MACULAR NEOVASCULARIZATION IN FAMILIAL EXUDATIVE VITREORETINOPATHY Kenneth Fung, MD, MBA,* Joe Mastellone,* Edward Chaum, MD, PHD*†
Purpose: To describe an unusual patient with autosomal dominant familial exudative vitreoretinopathy (FEVR) who also presented with preretinal fibrosis overlying the macula, extensive macular telangiectasis, and multiple foci of macular neovascularization. Methods: A clinical case is presented including fundus images and fluorescein angiography studies of the patient’s left eye containing the unusual manifestations. Results: To our knowledge, this is the first report of the formation of multifocal, preretinal macular neovascularization in FEVR. The sites of neovascularization corresponded to the attachment points of the vitreous stalk overlying the macula. Two small areas of intraretinal neovascularization were also noted. Conclusions: The concordance of the vitreoretinal adhesions with the sites of neovascularization suggests that the focal scaffolding may have played a direct mechanical role in encouraging the growth of the macular neovascular tissue in this patient. RETINAL CASES & BRIEF REPORTS 2:319 –321, 2008
From the *Department of Ophthalmology, Hamilton Eye Institute, and the †Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee.
inal branching, vascular sheathing, fibrous vitreous condensation, and exudative and tractional retinal detachments.1–3 The primary pathologic process in FEVR is believed to be a premature arrest of retinal vasculogenesis or retinal vascular differentiation, leading to incomplete vascularization of the peripheral retina. This peripheral zone of avascular retina is seen in all affected patients and may be the only manifestation of the condition in some patients. At the border of the avascular zone, arteriovenous shunt formation is common, and the peripheral retinal vessels are frequently dilated and sheathed. Neovascularization at the border of vascularized and avascular retina produces a fibrotic response manifesting with vitreous condensation and retinal traction. Tractional retinal detachments are associated with posterior hyaloid contracture in proliferative vitreoretinopathies including diabetic retinopathy, retinopathy of prematurity, and FEVR.4 Adhesions between the hyaloid and the inner retina may provide a mechanical stimulus or collagen scaffolding that promotes the development of preretinal neovascularization in conjunction with hypoxia-mediated gene expression (e.g., vascular endothelial growth factor) from peripheral avascular retina.
F
amilial exudative vitreoretinopathy (FEVR) is a genetically heterogeneous proliferative retinopathy that simulates retinopathy of prematurity. It is inherited in either autosomal dominant or X-linked recessive fashion and is characterized by bilateral avascular zones in the far periphery, vasodilation and arteriovenous anastomoses in the peripheral vascularized retina, and secondary peripheral neovascularization. Fibrovascular vitreous membranes can form and drag the macula temporally to produce macular ectopia and falciform retinal folds. Affected eyes may also have a Coats disease–like subretinal exudation, cicatricial mass formation in the periphery, abnormal ret-
Supported by a departmental grant from Research to Prevent Blindness, Inc. (New York, NY), and The Plough Foundation (Memphis, TN). The authors have no proprietary interest in this study. Reprint requests: Edward Chaum, MD, PhD, UTHSC Hamilton Eye Institute, 930 Madison Avenue, Suite 731, Memphis, TN 38163; e-mail: [email protected]
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Fig. 1. Red-free image of the peripheral retina of the left eye. The peripheral retina is avascular. There is marked telangiectasis and sheathing of abnormal peripheral retinal vessels, without exudation. A focus of condensed vitreous is also seen.
Retinal angiomatous proliferation is a sequence of pathologic vascular changes in the macula that has been described in a subset of patients with neovascular age-related macular degeneration.5 The earliest stage of retinal angiomatous proliferation, termed intraretinal neovascularization, is the proliferation of a plexus of capillaries within the paramacular retina and is commonly associated with a contiguous telangiectasis. These abnormal vessels are characterized by retinal– retinal anastomoses often with visible feeding arterioles and draining venules.5 Recently, intraretinal neovascularization was described in a patient with choroideremia without age-related macular degeneration.6 We describe a patient with autosomal dominant FEVR and extensive avascular retinal disease with peripheral vascular telangiectasis, sheathing, and neovascularization who presented with an unusual manifestation of an avascular stalk of condensed vitreous overlying the macula, multifocal premacular fibrosis, macular telangiectasis, and multiple foci of macular preretinal neovascularization and intraretinal neovascularization.
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Fig. 2. Red-free image of the macula of the left eye. A dense, avascular fibrous stalk overlies the macula. Numerous sites of preretinal macular neovascularization are seen (black arrows). The boundary between perfused and nonperfused retina is seen temporally (white arrowheads).
of preretinal parafoveal neovascularization were evident beneath a dense premacular stalk of condensed vitreous (Fig. 2). Fluorescein angiography of the left eye showed a broad area of nonperfusion in the temporal periphery, with late leakage and staining from telangiectatic vessels adjacent to the areas of nonperfusion (Fig. 3). The macula had multiple focal areas of hyperfluorescence (preretinal neovascularization) associated with a broad area of telangiectasis. The location of each of the foci of preretinal neovascularization was particularly notable because each was situated at a site of a focal adhesion of the vitreous stalk to the inner retina. Two sites of neovascularization appeared to have a feeding arteriole and a draining venule, suggestive of intraretinal neovascularization (Fig. 4). Subretinal neovascularization was not identified either clinically or angiographically.
Case Report A 24-year-old woman with a history of subnormal vision in both eyes since childhood and large-angle exotropia in the right eye was examined at the Hamilton Eye Institute (Memphis, TN) after a previous examination of her full-term son demonstrated a closed funnel retinal detachment in the right eye and 360° of avascular peripheral retina in the left eye, findings consistent with the diagnosis of FEVR. Examination of the woman’s right eye showed a dense epiretinal membrane with macular traction. The temporal periphery had an old subretinal mass and diffuse vitreous condensation. Examination of the left eye demonstrated vitreous condensation, peripheral telangiectasis associated with sheathed vessels, and bridging vessels consistent with FEVR (Fig. 1). Multiple foci
Fig. 3. Fluorescein angiography of the left eye showing a broad area of nonperfusion in the temporal periphery. Trace leakage and early staining of peripheral telangiectatic vessels are seen. There is a large bridging shunt vessel in the far periphery.
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Fig. 4. Fluorescein angiography of the left macula. Several sites of preretinal neovascularization and leakage are seen (arrows). Extensive telangiectatic vessel formation is seen in the central and inferior macula, adjacent to the foveal avascular zone (asterisks). Two sites of apparent intraretinal neovascularization are seen with feeding arterioles and draining venous plexuses (arrowheads). Focal intraretinal fluorescein hot spots are seen connecting these vessels. A, arterial branch; V, venous branch.
Discussion Our patient presented with autosomal dominant FEVR and had formation of multifocal, preretinal macular neovascularization associated with macular telangiectasia and overlying vitreous condensation with inner retinal adhesions. Angiography demonstrated multiple foci of hyperfluorescence associated with areas of central underlying telangiectasis and capillary dropout, corresponding to the areas of preretinal neovascularization. Retinal–retinal anastomoses appeared to be present at two sites with characteristic hyperfluorescent intraretinal angiomatous plexuses and feeding/draining vessels. The condensed vitreous stalk overlying the macula had numerous fine attachments to the surface of the retina. Each attachment was associated with a site of preretinal neovascularization. The patient was treated with panretinal photocoagulation to the areas of avascular retina, and the sites of macular neovascularization completely regressed. To our knowledge, this is the first described case of multifocal macular neovascularization in a patient with autosomal dominant FEVR. The disease arises
from premature arrest of vascularization of the retina, with formation of a peripheral avascular zone of retinal tissue. Neovascularization in FEVR is believed to arise secondary to vascular endothelial growth factor– mediated vasoproliferation similar to that seen in other peripheral ischemic diseases such as proliferative diabetic retinopathy and sickle cell retinopathy. What is striking and unusual about this patient is that the neovascularization occurred almost exclusively in the macula and only at sites of adhesions of condensed vitreous to the inner retina. We suggest that the unusual vitreoretinal adhesions and attachment sites of the posterior hyaloid face in the central macula provided mechanical contributions to the preretinal neovascularization seen in this patient, through the formation of focal scaffolding that encouraged the growth of the neovascularization tissue, focal irritation of the retina and release of proangiogenic cytokines, or both. Unlike the preretinal fibrovascular membranes associated with retinal folds and retinal detachments typically seen in patients with FEVR, these focal vitreous condensations appear to have contributed to the formation of multifocal premacular neovascularization in the setting of global retinal ischemia. Key words: familial exudative vitreoretinopathy, macula, neovascularization, intraretinal neovascularization, vascular endothelial growth factor.
References 1. 2.
3.
4.
5.
6.
Criswick VG, Schepens CL. Familial exudative vitreoretinopathy. Am J Ophthalmol 1969;68:578–594. Canny CL, Oliver GL. Fluorescein angiographic findings in familial exudative vitreoretinopathy. Arch Ophthalmol 1976; 94:1114–1120. van Nouhuys CE. Dominant exudative vitreoretinopathy and other vascular developmental disorders of the peripheral retina. Doc Ophthalmol 1982;54:1–414. Joshi MM, Ciaccia S, Trese MT, Capone A Jr. Posterior hyaloid contracture in pediatric vitreoretinopathies. Retina 2006;26:S38–S41. Yannuzzi LA, Negrao S, Iida T, et al. Retinal angiomatous proliferation in age-related macular degeneration. Retina 2001; 21:416–434. Sawa M, Tamaki Y, Klancnik JM Yannuzzi LA. Intraretinal foveal neovascularization in choroideremia. Retina 2006;26: 585–588.
Purpose: To describe an unusual patient with autosomal dominant familial exudative vitreoretinopathy (FEVR) who also presented with preretinal fibrosis overlying the macula, extensive macular telangiectasis, and multiple foci of macular neovascularization. Methods: A clinical case is presented including fundus images and fluorescein angiography studies of the patient’s left eye containing the unusual manifestations. Results: To our knowledge, this is the first report of the formation of multifocal, preretinal macular neovascularization in FEVR. The sites of neovascularization corresponded to the attachment points of the vitreous stalk overlying the macula. Two small areas of intraretinal neovascularization were also noted. Conclusions: The concordance of the vitreoretinal adhesions with the sites of neovascularization suggests that the focal scaffolding may have played a direct mechanical role in encouraging the growth of the macular neovascular tissue in this patient. RETINAL CASES & BRIEF REPORTS 2:319 –321, 2008
From the *Department of Ophthalmology, Hamilton Eye Institute, and the †Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee.
inal branching, vascular sheathing, fibrous vitreous condensation, and exudative and tractional retinal detachments.1–3 The primary pathologic process in FEVR is believed to be a premature arrest of retinal vasculogenesis or retinal vascular differentiation, leading to incomplete vascularization of the peripheral retina. This peripheral zone of avascular retina is seen in all affected patients and may be the only manifestation of the condition in some patients. At the border of the avascular zone, arteriovenous shunt formation is common, and the peripheral retinal vessels are frequently dilated and sheathed. Neovascularization at the border of vascularized and avascular retina produces a fibrotic response manifesting with vitreous condensation and retinal traction. Tractional retinal detachments are associated with posterior hyaloid contracture in proliferative vitreoretinopathies including diabetic retinopathy, retinopathy of prematurity, and FEVR.4 Adhesions between the hyaloid and the inner retina may provide a mechanical stimulus or collagen scaffolding that promotes the development of preretinal neovascularization in conjunction with hypoxia-mediated gene expression (e.g., vascular endothelial growth factor) from peripheral avascular retina.
F
amilial exudative vitreoretinopathy (FEVR) is a genetically heterogeneous proliferative retinopathy that simulates retinopathy of prematurity. It is inherited in either autosomal dominant or X-linked recessive fashion and is characterized by bilateral avascular zones in the far periphery, vasodilation and arteriovenous anastomoses in the peripheral vascularized retina, and secondary peripheral neovascularization. Fibrovascular vitreous membranes can form and drag the macula temporally to produce macular ectopia and falciform retinal folds. Affected eyes may also have a Coats disease–like subretinal exudation, cicatricial mass formation in the periphery, abnormal ret-
Supported by a departmental grant from Research to Prevent Blindness, Inc. (New York, NY), and The Plough Foundation (Memphis, TN). The authors have no proprietary interest in this study. Reprint requests: Edward Chaum, MD, PhD, UTHSC Hamilton Eye Institute, 930 Madison Avenue, Suite 731, Memphis, TN 38163; e-mail: [email protected]
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Fig. 1. Red-free image of the peripheral retina of the left eye. The peripheral retina is avascular. There is marked telangiectasis and sheathing of abnormal peripheral retinal vessels, without exudation. A focus of condensed vitreous is also seen.
Retinal angiomatous proliferation is a sequence of pathologic vascular changes in the macula that has been described in a subset of patients with neovascular age-related macular degeneration.5 The earliest stage of retinal angiomatous proliferation, termed intraretinal neovascularization, is the proliferation of a plexus of capillaries within the paramacular retina and is commonly associated with a contiguous telangiectasis. These abnormal vessels are characterized by retinal– retinal anastomoses often with visible feeding arterioles and draining venules.5 Recently, intraretinal neovascularization was described in a patient with choroideremia without age-related macular degeneration.6 We describe a patient with autosomal dominant FEVR and extensive avascular retinal disease with peripheral vascular telangiectasis, sheathing, and neovascularization who presented with an unusual manifestation of an avascular stalk of condensed vitreous overlying the macula, multifocal premacular fibrosis, macular telangiectasis, and multiple foci of macular preretinal neovascularization and intraretinal neovascularization.
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2008
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Fig. 2. Red-free image of the macula of the left eye. A dense, avascular fibrous stalk overlies the macula. Numerous sites of preretinal macular neovascularization are seen (black arrows). The boundary between perfused and nonperfused retina is seen temporally (white arrowheads).
of preretinal parafoveal neovascularization were evident beneath a dense premacular stalk of condensed vitreous (Fig. 2). Fluorescein angiography of the left eye showed a broad area of nonperfusion in the temporal periphery, with late leakage and staining from telangiectatic vessels adjacent to the areas of nonperfusion (Fig. 3). The macula had multiple focal areas of hyperfluorescence (preretinal neovascularization) associated with a broad area of telangiectasis. The location of each of the foci of preretinal neovascularization was particularly notable because each was situated at a site of a focal adhesion of the vitreous stalk to the inner retina. Two sites of neovascularization appeared to have a feeding arteriole and a draining venule, suggestive of intraretinal neovascularization (Fig. 4). Subretinal neovascularization was not identified either clinically or angiographically.
Case Report A 24-year-old woman with a history of subnormal vision in both eyes since childhood and large-angle exotropia in the right eye was examined at the Hamilton Eye Institute (Memphis, TN) after a previous examination of her full-term son demonstrated a closed funnel retinal detachment in the right eye and 360° of avascular peripheral retina in the left eye, findings consistent with the diagnosis of FEVR. Examination of the woman’s right eye showed a dense epiretinal membrane with macular traction. The temporal periphery had an old subretinal mass and diffuse vitreous condensation. Examination of the left eye demonstrated vitreous condensation, peripheral telangiectasis associated with sheathed vessels, and bridging vessels consistent with FEVR (Fig. 1). Multiple foci
Fig. 3. Fluorescein angiography of the left eye showing a broad area of nonperfusion in the temporal periphery. Trace leakage and early staining of peripheral telangiectatic vessels are seen. There is a large bridging shunt vessel in the far periphery.
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Fig. 4. Fluorescein angiography of the left macula. Several sites of preretinal neovascularization and leakage are seen (arrows). Extensive telangiectatic vessel formation is seen in the central and inferior macula, adjacent to the foveal avascular zone (asterisks). Two sites of apparent intraretinal neovascularization are seen with feeding arterioles and draining venous plexuses (arrowheads). Focal intraretinal fluorescein hot spots are seen connecting these vessels. A, arterial branch; V, venous branch.
Discussion Our patient presented with autosomal dominant FEVR and had formation of multifocal, preretinal macular neovascularization associated with macular telangiectasia and overlying vitreous condensation with inner retinal adhesions. Angiography demonstrated multiple foci of hyperfluorescence associated with areas of central underlying telangiectasis and capillary dropout, corresponding to the areas of preretinal neovascularization. Retinal–retinal anastomoses appeared to be present at two sites with characteristic hyperfluorescent intraretinal angiomatous plexuses and feeding/draining vessels. The condensed vitreous stalk overlying the macula had numerous fine attachments to the surface of the retina. Each attachment was associated with a site of preretinal neovascularization. The patient was treated with panretinal photocoagulation to the areas of avascular retina, and the sites of macular neovascularization completely regressed. To our knowledge, this is the first described case of multifocal macular neovascularization in a patient with autosomal dominant FEVR. The disease arises
from premature arrest of vascularization of the retina, with formation of a peripheral avascular zone of retinal tissue. Neovascularization in FEVR is believed to arise secondary to vascular endothelial growth factor– mediated vasoproliferation similar to that seen in other peripheral ischemic diseases such as proliferative diabetic retinopathy and sickle cell retinopathy. What is striking and unusual about this patient is that the neovascularization occurred almost exclusively in the macula and only at sites of adhesions of condensed vitreous to the inner retina. We suggest that the unusual vitreoretinal adhesions and attachment sites of the posterior hyaloid face in the central macula provided mechanical contributions to the preretinal neovascularization seen in this patient, through the formation of focal scaffolding that encouraged the growth of the neovascularization tissue, focal irritation of the retina and release of proangiogenic cytokines, or both. Unlike the preretinal fibrovascular membranes associated with retinal folds and retinal detachments typically seen in patients with FEVR, these focal vitreous condensations appear to have contributed to the formation of multifocal premacular neovascularization in the setting of global retinal ischemia. Key words: familial exudative vitreoretinopathy, macula, neovascularization, intraretinal neovascularization, vascular endothelial growth factor.
References 1. 2.
3.
4.
5.
6.
Criswick VG, Schepens CL. Familial exudative vitreoretinopathy. Am J Ophthalmol 1969;68:578–594. Canny CL, Oliver GL. Fluorescein angiographic findings in familial exudative vitreoretinopathy. Arch Ophthalmol 1976; 94:1114–1120. van Nouhuys CE. Dominant exudative vitreoretinopathy and other vascular developmental disorders of the peripheral retina. Doc Ophthalmol 1982;54:1–414. Joshi MM, Ciaccia S, Trese MT, Capone A Jr. Posterior hyaloid contracture in pediatric vitreoretinopathies. Retina 2006;26:S38–S41. Yannuzzi LA, Negrao S, Iida T, et al. Retinal angiomatous proliferation in age-related macular degeneration. Retina 2001; 21:416–434. Sawa M, Tamaki Y, Klancnik JM Yannuzzi LA. Intraretinal foveal neovascularization in choroideremia. Retina 2006;26: 585–588.
