The bestrophinopathies are a spectrum of inherited retinal dystrophies caused by mutations in the Bestrophin1 (BEST1) gene. The spectrum of variants within BEST1 is widely variable and the vast majority are heterozygous missense mutations inherited in an autosomal dominant pattern.1
In 2008 Burgess et al.2 reported a series of patients with biallelic mutations in BEST1 and defined this condition as a distinct category of bestrophinopathy by coining the term autosomal recessive bestrophinopathy (ARB). Clinical presentation of ARB includes multifocal vitelliform deposits with subretinal fluid, hypermetropia, and angle closure glaucoma.2 Choroidal neovascularization (CNV) is an uncommon complication of bestrophinopathies and, to the best of our knowledge, only five cases of ARB complicated by CNV have been reported.3–7
We reviewed the clinical records and multimodal retinal imaging of patients with molecularly confirmed ARB complicated by CNV in two tertiary referral centers, namely San Raffaele Scientific Institute in Milan and Moorfields Eye Hospital in London. We included two patients; one patient received anti-vascular endothelial growth factor (VEGF) treatment and the other was monitored by observation.
A 9-year-old girl presented to San Raffaele Scientific Institute with a reduction in the vision of the right eye (OD). She had been diagnosed as having ARB 3 years prior. At that time, electrooculography (EOG) showed an Arden ratio of 2.38 OD and 3.00 in the left eye (OS). Molecular genetic testing revealed two nonsense disease-causing mutations in BEST1: c.598 C>T, p.Arg200* and c.658 C>T, p.Gln220* (the latter being novel).
At presentation, best-corrected visual acuity (BCVA) was 20/50 OD and 20/500 OS. Fundus examination revealed retinal thickening at the right macula and extensive macular scarring OS. Multimodal imaging including fundus autofluorescence and optical coherence tomography (OCT) was consistent with ARB.2 EOG was repeated and showed significant reduction of light rise in both eyes (Arden ratio OD : 1.20; OS : 1.40).
Both parents were examined and had normal fundus appearance in both eyes.
Fluorescein angiography and indocyanine green angiography showed an active CNV OD, which was confirmed on OCT angiography (OCTA) (Figure 1). The patient received two monthly intravitreal injections of ranibizumab (Lucentis; Genentech, South San Francisco, CA) (0.5 mg per 0.05 mL). One month after the second injection, the BCVA was 20/63 OD, and OCTA showed response of the CNV to the treatment by revealing decreased vascular flow signal within the neovascular network (Figure 2). After 2 years of follow-up and seven further intravitreal injections of ranibizumab, BCVA in the right eye dropped to 20/200 because of recurrent CNV exudation and progressive retinal scarring; two satellite progressive fibrotic lesions were observed temporal to the macula (Figure 3).
Case 1. Multimodal imaging of autosomal recessive bestrophinopathy of the right eye at presentation. (a) Color fundus photograph. (b) Fundus autofluorescence (FAF) shows a foveal hyperautofluorescent ring with speckled hyper-FAF material temporal to the fovea. (c, d) Optical coherence tomography (OCT) angiography of the outer retina (c) and choriocapillaris (d) shows the presence of the choroidal neovascularization (CNV). (e, f) Fundus fluorescein angiography shows early hyperfluorescence (e) with late leakage (asterisk) of fluorescein (f). (g, h) Indocyanine green angiography shows the presence of the neovascular network (arrow) in the early frame (g) and leakage of indocyanine in the late frame (h). (i) Spectral-domain OCT shows subfoveal ill-defined subretinal hyperreflective material.
Multimodal imaging of autosomal recessive bestrophinopathy of the right eye after two anti-vascular endothelial growth factor injections. (a) Color fundus photograph shows presence of fibrotic macular scar tissue. (b) Fundus autofluorescence shows decreased autofluorescence in correspondence with the scar tissue. (c, d) Optical coherence tomography (OCT) angiography of the outer retina (c) and choriocapillaris (d) shows decreased vascular flow within the neovasculat network. (e) Spectral-domain OCT shows consolidation of the subretinal hyperreflective material.
Case 1. (a–e) Color fundus photograph (CFP) taken at presentation (a), and at months 3, 6, 12, and 24 (b, c, d, and e, respectively) shows chronologic progression of subretinal fibrosis in the right eye during 2 years of anti-vascular endothelial growth factor treatment. (f) CFP shows extensive subretinal fibrosis in the left eye at presentation.
A 12-year-old boy presented to Moorfields Eye Hospital with visual acuity (VA) deterioration OS. BCVA was 20/20 OD and 20/50 OS. Fundus examination revealed symmetrical pigmentary macular changes with a retinal hemorrhage in the left eye. Fluorescein angiography was undertaken 3 weeks later and revealed an active CNV OS (Figure 3). However, BCVA OS had spontaneously improved to 20/32 and observation was decided. During follow-up, the retinal hemorrhage resolved and a further spontaneous improvement in BCVA was observed. Full-field electroretinography was normal but EOG revealed absent light rise OD (Arden ratio 1.00) and significant reduction of light rise OS (Arden ratio 1.10). Molecular genetic testing revealed biallelic disease-causing mutations in BEST1: c.1066C>T, p.Arg356X and c.602T>C, p.Ile201Thr, which were consistent with diagnosis of ARB. After 6 years of follow-up, BCVA was 20/20 OD and 20/20 OS, and no recurrence of CNV activity was observed (Figure 4).
Case 2. Multimodal retinal imaging of autosomal recessive bestrophinopathy of the left eye at presentation (a–d) and after 6 years of follow-up (e, f). (a) Color fundus photograph shows macular pigment abnormalities and retinal hemorrhage. (b) Fluorescein angiography shows leakage of the fluorescein. (c) Fundus autofluorescence (FAF)imaging shows blockage of the background autofluorescence by the retinal hemorrhage surrounded by speckled hyperautofluorescent changes; (d) Spectral-domain optical coherence tomography (SD-OCT) shows ill-defined subretinal hyperreflectivity; (e) FAF after 6 years of follow-up; (f) SD-OCT shows consolidation of the subretinal hyperreflectivity.
Given the limited number of cases reported, little is known about the natural course and the clinical outcome of CNV in ARB. Indeed, anti-VEGF therapy has been reported in only a few cases of ARB complicated by CNV.3–5 In 2011, Iannaccone et al.3 first reported a case of ARB complicated by CNV in a 6-year-old girl who was successfully treated with serial bilateral intravitreal injections of bevacizumab (Avastin; Genentech, South San Francisco, CA).
Madhusudhan el al.4 described sustained improvement of VA after three monthly intravitreal injections of ranibizumab in a 26-year-old woman affected by ARB-related CNV despite persistence of macular schisis-like changes not related to CNV activity.
Similarly, Hussain et al.5 reported good visual outcome and good anatomical response in a 9-year-old female patient who was treated with three intravitreal injections of bevacizumab for a CNV complicating ARB with no recurrence of CNV activity.
By contrast, Moreira et al.6 reported successful surgical removal of CNV after failure of anti-VEGF treatment in a case of ARB complicated by CNV.
Khan et al.7 recently described clinical outcome of 12 patients with BEST1-related CNV; seven patients with Best disease were treated with anti-VEGF therapy and the remaining cases, including one case of ARB, were monitored by observation. Although they reported a high rate of spontaneous recovery, they concluded that anti-VEGF treatment was associated with better functional outcomes than observation alone.7 Our Case 2 was originally included in this series,7 but we herein first report detailed clinical history and retinal imaging.
Of note, it has been observed that CNV appears relatively early in the disease course of bestrophinopathies.3,7 In this scenario, CNV may go unnoticed as demonstrated by our Case 1, who came to our attention when she had already developed extensive retinal scarring OS.
Despite anti-VEGF therapy, VA deteriorated in the treated eye of Case 1 due to progressive subretinal fibrosis, and this may indicate that VEGF pathway blockade may not be sufficient to limit scar formation resulting from the CNV in some of these patients.
Of note, we report a novel mutation in the BEST1 gene in the first documented case of ARB complicated by CNV from Italy. We also report use of OCTA in this condition. Detection of CNV in bestrophinopathies may be challenging as the overlying vitelliform lesion can partially or completely obscure the CNV. Indeed, the leakage of the CNV on fluorescein angiography may be obscured by staining of the subretinal deposit. OCTA is a recent noninvasive imaging technique with the advantage of detecting CNV without injection of fluorescein. In a recent study conducted by Guduru et al.,8 it was shown that OCTA seemed to be a better alternative to fluorescein angiography to study the presence of CNVs, being able to overcome the challenges due to vitelliform deposits.
In view of these observations, we recommend that ARB requires regular follow-up with use of multimodal imaging including OCTA, which is able to detect the CNV and monitor response to treatment. However, interpretation of OCTA findings should take into account potential artifacts such as segmentation errors or shadowing from the consolidation of the overlying hyperreflective material. We acknowledge that such artifacts might have affected our judgement on the CNV activity of Case 1 with resulting undertreatment.
In summary, our report showed that CNV complicating ARB may have a variable course with a wide range of severity, including spontaneous regression and progressive subretinal fibrosis. Future studies on multimodal imaging and genotype-phenotype correlations may help to identify the subset of patients with bestrophinopathy-related CNV who may benefit most from early intervention with anti-VEGF therapy.