Review PEARLS AND PITFALLS IN DIAGNOSIS AND MANAGEMENT OF COATS DISEASE ANDREA GROSSO, MD,* MARCO PELLEGRINI, MD,† MATTEO G. CEREDA, MD,† CLAUDIO PANICO, MD,‡ GIOVANNI STAURENGHI, MD,† ERIC J. SIGLER, MD§¶ Purpose: To review current literature on Coats disease and provide a structured framework for differentiating challenging clinical features in Coats disease patients. Methods: We critically reappraise historical and current literature and present clinical methods for developing a thorough differential diagnosis and management strategy for Coats disease. Results: Coats disease is a sporadic, usually unilateral condition typically occurring in young males. When untreated, this disorder can lead to total exudative retinal detachment and secondary glaucoma. Conclusions: Anti-VEGF agents are currently a treatment option in combination with ablative therapy of telangiectatic vessels. Anti-VEGF agents appear particularly useful for patients with extensive areas of exudative retinal detachment, and are an effective treatment option for total retinal detachment. RETINA 35:614–623, 2015
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occurs in the evaluation of posterior uveitis, when one considers the differential diagnosis (i.e., “candle wax appearance”). There is no specific testing for Coats disease, and findings can be consistent with but not diagnostic of Coats disease. Additionally, systemic history is not typically suggestive of the diagnosis but may support a different probable diagnosis. Furthermore, it is also possible that a patient coincidentally has two distinct diseases or that retinal microvascular abnormalities lead to a continuum of signs depending on the stage of the natural course. One must consider all of these factors throughout the clinical management and patient counseling in Coats disease.
hen one deals with cases of exudative retinopathy, such as Coats disease, it is important to bear in mind the pattern recognition mechanism we unconsciously use to understand the meaning of a retinal image. Currently, patients commonly undergo multimodal retinal evaluation that may lead to detection of a myriad of retinal vascular changes. Only when we assemble all these signs, do we have a pattern consistent with a specific disease. A similar process From the *Department of Ophthalmology, Torino Eye Hospital and Centre for Macular Research and Allied Diseases, San Mauro, Italy; †Department of Biomedical and Clinical Science “Luigi Sacco”, Eye Clinic, Sacco Hospital, University of Milan, Milan, Italy; ‡Department of Ophthalmology, Torino Eye Hospital, Torino, Italy; §Ophthalmic Consultants of Long Island, Division of Retina and Vitreous, Rockville Centre, New York; and ¶Ophthalmic Consultants of Long Island, Division of Retina and Vitreous, Lynbrook, New York. None of the authors have any financial/conflicting interests to disclose. A. Grosso has had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Reprint requests: Andrea Grosso, MD, Department of Ophthalmology, Torino Eye Hospital and Centre for Macular Research and Allied Diseases, San Mauro T.se 10099 Via Roma 73, Italy; e-mail: [email protected]
Clinical Scenario and Differential Diagnoses Is Coats Disease a Sporadic Unilateral Condition? To date, based on our current understanding and accepted classification, we know that typical patients with Coats disease (Figure 1) are males with unilateral retinal vascular changes that include capillary telangiectasia, arterial aneurysms, retinal nonperfusion rarely associated with retinal neovascularization and with 614
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Fig. 1. Multimodal retinal imaging (fluorescein angiogram, color fundus photography, indocyanine green angiography) in Coats disease and retinal VPTs. Clinical (A and B) fluorescein angiography (C and D) and indocyanine green (E and F) of a 6-year-old patient affected by Coats disease (left column) and a case of 47-year-old man affected by retinal VPT (right column). Exudation in Coats disease displays a typical distribution, affecting areas remote from retinal telangiectasias with a preferential localization in the macular area. In retinal VPTs, exudation usually starts in proximity of the tumor and gradually extends to the posterior retina. VPT, vasoproliferative tumors.
exudative retinopathy sometimes leading to retinal detachment.1 However, a recent article2 pointed out that 22 of 32 patients with Coats disease had bilateral abnormal peripheral vasculature. The authors state that Coats disease may more often be a bilateral disease with asymmetry: when all patients undergo a peripheral fluorescein angiography with Retcam system (Clarity Medical System, Pleasanton, CA), bilateral vascular abnormalities are more common than previously reported. Do we miss something about the genetic contribution? Familial exudative vitreoretinopathy, in particular, manifests as a bilateral exudative retinopathy,3–12 and frequent marked asymmetry in clinical appearance may be present between eyes of the same patient. In such cases, genetic testing for Norrie disease protein, frizzled homolog 4, low-density lipoprotein receptor-related protein 5, and tetraspanin 12 mutations may reveal additional genetic abnormalities. The proteins coded for by these genes are known to be involved in the Norrin/Fz4/Wnt signaling pathway. Mutations in these genes can
preclude physiologic retinal vascular development. For the same reason, patients and their family members might be evaluated with indirect ophthalmoscopy and wide-field fluorescein angiography to rule out undiagnosed vascular abnormalities.3–14 What About Differential Diagnosis? Epidemiologic criteria (frequency and groups of age) may be used to differentiate: 1. The more common differential clinical diagnoses in adults and children (Table 1); 2. The less common genetically determined isolated or syndromic ocular conditions (Table 2); The differential diagnosis of retinal arterial macroaneurysms, a prominent finding in patients with Coats disease is listed in Table 3. Arterial macroaneurysms may be seen with hypertension or arteriosclerosis, which may be single or multiple. In these conditions, there is a chronic
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Table 1. List of More Common Differential Clinical Diagnoses in Adults and Children Adults15–23 Eales disease Sarcoidosis Tuberculosis IRVAN (idiopathic retinal vasculitis aneurysms and neuroretinitis) Vasoproliferative tumors (Figure 2) Sickle cell retinopathy Lipidemia retinalis (familial hypercholesterolemia)
Pediatrics24–29 Combined hamartoma of the retina and RPE (congenital ERM) ROP Retinoblastoma FEVR
Table 3. List of Differential Diagnosis of Retinal Arterial Macroaneurysms, a Prominent Finding in Patients With Coats Disease A. Hypertension B. Arteriosclerosis C. Postembolic D. Retinal vascular occlusion E. Idiopathic polypoidal choroidal vasculopathy F. Idiopathic retinal vasculitis, aneurysms, and neuroretinitis G. Sarcoid (segmental arterial ectasias)
Cat scratch disease Vasoproliferative tumors Retinal hemangioblastoma Persistent fetal vasculature Retinal arteriovenous malformation
FEVR, familiar exudative vitreoretinopathy; IRVAN, idiopathic retinal vasculitis, aneurysms, and neuroretinitis; ROP, retinopathy of prematurity; RPE, retinal pigment epithelium.
damage to the endothelial wall and a high transmural hydrostatic pressure according to Poiseuille law. Occasionally, these occur after retinal vascular emboli. In younger patients, an important cause of retinal arterial aneurysms, particularly when multiple and bilateral, is idiopathic retinal vasculitis, aneurysms, and neuroretinitis.30 Patients with idiopathic retinal vasculitis, aneurysms, and neuroretinitis have evidence of vasculitis; the aneurysms may occur on or near the optic nerve and are importantly (similar to sarcoidosis), frequently present at vascular branch points rather than at vessel terminations. Patients often develop capillary nonperfusion, especially in the peripheral retina and retinal neovascularization. They often have lipid exudation in proximity to the aneurysms and in the macula. They may have macular thickening.31–35 Retinal arterial macroaneurysms are well recognized to occur in types of uveitis other than idiopathic retinal vasculitis, aneurysms, and neuroretinitis, specifically sarcoidosis. Takagi et al36 first described arterial macroaneurysm formation in 2 patients with ocular sarcoidosis in 1994. Table 2. List of Less Common Genetically Determined Isolated or Syndromic Ocular Conditions Dyskeratosis congenita FSHD Turner syndrome Incontinentia pigmenti Kabuki syndrome Norrie disease Retinitis pigmentosa with coats-like retinopathy Senior–loken syndrome FSHD, facio–scapulo–humeral dystrophy.
Four years later, Rothova and Lardenoye37 reported the occurrence of arterial macroaneurysms in 17% of 48 patients with sarcoidosis including a subgroup with choroiditis. These findings were subsequently and independently confirmed by Verougstraete et al38 and Yamanaka et al,39 both of whom recommended that all patients with retinal arterial macroaneurysms and choroiditis be thoroughly evaluated for sarcoidosis. An association between polypoidal vasculopathy and macroaneurysms has also been published.40,41 Unresolved Questions About Pathogenesis Why do Coats Arterial Aneurysms not Bleed? The reasons why aneurysms in Coats disease do not typically bleed, but more commonly exudate fluids, is not completely understood and warrants further investigation. Histopathologic studies have shown diffuse thickening of retinal capillary adventitia and areas of total absence of pericytes and vascular endothelium consistent with two pathologic processes that are evident in Coats disease. The first consists of a breakdown of the blood–retinal barrier at the endothelial level that causes plasma leakage into and thickening of parts of the vessel wall, leading to necrosis and disorganization and producing what Egbert et al42 have described as a “sausage-like” shape of the vessel. The second concerns the presence of abnormal pericytes and endothelial cells in retinal blood vessels that subsequently degenerate, causing abnormal retinal vasculature and formation of aneurysms, as well as closure of vessels resulting in ischemia.43 In contrast to diabetic microaneurysms, these arteriolar aneurysms do not leak lipid or fluorescein. We hypothesize that Coats disease may be a defect in midcapillary angiogenesis, and that aneurysmal dilations are a secondary abortive feature. This hypothesis is consistent with a recent article showing bilateral microvascular abnormalities in patients with Coats disease.2
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Additionally, exudation in Coats disease displays a typical distribution. Hard exudates generally affect widespread areas often remote from retinal telangiectasias with a preferential localization in the macular area. In contrast, exudation in vasoproliferative tumors and retinal hemangioblastomas usually occurs in proximity of the vascular abnormalities.
Macular Fibrosis and Epiretinal Membrane Epiretinal membranes (ERMs) can rarely occur in Coats disease, usually after chronic retinal exudation. The fibrous scarring and the ERM could be the result of long-standing inflammation or neovascularization (Figure 2), or secondary to laser or cryotherapy. Any long-standing exudative process may lead to ERM; however, an epiretinal process is not typical of Coats
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disease and should warrant consideration of additional diagnoses, particularly retinal vasoproliferative tumor, in which ERM is a common feature. Resolved total retinal detachment after intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents frequently demonstrates focal areas of consolidated vitreous that may resemble ERM but is rarely if ever visually or anatomically significant.44 “Macular fibrosis,” previously referred to as “subretinal nodules” or “subretinal mounds” does not refer to an epiretinal process, however. George Coats described macular fibrosis as “located in the choroid,” and multiple histologic investigations have demonstrated this in the early 1900s.43,45 In fact, early histologic investigations referred to “retinochoroidal synechiae.” This point has been lost, however, likely because of the more recent recognition of choroidal neovascularization as an ocular pathologic process
Fig. 2. Multiple retinal imaging by Topcon, HRA II Heidelberg, and Zeiss Stratus optical coherence tomography. A–E. A case of a 22-year-old man complaining of progressive visual loss in his right eye secondary to an ERM in January 2010. B. In the inferior temporal quadrant, a vasoproliferative lesion is shown. E. A dense ERM extending from the optic disk to the fovea is also present with optical coherence tomography examination revealing mild intraretinal edema in the outer nuclear layer. C and D. The fluorescein angiogram shows deregulation of both internal and external blood–retinal barrier and arterial macroaneurysms. D. The indocyanine green angiography enhances the detection of multiple retinal vascular ectasias.
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and the paucity of enucleations performed during current clinical management of Coats disease. In a recent controversy, some authors hypothesized that the lesion was either a retinal angiomatous mass or the result of chronic submacular exudate. Sigler and Calzada46 have recently discovered that “macular fibrosis” is actually Type III choroidal neovascularization and have demonstrated the chorioretinal anastomosis with RetCam angiography and Doppler spectral domain optical coherence tomography in children as young as 1 year old (Figure 3).
Ischemia, retinal, and Papillary Neovascularization Retinal nonperfusion in Coats disease seldom develops neovascularization of the retina or the disk. In Coats disease, ischemia and retinal hemorrhages are usually seen in contrast to MacTel Type 2.47 However in MacTel 2, retinal–retinal and retinal–subretinal anastomoses are consistent with a neovascular process; in Coats disease, we do not have a similar vascular remodeling process. In a recent study of eyes obtained from donors who underwent enucleation through the Doheny Eye and Tissue Transplant Bank, an immunohistochemical analysis was performed.48 Macrophage infiltration was observed in the subretinal space in all cases examined. Vascular endothelial growth factor immunoreactivity
Fig. 3. Wide-field fluorescein angiography and intraoperative spectral domain optical coherence tomography of a 5-year-old patient with Coats disease and macular chorioretinal anastomosis. A. Arteriovenous wide-field fluorescein angiogram demonstrating typical Coats-like telangiectatic vessels in the temporal retinal periphery and macular fibrosis. B. High-magnification angiogram of the macula demonstrating a retinal vessel disappearing into the center of the submacular vascular mass. C. Late phase angiogram clearly demonstrating pooling within the central submacular pigment epithelial detachment, with chorioretinal anastomosis (retinal angiomatous proliferation). D. Intraoperative Doppler optical coherence tomography demonstrating chorioretinal anastomosis and choroidal neovascularization.
was observed in cells infiltrating the subretinal proliferative tissue obtained during vitrectomy in a 28-year-old male who was clinically diagnosed with Stage 3B Coats disease. These cells expressing VEGF were also positive for CD68, a marker for macrophages. In contrast, normal retina did not contain macrophage infiltration or vascular abnormalities. VEGFR-2 immunoreactivity was noted in endothelial cells located in abnormal retinal vessels with hyalinization. These results suggest that macrophages play a pivotal role in the promotion of vascular permeability and angiogenesis by expressing VEGF in Coats disease. Vascular endothelial growth factor induces a diabetic retinopathy phenotype. A possible explanation is correlated with the biological mechanisms that drive retinal angiogenesis: it is well known that angiogenesis is controlled by a delicate balance of proangiogenic and antiangiogenic factors in tissues.49 Dysregulation of this balance has been demonstrated to result in pathologic angiogenesis, such as diabetic retinopathy.50 Extensive studies have revealed that oxygen-sensing systems play important roles in maintaining the balance of angiogenesis regulation. In conditions such as retinal vein occlusion or diabetes, hypoxia is thought to be the stimulus to angiogenesis.49,51,52 In Coats disease, retinal ischemia may promote an immediate injury to the cellular architecture and an upregulation of VEGF53 that might be subsequently secreted into the vitreous. Vascular endothelial growth
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factor also contributes to vascular leakage in multiple retinal pathologies. Alterations of tight junction complex proteins during retinal diseases may lead to blood–retina barrier breakdown and subsequent vascular permeability and macular edema.54 Treatment of endothelial cells with VEGF increases occludin (a protein included in tight junctions) phosphorylation.55 Furthermore, intravitreal injection of VEGF induces occludin phosphorylation, ubiquitination, and redistribution from the blood retinal barrier in vivo, which is associated with increased permeability.55–58 It seems clear that VEGF and other factors contribute to exudation in Coats disease. In cases of exudative chronic retinal detachment, hypoxia also occurs; this may also explain why patients with Coats disease (Stage 3 or 4) may have neovascular glaucoma with no signs of intraretinal neovascularization: the retinal–glaucoma gap. Management Role of Anti-Vascular Endothelial Growth Factor Drugs Management of cases of Coats disease is primarily aimed at preserving macular function by trying to minimize macular edema and lipid exudation that can cause permanent scarring when it develops at the fovea. We prefer to treat the aneurysms responsible for visually threatening macular edema with focal thermal laser.59 These eyes seldom develop retinal neovascularization and vitreous hemorrhage. Therefore, we typically do not perform scatter laser treatment over areas of nonperfusion unless it seems that treating this ischemic retina might reduce vascular leakage. Although the literature provides conflicting reports regarding the benefit of intravitreal anti-VEGF drugs in controlling macular edema in Coats disease, clinical experience has been that these agents induce a short-lived response that is often inadequate to prevent disease progression after a single treatment.44,60–63 We lack evidence that young patients have a structurally immature retina or that physiologic revascularization occurs in the adult retina. However, VEGF-A is a critical molecule with multiple bioactivities: processes which involve VEGF-A are listed in the Table 4.64–69 Blocking VEGF secretion or activity or function may not always be a good thing; however, anti-VEGF agents have not demonstrated untoward effects on previously disease-free retina after millions of treatments in adults worldwide. As yet, anti-VEGF agents have been safely used even in young patients.70 Anti-VEGF agents are particularly useful in advanced stages of Coats71,72 disease with
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Table 4. Multiple Bioactivities of Vascular Endothelial Growth Factor Angiogenic Permeability factor Branching factor Proinflammatory Vessel survival factor Fenestration factor Neuroprotectant Thrombosis modulator Vasodilation/flow
large (greater than one quadrant or macula-involved) areas of exudative retinal detachment. In fact, multiple recent reports63,73 have demonstrated resolution of total retinal detachment after intravitreal Bevacizumab. Before this therapy, many patients with advanced Coats disease developed neovascular glaucoma, phthisis, or required enucleation. Even in the context of retina present immediately posterior to the lens, either anterior chamber or subretinal anti-VEGF therapy may be performed. Thermal ablative therapy remains the standard of care, however. Anti-VEGF is used as an adjunct to laser therapy,44,63,72 which can be performed even in the presence of subretinal fluid. We prefer to avoid cryotherapy because of its tissue destructive and proliferative vitreoretinopathy-inducing potential. Nevertheless, cryotherapy is a known-effective method to resolve serous detachment and resolution of exudate, telangiectasias, and vascular ablation in Coats retinopathy.63 Furthermore, with the recent discovery that chorioretinal anastomosis and Type III choroidal neovascularization46 occurs in Coats disease, anti-VEGF therapy may be increasingly indicated. The major challenge to this approach in young patients is the need for repeated examinations under anesthesia if anti-VEGF therapy is continued, and thus the approach to treatment must be individually tailored based on disease severity. Currently, we recommend combined anti-VEGF and peripheral laser therapy as initial treatment for patients with exudative retinal detachment or macular retinal angiomatous proliferation and Coats disease. Laser therapy alone is performed for patients with aneurysmal dilations without greater than one quadrant of subretinal fluid or localized exudates. It is important to “stay ahead” of the disease in these cases by treating early, before lipid accumulates in the fovea. Despite prompt therapy, however, peripheral exudate often accumulates in the macular region even after complete ablation of abnormal peripheral aneurysms. Mild lipid exudates typically
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resolve over 2 months to 3 months in the absence of active exudation. In more severe cases, laser alone may not be sufficient to control the degree of exudation. In cases of more marked exudation, it may take many months and even years for the lipid exudation to resolve. Often, this leakage may be because of diffuse leakage from the telangiectatic capillaries. In these cases, injections of sub-Tenon triamcinolone acetonide (40 mg/1.0 mL) were used with success (Discussion of a diagnostic and clinical challenge, Retina 2013, volume 33, number 1). Anti-vascular endothelial growth factor therapy is an additional reasonable and efficacious treatment option in this context. Is there a Role for Vitreoretinal Surgery? Before the advent of anti-VEGF therapy, vitreoretinal surgery was indicated to manage complications in selected cases of stage 4 Coats disease.63,74,75 Now, the treatment paradigm is changing towards a sequential combined treatment strategy by including first the use of anti-VEGF drugs associated with vitreoretinal surgery. The aim is to resolve the subretinal exudative detachment as early as possible and to treat the macular edema. Depending on the natural course of the disease, the legacy of a serous detachment is subretinal fibrosis unresponsive to the anti-VEGF. In some cases of Coats disease, an epiretinal macular proliferation may occur (Figure 2) as result of persistent inflammation thrombosis. Additional pathologic vitreoretinal tractions may also develop close to the exudative mass. During vitrectomy, macular ERM peeling is mandatory to preserve the function of photoreceptors. Additionally, the removal of the vitreous reduces the concentration of cytokines in the vitreous.76–80 Small gauge core or complete vitrectomy (23 or 25 gauge) coupled with high speed vitrectomy platforms may be routinely used and may reduce the risk of peripheral iatrogenic retinal tears. A double peeling of hyaloid and internal limiting membrane is warranted, often assisted by vital dyes (chromovitrectomy with triamcinolone, membrane blue, dual blue). As internal tamponade air or gas are normally used to fill the vitreous cavity. In selected cases, an external drainage of subretinal fluid may be performed.81–83 During the vitrectomy the peripheral telangiectasia may be simultaneously photocoagulated or selectively treated by exocryo coagulation. According to the literature,80 the risk of recurrence of ERM is low.
Prognostic Factors Long-term visual prognosis was historically poor.63,83,84 The advent of anti-VEGF agents represent a game changer in the management of Coats disease. We recommend a tailored approach based on patient factors (age, comorbidities) and severity of disease. In Shields et al,83 Stage 1 close observation is recommended. We prefer to treat initially leaking macroaneurysms and telangiectasias with thermal laser because of its minimal risk and the potential to prevent exudates. Exocryo coagulation should be used as well. For Stages 2 and 3, a combination of anti-VEGF and coagulation is indicated: in these patients, a close monthly follow-up until disease stabilization should be recommended. In cases of significant macular edema, marked exudation, and serous retinal detachment, a sequential combination strategy63,72 with antiVEGF first followed by prompt laser by no more than 2 weeks is normally preferred. Exocryo coagulation may be used as well. Patients with extrafoveal abnormal vasculature and telangiectasias, especially if associated with ischemia as seen by fluoroangiography, may undergo extensive peripheral photocoagulation of the anomalous areas associated with anti-VEGF. However, we stress the importance of recurrent nature of Coats disease and the need for regular follow-up. Conclusion The advancements in wide-field imaging techniques85 will allow early detection of peripheral vascular abnormalities even in the asymptomatic patients and a better management of the disease. Given the broad spectrum of disease phenotype and clinical behavior in Coats disease, early diagnosis and prompt initiation of treatment may lead to an improved clinical outcome. As far as the therapeutical options are concerned, thermal ablative therapy coupled with anti-VEGF drugs represent the standard of care. Exocryo coagulation may be used as well depending on the surgeon’s experience. Small gauge (23 or 25 gauge) surgery may play a role in the management of complications (Stage 4) or in cases of tractional retinal detachment or macular edema sustained by ERMs. In conclusion, we stress the importance of being cautious with patients to discuss the pros and cons of treatment options and the importance of the therapeutical alliance because Coats disease is a chronic disease.86,87 Coats disease can recur, so it is crucial to keep patients aware of the necessity of regular
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long-term follow-up even in the absence of subjective visual loss. Key words: eye, retina, coats disease, macular edema, VEGF, retinal telangiectasia, small gauge surgery, macroaneurysms, retinal ischemia. References 1. Shields JA, Shields CL. Review: coats disease: the 2001 LuEsther T. Mertz lecture. Retina 2002;22:80–91. 2. Blair MP, Ulrich JN, Elizabeth Hartnett M, Shapiro MJ. Peripheral retinal nonperfusion in fellow eyes in coats disease. Retina 2013;33:1694–1699. 3. Miyakubo H, Hashimoto K, Miyakubo S. Retinal vascular pattern in familial exudative vitreoretinopathy. Ophthalmology 1984;91:1524–1530. 4. Kashani AH, Learned D, Nudleman E, et al. High prevalence of peripheral retinal vascular anomalies in family members of patients with familial exudative vitreoretinopathy. Ophthalmology 2014;121:262–268. 5. Criswick VG, Schepens CL. Familial exudative vitreoretinopathy. Am J Ophthalmol 1969;68:578–594. 6. Shukla SY, Kaliki S, Shields CL. Asymmetry of familial exudative vitreoretinopathy. J Pediatr Ophthalmol Strabismus 2012;28:49. 7. Toomes C, Bottomley HM, Jackson RM, et al. Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q. Am J Hum Genet 2004;74:721–730. 8. Chen ZY, Battinelli EM, Fielder A, et al. A mutation in the norrie disease gene (NDP) associated with X-linked familial exudative vitreoretinopathy. Nat Genet 1993;5:180–183. 9. Robitaille J, MacDonald ML, Kaykas A, et al. Mutant frizzled4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Nat Genet 2002;32:326–330. 10. Nikopoulos K, Gilissen C, Hoischen A, et al. Next-generation sequencing of a 40 Mb linkage interval reveals TSPAN12 mutations in patients with familial exudative vitreoretinopathy. Am J Hum Genet 2010;86:240–247. 11. Robitaille JM, Zheng B, Wallace K, et al. The role of Frizzled4 mutations in familial exudative vitreoretinopathy and coats disease. Br J Ophthalmol 2011;95:574–579. 12. Benson WE. Familial exudative vitreoretinopathy. Trans Am Ophthalmol Soc 1995;93:473–521. 13. Tasman W, Augsburger JJ, Shields JA, et al. Familial exudative vitreoretinopathy. Trans Am Ophthalmol Soc 1981;79:211–226. 14. Canny CL, Oliver GL. Fluorescein angiographic findings in familial exudative vitreoretinopathy. Arch Ophthalmol 1976; 94:1114–1120. 15. Chang TS, Aylward GW, Davis JL, et al. Idiopathic retinal vasculitis, aneurysms, and neuro-retinitis. Retinal vasculitis study. Ophthalmology 1995;102:1089–1097. 16. Samuel MA, Equi RA, Chang TS, et al. Idiopathic retinitis, vasculitis, aneurysms, and neuroretinitis (IRVAN): new observations and a proposed staging system. Ophthalmology 2007; 114:1526–1529. 17. Das T, Pathengay A, Hussain N, Biswas J. Eales’ disease: diagnosis and management. Eye 2010;24:472–482. 18. Biswas J, Ravi RK, Naryanasamy A, et al. Eales’ disease current concepts in diagnosis and management. J Ophthalmic Inflamm Infect 2013;3:11. 19. Hoover DL, Khan JA, Giangiacomo J. Pediatric ocular sarcoidosis. Surv Ophthalmol 1986;30:215–228.
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20. Kawaguchi T, Hanada A, Horie S, et al. Evaluation of characteristic ocular signs and systemic investigations in ocular sarcoidosis. Jpn J Ophthalmol 2007;51:121–126. 21. Cimino L, Herbort CP, Aldigeri R, et al. Tuberculous uveitis, a resurgent and underdiagnosed disease. Int Ophthalmol 2009; 29:67–74. 22. Shields CL, Kaliki S, Al-Dahmash S, et al. Retinal vasoproliferative tumors: comparative clinical features of primary vs secondary tumors in 334 cases. JAMA Ophthalmol 2013; 131:328–334. 23. Elagouz M, Jyothi S, Gupta B, Sivaprasad S. Sickle cell disease and the eye: old and new concepts. Surv Ophthalmol 2010;55:359–367. 24. Xue K, Mellington F, Gout I, et al. Combined hamartoma of the retina and retinal pigment epithelium. BMJ Case Rep 2012; doi: 10.1136/bcr-2012-006944. 25. Shields CL, Thangappan A, Hartzell K, et al. Combined hamartoma of the retina and retinal pigment epithelium in 77 consecutive patients visual outcome based on macular versus extramacular tumor location. Ophthalmology 2008;115:2246–2252. 26. Salcone EM, Johnston S, VanderVeen D. Review of the use of digital imaging in retinopathy of prematurity screening. Semin Ophthalmol 2010;25:214–217. 27. Shields CL, Fulco EM, Arias JD, et al. Retinoblastoma frontiers with intravenous, intra-arterial, periocular, and intravitreal chemotherapy. Eye 2013;27:253–264. 28. Heimann H, Jmor F, Damato B. Imaging of retinal and choroidal vascular tumours. Eye 2013;27:208–216. 29. Biancardi AL, Curi AL. Cat-scratch disease. Ocul Immunol Inflamm 2014;22:148–154. 30. Tomita M, Matsubara T, Yamada H, et al. Long term follow up in a case of successfully treated idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN). Br J Ophthalmol 2004;88:302–303. 31. McDonald HR. Diagnostics and therapeutic challenges. IRVAN syndrome. Retina 2003;23:392–399. 32. Kincaid J, Schatz H. Bilateral retinal arteritis with multiple aneurysmal dilatations. Retina 1983;3:171–178. 33. Owens SL, Gregor ZJ. Vanishing retinal arterial aneurysms: a case report. Br J Ophthalmol 1992;76:637–638. 34. Sashihara H, Hayashi H, Oshima K. Regression of retinal arterial aneurysms in a case of idiopathic retinal vasculitis, aneurysms, and neuroretinitis. Retina 1999;19:250–251. 35. Yeshurun I, Recillas-Gispect C, Navarro-Lopez P, et al. Extensive dynamics in location, sharp, and size of aneurysm in a patient with idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome. Am J Ophthalmol 2003;135:118–120. 36. Takagi T, Nakajima A, Sawada Y, Sakuragi S. Macroaneurysms in ocular sarcoidosis. Folia Ophthalmol Jpn 1994;45:555–559. 37. Rothova A, Lardenoye C. Arterial macroaneurysms in peripheral multifocal chorioretinitis associated with sarcoidosis. Ophthalmology 1998;105:1393–1397. 38. Verougstraete C, Snyers B, Leys A, Caspers LE. Multiple arterial ectasias in patients with sarcoidosis and uveitis. Am J Ophthalmol 2001;131:223–231. 39. Yamanaka E, Ohguro N, Kubota A, et al. Features of retinal arterial macroaneurysms in patients with uveitis. Br J Ophthalmol 2004;88:884–886. 40. Ross RD, Gitter KA, Cohen G, Schomaker KS. Idiopathic polypoidal choroidal vasculopathy associated with retinal arterial macroaneurysm and hypertensive retinopathy. Retina 1996;16:105–111. 41. Coscas F, Coscas G, Souïed E. Polypoidal choroidal vasculopathy and macroaneurysm: respective roles of scanning
622
42.
43.
44.
45. 46.
47.
48.
49. 50. 51.
52.
53.
54.
55.
56.
57. 58.
59.
60.
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laser ophthalmoscopy-indocyanine green angiography and optical coherence tomography. Eur J Ophthalmol 2011;21: 331–335. Egbert PR, Chan CC, Winter FC. Flat preparations of the retinal vessels in coats’ disease. J Pediatr Ophthalmol 1976; 13:336–339. Fernandes BF, Odashiro AN, Maloney S, et al. Clinicalhistopathological correlation in a case of coats’ disease. Diagn Pathol 2006;1:24. Zheng XX, Jiang YR. The effect of intravitreal bevacizumab injection as the initial treatment for coats’ disease. Graefes Arch Clin Exp Ophthalmol 2014;252:35–42. Jumper JM, Pomerleau D, McDonald HR, et al. Macular fibrosis in Coats disease. Retina 2010;30(suppl 4):S9–S14. Sigler EJ, Calzada JI. Retinal angiomatous proliferation with chorioretinal anastomosis in childhood coats disease: a reappraisal of macular fibrosis using multimodal imaging. Retina 2014. Epub ahead of print. Engelbert M, Yannuzzi LA. Idiopathic macular telangiectasia type 2: the progressive vasculopathy. Eur J Ophthalmol 2013;23:1–6. Kase S, Rao NA, Yoshikawa H, et al. Expression of vascular endothelial growth factor in eyes with coats’ disease. Invest Ophthalmol Vis Sci 2013;54:57–62. Scott A, Fruttiger M. Oxygen-induced retinopathy: a model for vascular pathology in the retina. Eye 2010;24:416–421. Carmeliet P. Angiogenesis in life, disease and medicine. Nature 2005;438:932–936. Adamis AP, Shima DT, Yeo KT, et al. Synthesis and secretion of vascular permeability factor/vascular endothelial growth factor by human retinal pigment epithelial cells. Biochem Biophys Res Commun 1993;193:631–638. Shima DT, Adamis AP, Ferrara N, et al. Hypoxic induction of endothelial cell growth factors in retinal cells: identification and characterization of vascular endothelial growth factor (VEGF) as the mitogen. Mol Med 1995;1:182–193. He YG, Wang H, Zhao B, et al. Elevated vascular endothelial growth factor level in Coats’ disease and possible therapeutic role of bevacizumab. Graefes Arch Clin Exp Ophthalmol 2010; 248:1519–1521. Scholl S, Augustin A, Loewenstein A, et al. General pathophysiology of macular edema. Eur J Ophthalmol 2011;21 (suppl 6):S10–S19. Antonetti DA, Barber AJ, Hollinger LA, et al. Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors. J Biol Chem 1999;274:23463–23467. Murakami T, Frey T, Lin C, Antonetti DA. Protein kinase cbeta phosphorylates occludin regulating tight junction trafficking in vascular endothelial growth factor-induced permeability in vivo. Diabetes 2012;61:1573–1583. Miller JW. Vascular endothelial growth factor and ocular neovascularization. Am J Pathol 1997;151:13–23. Shima DT, Gougos A, Miller JW, et al. Cloning and mRNA expression of vascular endothelial growth factor in ischemic retinas of macaca fascicularis. Invest Ophthalmol Vis Sci 1996; 37:1334–1340. Nucci P, Bandello F, Serafino M, Wilson ME. Selective photocoagulation in coats’ disease: ten-year follow-up. Eur J Ophthalmol 2002;12:501–505. Gamulescu MA, Walter A, Sachs H, Helbig H. Bevacizumab in the treatment of idiopathic macular telangiectasia. Graefes Arch Clin Exp Ophthalmol 2008;246:1189–1193.
61. Takayama K, Ooto S, Tamura H, et al. Intravitreal bevacizumab for type 1 idiopathic macular telangiectasia. Eye 2010;24: 1492–1497. 62. Ray R, Baranano DE, Hubbard GB. Treatment of coats’ disease with intravitreal bevacizumab. Br J Ophthalmol 2013;97:272–277. 63. Sigler EJ, Randolph JC, Calzada JI, et al. Current management of coats disease. Surv Ophthalmol 2014;59:30–46. 64. Baffert F, Thurston G, Rochon-Duck M, et al. Age-related changes in vascular endothelial growth factor dependency and angiopoietin-1-induced plasticity of adult blood vessels. Circ Res 2004;94:984–992. 65. Saint-Geniez M, Maharaj AS, Walshe TE, et al. Endogenous VEGF is required for visual function: evidence for a survival role on müller cells and photoreceptors. PLoS One 2008;3:e3554. 66. Lambrechts D, Storkebaum E, Morimoto M, et al. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet 2003;34:383–394. 67. Skinner SA, Tutton PJ, O’Brien PE. Microvascular architecture of experimental colon tumors in the rat. Cancer Res 1990;50: 2411–2417. 68. Marneros AG, Fan J, Yokoyama Y, et al. Vascular endothelial growth factor expression in the retinal pigment epithelium is essential for choriocapillaris development and visual function. Am J Pathol 2005;167:1451–1459. 69. Peters S, Heiduschka P, Julien S, et al. Ultrastructural findings in the primate eye after intravitreal injection of bevacizumab. Am J Ophthalmol 2007;143:995–1002. 70. Sisk RA, Berrocal AM, Albini TA, Murray T. Bevacizumab for the treatment of pediatric retinal and choroidal diseases. Ophthalmic Surg Lasers Imaging 2010;41:582–592. 71. Mataftsi A, Balmer A, Houghton S, et al. Ranibizumab in the management of advanced coats disease stages 3b and 4: longterm outcomes. Retina 2014;34:2275–2281. 72. Lin CJ, Chen SN, Hwang JF, Yang CM. Combination treatment of pediatric coats’ disease: a bicenter study in Taiwan. J Pediatr Ophthalmol Strabismus 2013;50:356–362. 73. Ramasubramanian A, Shields CL. Bevacizumab for coats’ disease with exudative retinal detachment and risk of vitreoretinal traction. Br J Ophthalmol 2012;96:356–359. 74. Mrejen S, Metge F, Denion E, et al. Management of retinal detachment in coats disease. Study of 15 cases. Retina 2008;28 (suppl 3):S26–32. 75. Suesskind D, Altpeter E, Schrader M, et al. Pars plana vitrectomy for treatment of advanced coats’ disease–presentation of a modified surgical technique and long-term follow-up. Graefes Arch Clin Exp Ophthalmol 2014;252:873–879. 76. Zhang X, Dong F, Dai R, Yu W. Surgical management of epiretinal membrane in combined hamartomas of the retina and retinal pigment epithelium. Retina 2010;30:305–309. 77. Kiryu J, Kita M, Tanabe T, et al. Pars plana vitrectomy for epiretinal membrane associated with sarcoidosis. Jpn J Ophthalmol 2003;47:479–483. 78. Mulvihill A, Morris B. A population-based study of coats disease in the United Kingdom II: investigation, treatment, and outcomes. Eye (Lond) 2010;24:1802–1807. 79. Yadav NK, Vasudha K, Gupta K, Shetty KB. Vitrectomy for epiretinal membrane secondary to treatment for juvenile coats’ disease. Eye 2013;27:278–280. 80. Ferrone PJ, Chaudhary KM. Macular epiretinal membrane peeling treatment outcomes in young children. Retina 2012; 32:530–536. 81. Haik BG Advanced coats disease. Trans Am Ophthalmol Soc 1991;89:371–476.
DIAGNOSIS AND MANAGEMENT OF COATS DISEASE GROSSO ET AL 82. Adam RS, Kertes PJ, Lam WC. Observations on the management of coats’ disease: less is more. Br J Ophthalmol 2007;91: 303–306. Epub 2006 Oct 4. 83. Shields JA, Shields CL, Honavar SG, et al. Classification and management of coats disease: the 2000 proctor lecture. Am J Ophthalmol 2001;131:572–583. 84. Budning AS, Heon E, Gallie BL. Visual prognosis of coats disease. J AAPOS 1998;2:356–359.
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85. Kang KB, Wessel MM, Tong J, et al. Ultra-widefield imaging for the management of pediatric retinal diseases. J Pediatr Ophthalmol Strabismus 2013;50:282–288. 86. Shienbaum G, Tasman WS. Coats disease: a lifetime disease. Retina 2006;26:422–424. 87. Pérez-Campagne E, Wolfensberger TJ. Reemergence of dormant coats disease after 30 years. Eur J Ophthalmol 2012;22: 509–512.
W
occurs in the evaluation of posterior uveitis, when one considers the differential diagnosis (i.e., “candle wax appearance”). There is no specific testing for Coats disease, and findings can be consistent with but not diagnostic of Coats disease. Additionally, systemic history is not typically suggestive of the diagnosis but may support a different probable diagnosis. Furthermore, it is also possible that a patient coincidentally has two distinct diseases or that retinal microvascular abnormalities lead to a continuum of signs depending on the stage of the natural course. One must consider all of these factors throughout the clinical management and patient counseling in Coats disease.
hen one deals with cases of exudative retinopathy, such as Coats disease, it is important to bear in mind the pattern recognition mechanism we unconsciously use to understand the meaning of a retinal image. Currently, patients commonly undergo multimodal retinal evaluation that may lead to detection of a myriad of retinal vascular changes. Only when we assemble all these signs, do we have a pattern consistent with a specific disease. A similar process From the *Department of Ophthalmology, Torino Eye Hospital and Centre for Macular Research and Allied Diseases, San Mauro, Italy; †Department of Biomedical and Clinical Science “Luigi Sacco”, Eye Clinic, Sacco Hospital, University of Milan, Milan, Italy; ‡Department of Ophthalmology, Torino Eye Hospital, Torino, Italy; §Ophthalmic Consultants of Long Island, Division of Retina and Vitreous, Rockville Centre, New York; and ¶Ophthalmic Consultants of Long Island, Division of Retina and Vitreous, Lynbrook, New York. None of the authors have any financial/conflicting interests to disclose. A. Grosso has had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Reprint requests: Andrea Grosso, MD, Department of Ophthalmology, Torino Eye Hospital and Centre for Macular Research and Allied Diseases, San Mauro T.se 10099 Via Roma 73, Italy; e-mail: [email protected]
Clinical Scenario and Differential Diagnoses Is Coats Disease a Sporadic Unilateral Condition? To date, based on our current understanding and accepted classification, we know that typical patients with Coats disease (Figure 1) are males with unilateral retinal vascular changes that include capillary telangiectasia, arterial aneurysms, retinal nonperfusion rarely associated with retinal neovascularization and with 614
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Fig. 1. Multimodal retinal imaging (fluorescein angiogram, color fundus photography, indocyanine green angiography) in Coats disease and retinal VPTs. Clinical (A and B) fluorescein angiography (C and D) and indocyanine green (E and F) of a 6-year-old patient affected by Coats disease (left column) and a case of 47-year-old man affected by retinal VPT (right column). Exudation in Coats disease displays a typical distribution, affecting areas remote from retinal telangiectasias with a preferential localization in the macular area. In retinal VPTs, exudation usually starts in proximity of the tumor and gradually extends to the posterior retina. VPT, vasoproliferative tumors.
exudative retinopathy sometimes leading to retinal detachment.1 However, a recent article2 pointed out that 22 of 32 patients with Coats disease had bilateral abnormal peripheral vasculature. The authors state that Coats disease may more often be a bilateral disease with asymmetry: when all patients undergo a peripheral fluorescein angiography with Retcam system (Clarity Medical System, Pleasanton, CA), bilateral vascular abnormalities are more common than previously reported. Do we miss something about the genetic contribution? Familial exudative vitreoretinopathy, in particular, manifests as a bilateral exudative retinopathy,3–12 and frequent marked asymmetry in clinical appearance may be present between eyes of the same patient. In such cases, genetic testing for Norrie disease protein, frizzled homolog 4, low-density lipoprotein receptor-related protein 5, and tetraspanin 12 mutations may reveal additional genetic abnormalities. The proteins coded for by these genes are known to be involved in the Norrin/Fz4/Wnt signaling pathway. Mutations in these genes can
preclude physiologic retinal vascular development. For the same reason, patients and their family members might be evaluated with indirect ophthalmoscopy and wide-field fluorescein angiography to rule out undiagnosed vascular abnormalities.3–14 What About Differential Diagnosis? Epidemiologic criteria (frequency and groups of age) may be used to differentiate: 1. The more common differential clinical diagnoses in adults and children (Table 1); 2. The less common genetically determined isolated or syndromic ocular conditions (Table 2); The differential diagnosis of retinal arterial macroaneurysms, a prominent finding in patients with Coats disease is listed in Table 3. Arterial macroaneurysms may be seen with hypertension or arteriosclerosis, which may be single or multiple. In these conditions, there is a chronic
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Table 1. List of More Common Differential Clinical Diagnoses in Adults and Children Adults15–23 Eales disease Sarcoidosis Tuberculosis IRVAN (idiopathic retinal vasculitis aneurysms and neuroretinitis) Vasoproliferative tumors (Figure 2) Sickle cell retinopathy Lipidemia retinalis (familial hypercholesterolemia)
Pediatrics24–29 Combined hamartoma of the retina and RPE (congenital ERM) ROP Retinoblastoma FEVR
Table 3. List of Differential Diagnosis of Retinal Arterial Macroaneurysms, a Prominent Finding in Patients With Coats Disease A. Hypertension B. Arteriosclerosis C. Postembolic D. Retinal vascular occlusion E. Idiopathic polypoidal choroidal vasculopathy F. Idiopathic retinal vasculitis, aneurysms, and neuroretinitis G. Sarcoid (segmental arterial ectasias)
Cat scratch disease Vasoproliferative tumors Retinal hemangioblastoma Persistent fetal vasculature Retinal arteriovenous malformation
FEVR, familiar exudative vitreoretinopathy; IRVAN, idiopathic retinal vasculitis, aneurysms, and neuroretinitis; ROP, retinopathy of prematurity; RPE, retinal pigment epithelium.
damage to the endothelial wall and a high transmural hydrostatic pressure according to Poiseuille law. Occasionally, these occur after retinal vascular emboli. In younger patients, an important cause of retinal arterial aneurysms, particularly when multiple and bilateral, is idiopathic retinal vasculitis, aneurysms, and neuroretinitis.30 Patients with idiopathic retinal vasculitis, aneurysms, and neuroretinitis have evidence of vasculitis; the aneurysms may occur on or near the optic nerve and are importantly (similar to sarcoidosis), frequently present at vascular branch points rather than at vessel terminations. Patients often develop capillary nonperfusion, especially in the peripheral retina and retinal neovascularization. They often have lipid exudation in proximity to the aneurysms and in the macula. They may have macular thickening.31–35 Retinal arterial macroaneurysms are well recognized to occur in types of uveitis other than idiopathic retinal vasculitis, aneurysms, and neuroretinitis, specifically sarcoidosis. Takagi et al36 first described arterial macroaneurysm formation in 2 patients with ocular sarcoidosis in 1994. Table 2. List of Less Common Genetically Determined Isolated or Syndromic Ocular Conditions Dyskeratosis congenita FSHD Turner syndrome Incontinentia pigmenti Kabuki syndrome Norrie disease Retinitis pigmentosa with coats-like retinopathy Senior–loken syndrome FSHD, facio–scapulo–humeral dystrophy.
Four years later, Rothova and Lardenoye37 reported the occurrence of arterial macroaneurysms in 17% of 48 patients with sarcoidosis including a subgroup with choroiditis. These findings were subsequently and independently confirmed by Verougstraete et al38 and Yamanaka et al,39 both of whom recommended that all patients with retinal arterial macroaneurysms and choroiditis be thoroughly evaluated for sarcoidosis. An association between polypoidal vasculopathy and macroaneurysms has also been published.40,41 Unresolved Questions About Pathogenesis Why do Coats Arterial Aneurysms not Bleed? The reasons why aneurysms in Coats disease do not typically bleed, but more commonly exudate fluids, is not completely understood and warrants further investigation. Histopathologic studies have shown diffuse thickening of retinal capillary adventitia and areas of total absence of pericytes and vascular endothelium consistent with two pathologic processes that are evident in Coats disease. The first consists of a breakdown of the blood–retinal barrier at the endothelial level that causes plasma leakage into and thickening of parts of the vessel wall, leading to necrosis and disorganization and producing what Egbert et al42 have described as a “sausage-like” shape of the vessel. The second concerns the presence of abnormal pericytes and endothelial cells in retinal blood vessels that subsequently degenerate, causing abnormal retinal vasculature and formation of aneurysms, as well as closure of vessels resulting in ischemia.43 In contrast to diabetic microaneurysms, these arteriolar aneurysms do not leak lipid or fluorescein. We hypothesize that Coats disease may be a defect in midcapillary angiogenesis, and that aneurysmal dilations are a secondary abortive feature. This hypothesis is consistent with a recent article showing bilateral microvascular abnormalities in patients with Coats disease.2
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Additionally, exudation in Coats disease displays a typical distribution. Hard exudates generally affect widespread areas often remote from retinal telangiectasias with a preferential localization in the macular area. In contrast, exudation in vasoproliferative tumors and retinal hemangioblastomas usually occurs in proximity of the vascular abnormalities.
Macular Fibrosis and Epiretinal Membrane Epiretinal membranes (ERMs) can rarely occur in Coats disease, usually after chronic retinal exudation. The fibrous scarring and the ERM could be the result of long-standing inflammation or neovascularization (Figure 2), or secondary to laser or cryotherapy. Any long-standing exudative process may lead to ERM; however, an epiretinal process is not typical of Coats
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disease and should warrant consideration of additional diagnoses, particularly retinal vasoproliferative tumor, in which ERM is a common feature. Resolved total retinal detachment after intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents frequently demonstrates focal areas of consolidated vitreous that may resemble ERM but is rarely if ever visually or anatomically significant.44 “Macular fibrosis,” previously referred to as “subretinal nodules” or “subretinal mounds” does not refer to an epiretinal process, however. George Coats described macular fibrosis as “located in the choroid,” and multiple histologic investigations have demonstrated this in the early 1900s.43,45 In fact, early histologic investigations referred to “retinochoroidal synechiae.” This point has been lost, however, likely because of the more recent recognition of choroidal neovascularization as an ocular pathologic process
Fig. 2. Multiple retinal imaging by Topcon, HRA II Heidelberg, and Zeiss Stratus optical coherence tomography. A–E. A case of a 22-year-old man complaining of progressive visual loss in his right eye secondary to an ERM in January 2010. B. In the inferior temporal quadrant, a vasoproliferative lesion is shown. E. A dense ERM extending from the optic disk to the fovea is also present with optical coherence tomography examination revealing mild intraretinal edema in the outer nuclear layer. C and D. The fluorescein angiogram shows deregulation of both internal and external blood–retinal barrier and arterial macroaneurysms. D. The indocyanine green angiography enhances the detection of multiple retinal vascular ectasias.
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and the paucity of enucleations performed during current clinical management of Coats disease. In a recent controversy, some authors hypothesized that the lesion was either a retinal angiomatous mass or the result of chronic submacular exudate. Sigler and Calzada46 have recently discovered that “macular fibrosis” is actually Type III choroidal neovascularization and have demonstrated the chorioretinal anastomosis with RetCam angiography and Doppler spectral domain optical coherence tomography in children as young as 1 year old (Figure 3).
Ischemia, retinal, and Papillary Neovascularization Retinal nonperfusion in Coats disease seldom develops neovascularization of the retina or the disk. In Coats disease, ischemia and retinal hemorrhages are usually seen in contrast to MacTel Type 2.47 However in MacTel 2, retinal–retinal and retinal–subretinal anastomoses are consistent with a neovascular process; in Coats disease, we do not have a similar vascular remodeling process. In a recent study of eyes obtained from donors who underwent enucleation through the Doheny Eye and Tissue Transplant Bank, an immunohistochemical analysis was performed.48 Macrophage infiltration was observed in the subretinal space in all cases examined. Vascular endothelial growth factor immunoreactivity
Fig. 3. Wide-field fluorescein angiography and intraoperative spectral domain optical coherence tomography of a 5-year-old patient with Coats disease and macular chorioretinal anastomosis. A. Arteriovenous wide-field fluorescein angiogram demonstrating typical Coats-like telangiectatic vessels in the temporal retinal periphery and macular fibrosis. B. High-magnification angiogram of the macula demonstrating a retinal vessel disappearing into the center of the submacular vascular mass. C. Late phase angiogram clearly demonstrating pooling within the central submacular pigment epithelial detachment, with chorioretinal anastomosis (retinal angiomatous proliferation). D. Intraoperative Doppler optical coherence tomography demonstrating chorioretinal anastomosis and choroidal neovascularization.
was observed in cells infiltrating the subretinal proliferative tissue obtained during vitrectomy in a 28-year-old male who was clinically diagnosed with Stage 3B Coats disease. These cells expressing VEGF were also positive for CD68, a marker for macrophages. In contrast, normal retina did not contain macrophage infiltration or vascular abnormalities. VEGFR-2 immunoreactivity was noted in endothelial cells located in abnormal retinal vessels with hyalinization. These results suggest that macrophages play a pivotal role in the promotion of vascular permeability and angiogenesis by expressing VEGF in Coats disease. Vascular endothelial growth factor induces a diabetic retinopathy phenotype. A possible explanation is correlated with the biological mechanisms that drive retinal angiogenesis: it is well known that angiogenesis is controlled by a delicate balance of proangiogenic and antiangiogenic factors in tissues.49 Dysregulation of this balance has been demonstrated to result in pathologic angiogenesis, such as diabetic retinopathy.50 Extensive studies have revealed that oxygen-sensing systems play important roles in maintaining the balance of angiogenesis regulation. In conditions such as retinal vein occlusion or diabetes, hypoxia is thought to be the stimulus to angiogenesis.49,51,52 In Coats disease, retinal ischemia may promote an immediate injury to the cellular architecture and an upregulation of VEGF53 that might be subsequently secreted into the vitreous. Vascular endothelial growth
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factor also contributes to vascular leakage in multiple retinal pathologies. Alterations of tight junction complex proteins during retinal diseases may lead to blood–retina barrier breakdown and subsequent vascular permeability and macular edema.54 Treatment of endothelial cells with VEGF increases occludin (a protein included in tight junctions) phosphorylation.55 Furthermore, intravitreal injection of VEGF induces occludin phosphorylation, ubiquitination, and redistribution from the blood retinal barrier in vivo, which is associated with increased permeability.55–58 It seems clear that VEGF and other factors contribute to exudation in Coats disease. In cases of exudative chronic retinal detachment, hypoxia also occurs; this may also explain why patients with Coats disease (Stage 3 or 4) may have neovascular glaucoma with no signs of intraretinal neovascularization: the retinal–glaucoma gap. Management Role of Anti-Vascular Endothelial Growth Factor Drugs Management of cases of Coats disease is primarily aimed at preserving macular function by trying to minimize macular edema and lipid exudation that can cause permanent scarring when it develops at the fovea. We prefer to treat the aneurysms responsible for visually threatening macular edema with focal thermal laser.59 These eyes seldom develop retinal neovascularization and vitreous hemorrhage. Therefore, we typically do not perform scatter laser treatment over areas of nonperfusion unless it seems that treating this ischemic retina might reduce vascular leakage. Although the literature provides conflicting reports regarding the benefit of intravitreal anti-VEGF drugs in controlling macular edema in Coats disease, clinical experience has been that these agents induce a short-lived response that is often inadequate to prevent disease progression after a single treatment.44,60–63 We lack evidence that young patients have a structurally immature retina or that physiologic revascularization occurs in the adult retina. However, VEGF-A is a critical molecule with multiple bioactivities: processes which involve VEGF-A are listed in the Table 4.64–69 Blocking VEGF secretion or activity or function may not always be a good thing; however, anti-VEGF agents have not demonstrated untoward effects on previously disease-free retina after millions of treatments in adults worldwide. As yet, anti-VEGF agents have been safely used even in young patients.70 Anti-VEGF agents are particularly useful in advanced stages of Coats71,72 disease with
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Table 4. Multiple Bioactivities of Vascular Endothelial Growth Factor Angiogenic Permeability factor Branching factor Proinflammatory Vessel survival factor Fenestration factor Neuroprotectant Thrombosis modulator Vasodilation/flow
large (greater than one quadrant or macula-involved) areas of exudative retinal detachment. In fact, multiple recent reports63,73 have demonstrated resolution of total retinal detachment after intravitreal Bevacizumab. Before this therapy, many patients with advanced Coats disease developed neovascular glaucoma, phthisis, or required enucleation. Even in the context of retina present immediately posterior to the lens, either anterior chamber or subretinal anti-VEGF therapy may be performed. Thermal ablative therapy remains the standard of care, however. Anti-VEGF is used as an adjunct to laser therapy,44,63,72 which can be performed even in the presence of subretinal fluid. We prefer to avoid cryotherapy because of its tissue destructive and proliferative vitreoretinopathy-inducing potential. Nevertheless, cryotherapy is a known-effective method to resolve serous detachment and resolution of exudate, telangiectasias, and vascular ablation in Coats retinopathy.63 Furthermore, with the recent discovery that chorioretinal anastomosis and Type III choroidal neovascularization46 occurs in Coats disease, anti-VEGF therapy may be increasingly indicated. The major challenge to this approach in young patients is the need for repeated examinations under anesthesia if anti-VEGF therapy is continued, and thus the approach to treatment must be individually tailored based on disease severity. Currently, we recommend combined anti-VEGF and peripheral laser therapy as initial treatment for patients with exudative retinal detachment or macular retinal angiomatous proliferation and Coats disease. Laser therapy alone is performed for patients with aneurysmal dilations without greater than one quadrant of subretinal fluid or localized exudates. It is important to “stay ahead” of the disease in these cases by treating early, before lipid accumulates in the fovea. Despite prompt therapy, however, peripheral exudate often accumulates in the macular region even after complete ablation of abnormal peripheral aneurysms. Mild lipid exudates typically
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resolve over 2 months to 3 months in the absence of active exudation. In more severe cases, laser alone may not be sufficient to control the degree of exudation. In cases of more marked exudation, it may take many months and even years for the lipid exudation to resolve. Often, this leakage may be because of diffuse leakage from the telangiectatic capillaries. In these cases, injections of sub-Tenon triamcinolone acetonide (40 mg/1.0 mL) were used with success (Discussion of a diagnostic and clinical challenge, Retina 2013, volume 33, number 1). Anti-vascular endothelial growth factor therapy is an additional reasonable and efficacious treatment option in this context. Is there a Role for Vitreoretinal Surgery? Before the advent of anti-VEGF therapy, vitreoretinal surgery was indicated to manage complications in selected cases of stage 4 Coats disease.63,74,75 Now, the treatment paradigm is changing towards a sequential combined treatment strategy by including first the use of anti-VEGF drugs associated with vitreoretinal surgery. The aim is to resolve the subretinal exudative detachment as early as possible and to treat the macular edema. Depending on the natural course of the disease, the legacy of a serous detachment is subretinal fibrosis unresponsive to the anti-VEGF. In some cases of Coats disease, an epiretinal macular proliferation may occur (Figure 2) as result of persistent inflammation thrombosis. Additional pathologic vitreoretinal tractions may also develop close to the exudative mass. During vitrectomy, macular ERM peeling is mandatory to preserve the function of photoreceptors. Additionally, the removal of the vitreous reduces the concentration of cytokines in the vitreous.76–80 Small gauge core or complete vitrectomy (23 or 25 gauge) coupled with high speed vitrectomy platforms may be routinely used and may reduce the risk of peripheral iatrogenic retinal tears. A double peeling of hyaloid and internal limiting membrane is warranted, often assisted by vital dyes (chromovitrectomy with triamcinolone, membrane blue, dual blue). As internal tamponade air or gas are normally used to fill the vitreous cavity. In selected cases, an external drainage of subretinal fluid may be performed.81–83 During the vitrectomy the peripheral telangiectasia may be simultaneously photocoagulated or selectively treated by exocryo coagulation. According to the literature,80 the risk of recurrence of ERM is low.
Prognostic Factors Long-term visual prognosis was historically poor.63,83,84 The advent of anti-VEGF agents represent a game changer in the management of Coats disease. We recommend a tailored approach based on patient factors (age, comorbidities) and severity of disease. In Shields et al,83 Stage 1 close observation is recommended. We prefer to treat initially leaking macroaneurysms and telangiectasias with thermal laser because of its minimal risk and the potential to prevent exudates. Exocryo coagulation should be used as well. For Stages 2 and 3, a combination of anti-VEGF and coagulation is indicated: in these patients, a close monthly follow-up until disease stabilization should be recommended. In cases of significant macular edema, marked exudation, and serous retinal detachment, a sequential combination strategy63,72 with antiVEGF first followed by prompt laser by no more than 2 weeks is normally preferred. Exocryo coagulation may be used as well. Patients with extrafoveal abnormal vasculature and telangiectasias, especially if associated with ischemia as seen by fluoroangiography, may undergo extensive peripheral photocoagulation of the anomalous areas associated with anti-VEGF. However, we stress the importance of recurrent nature of Coats disease and the need for regular follow-up. Conclusion The advancements in wide-field imaging techniques85 will allow early detection of peripheral vascular abnormalities even in the asymptomatic patients and a better management of the disease. Given the broad spectrum of disease phenotype and clinical behavior in Coats disease, early diagnosis and prompt initiation of treatment may lead to an improved clinical outcome. As far as the therapeutical options are concerned, thermal ablative therapy coupled with anti-VEGF drugs represent the standard of care. Exocryo coagulation may be used as well depending on the surgeon’s experience. Small gauge (23 or 25 gauge) surgery may play a role in the management of complications (Stage 4) or in cases of tractional retinal detachment or macular edema sustained by ERMs. In conclusion, we stress the importance of being cautious with patients to discuss the pros and cons of treatment options and the importance of the therapeutical alliance because Coats disease is a chronic disease.86,87 Coats disease can recur, so it is crucial to keep patients aware of the necessity of regular
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long-term follow-up even in the absence of subjective visual loss. Key words: eye, retina, coats disease, macular edema, VEGF, retinal telangiectasia, small gauge surgery, macroaneurysms, retinal ischemia. References 1. Shields JA, Shields CL. Review: coats disease: the 2001 LuEsther T. Mertz lecture. Retina 2002;22:80–91. 2. Blair MP, Ulrich JN, Elizabeth Hartnett M, Shapiro MJ. Peripheral retinal nonperfusion in fellow eyes in coats disease. Retina 2013;33:1694–1699. 3. Miyakubo H, Hashimoto K, Miyakubo S. Retinal vascular pattern in familial exudative vitreoretinopathy. Ophthalmology 1984;91:1524–1530. 4. Kashani AH, Learned D, Nudleman E, et al. High prevalence of peripheral retinal vascular anomalies in family members of patients with familial exudative vitreoretinopathy. Ophthalmology 2014;121:262–268. 5. Criswick VG, Schepens CL. Familial exudative vitreoretinopathy. Am J Ophthalmol 1969;68:578–594. 6. Shukla SY, Kaliki S, Shields CL. Asymmetry of familial exudative vitreoretinopathy. J Pediatr Ophthalmol Strabismus 2012;28:49. 7. Toomes C, Bottomley HM, Jackson RM, et al. Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q. Am J Hum Genet 2004;74:721–730. 8. Chen ZY, Battinelli EM, Fielder A, et al. A mutation in the norrie disease gene (NDP) associated with X-linked familial exudative vitreoretinopathy. Nat Genet 1993;5:180–183. 9. Robitaille J, MacDonald ML, Kaykas A, et al. Mutant frizzled4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Nat Genet 2002;32:326–330. 10. Nikopoulos K, Gilissen C, Hoischen A, et al. Next-generation sequencing of a 40 Mb linkage interval reveals TSPAN12 mutations in patients with familial exudative vitreoretinopathy. Am J Hum Genet 2010;86:240–247. 11. Robitaille JM, Zheng B, Wallace K, et al. The role of Frizzled4 mutations in familial exudative vitreoretinopathy and coats disease. Br J Ophthalmol 2011;95:574–579. 12. Benson WE. Familial exudative vitreoretinopathy. Trans Am Ophthalmol Soc 1995;93:473–521. 13. Tasman W, Augsburger JJ, Shields JA, et al. Familial exudative vitreoretinopathy. Trans Am Ophthalmol Soc 1981;79:211–226. 14. Canny CL, Oliver GL. Fluorescein angiographic findings in familial exudative vitreoretinopathy. Arch Ophthalmol 1976; 94:1114–1120. 15. Chang TS, Aylward GW, Davis JL, et al. Idiopathic retinal vasculitis, aneurysms, and neuro-retinitis. Retinal vasculitis study. Ophthalmology 1995;102:1089–1097. 16. Samuel MA, Equi RA, Chang TS, et al. Idiopathic retinitis, vasculitis, aneurysms, and neuroretinitis (IRVAN): new observations and a proposed staging system. Ophthalmology 2007; 114:1526–1529. 17. Das T, Pathengay A, Hussain N, Biswas J. Eales’ disease: diagnosis and management. Eye 2010;24:472–482. 18. Biswas J, Ravi RK, Naryanasamy A, et al. Eales’ disease current concepts in diagnosis and management. J Ophthalmic Inflamm Infect 2013;3:11. 19. Hoover DL, Khan JA, Giangiacomo J. Pediatric ocular sarcoidosis. Surv Ophthalmol 1986;30:215–228.
621
20. Kawaguchi T, Hanada A, Horie S, et al. Evaluation of characteristic ocular signs and systemic investigations in ocular sarcoidosis. Jpn J Ophthalmol 2007;51:121–126. 21. Cimino L, Herbort CP, Aldigeri R, et al. Tuberculous uveitis, a resurgent and underdiagnosed disease. Int Ophthalmol 2009; 29:67–74. 22. Shields CL, Kaliki S, Al-Dahmash S, et al. Retinal vasoproliferative tumors: comparative clinical features of primary vs secondary tumors in 334 cases. JAMA Ophthalmol 2013; 131:328–334. 23. Elagouz M, Jyothi S, Gupta B, Sivaprasad S. Sickle cell disease and the eye: old and new concepts. Surv Ophthalmol 2010;55:359–367. 24. Xue K, Mellington F, Gout I, et al. Combined hamartoma of the retina and retinal pigment epithelium. BMJ Case Rep 2012; doi: 10.1136/bcr-2012-006944. 25. Shields CL, Thangappan A, Hartzell K, et al. Combined hamartoma of the retina and retinal pigment epithelium in 77 consecutive patients visual outcome based on macular versus extramacular tumor location. Ophthalmology 2008;115:2246–2252. 26. Salcone EM, Johnston S, VanderVeen D. Review of the use of digital imaging in retinopathy of prematurity screening. Semin Ophthalmol 2010;25:214–217. 27. Shields CL, Fulco EM, Arias JD, et al. Retinoblastoma frontiers with intravenous, intra-arterial, periocular, and intravitreal chemotherapy. Eye 2013;27:253–264. 28. Heimann H, Jmor F, Damato B. Imaging of retinal and choroidal vascular tumours. Eye 2013;27:208–216. 29. Biancardi AL, Curi AL. Cat-scratch disease. Ocul Immunol Inflamm 2014;22:148–154. 30. Tomita M, Matsubara T, Yamada H, et al. Long term follow up in a case of successfully treated idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN). Br J Ophthalmol 2004;88:302–303. 31. McDonald HR. Diagnostics and therapeutic challenges. IRVAN syndrome. Retina 2003;23:392–399. 32. Kincaid J, Schatz H. Bilateral retinal arteritis with multiple aneurysmal dilatations. Retina 1983;3:171–178. 33. Owens SL, Gregor ZJ. Vanishing retinal arterial aneurysms: a case report. Br J Ophthalmol 1992;76:637–638. 34. Sashihara H, Hayashi H, Oshima K. Regression of retinal arterial aneurysms in a case of idiopathic retinal vasculitis, aneurysms, and neuroretinitis. Retina 1999;19:250–251. 35. Yeshurun I, Recillas-Gispect C, Navarro-Lopez P, et al. Extensive dynamics in location, sharp, and size of aneurysm in a patient with idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome. Am J Ophthalmol 2003;135:118–120. 36. Takagi T, Nakajima A, Sawada Y, Sakuragi S. Macroaneurysms in ocular sarcoidosis. Folia Ophthalmol Jpn 1994;45:555–559. 37. Rothova A, Lardenoye C. Arterial macroaneurysms in peripheral multifocal chorioretinitis associated with sarcoidosis. Ophthalmology 1998;105:1393–1397. 38. Verougstraete C, Snyers B, Leys A, Caspers LE. Multiple arterial ectasias in patients with sarcoidosis and uveitis. Am J Ophthalmol 2001;131:223–231. 39. Yamanaka E, Ohguro N, Kubota A, et al. Features of retinal arterial macroaneurysms in patients with uveitis. Br J Ophthalmol 2004;88:884–886. 40. Ross RD, Gitter KA, Cohen G, Schomaker KS. Idiopathic polypoidal choroidal vasculopathy associated with retinal arterial macroaneurysm and hypertensive retinopathy. Retina 1996;16:105–111. 41. Coscas F, Coscas G, Souïed E. Polypoidal choroidal vasculopathy and macroaneurysm: respective roles of scanning
622
42.
43.
44.
45. 46.
47.
48.
49. 50. 51.
52.
53.
54.
55.
56.
57. 58.
59.
60.
RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2015 VOLUME 35 NUMBER 4
laser ophthalmoscopy-indocyanine green angiography and optical coherence tomography. Eur J Ophthalmol 2011;21: 331–335. Egbert PR, Chan CC, Winter FC. Flat preparations of the retinal vessels in coats’ disease. J Pediatr Ophthalmol 1976; 13:336–339. Fernandes BF, Odashiro AN, Maloney S, et al. Clinicalhistopathological correlation in a case of coats’ disease. Diagn Pathol 2006;1:24. Zheng XX, Jiang YR. The effect of intravitreal bevacizumab injection as the initial treatment for coats’ disease. Graefes Arch Clin Exp Ophthalmol 2014;252:35–42. Jumper JM, Pomerleau D, McDonald HR, et al. Macular fibrosis in Coats disease. Retina 2010;30(suppl 4):S9–S14. Sigler EJ, Calzada JI. Retinal angiomatous proliferation with chorioretinal anastomosis in childhood coats disease: a reappraisal of macular fibrosis using multimodal imaging. Retina 2014. Epub ahead of print. Engelbert M, Yannuzzi LA. Idiopathic macular telangiectasia type 2: the progressive vasculopathy. Eur J Ophthalmol 2013;23:1–6. Kase S, Rao NA, Yoshikawa H, et al. Expression of vascular endothelial growth factor in eyes with coats’ disease. Invest Ophthalmol Vis Sci 2013;54:57–62. Scott A, Fruttiger M. Oxygen-induced retinopathy: a model for vascular pathology in the retina. Eye 2010;24:416–421. Carmeliet P. Angiogenesis in life, disease and medicine. Nature 2005;438:932–936. Adamis AP, Shima DT, Yeo KT, et al. Synthesis and secretion of vascular permeability factor/vascular endothelial growth factor by human retinal pigment epithelial cells. Biochem Biophys Res Commun 1993;193:631–638. Shima DT, Adamis AP, Ferrara N, et al. Hypoxic induction of endothelial cell growth factors in retinal cells: identification and characterization of vascular endothelial growth factor (VEGF) as the mitogen. Mol Med 1995;1:182–193. He YG, Wang H, Zhao B, et al. Elevated vascular endothelial growth factor level in Coats’ disease and possible therapeutic role of bevacizumab. Graefes Arch Clin Exp Ophthalmol 2010; 248:1519–1521. Scholl S, Augustin A, Loewenstein A, et al. General pathophysiology of macular edema. Eur J Ophthalmol 2011;21 (suppl 6):S10–S19. Antonetti DA, Barber AJ, Hollinger LA, et al. Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors. J Biol Chem 1999;274:23463–23467. Murakami T, Frey T, Lin C, Antonetti DA. Protein kinase cbeta phosphorylates occludin regulating tight junction trafficking in vascular endothelial growth factor-induced permeability in vivo. Diabetes 2012;61:1573–1583. Miller JW. Vascular endothelial growth factor and ocular neovascularization. Am J Pathol 1997;151:13–23. Shima DT, Gougos A, Miller JW, et al. Cloning and mRNA expression of vascular endothelial growth factor in ischemic retinas of macaca fascicularis. Invest Ophthalmol Vis Sci 1996; 37:1334–1340. Nucci P, Bandello F, Serafino M, Wilson ME. Selective photocoagulation in coats’ disease: ten-year follow-up. Eur J Ophthalmol 2002;12:501–505. Gamulescu MA, Walter A, Sachs H, Helbig H. Bevacizumab in the treatment of idiopathic macular telangiectasia. Graefes Arch Clin Exp Ophthalmol 2008;246:1189–1193.
61. Takayama K, Ooto S, Tamura H, et al. Intravitreal bevacizumab for type 1 idiopathic macular telangiectasia. Eye 2010;24: 1492–1497. 62. Ray R, Baranano DE, Hubbard GB. Treatment of coats’ disease with intravitreal bevacizumab. Br J Ophthalmol 2013;97:272–277. 63. Sigler EJ, Randolph JC, Calzada JI, et al. Current management of coats disease. Surv Ophthalmol 2014;59:30–46. 64. Baffert F, Thurston G, Rochon-Duck M, et al. Age-related changes in vascular endothelial growth factor dependency and angiopoietin-1-induced plasticity of adult blood vessels. Circ Res 2004;94:984–992. 65. Saint-Geniez M, Maharaj AS, Walshe TE, et al. Endogenous VEGF is required for visual function: evidence for a survival role on müller cells and photoreceptors. PLoS One 2008;3:e3554. 66. Lambrechts D, Storkebaum E, Morimoto M, et al. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet 2003;34:383–394. 67. Skinner SA, Tutton PJ, O’Brien PE. Microvascular architecture of experimental colon tumors in the rat. Cancer Res 1990;50: 2411–2417. 68. Marneros AG, Fan J, Yokoyama Y, et al. Vascular endothelial growth factor expression in the retinal pigment epithelium is essential for choriocapillaris development and visual function. Am J Pathol 2005;167:1451–1459. 69. Peters S, Heiduschka P, Julien S, et al. Ultrastructural findings in the primate eye after intravitreal injection of bevacizumab. Am J Ophthalmol 2007;143:995–1002. 70. Sisk RA, Berrocal AM, Albini TA, Murray T. Bevacizumab for the treatment of pediatric retinal and choroidal diseases. Ophthalmic Surg Lasers Imaging 2010;41:582–592. 71. Mataftsi A, Balmer A, Houghton S, et al. Ranibizumab in the management of advanced coats disease stages 3b and 4: longterm outcomes. Retina 2014;34:2275–2281. 72. Lin CJ, Chen SN, Hwang JF, Yang CM. Combination treatment of pediatric coats’ disease: a bicenter study in Taiwan. J Pediatr Ophthalmol Strabismus 2013;50:356–362. 73. Ramasubramanian A, Shields CL. Bevacizumab for coats’ disease with exudative retinal detachment and risk of vitreoretinal traction. Br J Ophthalmol 2012;96:356–359. 74. Mrejen S, Metge F, Denion E, et al. Management of retinal detachment in coats disease. Study of 15 cases. Retina 2008;28 (suppl 3):S26–32. 75. Suesskind D, Altpeter E, Schrader M, et al. Pars plana vitrectomy for treatment of advanced coats’ disease–presentation of a modified surgical technique and long-term follow-up. Graefes Arch Clin Exp Ophthalmol 2014;252:873–879. 76. Zhang X, Dong F, Dai R, Yu W. Surgical management of epiretinal membrane in combined hamartomas of the retina and retinal pigment epithelium. Retina 2010;30:305–309. 77. Kiryu J, Kita M, Tanabe T, et al. Pars plana vitrectomy for epiretinal membrane associated with sarcoidosis. Jpn J Ophthalmol 2003;47:479–483. 78. Mulvihill A, Morris B. A population-based study of coats disease in the United Kingdom II: investigation, treatment, and outcomes. Eye (Lond) 2010;24:1802–1807. 79. Yadav NK, Vasudha K, Gupta K, Shetty KB. Vitrectomy for epiretinal membrane secondary to treatment for juvenile coats’ disease. Eye 2013;27:278–280. 80. Ferrone PJ, Chaudhary KM. Macular epiretinal membrane peeling treatment outcomes in young children. Retina 2012; 32:530–536. 81. Haik BG Advanced coats disease. Trans Am Ophthalmol Soc 1991;89:371–476.
DIAGNOSIS AND MANAGEMENT OF COATS DISEASE GROSSO ET AL 82. Adam RS, Kertes PJ, Lam WC. Observations on the management of coats’ disease: less is more. Br J Ophthalmol 2007;91: 303–306. Epub 2006 Oct 4. 83. Shields JA, Shields CL, Honavar SG, et al. Classification and management of coats disease: the 2000 proctor lecture. Am J Ophthalmol 2001;131:572–583. 84. Budning AS, Heon E, Gallie BL. Visual prognosis of coats disease. J AAPOS 1998;2:356–359.
623
85. Kang KB, Wessel MM, Tong J, et al. Ultra-widefield imaging for the management of pediatric retinal diseases. J Pediatr Ophthalmol Strabismus 2013;50:282–288. 86. Shienbaum G, Tasman WS. Coats disease: a lifetime disease. Retina 2006;26:422–424. 87. Pérez-Campagne E, Wolfensberger TJ. Reemergence of dormant coats disease after 30 years. Eur J Ophthalmol 2012;22: 509–512.
