED magnifier, a +20 DS (5X) stand magnifier, high-powered reading glasses and 3X Galilean binoculars. He appreciated improvement in contrast with yellow filter shields and better lighting. A bold felt tip pen and bold lined paper were issued to the patient along with instructions to write slower and larger. Several large-print books were also ordered for him.

After thorough instruction of device usage and recommendations to minimize risks to health and safety, the patient was advised to follow up as needed.

Disclosures: Ragha, Rixon and Semes reported no relevant financial disclosures.