Grand Rounds at the New England Eye Center

Young man presents with subacute binocular diplopia

OCT of the right eye showed a sharply elevated intraretinal lesion.

A 22-year-old otherwise healthy man was referred to the New England Eye Center by his primary care physician for 1 to 2 months of intermittent binocular diplopia. He described that his vision had “not felt right” for the last few months. The doubling seemed to occur mostly at night and when he was tired. Subjectively he also felt the acuity was mildly worse in the right eye. His last eye exam was 10 years prior without any reported significant findings. He denied any headaches, flashes or floaters. He had no recent illness or trauma. His medical and family history was unremarkable.

Examination

The patient’s best corrected visual acuity was 20/20-1 in the right eye and 20/20 in the left eye. Pupils were equal, round and briskly reactive with no afferent pupillary defect. Extraocular movements were significant only for a small left hypertropia that was comitant in all gazes. Ishihara color vision testing was full, and IOPs were within normal limits. On slit lamp biomicroscopy, anterior segment examination was normal with no evidence of inflammation. Fundus exam in the right eye revealed a large irregular elevated peripapillary white mass with fine visible internal vasculature and adjacent retinal striae. There was no visible vitritis, hemorrhage or exudate (Figure 1). Peripheral retinal exam was unremarkable, and left posterior segment was normal.

Additional questioning revealed that the patient traveled recently to Iceland, France and Morocco. A review of systems was otherwise negative. He had no family history of tumors, and his skin exam was negative for café au lait macules or other lesions.

OCT of the right eye showed a sharply elevated intraretinal lesion with heterogeneous reflectivity, inner retinal thickening, posterior shadowing and adjacent retinal folds (Figure 2). Fluorescein angiography of the right eye revealed early blockage and intrinsic tortuous vasculature within the lesion, with diffuse late staining (Figure 3). B-scan ultrasonography revealed high internal reflectivity and orbital shadowing.

Figure 1. Color fundus photos of the right eye revealing a large elevated irregular peripapillary mass with faintly visible internal vasculature and adjacent retinal striae.

Images: Hansen B, Morkin M and Witkin A

Figure 2. OCT showing a sharply elevated irregular intraretinal lesion with heterogeneous reflectivity, inner retinal thickening, posterior shadowing and adjacent retinal folds.
Figure 3. Fluorescein angiography of the right eye showing early blockage and intrinsic tortuous tumor vasculature absent of any dilated feeder vessel with diffuse late staining.

Given the patient’s rather acute visual disturbance with diplopia, he had additional work-up that included a CBC, CMP, RPR, FTA-Abs, ACE, lysozyme, QuantiFERON, toxoplasma titers, and MRI of the brain and orbits. These tests were within normal limits.

What is your diagnosis?

Binocular diplopia

The diagnosis of retinal astrocytic hamartoma is primarily based on clinical appearance. Most commonly, patients are asymptomatic, and the lesions are detected either on routine eye exam or during a work-up for patients with dysgenic syndromes such as tuberous sclerosis complex or neurofibromatosis type 1. Clinically, appearance of the lesions can vary from faint translucent intraretinal patches to dense elevated gray-white lesions with irregular “mulberry-like” edges (depending on the amount of calcification). When associated with a systemic syndrome, they may be multifocal and bilateral (25%). Otherwise, they are typically unilateral and isolated. They can arise from any location in the retina but are more common in the posterior pole in sporadic non-syndromic cases. Often, the retinal vascular is obscured, from thickening of the inner retinal layers, with visible intrinsic vasculature and no dilated feeder vessels.

Fluorescein angiography typically reveals early blockade, highlighting of the intrinsic vasculature during middle and late phases, absence of dilated afferent or efferent vessels, and late diffuse staining. Some lesions, particularly those of the more calcified variant, show autofluorescence. OCT may reveal irregular inner retinal thickening, intraretinal fluid, multiple ovoid hypolucencies and, in some cases, intravitreal spread of cells. B-scan ultrasonography may show an ill-defined lesion with reflectivity similar to normal retinal tissue and may demonstrate focal intralesional hyper-reflective regions with associated orbital shadowing, depending on the intrinsic calcification. In patients in whom a retinal astrocytoma is suspected, an assessment aimed at the detection of other features of tuberous sclerosis or neurofibromatosis (ie, MRI/CT of the brain) may be warranted.

The differential diagnosis for an acquired lesion depends on the clinical setting. In our patient, his acute symptoms prompted a work-up that included both infectious and inflammatory conditions (syphilis, tuberculosis, toxoplasmosis, toxocariasis and sarcoidosis). The more typical differential diagnosis would also include retinoblastoma, massive retinal gliosis, myelinated retinal nerve fiber layers, osteoma, amelanotic choroidal melanoma, metastasis and exaggerated exudative lesions (idiopathic retinal telangiectasia, retinal capillary hemangiomatosis).

Discussion

Retinal astrocytomas are benign acquired neoplasias that arise from well-differentiated astrocytes of the neurosensory retina. They fall into a group of retinal glial tumors described by Shields and colleagues and are further categorized based on clinical features into retinal astrocytic hamartomas and acquired retinal astrocytomas. Retinal astrocytic hamartomas are thought to be primarily congenital and commonly associated with tuberous sclerosis complex and rarely neurofibromatosis type 1. Genetic testing for tuberous sclerosis complex has located multiple alterations in tumor suppressor genes on chromosomes 9 and 16, with autosomal dominant inheritance and variable expressivity. These lesions may be multifocal, bilateral and more peripheral in their location on the retina. Although there is a great deal of variance, these lesions may also have more calcification within the tumor stroma. This manifests clinically as irregular lesions with glistening yellow spherules. In contrast, acquired retinal astrocytomas tend to be isolated unilateral lesions located in the posterior pole with less evidence of calcification, more commonly occurring in older patients with no family history.

Although primarily a clinical diagnosis, ancillary testing may be helpful in ruling out other more ominous retinal tumors such as retinoblastoma or amelanotic melanoma. Fluorescein angiography can help highlight characteristic fine intrinsic vasculature and also rule out any dilated feeder vessels that are more commonly seen in malignant tumors. B-scan ultrasonography and OCT can help identify high internal reflectivity, calcification, intra-retinal fluid, exudative retinal detachments or extraocular extension. When considering further investigation into a syndromic association, it is important to recall the additional findings associated with tuberous sclerosis complex, which include brain astrocytomas, cutaneous angiofibromas (adenoma sebaceum), cutaneous depigmented macules (ash-leaf sign), cardiac rhabdomyoma and renal angiomyolipomas.

Generally, these retinal tumors are thought to have a limited tendency for progression. However, there have been reports of aggressive subtypes that lead to lesion growth, exudative retinal detachments, neovascular glaucoma and extraocular extension. Pathologic differentiation may account for theses variances. Retinal astrocytomas have been shown to have two distinct histologies. The first is comprised of interlacing bundles of spindle-shaped cells mixed with a minority of polygonal cells. The second consists of large or “giant” cells with abundant glassy cytoplasm (gemistocytic astrocytes). The gemistocytic type demonstrates a greater propensity for invasive growth. Fine needle aspiration may rarely be considered for atypical cases.

Given that the majority of retinal astrocytic hamartomas and acquired astrocytomas are stationary lesions, the general consensus for treatment is observation only. A 2006 review by Mennel and colleagues compared treatment modalities for symptomatic retinal hamartomas. In this evaluation of 93 patients with retinal hamartomas, 11 were treated for symptomatic changes. The visual symptoms were caused by macular edema, lipid exudates, serous retinal detachments and vitreous hemorrhage. Three patients had complete resolution of exudation within 4 weeks with no treatment. The remainder were treated with laser argon photocoagulation (leading to choroidal neovascularization in one patient), vitrectomy (for vitreous hemorrhage) or photodynamic therapy. Each of these modalities resulted in improved visual acuity and eventual resorption of subretinal fluid. Cryotherapy has also been suggested as an alternative therapy for progressive tumors. Radiotherapy by plaque or charged particle beam has not been shown to be effective, and enucleation should be reserved only for blind painful eyes because the risk for extension is extremely low.

Follow-up

After the initial work-up, our patient was given the presumptive diagnosis of acquired retinal astrocytoma. The binocular nature of his diplopia was thought to likely be unrelated to his retinal findings. He had negative testing for myasthenia gravis and is being followed closely without therapy. An MRI of the brain and orbits was unremarkable. Because of a negative MRI, absence of skin lesions and negative family history, genetic testing for tuberous sclerosis and neurofibromatosis was not performed.

A 22-year-old otherwise healthy man was referred to the New England Eye Center by his primary care physician for 1 to 2 months of intermittent binocular diplopia. He described that his vision had “not felt right” for the last few months. The doubling seemed to occur mostly at night and when he was tired. Subjectively he also felt the acuity was mildly worse in the right eye. His last eye exam was 10 years prior without any reported significant findings. He denied any headaches, flashes or floaters. He had no recent illness or trauma. His medical and family history was unremarkable.

Examination

The patient’s best corrected visual acuity was 20/20-1 in the right eye and 20/20 in the left eye. Pupils were equal, round and briskly reactive with no afferent pupillary defect. Extraocular movements were significant only for a small left hypertropia that was comitant in all gazes. Ishihara color vision testing was full, and IOPs were within normal limits. On slit lamp biomicroscopy, anterior segment examination was normal with no evidence of inflammation. Fundus exam in the right eye revealed a large irregular elevated peripapillary white mass with fine visible internal vasculature and adjacent retinal striae. There was no visible vitritis, hemorrhage or exudate (Figure 1). Peripheral retinal exam was unremarkable, and left posterior segment was normal.

Additional questioning revealed that the patient traveled recently to Iceland, France and Morocco. A review of systems was otherwise negative. He had no family history of tumors, and his skin exam was negative for café au lait macules or other lesions.

OCT of the right eye showed a sharply elevated intraretinal lesion with heterogeneous reflectivity, inner retinal thickening, posterior shadowing and adjacent retinal folds (Figure 2). Fluorescein angiography of the right eye revealed early blockage and intrinsic tortuous vasculature within the lesion, with diffuse late staining (Figure 3). B-scan ultrasonography revealed high internal reflectivity and orbital shadowing.

Figure 1. Color fundus photos of the right eye revealing a large elevated irregular peripapillary mass with faintly visible internal vasculature and adjacent retinal striae.

Images: Hansen B, Morkin M and Witkin A

Figure 2. OCT showing a sharply elevated irregular intraretinal lesion with heterogeneous reflectivity, inner retinal thickening, posterior shadowing and adjacent retinal folds.
Figure 3. Fluorescein angiography of the right eye showing early blockage and intrinsic tortuous tumor vasculature absent of any dilated feeder vessel with diffuse late staining.

Given the patient’s rather acute visual disturbance with diplopia, he had additional work-up that included a CBC, CMP, RPR, FTA-Abs, ACE, lysozyme, QuantiFERON, toxoplasma titers, and MRI of the brain and orbits. These tests were within normal limits.

What is your diagnosis?

Binocular diplopia

The diagnosis of retinal astrocytic hamartoma is primarily based on clinical appearance. Most commonly, patients are asymptomatic, and the lesions are detected either on routine eye exam or during a work-up for patients with dysgenic syndromes such as tuberous sclerosis complex or neurofibromatosis type 1. Clinically, appearance of the lesions can vary from faint translucent intraretinal patches to dense elevated gray-white lesions with irregular “mulberry-like” edges (depending on the amount of calcification). When associated with a systemic syndrome, they may be multifocal and bilateral (25%). Otherwise, they are typically unilateral and isolated. They can arise from any location in the retina but are more common in the posterior pole in sporadic non-syndromic cases. Often, the retinal vascular is obscured, from thickening of the inner retinal layers, with visible intrinsic vasculature and no dilated feeder vessels.

Fluorescein angiography typically reveals early blockade, highlighting of the intrinsic vasculature during middle and late phases, absence of dilated afferent or efferent vessels, and late diffuse staining. Some lesions, particularly those of the more calcified variant, show autofluorescence. OCT may reveal irregular inner retinal thickening, intraretinal fluid, multiple ovoid hypolucencies and, in some cases, intravitreal spread of cells. B-scan ultrasonography may show an ill-defined lesion with reflectivity similar to normal retinal tissue and may demonstrate focal intralesional hyper-reflective regions with associated orbital shadowing, depending on the intrinsic calcification. In patients in whom a retinal astrocytoma is suspected, an assessment aimed at the detection of other features of tuberous sclerosis or neurofibromatosis (ie, MRI/CT of the brain) may be warranted.

The differential diagnosis for an acquired lesion depends on the clinical setting. In our patient, his acute symptoms prompted a work-up that included both infectious and inflammatory conditions (syphilis, tuberculosis, toxoplasmosis, toxocariasis and sarcoidosis). The more typical differential diagnosis would also include retinoblastoma, massive retinal gliosis, myelinated retinal nerve fiber layers, osteoma, amelanotic choroidal melanoma, metastasis and exaggerated exudative lesions (idiopathic retinal telangiectasia, retinal capillary hemangiomatosis).

Discussion

Retinal astrocytomas are benign acquired neoplasias that arise from well-differentiated astrocytes of the neurosensory retina. They fall into a group of retinal glial tumors described by Shields and colleagues and are further categorized based on clinical features into retinal astrocytic hamartomas and acquired retinal astrocytomas. Retinal astrocytic hamartomas are thought to be primarily congenital and commonly associated with tuberous sclerosis complex and rarely neurofibromatosis type 1. Genetic testing for tuberous sclerosis complex has located multiple alterations in tumor suppressor genes on chromosomes 9 and 16, with autosomal dominant inheritance and variable expressivity. These lesions may be multifocal, bilateral and more peripheral in their location on the retina. Although there is a great deal of variance, these lesions may also have more calcification within the tumor stroma. This manifests clinically as irregular lesions with glistening yellow spherules. In contrast, acquired retinal astrocytomas tend to be isolated unilateral lesions located in the posterior pole with less evidence of calcification, more commonly occurring in older patients with no family history.

Although primarily a clinical diagnosis, ancillary testing may be helpful in ruling out other more ominous retinal tumors such as retinoblastoma or amelanotic melanoma. Fluorescein angiography can help highlight characteristic fine intrinsic vasculature and also rule out any dilated feeder vessels that are more commonly seen in malignant tumors. B-scan ultrasonography and OCT can help identify high internal reflectivity, calcification, intra-retinal fluid, exudative retinal detachments or extraocular extension. When considering further investigation into a syndromic association, it is important to recall the additional findings associated with tuberous sclerosis complex, which include brain astrocytomas, cutaneous angiofibromas (adenoma sebaceum), cutaneous depigmented macules (ash-leaf sign), cardiac rhabdomyoma and renal angiomyolipomas.

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Generally, these retinal tumors are thought to have a limited tendency for progression. However, there have been reports of aggressive subtypes that lead to lesion growth, exudative retinal detachments, neovascular glaucoma and extraocular extension. Pathologic differentiation may account for theses variances. Retinal astrocytomas have been shown to have two distinct histologies. The first is comprised of interlacing bundles of spindle-shaped cells mixed with a minority of polygonal cells. The second consists of large or “giant” cells with abundant glassy cytoplasm (gemistocytic astrocytes). The gemistocytic type demonstrates a greater propensity for invasive growth. Fine needle aspiration may rarely be considered for atypical cases.

Given that the majority of retinal astrocytic hamartomas and acquired astrocytomas are stationary lesions, the general consensus for treatment is observation only. A 2006 review by Mennel and colleagues compared treatment modalities for symptomatic retinal hamartomas. In this evaluation of 93 patients with retinal hamartomas, 11 were treated for symptomatic changes. The visual symptoms were caused by macular edema, lipid exudates, serous retinal detachments and vitreous hemorrhage. Three patients had complete resolution of exudation within 4 weeks with no treatment. The remainder were treated with laser argon photocoagulation (leading to choroidal neovascularization in one patient), vitrectomy (for vitreous hemorrhage) or photodynamic therapy. Each of these modalities resulted in improved visual acuity and eventual resorption of subretinal fluid. Cryotherapy has also been suggested as an alternative therapy for progressive tumors. Radiotherapy by plaque or charged particle beam has not been shown to be effective, and enucleation should be reserved only for blind painful eyes because the risk for extension is extremely low.

Follow-up

After the initial work-up, our patient was given the presumptive diagnosis of acquired retinal astrocytoma. The binocular nature of his diplopia was thought to likely be unrelated to his retinal findings. He had negative testing for myasthenia gravis and is being followed closely without therapy. An MRI of the brain and orbits was unremarkable. Because of a negative MRI, absence of skin lesions and negative family history, genetic testing for tuberous sclerosis and neurofibromatosis was not performed.