Grand Rounds at the New England Eye Center

Elderly man presents with acute-onset nonprogressive blurred vision in right eye

On examination, the peripheral retina showed 360° of retinal pigment epithelium mottling with an area of subretinal fluid inferiorly.

A 79-year-old man presented to Tufts New England Eye Center with a 6-week history of acute-onset nonprogressive blurred vision and reduced color vision in the right eye. The patient’s complete ocular and systemic review of systems was otherwise negative, including headache, weight loss, fevers or night sweats.

The patient’s medical history was notable for a remote history of prostate cancer that had been treated with radioactive seed implant in 1998. He had been recently hospitalized for renal failure of unclear etiology. His other medical conditions included insulin-dependent diabetes and hypertension. In terms of his ocular history, he had uncomplicated cataract surgery in both eyes 1 year prior. His prescribed medications included aspirin, doxazosin, enzalutamide, insulin, metoprolol, oxycodone and simvastatin. He was allergic to Keflex (cephalexin), was a former smoker and denied alcohol use.

The patient had undergone examination by an outside ophthalmologist who referred the patient to NEEC for evaluation of a chronic-appearing retinal detachment in the right eye.

Examination

Figure 1. Fundus photo of the right eye showing clear vitreous, healthy optic nerve and mild increased vessel tortuosity. Macula reveals orange deposits consistent with lipofuscin. Periphery shows 360° pattern of RPE mottling. Subretinal fluid is present inferiorly.

Source: Sarah Thornton, MD

Figure 2. OCT through the fovea of the right eye reveals subfoveal fluid, thickened choroid and disruption of the ellipsoid zone.
Figure 3. Fundus autofluorescence photo of the right eye showing spotted pattern of hyperautofluorescence peripherally.
Figure 4. Fluorescein angiography of the right eye at 40 seconds after administration of fluorescein dye through peripheral IV site reveals diffuse hyperfluorescence consistent with a window defect from RPE atrophy, with hypofluorescence corresponding to blockage from lipofuscin deposits.
Figure 5. Posterior B-scan reveals normal axial length (22.48 mm) with exudative retinal detachment and diffuse sclerochoroidal thickening.

Upon examination at NEEC, best corrected visual acuity was 20/70 in the right eye and 20/25 in the left eye. Pupils were equally round and reactive to light with no afferent pupillary defect. IOP was within normal limits, and anterior segment slit lamp examination was unremarkable in both eyes.

Dilated fundus examination of the right eye revealed clear vitreous and a healthy optic nerve (Figure 1). The vessels appeared tortuous, and the macula contained yellow-orange deposits consistent with lipofuscin. The peripheral retina showed 360° of retinal pigment epithelium (RPE) mottling with an area of subretinal fluid inferiorly. No retinal breaks or areas of preretinal traction were identified. Dilated fundus examination of the left eye was within normal limits.

Imaging

OCT of the right eye revealed a thickened choroid, subfoveal fluid and disruption of the ellipsoid zone (Figure 2). Fundus autofluorescence imaging of the right eye revealed a spotted pattern of hyperautofluorescence in the peripheral retina (Figure 3). Fluorescein angiography of the right eye revealed early diffuse hyperfluorescence consistent with a window defect from RPE atrophy, with hypofluorescence corresponding to blockage from lipofuscin deposits (Figure 4). B-scan revealed exudative retinal detachment and diffuse sclerochoroidal thickening in the setting of a normal axial length (22.48 mm) (Figure 5). Imaging of the left eye revealed no significant abnormalities.

What is your diagnosis?

See answer on next page.

Retinal detachment

Retinal detachment occurs when the neurosensory retina becomes separated from the underlying RPE due to disruption of the normal mechanisms of adherence. The three main categories of retinal detachments are rhegmatogenous, tractional and exudative. Rhegmatogenous retinal detachments occur when vitreous enters the subretinal space through a break in the retina, while tractional detachments occur when the retina is pulled from the RPE by a proliferative fibrovascular membrane. Exudative or serous retinal detachments are the result of fluid accumulation between the neurosensory retina and the retinal pigment epithelial layer due to disruption of the blood-retinal barrier. Under normal conditions, the RPE actively pumps ions and fluid from the vitreous to the choroid. Any disease process causing RPE dysfunction, alterations in retinal or choroidal flow, or vascular hyperpermeability may overwhelm the normal mechanisms of fluid homeostasis and cause a resultant exudative retinal detachment.

Clinically, these detachments usually manifest as smooth elevations of the retina with clear to somewhat cloudy exudative fluid that may shift with the patient’s head position. Patients may complain of varying degrees of vision loss and metamorphopsia or scotomas that correspond to the area of involved retina. While classically associated with rhegmatogenous tears, photopsias are a common symptom in exudative detachments as well.

The differential diagnosis for exudative retinal detachment is quite broad and includes many systemic and localized orbital or ocular conditions that break down the blood-retinal barrier and disrupt the normal fluid homeostasis in the eye. These conditions may be inflammatory, infectious, infiltrative, vascular, neoplastic, degenerative or idiopathic in nature.

Diseases that disrupt normal choroidal and retinal blood flow can lead to serous retinal detachments. Central serous chorioretinopathy is thought to cause serous detachments of the macula secondary to choroidal hyperpermeability, although there is some debate as to whether the RPE is the primary site of disease. Retinal or choroidal tumors such as choroidal melanoma, hemangioma or choroidal metastatic carcinoma can present with a localized area of overlying subretinal fluid due to a similar mechanism. Malignant hypertension, renal failure, pre-eclampsia, disseminated intravascular coagulation and thrombotic thrombocytopenic purpura are systemic diseases that can cause choroidal and retinal ischemia and resultant leakage. Similarly, the vasculitides (systemic lupus erythematosus, granulomatosis with polyangiitis, relapsing polychondritis and polyarteritis nodosa) produce exudation via a similar process. Primary retinal vascular diseases such as Coats’ disease, familial exudative vitreoretinopathy and macular degeneration cause serous detachments without associated choroidal vascular pathology.

Damage to the retina, RPE and choroid resulting in exudative detachment can occur in infectious and inflammatory disease. Important systemic infectious considerations include tuberculosis, syphilis, Lyme disease and dengue fever, while ocular infectious causes include cytomegalovirus retinitis, toxoplasmosis, Bartonella henselae, nematode infection and fungal endophthalmitis. Noninfectious uveitic associations include posterior scleritis (frequently in association with an underlying systemic inflammatory disease), sarcoidosis, intermediate uveitis, Vogt-Koyanagi-Harada disease and sympathetic ophthalmia. Orbital infectious or inflammatory disease may produce adjacent localized ocular inflammation; exudative detachment has been reported in cases of idiopathic orbital inflammation, cellulitis or tumor.

Poor scleral outflow can result in exudative detachments due to outflow obstruction. This can occur due to constitutive scleral abnormalities in nanophthalmic eyes and in some cases of uveal effusion syndrome, or can result from scleral depositions associated with multiple myeloma, IgA nephropathy or light chain disease. Outflow resistance from inflamed sclera is one proposed mechanism for exudative detachment in posterior scleritis.

Workup and management

Because of the patient’s history of prostate cancer, metastatic disease was of particular concern, especially given the unilateral presentation. His history of recent renal failure also raised the possibility of an underlying hematologic disease such as IgA nephropathy, multiple myeloma or light chain disease. The appearance of a “leopard spot” pattern on fluorescein angiography, which is classically associated with leukemia, lymphoma, metastatic carcinoma, posterior scleritis and uveal effusion syndrome, further focused the diagnostic workup. Posterior scleritis seemed less likely given the lack of pain and normal B-scan, while uveal effusion syndrome is considered a diagnosis of exclusion.

The patient was sent for laboratory testing as well as MRI of the brain and orbits. His laboratory test results, including complete blood count and serum protein electrophoresis, were unremarkable. The MRI revealed a right intraorbital mass with faint enhancement, which was subsequently biopsied without complication. Biopsy results demonstrated orbital tissue infiltrated by malignant adenocarcinoma cells consistent with a diagnosis of metastatic disease from a primary prostate tumor.

Discussion

Prostate cancer is the most common lethal malignancy among men in the United States. When metastatic, it primarily involves bone, but it may also spread to pelvic lymph nodes, liver and lungs. Ocular metastasis is a rare occurrence. In one study examining 93 patients with intraocular metastasis, only two patients had a primary prostate malignancy. Uveal metastasis occurs more commonly in breast, lung or gastrointestinal cancer. Orbital metastasis, on the other hand, is somewhat more common in prostate cancer but still represents a minority of all orbital metastatic disease (6% to 17% of cases). Prostate cancer spreads to the orbit and eye by two main routes: via the pulmonary circulation to the carotid and ophthalmic arteries in patients with lung lesions, and via Batson’s plexus to the cranial venous sinuses to ophthalmic and vortex veins in patients without lung lesions.

Presenting symptoms of oculo-orbital metastasis from primary prostate adenocarcinoma include vision loss, ptosis, pain and double vision. Diagnostic workup may be assisted by laboratory workup, including prostate-specific antigen and complete blood count, as well as radiologic studies. The most typical finding on head CT scan is a well-defined, contrast-enhancing intraconal lesion with osteoblastic changes. Definitive diagnosis is achieved through biopsy of the lesion, with cytologic studies most commonly demonstrating nuclear crowding and enlargement, nucleolar enlargement and variable pleomorphism.

Treatment of metastatic orbital tumors is often palliative given the poor prognosis. Treatment options include chemotherapy, hormonal therapy, radiotherapy, surgery or a combination.

Exudative retinal detachment occurs when the blood-retinal barrier is compromised as a result of inflammatory, infectious, vascular or neoplastic processes. In this case, unilateral exudative retinal detachment was caused by orbital metastatic disease from a primary prostate adenocarcinoma. In patients with a known history of prior malignancy, suspicion for an underlying neoplastic process must be high.

A 79-year-old man presented to Tufts New England Eye Center with a 6-week history of acute-onset nonprogressive blurred vision and reduced color vision in the right eye. The patient’s complete ocular and systemic review of systems was otherwise negative, including headache, weight loss, fevers or night sweats.

The patient’s medical history was notable for a remote history of prostate cancer that had been treated with radioactive seed implant in 1998. He had been recently hospitalized for renal failure of unclear etiology. His other medical conditions included insulin-dependent diabetes and hypertension. In terms of his ocular history, he had uncomplicated cataract surgery in both eyes 1 year prior. His prescribed medications included aspirin, doxazosin, enzalutamide, insulin, metoprolol, oxycodone and simvastatin. He was allergic to Keflex (cephalexin), was a former smoker and denied alcohol use.

The patient had undergone examination by an outside ophthalmologist who referred the patient to NEEC for evaluation of a chronic-appearing retinal detachment in the right eye.

Examination

Figure 1. Fundus photo of the right eye showing clear vitreous, healthy optic nerve and mild increased vessel tortuosity. Macula reveals orange deposits consistent with lipofuscin. Periphery shows 360° pattern of RPE mottling. Subretinal fluid is present inferiorly.

Source: Sarah Thornton, MD

Figure 2. OCT through the fovea of the right eye reveals subfoveal fluid, thickened choroid and disruption of the ellipsoid zone.
Figure 3. Fundus autofluorescence photo of the right eye showing spotted pattern of hyperautofluorescence peripherally.
Figure 4. Fluorescein angiography of the right eye at 40 seconds after administration of fluorescein dye through peripheral IV site reveals diffuse hyperfluorescence consistent with a window defect from RPE atrophy, with hypofluorescence corresponding to blockage from lipofuscin deposits.
Figure 5. Posterior B-scan reveals normal axial length (22.48 mm) with exudative retinal detachment and diffuse sclerochoroidal thickening.

Upon examination at NEEC, best corrected visual acuity was 20/70 in the right eye and 20/25 in the left eye. Pupils were equally round and reactive to light with no afferent pupillary defect. IOP was within normal limits, and anterior segment slit lamp examination was unremarkable in both eyes.

Dilated fundus examination of the right eye revealed clear vitreous and a healthy optic nerve (Figure 1). The vessels appeared tortuous, and the macula contained yellow-orange deposits consistent with lipofuscin. The peripheral retina showed 360° of retinal pigment epithelium (RPE) mottling with an area of subretinal fluid inferiorly. No retinal breaks or areas of preretinal traction were identified. Dilated fundus examination of the left eye was within normal limits.

Imaging

OCT of the right eye revealed a thickened choroid, subfoveal fluid and disruption of the ellipsoid zone (Figure 2). Fundus autofluorescence imaging of the right eye revealed a spotted pattern of hyperautofluorescence in the peripheral retina (Figure 3). Fluorescein angiography of the right eye revealed early diffuse hyperfluorescence consistent with a window defect from RPE atrophy, with hypofluorescence corresponding to blockage from lipofuscin deposits (Figure 4). B-scan revealed exudative retinal detachment and diffuse sclerochoroidal thickening in the setting of a normal axial length (22.48 mm) (Figure 5). Imaging of the left eye revealed no significant abnormalities.

What is your diagnosis?

See answer on next page.

PAGE BREAK

Retinal detachment

Retinal detachment occurs when the neurosensory retina becomes separated from the underlying RPE due to disruption of the normal mechanisms of adherence. The three main categories of retinal detachments are rhegmatogenous, tractional and exudative. Rhegmatogenous retinal detachments occur when vitreous enters the subretinal space through a break in the retina, while tractional detachments occur when the retina is pulled from the RPE by a proliferative fibrovascular membrane. Exudative or serous retinal detachments are the result of fluid accumulation between the neurosensory retina and the retinal pigment epithelial layer due to disruption of the blood-retinal barrier. Under normal conditions, the RPE actively pumps ions and fluid from the vitreous to the choroid. Any disease process causing RPE dysfunction, alterations in retinal or choroidal flow, or vascular hyperpermeability may overwhelm the normal mechanisms of fluid homeostasis and cause a resultant exudative retinal detachment.

Clinically, these detachments usually manifest as smooth elevations of the retina with clear to somewhat cloudy exudative fluid that may shift with the patient’s head position. Patients may complain of varying degrees of vision loss and metamorphopsia or scotomas that correspond to the area of involved retina. While classically associated with rhegmatogenous tears, photopsias are a common symptom in exudative detachments as well.

The differential diagnosis for exudative retinal detachment is quite broad and includes many systemic and localized orbital or ocular conditions that break down the blood-retinal barrier and disrupt the normal fluid homeostasis in the eye. These conditions may be inflammatory, infectious, infiltrative, vascular, neoplastic, degenerative or idiopathic in nature.

Diseases that disrupt normal choroidal and retinal blood flow can lead to serous retinal detachments. Central serous chorioretinopathy is thought to cause serous detachments of the macula secondary to choroidal hyperpermeability, although there is some debate as to whether the RPE is the primary site of disease. Retinal or choroidal tumors such as choroidal melanoma, hemangioma or choroidal metastatic carcinoma can present with a localized area of overlying subretinal fluid due to a similar mechanism. Malignant hypertension, renal failure, pre-eclampsia, disseminated intravascular coagulation and thrombotic thrombocytopenic purpura are systemic diseases that can cause choroidal and retinal ischemia and resultant leakage. Similarly, the vasculitides (systemic lupus erythematosus, granulomatosis with polyangiitis, relapsing polychondritis and polyarteritis nodosa) produce exudation via a similar process. Primary retinal vascular diseases such as Coats’ disease, familial exudative vitreoretinopathy and macular degeneration cause serous detachments without associated choroidal vascular pathology.

PAGE BREAK

Damage to the retina, RPE and choroid resulting in exudative detachment can occur in infectious and inflammatory disease. Important systemic infectious considerations include tuberculosis, syphilis, Lyme disease and dengue fever, while ocular infectious causes include cytomegalovirus retinitis, toxoplasmosis, Bartonella henselae, nematode infection and fungal endophthalmitis. Noninfectious uveitic associations include posterior scleritis (frequently in association with an underlying systemic inflammatory disease), sarcoidosis, intermediate uveitis, Vogt-Koyanagi-Harada disease and sympathetic ophthalmia. Orbital infectious or inflammatory disease may produce adjacent localized ocular inflammation; exudative detachment has been reported in cases of idiopathic orbital inflammation, cellulitis or tumor.

Poor scleral outflow can result in exudative detachments due to outflow obstruction. This can occur due to constitutive scleral abnormalities in nanophthalmic eyes and in some cases of uveal effusion syndrome, or can result from scleral depositions associated with multiple myeloma, IgA nephropathy or light chain disease. Outflow resistance from inflamed sclera is one proposed mechanism for exudative detachment in posterior scleritis.

Workup and management

Because of the patient’s history of prostate cancer, metastatic disease was of particular concern, especially given the unilateral presentation. His history of recent renal failure also raised the possibility of an underlying hematologic disease such as IgA nephropathy, multiple myeloma or light chain disease. The appearance of a “leopard spot” pattern on fluorescein angiography, which is classically associated with leukemia, lymphoma, metastatic carcinoma, posterior scleritis and uveal effusion syndrome, further focused the diagnostic workup. Posterior scleritis seemed less likely given the lack of pain and normal B-scan, while uveal effusion syndrome is considered a diagnosis of exclusion.

The patient was sent for laboratory testing as well as MRI of the brain and orbits. His laboratory test results, including complete blood count and serum protein electrophoresis, were unremarkable. The MRI revealed a right intraorbital mass with faint enhancement, which was subsequently biopsied without complication. Biopsy results demonstrated orbital tissue infiltrated by malignant adenocarcinoma cells consistent with a diagnosis of metastatic disease from a primary prostate tumor.

Discussion

Prostate cancer is the most common lethal malignancy among men in the United States. When metastatic, it primarily involves bone, but it may also spread to pelvic lymph nodes, liver and lungs. Ocular metastasis is a rare occurrence. In one study examining 93 patients with intraocular metastasis, only two patients had a primary prostate malignancy. Uveal metastasis occurs more commonly in breast, lung or gastrointestinal cancer. Orbital metastasis, on the other hand, is somewhat more common in prostate cancer but still represents a minority of all orbital metastatic disease (6% to 17% of cases). Prostate cancer spreads to the orbit and eye by two main routes: via the pulmonary circulation to the carotid and ophthalmic arteries in patients with lung lesions, and via Batson’s plexus to the cranial venous sinuses to ophthalmic and vortex veins in patients without lung lesions.

PAGE BREAK

Presenting symptoms of oculo-orbital metastasis from primary prostate adenocarcinoma include vision loss, ptosis, pain and double vision. Diagnostic workup may be assisted by laboratory workup, including prostate-specific antigen and complete blood count, as well as radiologic studies. The most typical finding on head CT scan is a well-defined, contrast-enhancing intraconal lesion with osteoblastic changes. Definitive diagnosis is achieved through biopsy of the lesion, with cytologic studies most commonly demonstrating nuclear crowding and enlargement, nucleolar enlargement and variable pleomorphism.

Treatment of metastatic orbital tumors is often palliative given the poor prognosis. Treatment options include chemotherapy, hormonal therapy, radiotherapy, surgery or a combination.

Exudative retinal detachment occurs when the blood-retinal barrier is compromised as a result of inflammatory, infectious, vascular or neoplastic processes. In this case, unilateral exudative retinal detachment was caused by orbital metastatic disease from a primary prostate adenocarcinoma. In patients with a known history of prior malignancy, suspicion for an underlying neoplastic process must be high.