Williams-Beuren syndrome (WBS) is a rare, multisystem disorder caused by de novo deletion of approximately 28 contiguous genes on chromosome 7q11.23. The classic clinical phenotype is characterized by cardiovascular disorders, facial dysmorphisms, mental retardation, skeletal and renal abnormalities, and a peculiar cognitive profile. The symptoms and physical features vary greatly in range and severity, even among familial cases, depending on the extent of the deletion.1
Various ophthalmic manifestations have been reported including the characteristic stellate pattern on iris, strabismus, hypermetropia, and tortuosity of retinal vessels.2 Herein, we described novel multimodal retinal imaging findings of foveal hypoplasia and bilateral prepapillary venous loops (PVL) in a patient with WBS. Furthermore, we reported the results of intravitreal bevacizumab (IVB) (Avastin; Genentech, South San Francisco, CA) and triamcinolone acetonide (IVTA) injection for the treatment of macular edema in this patient.
A 17-year-old male patient with a genetic diagnosis of WBS presented to the ophthalmology clinic with decreased vision in both eyes (OU) for 3 years. He had a history of operation for supravalvular aortic stenosis and inguinal hernia. There was parental consanguinity with no affected siblings or family member. He was under control with respect to cardiovascular function. All inflammatory markers were negative. Ophthalmologic examination revealed a best-corrected visual acuity (BCVA) of 0.5 OU (right eye [OD]: −0.25 −0.50 × 50; left eye [OS]: −0.75-0.50 × 38). Anterior segment examination was significant for a stellate pattern of a green iris. Funduscopic examination showed bilateral obliteration of optic disc cupping, Bergmeister's papilla, and numerous loop-shaped tortuous vessels accompanying normal appearing retinal vessels on the macula and around the optic disc (Figures 1A and 1B). Fundus autofluorescence imaging revealed a perimacular hyperautofluorescent ring and hyperautofluorescent dots (Figures 1C and 1D). Fundus fluorescein angiography showed filling of the loops at venous phase, a filling defect in some loops, and diffuse leakage at the macula. There was no leakage from retinal vessels, peripheral retinal vascular changes, or avascularity (Figures 1E–1J). Optical coherence tomography (OCT) examination showed an increased retinal nerve fiber layer thickness, mild foveal hypoplasia with a persistence of inner retinal layers and hyperreflective dots (HRD) in vitreous and retinal layers, and cystoid spaces in the retina (Figures 2A and 2B). OCT angiography (OCTA) revealed that the abnormal vessels were located 230 μm above the internal limiting membrane forming arcades originating from the optic disc, with some returning back to optic disc and some ending at retina (Figures 3A and 3B). The area of the foveal avascular zone at the level of the superficial capillary plexus was 0.159 mm2 OD and 0.143 mm2 OS, and at the level of the deep capillary plexus was 0.374 mm2 OD and 0.413 mm2 OS. Conservative treatment with topical carbonic anhydrase eyedrops three times daily initiated. However, 3 months later the BCVA declined to 20/100 OU. Diffuse cystoid macular edema OU was diagnosed (Figures 2C and 2D). After cardiology consultation, the patient's right eye was treated with IVB (1.25 mg). One month later, the macular thickness decreased from 647 μm to 473 μm and BCVA increased from 0.2 to 0.3, and a very slight decrease was observed in the number of HRD (Figure 2E). In this visit, the patient received bilateral intravitreal injections. The BCVA increased 0.3 to 0.4 OD and from 0.2 to 0.4 OS; the central macular thickness (CMT) decreased from 473 μm to 437 μm OD, and from 663 μm to 472 μm OS. The patient received five more intravitreal injections OD and OS for recurrent macular edema bimonthly. Despite these injections, the macular edema and the number of HRD increased at each visit. At 27 months' follow-up, the BCVA declined to 0.1 OD and 0.2 OS, and CMT increased to 1,008 μm OD and 954 μm OS (Figures 2G and 2H). An IVTA injection was performed OD. A month later, the BCVA increased from 0.1 to 0.3, and CMT decreased to 156 μm (Figure 2I). No increase in intraocular pressure was observed, and this time IVTA injection was performed OS. A month later, the BCVA increased from 0.2 to 0.3, and CMT decreased to 179 μm (Figure 2J). No recurrence in macular edema was observed 4 months and 3 months after IVTA injection OD and OS, respectively.
Fundus photographs demonstrating abnormal loop-shaped, tortuous vessels radiating from the optic disc (A, B). Fundus autofluorescence imaging revealing a perimacular hyperautofluorescent ring and hyperautofluorescent dots (C, D). Fluorescein angiography showing arterial phase in the right eye (OD) (E), early venous phase in the left eye (OS) (F), venous phase showing filling of the loops OD (G) and OS (H), late phase revealing filling defect in some loops, and diffuse leakage OD (I) and OS (J).
Spectral-domain optical coherence tomography and follow-up of visual acuity (VA) of the patient. At the initial presentation, persistence of inner retinal layers is indicated by green arrow and hyperreflective dots (HRDs) in the vitreous, and cystoid spaces in the retina in the right eye (OD) (A) and the left eye (OS) (B). Three months later, cystoid macular edema (CME) and increase in HRD were observed OD (C) and OS (D). After unilateral intravitreal bevacizumab (IVB) injection, VA and CME were mildly improved OD (E), and edema increased slightly in the untreated OS (F). The macular edema was increased and VA worsened despite six IVB injections OD (E) and five IVB injections OS (F). The rapid improvement of macular edema and VA after intravitreal triamcinolone acetonide (IVTA) injection OD (G), OS (H).
Optical coherence tomography angiography, vitreous segmentation, and widefield montage showing prepapillary venous loops forming arcades in the right (A) and left eyes (B).
Foveal hypoplasia has been reported in various genetic disorders including Stickler's syndrome, familial exudative vitreoretinopathy, albinism, aniridia, microphthalmus, and achromatopsia.3 As some of the genes deleted in WBS are involved in the differentiation of retinal layers, foveal hypoplasia might be an expected finding in this syndrome. On the other hand, Castelo-Branco et al. reported a normal foveal structure in WBS. They also studied optic disc morphology and, similarly to our patient, observed loss of concavity of the cup region either by obliteration or partial covering by a thin membrane.4
Prepapillary vascular loops are usually asymptomatic; rarely, hyphema, vitreous hemorrhage, and retinal vascular occlusive disease are observed.5 Leakage from these vessels was an unanticipated finding. On the contrary to accustomed single, small arterial loops; in our patient, there were numerous thin, venous loops. As lipofuscin was shown in aged retinal vascular cells,6 autofluorescent areas over the loops suggested turbulent flow in the long, angulated venous channels leading to endothelial damage, causing leakage.
Macular edema is a common complication of various ocular diseases including diabetic retinopathy, age-related macular degeneration (AMD), and uveitis, causing increased vascular permeability and accumulation of fluid in the macula. In these diseases, the current standard of care was directed toward reduction of leakage of fluid from the vessels.7 The young age of the patient and potential complications associated with intravitreal steroid injection made IVB to be considered as the first-line treatment.8 After initial IVB, a partial response (more than 25% reduction in CMT from the baseline OCT and an increase in visual acuity OD) was observed. After the second injection OD and the first injection OS, IVB treatment provided limited efficacy. The macular edema increased despite five additional treatments of IVB.
Hyperreflective dots in retina on OCT have been reported in diabetic maculopathy, retinal vein occlusion, AMD, central serous chorioretinopathy, uveitis, and macular telangiectasia.9 They are thought to represent either extravasated lipoproteins after blood-retinal barrier breakdown or microglia aggregated as an inflammatory response.10,11 The number of HRDs have been proposed as a predictive indicator of the response to anti-VEGF injection.12,13 In responsive patients with diabetic macular edema (DME), after anti-VEGF treatment, HRDs disappeared or reduced significantly. On the other hand, DME associated with a high number of HRDs was predicted to respond poorly to anti-VEGF treatment.12,13 In our patient, after initial IVB only a slight reduction in the number of HRDs was observed, After the second injection OD and the first injection OS, the number of HRDs increased.
In DME or macular edema due to retinal vein occlusion with multiple HRDs on OCT, dexamethasone implants (Ozurdex; Allergan, Dublin, Ireland) were found more effective compared to anti-VEGF.12,13 In our patient, because macular edema was not responsive to IVB and was associated with multiple HRDs, we thought that inflammation mainly contributed to the development of macular edema and intravitreal steroids might be effective. As the cost of the dexamethazone implant was not covered by our social security system in this disease, IVTA injection was performed in our patient. The complete resolution of intraretinal fluid in the macula and reduction in the number of HRDs were achieved after this treatment, suggesting a vasoactive and inflammatory retinal process going on in this particular patient with WBS.
Atypical retinal vessels, hemorrhage next to the optic disc, and epipapillary connective tissue have been reported in WBS.14 In our patient, en face images of OCTA distinguished the atypical vessels from retinal vessels. It can, thus, be suggested that PVL might be an underdiagnosed finding in this syndrome before the advent of OCTA. Further research, aided by the advances in ophthalmic imaging systems, might clarify the pathophysiology and refine the treatment of macular edema in this syndrome.
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- Degenhart W, Brown GC, Augsburger JJ, Magargal L. Prepapillary vascular loops. Ophthalmology. 1981;88(11):1126–1131. doi:10.1016/S0161-6420(81)34894-5 [CrossRef]
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- Cunningham MA, Edelman JL, Kaushal S. Intravitreal steroids for macular edema: The past, the present, and the future. Surv Ophthalmol. 2008;53(2):139–149. doi:10.1016/j.survophthal.2007.12.005 [CrossRef]
- Turgut B, Yildirim H. The causes of hyperreflective dots in optical coherence tomography excluding diabetic macular edema and retinal venous occlusion. Open Ophthalmol J. 2015;31(9):36–40. doi:10.2174/1874364101509010036 [CrossRef]
- Bolz M, Schmidt-Erfurth U, Deak G, et al. Optical coherence omographic hyperreflective foci: A morphologic sign of lipid extravasation in diabetic macular edema. Ophthalmology. 2009;116(5):914–920. doi:10.1016/j.ophtha.2008.12.039 [CrossRef]
- Coscas G, De Benedetto U, Coscas F, et al. Hyperreflective dots: A new spectral-domain optical coherence tomography entity for follow-up and prognosis in exudative age-related macular degeneration. Ophthalmologica. 2013;229(1):32–37. doi:10.1159/000342159 [CrossRef]
- Vujosevic S, Torresin T, Bini S, et al. Imaging retinal inflammatory biomarkers after intravitreal steroid and anti-VEGF treatment in diabetic macular oedema. Acta Ophthalmol. 2017;95(5):464–471. doi:10.1111/aos.13294 [CrossRef]
- Hwang HS, Chae JB, Kim JY, Kim DY. Association between hyperreflective dots on spectral-domain optical coherence tomography in macular edema and response to treatment. Invest Ophthalmol Vis Sci. 2017;58(13):5958–5967. doi:10.1167/iovs.17-22725 [CrossRef]
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