Best macular dystrophy (BMD) is an autosomal dominant macular dystrophy associated with alterations in the BEST1 gene (OMIM # 607854). BMD generally appears in childhood with a yellowish yolk-like lesion in the macula and progresses through various stages: vitelliform, pseudohypopyon, vitelliruptive (scrambled egg), atrophic, and cicatricial. The most severe complication is the development of secondary choroidal neovascularization (CNV). Although treatment of BMD young patients with CNV is still controversial, several treatments have been reported in literature: photodynamic therapy (PDT), laser photocoagulation, and intravitreal injection of anti-VEGF drugs.1 Conventional fluorescein angiography (FA), is the current gold standard for diagnosing of the CNV. Optical coherence tomography angiography (OCTA) provides a new, noninvasive imaging modality to study the morphology of neovascular membranes and vascular structures of CNV.2 In this article we reported the onset of a CNV in a young patient with BMD using OCTA, and we described its changes after PDT.
An 11-year-old male was referred to the Eye Clinic of the University of Florence for bilateral macular dystrophy. The parents, evaluated at our center, did not show any funduscopic abnormalities, whereas the paternal uncle presented vitelliform macular lesion in both eyes, suggesting incomplete penetrance for the father of the patient. The electrooculogram examination of the patient showed abnormal responses: Arden ratio was 1.51 in the right eye (OD) and 1.28 in the left eye (OS). The child complained visual loss and metamorphopsia in OD 15 days before. Best-corrected visual acuity (BCVA) was 20/40 OD and 20/20 OS. Anterior segment examination was unremarkable in both eyes, whereas funduscopic examinations revealed vitelliform disc in the vitelliruptive stage at the posterior pole in both eyes. In the right eye, a macular hemorrhage was present. FA showed a well-demarcated macular hyperfluorescence lesion with late leakage suspicious for a classic CNV (type 2 CNV) OD (Figure 1). The lesion OS did not show any leakage, but staining was suggestive of no active CNV. OCT revealed bilateral macular neurosensory retinal detachment with subretinal hyperreflective material. OCT scan OD showed disorganization of the retinal pigment epithelium (RPE)–choriocapillaris complex corresponding to the CNV (Figure 1). OCTA scans demonstrated a large, tangled, and well-demarcated vascular network at the outer retinal (OR) and choriocapillaris (CC) layers. A diagnosis of CNV was made, and we performed standard-fluence PDT. Twenty days later, BCVA OD improved (20/30), and the macular hemorrhage was significantly reduced. OCTA showed regression of the vascular network both in the OR and CC layers with a significant reduction of the internal anastomosis and connection in absence of ischemic complication of the choriocapillaris (Figures 2 and 3). More specifically, we reported a quantitative analysis of the CNV before and after PDT using ImageJ software V1.47 (NIH, Bethesda, MD) (Figure 3). We measured CNV vessel area, CNV membrane area and vessel density pre- and post-treatment.
Color fundus (A) and red-free (B) photographs of the right eye show vitelliform lesion centered on the fovea and subretinal hemorrhage. The early phase (C) and the late-phase (D) angiogram of fluorescein angiography (FA) (Zeiss Retinograph; Carl Zeiss, Dublin, CA) reveal the choroidal neovascularization showing an early, well-demarcated hyperfluorescence, which increases in intensity and size in late phase. Blocked fluorescence corresponding to the subretinal hemorrage. Optical coherence tomography angiography (OCTA) scans at the level of outer retinal (E) and choriocapillaris (F) layer (Topcon Medical Systems, Oakland, NJ) show a large, tangled, and well-demarcated vascular network in a “lacy-wheel” pattern (green circle) with loop and arcades at the termini of the lesion and perilesional hyporeflective halo. The area of the neovascular lesion manually outlined using a free-hand selection tool included in the OCTA at the diagnosis was 670,781 μm2. (G) The overlap of the OCTA outer retinal layer (E) and FA late-stage angiogram (D) showing leakage of neovascular network. In particular, in (C), it is possible to recognize the neovascular membrane in the early-phase angiogram (green circle). Swept-source OCT scans (H, I) show serous macular detachment, hyperreflectivity of vitelliform material, and blood in the subretinal space. In particular, OCT examination (I) reveals hyperreflective alterations correlated with the presence of neovessels. Central macular thickness at the CNV diagnosis was 339 µm.
Color fundus (A) and red-free imaging (B) of the right eye after photodynamic therapy (PDT). At the optical coherence tomography angiography (OCTA) scans, the neovascular membrane appears smaller with clearly defined margins and significant reduction of the internal anastomosis and connection (area of the vascular lesion manually outlined using a free-hand selection tool included in the OCTA after PDT was 269,385 μm2) (C,D). (E) The overlap of color fundus image and image (C) showing partial fibrous evolution of the neovascular membrane. At structural OCT scans, intraretinal fluid resolves with persistence of subfoveal hyperreflective material after PDT (F,G). The post-PDT central macular thickness was 248 µm.
(A, B, C, D) Quantitative analysis of choroidal neovascularization (CNV) pre- (A,B) and post-photodynamic therapy (PDT) (C,D). (A, B) These images show the flow metrics of the CNV vessel area (0.205 mm2) and CNV membrane area (0.643 mm2), respectively, pre-PDT treatment. Vessel density (ratio of the area occupied by the vessels to the total area of the lesion) pre-treatment was 0.318. (C, D) These images show CNV vessel area (0.07 mm2) and CNV membrane area (0.250 mm2), respectively, post-PDT treatment. Vessel density post-treatment was 0.280. (E, G) Outer retina swept-source optical coherence tomography angiography scans (3 mm × 3 mm) and (F, H) co-registered conventional B-scans with flow overlay pre- (E,F) and post-PDT treatment (G, H). (E) This image shows a well-circumscribed neovascular network in the subfoveal area with a “lacy-wheel” shape, several large central vessels branching into smaller vessels toward the periphery, anastomoses and loops surrounded by an hypointense halo, and the corresponding abnormal flow above the retinal pigment epithelium, consistent with a type 2 CNV (F). (G) This image shows the changes of the CNV morphology: CNV appears decreased in size with reduction of the internal anastomoses. (H) This image shows the reduction of the flow signal post PDT treatment.
CNV is a rare complication of BMD in children.3 In our case, genetic testing was not available, and this is a limitation of our study. However, the clinical picture and the family history were consistent with a diagnosis of BMD complicated by a CNV. FA provides indirect evidence of neovascular membranes by leakage of dye from the suspected subretinal lesion. However, these membranes can be difficult to visualize due to the staining of the vitelliform lesions which can partially or completely obscure the leakage of CNV at the angiographic exam.1 OCTA seems an attractive alternative to traditional angiography in children to detect CNV: it does not require intravenous injection of a dye, is much faster, and may be repeated frequently without side effects. Furthermore OCTA appears to be a better alternative than FA to study vascular abnormalities and to detect the presence of choroidal neovascular complex in BMD.3,4 In fact previous works reported that eyes with Best disease have abnormal foveal avascular zone, patchy vascularity loss in the superficial, and deep layers of the retina and capillary dropout with a hyporeflective center in CC layer at OCTA.4,5 Another advantage of OCTA is the lack of blurring of CNV margins due to dye leakage, which allows for the full extent and characteristics of CNV showing different morphology of neovascular membranes.3,4,6,7 In our case, OCTA was useful in the diagnosis demonstrating a well-defined pathological vascular network. There are few reports on specificity and sensitivity of OCTA in detecting CNV in patients affected with pseudovitelliform macular dystrophy.8,9 Lupidi et al. showed high sensitivity and specificity of CNV detection on OCTA (80% and 100%, respectively). The therapeutic approach to pediatric CNV is controversial due to the lack of evidence-based treatment protocol. Thanks to the good results of our clinical experience in children,1 and to the experience of other authors,10–12 we performed standard-fluence PDT in our patient. Even if several works suggest that CNV in vitelliform macular dystrophy can be successfully treated with intravitreal injection of anti-vascular endothelial growth factor (VEGF) drugs,13–17 very little information is available about single or repeated intravitreal injection of anti-VEGF drugs in pediatric population regarding long-term ocular or systemic side-effects.18,19 In fact, a single dose of intravitreal anti-VEGF is not always effective in inducing morphological and functional improvement in a juvenile suffering from subfoveal CNV secondary to Best disease.13,20 Furthermore, intravitreal injection in pediatric population usually requires sedation, analgesia, or general anesthesia to optimize safety and reduce the risk of iatrogenic cataract or damage to the sclera. After PDT treatment, the quantitative analysis demonstrated the reduction of the CNV size and flow (Figure 3). Although we reported a single case with a short-term follow-up, we showed that OCTA is the best imaging technique for precise diagnosis and follow-up of choroidal neovascularization in children affected with BMD.
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