Grand Rounds at the New England Eye Center

Woman presents with blurred vision 1 year after cataract surgery

There was a subtle yellow subretinal infiltrate in the right eye, along with a diffuse band of hyperreflective material between Bruch's membrane and the retinal pigment epithelium.

A 65-year-old retired grocery store clerk was referred to the New England Eye Center with more than a year of progressive vision loss in the right eye. Two and a half years before presentation, she underwent uncomplicated cataract surgery on the right eye. Her vision was excellent immediately after the surgery. However, 1 year after the surgery, a “smudge” began obscuring the central vision in the right eye. Over the subsequent year, exams by outside providers revealed only scattered drusen. Yet, the vision continued to decline to the point that she felt that she was “looking through a dense film.” In addition to the declining acuity, the patient also noticed new floaters. She denied any flashes or photophobia.

Her medical history included osteoarthritis with prior hip, knee and cervical spinal surgeries. Her ocular history was remarkable for moderate myopia and prior LASIK and cataract surgeries. Her mother had colon cancer and father had throat cancer, but there was no family history of ocular disease. Her only medication was diclofenac for osteoarthritis. She did not smoke or drink alcohol.

Examination

On examination, the patient was an otherwise healthy woman. Best corrected visual acuity was 20/100 in the right eye and 20/30+ in the left eye. She missed all HRR color plates on the right but saw all of them on the left. There was a 2+ relative afferent pupillary defect on the right. IOPs were 16 mm Hg on the right and 15 mm Hg on the left. External exam revealed normal lids and adnexa. Conjunctiva, sclera, corneas and anterior chambers were quiet. Irises were normal. Posterior chamber IOLs were in good position with open posterior capsules bilaterally.

Figure 1. Fundus photo of the right eye demonstrates vitreous haze and a subtle yellow subretinal infiltrate along the superior arcade extending into the macula (a). An OCT B-scan through the fovea of the right eye reveals an irregular RPE with underlying hyperreflective material between Bruch’s membrane and the RPE (b). In this fundus photo of the left eye, the vitreous appears clear. There is a mild epiretinal membrane, but there are no apparent lesions of the posterior pole (c). OCT B-scan through the fovea of the left eye demonstrates a mild epiretinal membrane and intact retinal layers without any infiltrate (d).

Source: Adam T. Chin, MD, Shilpa J. Desai, MD, and Thomas R. Hedges III, MD

On dilated exam of the right eye, there were some anterior vitreous cells and 1+ vitreous haze. The optic nerve was pink with a small cup-to-disc ratio without any disc edema. There was a subtle yellow subretinal infiltrate along the superior arcade extending into the macula (Figure 1a). In the left eye, the vitreous was clear. The optic nerve was pink with a small cup-to-disc ratio. There was an epiretinal membrane in the nasal macula.

OCT of the macula revealed a diffuse band of hyperreflective material between Bruch’s membrane and an irregular retinal pigment epithelium (RPE) in the right eye (Figure 1b).

What is your diagnosis?

See answer on next page.

Yellow subretinal infiltrate

The differential diagnosis of yellow placoid subretinal lesions in the posterior pole with associated vitritis includes a number of inflammatory, infectious and neoplastic etiologies.

Of the inflammatory etiologies, acute posterior multifocal placoid pigment epitheliopathy (APMPPE) may have a similar clinical appearance. It typically presents with mild vitritis and multiple yellow-white lesions in the posterior pole. OCT through these plaques reveals hyperreflective lesions in the outer retina on the OCT. Unlike our case, the typical APMPPE patient is a young woman in her 20s to 40s with an acute change in her vision. Further, APMPPE tends to resolve spontaneously over the course of weeks to months with a good visual prognosis.

Yellow-white retinal lesions can be seen in numerous infectious conditions including syphilis, herpes simplex virus retinitis, cytomegalovirus retinitis and endophthalmitis. The placoid appearance of these outer retinal lesions is particularly concerning for syphilitic chorioretinitis. In syphilis chorioretinitis, OCT typically reveals disruption of the ellipsoid and nodular or irregular-appearing RPE. On fluorescein angiography, syphilitic chorioretinitis most often appears as a progressive staining with areas of scattered hypofluorescence in a leopard spot pattern.

Figure 2. Fundus autofluorescence of the right eye reveals mottled hypoautofluorescence throughout the macula. The left eye appears to have a hyperautofluorescent pattern around the nerve and superior temporal arcade.
Figure 3. On fluorescein angiography of the right eye, there is staining of the subretinal deposits and mottled hyper- and hypofluorescence throughout the macula. There is late staining of sheathed vessels along the superior temporal arcade. In the left eye, there is diffuse staining in the peripapillary region and along the superior temporal arcade.

Neoplastic etiologies include vitreoretinal lymphoma, choroidal lymphoma and amelanotic melanoma. Of these, only primary vitreoretinal lymphoma would be expected to present with concurrent vitritis.

Additional workup

A laboratory workup including RPR/FTA-ABS, HIV, ACE, lysozyme, QuantiFERON Gold and CBC was unrevealing. The patient underwent fundus autofluorescence (Figure 2) and fluorescein angiography (Figure 3).

OCT is particularly helpful in narrowing the differential diagnosis. The findings of sub-RPE hyperreflective material on OCT, vitritis and subtle changes in the fundus are highly suspicious for primary vitreoretinal lymphoma in a patient with vague indolent visual symptoms. Given the concern for lymphoma, she underwent a vitreous biopsy and pars plana vitrectomy, which was positive for highly atypical B lymphocytes. Polymerase chain reaction (PCR) showed clonal heavy chain immunoglobulin gene rearrangement.

Our patient was referred to oncology for evaluation. An MRI of the brain and orbits did not reveal any central nervous system lesions. A PET CT found no metabolically active areas to suggest systemic disease. A diagnosis of primary vitreoretinal lymphoma was established.

Discussion

Primary vitreoretinal lymphoma (PVRL) is a rare presentation of non-Hodgkin’s lymphoma in the retina and vitreous. In the vast majority of cases, it is a diffuse B-cell lymphoma and closely associated with primary central nervous system lymphoma (PCNSL). Up to one-quarter of patients with PCNSL develop ocular disease, and half of patients with PVRL eventually develop central nervous system disease. This life-threatening association with systemic disease makes the recognition of ocular signs and symptoms essential. Unfortunately, its rare incidence and tendency to mimic other posterior inflammatory and infectious conditions make the diagnosis challenging.

PVRL typically occurs in patients after their fifth decade with a mean age at diagnosis of 63 years. It affects men and women equally. While there is an increased incidence in immunocompromised patients, particularly those with HIV and Epstein-Barr virus, PVRL still most commonly affects immunocompetent individuals.

As a masquerade syndrome, PVRL may present with a varied spectrum of clinical findings. The majority of cases are bilateral at presentation, but findings may be asymmetric or unilateral. Vitritis in the form of fine cell, haze or even diffuse sheets of cells may be the most prominent clinical sign even when retinal findings are subtle. Therefore, it is often mistaken for chronic endophthalmitis or posterior uveitis. When treated with steroid, vitreous inflammation may wane, thereby further delaying definitive diagnosis.

In the retina, lymphomatous deposits typically appear as multiple or confluent yellow to cream-colored subretinal lesions in the posterior pole and may be mistaken for drusen, inflammatory white dots or infectious lesions. In these lesions, lymphoid cells form deposits between Bruch’s membrane and the RPE. Lymphoid cells may extend beyond the sub-RPE space, forming sheaths around retinal vessels, which mimics vasculitis and even causes vessel leakage visible on fluorescein.

Multimodal imaging may be helpful in establishing clinical suspicion for PVRL. On OCT, a diffuse confluent hyperreflective subretinal or sub-RPE band of infiltrate is highly suggestive of PVRL. However, irregularity of the RPE, pre-RPE nodules, and mixed intra- and subretinal infiltrates can also be seen on OCT. On fluorescein angiography, there may be staining of the subretinal deposits, mottled hyper- and hypofluorescence (known as a leopard spot pattern), window defects, and less commonly vascular sheathing and leakage. Similarly, fundus autofluorescence typically reveals diffuse hyper- and hypoautofluorescent spots.

While some patients present with the classic findings, high clinical suspicion must be maintained to make the diagnosis of PVRL as signs and symptoms may overlap with other conditions. The gold standard for diagnosis is a cytologic specimen. Vitreous biopsy via a pars plana vitrectomy is typically the first-line diagnostic approach. Cytology reveals medium to large atypical lymphocytes with large irregular nuclei with high nuclear-to-cytoplasmic ratio. Further, cytokine analysis showing an elevation of IL-10 compared with IL-6 in the vitreous is suggestive of PVRL over other non-neoplastic posterior uveitis but is not by itself diagnostic. Likewise, flow cytometry showing a clonal expansion of lymphocytes with the same rearrangements of the immunoglobulin heavy chain locus or PCR detection of these heavy chains loci is highly suggestive of PVRL. Finally, PCR showing mutations in the MYD88 oncogene associated with PVRL may further aid in diagnosis.

While there are no established guidelines for the treatment of PVRL, a recent review by Pulido et al suggested local therapy for unilateral involvement and adjuvant systemic therapy for bilateral PVRL. In unilateral disease, they suggest intravitreal methotrexate and rituximab as first-line therapy with local external beam radiation reserved for salvage therapy. In patients with bilateral involvement, intravenous methotrexate is administered along with intravitreal methotrexate and rituximab. Despite these suggested protocols, there is no consensus treatment for PVRL.

Figure 4. Fundus photo of the right eye demonstrates improving vitreous haze. There is atrophy along the superior arcade and macula in the area of the yellow infiltrate (a). An OCT B-scan through the fovea of the right eye reveals RPE and outer retinal atrophy. The hyperreflective material between Bruch’s membrane and the RPE is no longer apparent (b). In this fundus photo of the left eye, the vitreous appears clear. There is a mild epiretinal membrane, but there are no apparent lesions of the posterior pole (c). OCT B-scan through the fovea of the left eye demonstrates a mild epiretinal membrane and intact retinal layers without any infiltrate (d).

Clinical course continued

In coordination with oncology, our patient was started on rituximab infusions. At the 1-month visit after four weekly rituximab infusions, the sub-RPE infiltrate had resolved centrally, leaving subfoveal atrophy with residual infiltrates in the temporal macula. Only trace vitreous haze and cell remained in the right eye (Figure 4). Her vision remains stable, and there are no signs of central nervous system involvement at the most recent follow-up visit.

A 65-year-old retired grocery store clerk was referred to the New England Eye Center with more than a year of progressive vision loss in the right eye. Two and a half years before presentation, she underwent uncomplicated cataract surgery on the right eye. Her vision was excellent immediately after the surgery. However, 1 year after the surgery, a “smudge” began obscuring the central vision in the right eye. Over the subsequent year, exams by outside providers revealed only scattered drusen. Yet, the vision continued to decline to the point that she felt that she was “looking through a dense film.” In addition to the declining acuity, the patient also noticed new floaters. She denied any flashes or photophobia.

Her medical history included osteoarthritis with prior hip, knee and cervical spinal surgeries. Her ocular history was remarkable for moderate myopia and prior LASIK and cataract surgeries. Her mother had colon cancer and father had throat cancer, but there was no family history of ocular disease. Her only medication was diclofenac for osteoarthritis. She did not smoke or drink alcohol.

Examination

On examination, the patient was an otherwise healthy woman. Best corrected visual acuity was 20/100 in the right eye and 20/30+ in the left eye. She missed all HRR color plates on the right but saw all of them on the left. There was a 2+ relative afferent pupillary defect on the right. IOPs were 16 mm Hg on the right and 15 mm Hg on the left. External exam revealed normal lids and adnexa. Conjunctiva, sclera, corneas and anterior chambers were quiet. Irises were normal. Posterior chamber IOLs were in good position with open posterior capsules bilaterally.

Figure 1. Fundus photo of the right eye demonstrates vitreous haze and a subtle yellow subretinal infiltrate along the superior arcade extending into the macula (a). An OCT B-scan through the fovea of the right eye reveals an irregular RPE with underlying hyperreflective material between Bruch’s membrane and the RPE (b). In this fundus photo of the left eye, the vitreous appears clear. There is a mild epiretinal membrane, but there are no apparent lesions of the posterior pole (c). OCT B-scan through the fovea of the left eye demonstrates a mild epiretinal membrane and intact retinal layers without any infiltrate (d).

Source: Adam T. Chin, MD, Shilpa J. Desai, MD, and Thomas R. Hedges III, MD

On dilated exam of the right eye, there were some anterior vitreous cells and 1+ vitreous haze. The optic nerve was pink with a small cup-to-disc ratio without any disc edema. There was a subtle yellow subretinal infiltrate along the superior arcade extending into the macula (Figure 1a). In the left eye, the vitreous was clear. The optic nerve was pink with a small cup-to-disc ratio. There was an epiretinal membrane in the nasal macula.

OCT of the macula revealed a diffuse band of hyperreflective material between Bruch’s membrane and an irregular retinal pigment epithelium (RPE) in the right eye (Figure 1b).

What is your diagnosis?

See answer on next page.

PAGE BREAK

Yellow subretinal infiltrate

The differential diagnosis of yellow placoid subretinal lesions in the posterior pole with associated vitritis includes a number of inflammatory, infectious and neoplastic etiologies.

Of the inflammatory etiologies, acute posterior multifocal placoid pigment epitheliopathy (APMPPE) may have a similar clinical appearance. It typically presents with mild vitritis and multiple yellow-white lesions in the posterior pole. OCT through these plaques reveals hyperreflective lesions in the outer retina on the OCT. Unlike our case, the typical APMPPE patient is a young woman in her 20s to 40s with an acute change in her vision. Further, APMPPE tends to resolve spontaneously over the course of weeks to months with a good visual prognosis.

Yellow-white retinal lesions can be seen in numerous infectious conditions including syphilis, herpes simplex virus retinitis, cytomegalovirus retinitis and endophthalmitis. The placoid appearance of these outer retinal lesions is particularly concerning for syphilitic chorioretinitis. In syphilis chorioretinitis, OCT typically reveals disruption of the ellipsoid and nodular or irregular-appearing RPE. On fluorescein angiography, syphilitic chorioretinitis most often appears as a progressive staining with areas of scattered hypofluorescence in a leopard spot pattern.

Figure 2. Fundus autofluorescence of the right eye reveals mottled hypoautofluorescence throughout the macula. The left eye appears to have a hyperautofluorescent pattern around the nerve and superior temporal arcade.
Figure 3. On fluorescein angiography of the right eye, there is staining of the subretinal deposits and mottled hyper- and hypofluorescence throughout the macula. There is late staining of sheathed vessels along the superior temporal arcade. In the left eye, there is diffuse staining in the peripapillary region and along the superior temporal arcade.

Neoplastic etiologies include vitreoretinal lymphoma, choroidal lymphoma and amelanotic melanoma. Of these, only primary vitreoretinal lymphoma would be expected to present with concurrent vitritis.

Additional workup

A laboratory workup including RPR/FTA-ABS, HIV, ACE, lysozyme, QuantiFERON Gold and CBC was unrevealing. The patient underwent fundus autofluorescence (Figure 2) and fluorescein angiography (Figure 3).

OCT is particularly helpful in narrowing the differential diagnosis. The findings of sub-RPE hyperreflective material on OCT, vitritis and subtle changes in the fundus are highly suspicious for primary vitreoretinal lymphoma in a patient with vague indolent visual symptoms. Given the concern for lymphoma, she underwent a vitreous biopsy and pars plana vitrectomy, which was positive for highly atypical B lymphocytes. Polymerase chain reaction (PCR) showed clonal heavy chain immunoglobulin gene rearrangement.

PAGE BREAK

Our patient was referred to oncology for evaluation. An MRI of the brain and orbits did not reveal any central nervous system lesions. A PET CT found no metabolically active areas to suggest systemic disease. A diagnosis of primary vitreoretinal lymphoma was established.

Discussion

Primary vitreoretinal lymphoma (PVRL) is a rare presentation of non-Hodgkin’s lymphoma in the retina and vitreous. In the vast majority of cases, it is a diffuse B-cell lymphoma and closely associated with primary central nervous system lymphoma (PCNSL). Up to one-quarter of patients with PCNSL develop ocular disease, and half of patients with PVRL eventually develop central nervous system disease. This life-threatening association with systemic disease makes the recognition of ocular signs and symptoms essential. Unfortunately, its rare incidence and tendency to mimic other posterior inflammatory and infectious conditions make the diagnosis challenging.

PVRL typically occurs in patients after their fifth decade with a mean age at diagnosis of 63 years. It affects men and women equally. While there is an increased incidence in immunocompromised patients, particularly those with HIV and Epstein-Barr virus, PVRL still most commonly affects immunocompetent individuals.

As a masquerade syndrome, PVRL may present with a varied spectrum of clinical findings. The majority of cases are bilateral at presentation, but findings may be asymmetric or unilateral. Vitritis in the form of fine cell, haze or even diffuse sheets of cells may be the most prominent clinical sign even when retinal findings are subtle. Therefore, it is often mistaken for chronic endophthalmitis or posterior uveitis. When treated with steroid, vitreous inflammation may wane, thereby further delaying definitive diagnosis.

In the retina, lymphomatous deposits typically appear as multiple or confluent yellow to cream-colored subretinal lesions in the posterior pole and may be mistaken for drusen, inflammatory white dots or infectious lesions. In these lesions, lymphoid cells form deposits between Bruch’s membrane and the RPE. Lymphoid cells may extend beyond the sub-RPE space, forming sheaths around retinal vessels, which mimics vasculitis and even causes vessel leakage visible on fluorescein.

Multimodal imaging may be helpful in establishing clinical suspicion for PVRL. On OCT, a diffuse confluent hyperreflective subretinal or sub-RPE band of infiltrate is highly suggestive of PVRL. However, irregularity of the RPE, pre-RPE nodules, and mixed intra- and subretinal infiltrates can also be seen on OCT. On fluorescein angiography, there may be staining of the subretinal deposits, mottled hyper- and hypofluorescence (known as a leopard spot pattern), window defects, and less commonly vascular sheathing and leakage. Similarly, fundus autofluorescence typically reveals diffuse hyper- and hypoautofluorescent spots.

PAGE BREAK

While some patients present with the classic findings, high clinical suspicion must be maintained to make the diagnosis of PVRL as signs and symptoms may overlap with other conditions. The gold standard for diagnosis is a cytologic specimen. Vitreous biopsy via a pars plana vitrectomy is typically the first-line diagnostic approach. Cytology reveals medium to large atypical lymphocytes with large irregular nuclei with high nuclear-to-cytoplasmic ratio. Further, cytokine analysis showing an elevation of IL-10 compared with IL-6 in the vitreous is suggestive of PVRL over other non-neoplastic posterior uveitis but is not by itself diagnostic. Likewise, flow cytometry showing a clonal expansion of lymphocytes with the same rearrangements of the immunoglobulin heavy chain locus or PCR detection of these heavy chains loci is highly suggestive of PVRL. Finally, PCR showing mutations in the MYD88 oncogene associated with PVRL may further aid in diagnosis.

While there are no established guidelines for the treatment of PVRL, a recent review by Pulido et al suggested local therapy for unilateral involvement and adjuvant systemic therapy for bilateral PVRL. In unilateral disease, they suggest intravitreal methotrexate and rituximab as first-line therapy with local external beam radiation reserved for salvage therapy. In patients with bilateral involvement, intravenous methotrexate is administered along with intravitreal methotrexate and rituximab. Despite these suggested protocols, there is no consensus treatment for PVRL.

Figure 4. Fundus photo of the right eye demonstrates improving vitreous haze. There is atrophy along the superior arcade and macula in the area of the yellow infiltrate (a). An OCT B-scan through the fovea of the right eye reveals RPE and outer retinal atrophy. The hyperreflective material between Bruch’s membrane and the RPE is no longer apparent (b). In this fundus photo of the left eye, the vitreous appears clear. There is a mild epiretinal membrane, but there are no apparent lesions of the posterior pole (c). OCT B-scan through the fovea of the left eye demonstrates a mild epiretinal membrane and intact retinal layers without any infiltrate (d).

Clinical course continued

In coordination with oncology, our patient was started on rituximab infusions. At the 1-month visit after four weekly rituximab infusions, the sub-RPE infiltrate had resolved centrally, leaving subfoveal atrophy with residual infiltrates in the temporal macula. Only trace vitreous haze and cell remained in the right eye (Figure 4). Her vision remains stable, and there are no signs of central nervous system involvement at the most recent follow-up visit.