Perspectives and Update on the Global Shortage of Verteporfin (Visudyne®).

An ongoing global shortage of verteporfin (Visudyne®) limits the treatment possibilities for several chorioretinal diseases, including central serous chorioretinopathy, choroidal hemangioma, and polypoidal choroidal vasculopathy. Verteporfin is required to perform photodynamic therapy in these ocular diseases. Therefore, the current situation has a substantial impact on eye care worldwide. The worldwide supply of verteporfin appears to be manufactured by a single factory, which is situated in the United States. The distribution of verteporfin is done by different companies for different regions of the world. Official communication on the shortage by the responsible companies has been scarce and over the past years several promises with regards to resolution of the shortage have not been fulfilled. The delivery of new batches of verteporfin is at irregular intervals, unpredictable, and may not be fairly balanced between different regions or countries in the world. To ensure a fair distribution of available verteporfin within a country, several measures can be taken. In the Netherlands, a national committee, consisting of ophthalmologists, is in place to arrange this. On the European level, the European Union and European Medicine Agency have plans to monitor medicine shortages more closely and to intervene if necessary. With a more intensified monitoring and regulation of medicine supplies, future impending shortages may be prevented. Remarkably, the amount of medicine shortages is increasing, having a significant and sometimes irreversible impact on patient care. Thus, efforts should be undertaken to minimize the consequences and, whenever possible, to prevent future medicine shortages.

Central serous chorioretinopathy: An evidence-based treatment guideline.

Central serous chorioretinopathy (CSC) is a relatively common disease that causes vision loss due to macular subretinal fluid leakage and it is often associated with reduced vision-related quality of life. In CSC, the leakage of subretinal fluid through defects in the retinal pigment epithelial layer's outer blood-retina barrier appears to occur secondary to choroidal abnormalities and dysfunction. The treatment of CSC is currently the subject of controversy, although recent data obtained from several large randomized controlled trials provide a wealth of new information that can be used to establish a treatment algorithm. Here, we provide a comprehensive overview of our current understanding regarding the pathogenesis of CSC, current therapeutic strategies, and an evidence-based treatment guideline for CSC. In acute CSC, treatment can often be deferred for up to 3-4 months after diagnosis; however, early treatment with either half-dose or half-fluence photodynamic therapy (PDT) with the photosensitive dye verteporfin may be beneficial in selected cases. In chronic CSC, half-dose or half-fluence PDT, which targets the abnormal choroid, should be considered the preferred treatment. If PDT is unavailable, chronic CSC with focal, non-central leakage on angiography may be treated using conventional laser photocoagulation. CSC with concurrent macular neovascularization should be treated with half-dose/half-fluence PDT and/or intravitreal injections of an anti-vascular endothelial growth factor compound. Given the current shortage of verteporfin and the paucity of evidence supporting the efficacy of other treatment options, future studies-ideally, well-designed randomized controlled trials-are needed in order to evaluate new treatment options for CSC.

Incidence and Risk Factors of Second Eye Involvement in Myopic Macular Neovascularization.

PURPOSE: To report the cumulative incidence and risk factors of second eye involvement after diagnosis of myopic macular neovascularization (MNV) in the first eye. DESIGN: Retrospective analysis of longitudinal data from a tertiary hospital in the Netherlands. PARTICIPANTS: Patients with high myopia (spherical equivalent [SE] ≤ - 6 diopters [D]), of European ethnicity, who were diagnosed with active MNV lesion in 1 eye between 2005 and 2018. Fellow eyes were free of MNV or macular atrophy at baseline, and data were collected on the SE, axial length, and presence of diffuse or patchy chorioretinal atrophy and lacquer cracks. METHODS: Incidence rate and 2-, 5-, and 10-year cumulative incidences were calculated; hazard ratios (HRs) of second eye involvement were analyzed for potential risk factors using Cox proportional hazard models. MAIN OUTCOMES MEASURES: Incidence of second eye involvement after onset of myopic MNV in the first eye. RESULTS: We included 88 patients over a period of 13 years with a mean age of 58 ± 15 years, mean axial length of 30 ± 1.7 mm and SE -14 ± 4 D at baseline. Twenty-four fellow eyes (27%) developed a myopic MNV during follow-up. This resulted in an incidence rate of 4.6 (95% confidence interval [CI], 2.9-6.7) per 100 person-years and a cumulative incidence of 8%, 21%, and 38% at 2, 5, and 10 years, respectively. Mean time until MNV development in the fellow eye was 48 ± 37 months. Patients aged < 40 years at the initial presentation had a 3.8 times higher risk of bilateral myopic MNV (HR, 3.8; 95% CI, 1.65-8.69; P = 0.002). The presence of lacquer cracks in the second eye seemed to increase risk, but this did not reach statistical significance (HR, 2.25; 95% CI, 0.94-5.39; P = 0.07). CONCLUSIONS: Our study of high myopes of European descent shows very similar incidence rates for second eye myopic MNV compared with Asian studies. Our findings substantiate the importance for clinicians to monitor closely and create awareness, especially in younger patients. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

LONG-TERM TREATMENT OUTCOMES AFTER BEVACIZUMAB THERAPY FOR MACULAR NEOVASCULARIZATION IN WHITE PATIENTS WITH HIGH MYOPIA.

PURPOSE: To report long-term treatment outcomes of intravitreal bevacizumab in myopic macular neovascularization (MNV). METHODS: Retrospective analysis of longitudinal, clinical data of patients with high myopic MNV treated with intravitreal bevacizumab. One-hundred and seventeen eyes of 106 patients were followed from first injection up to 12 years. Outcome measures were best-corrected visual acuity change during follow-up and myopic MNV recurrence. RESULTS: Mean (±SD) baseline best-corrected visual acuity (0.56 ± 0.46 logMAR, 20/80) significantly improved after first treatment (0.33 ± 0.33, 20/50, P < 0.001). At 4 years (n = 86), best-corrected visual acuity was no longer significantly better than at baseline (0.55 ± 0.57, P = 0.30) and continued to deteriorate to 0.84 ± 0.76 (20/125) at 10 years (n = 27). Of the 27 eyes (23%) who reached 10 years of follow-up, 53% developed MNV-related chorioretinal atrophy. The cumulative incidence of recurrent myopic MNV was 34% at 2 years and 59% at 5 years. Best-corrected visual acuity decrease in eyes with or without recurrent MNV was similar ( P = 0.58). Patchy chorioretinal atrophy (hazard ratio 3.0, P = 0.02) and subfoveal MNVs (hazard ratio 2.5, P = 0.048) were significantly associated with recurrent MNV. CONCLUSION: This retrospective myopic MNV study revealed that visual improvement after intravitreal bevacizumab injections was not maintained over time. Macular neovascularization recurrences occurred frequently but did not alter the already poor visual prognosis.

Prevalence and Severity of Diabetic Retinopathy in Patients with Macular Telangiectasia Type 2.

PURPOSE: To study the prevalence and severity of diabetic retinopathy (DR) in patients with macular telangiectasia type 2 (MacTel 2). DESIGN: Retrospective case series. PARTICIPANTS: Patients with a diagnosis of MacTel 2 treated at the Rotterdam Eye Hospital or Erasmus Medical Center between 2014 and 2018 were included. METHODS: The following information was retrieved from patient files: demographics, history of diabetes mellitus and hypertension, presence of DR, and severity of DR, that is, mild, moderate, severe, or proliferative. Presence of diabetic macular edema (DME) was assessed using OCT. MAIN OUTCOME MEASURES: Presence and severity of DR. RESULTS: Two hundred six eyes of 103 patients were included. At the onset of MacTel 2, the mean age was 61 years (standard deviation [SD], 9.8 years) and 64 (62%) were women. Mean follow-up was 71 months (SD, 60 months). Diabetes mellitus type 2 was present in 50 patients (49%) and hypertension was present in 47 patients (46%). Mild DR was present in 22 eyes (11%), of which 14 eyes (7%) showed signs at baseline and 8 eyes (4%) showed signs at a later time during follow-up. Ten eyes (5%) demonstrated remission of mild DR during follow-up. Both eyes (1%) in 1 patient progressed to moderate DR. Severe DR, proliferative DR, and DME did not occur. CONCLUSIONS: Although diabetes mellitus was highly prevalent among MacTel 2 patients, no patients showed severe or proliferative DR or DME. These findings suggest that MacTel 2 could have a protective effect on the progression of DR. We hypothesize that our results may be explained by the role of Müller cells in the development of MacTel 2 and DR, and therefore a link between both diseases warrants additional studies.

ANATOMICAL CHANGES ON SEQUENTIAL MULTIMODAL IMAGING IN PERIFOVEAL EXUDATIVE VASCULAR ANOMALOUS COMPLEX.

PURPOSE: To report a series of 21 patients with perifoveal exudative vascular anomalous complex (PEVAC) and to investigate the anatomical changes over time. METHODS: We conducted a retrospective study. Clinical data of consecutive patients, presenting at the Rotterdam Eye Hospital between 2014 and 2019, were analyzed. The data collected included best-corrected visual acuity, fundus photography, optical coherence tomography (OCT), OCT-angiography, fluorescence angiography, and indocyanine green angiography. RESULTS: We included 21 patients with a PEVAC lesion with a mean follow-up of 24.3 ± 13.8 months (range, 9-46 months). Patients with PEVAC were on average 75.3 ± 11.1 years (range, 53-90 years). The large perifoveal vascular aneurysmal abnormality was associated with small retinal hemorrhages in six patients and hard exudates in three patients. The PEVAC lesion was associated with intraretinal cystic spaces on OCT in 15 patients. Twelve of 21 patients showed no changes in cystic spaces on OCT during follow-up: 9 patients had stable cystic spaces and 3 patients had no cystic spaces. In contrast, in 9 of 21 patients, we observed changes in cystic spaces on OCT during follow-up. In two patients, cystic spaces appeared during follow-up, and in seven patients, there was a spontaneous resolution of cystic spaces. In three of these seven patients, the PEVAC lesion completely disappeared. Two patients, with stable intraretinal cystic spaces on OCT, were treated with intravitreal injections of anti-vascular endothelial growth factor without improvement. CONCLUSION: Perifoveal exudative vascular anomalous complex is an idiopathic perifoveal retinal vascular abnormality that is associated with intraretinal cystic spaces. These intraretinal cystic spaces associated with a PEVAC lesion, and even the PEVAC lesion itself, can have a spontaneous resolution over time.

SEROUS MACULAR DETACHMENT IN BEST DISEASE: A Masquerade Syndrome.

PURPOSE: To describe the clinical and multimodal imaging findings of a series of cases of serous macular detachment (SMD) caused by Best disease (BD) masquerading as neovascular age-related macular degeneration or central serous chorioretinopathy that were inappropriately treated with intravitreal anti-vascular endothelial growth factor or laser therapy. This study will also present data to support age-related progressive choroidal thickening in BD patients, which may play a role in the development of SMD in this population. METHODS: Clinical examination and multimodal imaging findings, including color fundus photography, spectral-domain optical coherence tomography, fundus autofluorescence, fluorescein angiography, and optical coherence tomography-angiography, were reviewed and analyzed. Subfoveal choroidal thickness was also formally measured, and an age-related choroidal thickness analysis was performed and compared with a normal population. RESULTS: Twenty-six eyes of 13 patients (5 women) were included. Median age was 44 years. Nine patients presented with a history of SMD and subretinal fluid recalcitrant to various therapies, including intravitreal anti-vascular endothelial growth factor injections and photodynamic therapy. Best disease was subsequently diagnosed genetically in six patients and by detailed family history in seven. Mean logarithm of the minimum angle of resolution best-corrected visual acuity for all 26 eyes at last follow-up was +0.36 (Snellen equivalent of 20/46). Subfoveal choroidal thickness positively correlated with age for our cohort, increasing linearly at a rate of 25.6 µm per decade (R = 0.64; P < 0.001). Choroidal neovascularization was identified in four eyes on optical coherence tomography angiography, but these eyes did not respond to anti-vascular endothelial growth factor treatment. CONCLUSION: The diagnosis of BD should be considered in patients presenting with SMD and recalcitrant subretinal fluid masquerading as neovascular age-related macular degeneration or chronic central serous chorioretinopathy to avoid unnecessary treatment procedures. The positive correlation of subfoveal choroidal thickness with age in BD patients may be a factor in the pathogenesis and development of SMD in this population. Recognizing the multimodal imaging features of SMD associated with BD, described in detail in this study, will guide practitioners to the accurate diagnosis of BD and reduce the risk of unnecessary intraocular procedures with potential complications.

CLINICAL CHARACTERISTICS AND OUTCOME OF POSTERIOR CYSTOID MACULAR DEGENERATION IN CHRONIC CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To assess clinical characteristics and visual outcome in chronic central serous chorioretinopathy patients with posterior cystoid retinal degeneration (PCRD). METHODS: Patients' medical records were reviewed retrospectively in 62 cases (83 eyes, mean age = 59 years, 88% male). Data were collected at central serous chorioretinopathy diagnosis, at PCRD manifestation, and at final visit. All treatment modalities were reviewed. Main outcome measures were treatment efficacy in achieving PCRD resolution, and final best-corrected visual acuity. RESULTS: In 63 eyes (76%), subretinal fluid was present at first PCRD manifestation, whereas fluorescein angiography showed active focal or diffuse leakage in 65 eyes (78%). Seventy-six eyes (81%) received treatment, and PCRD had resolved completely in 31 eyes (37%) at the final visit. Photodynamic therapy was most successful in achieving a complete PCRD resolution. Best-corrected visual acuity did not improve, even after complete PCRD resolution (mean baseline best corrected visual acuity = 69 ± 19, and mean final best corrected visual acuity = 67 ± 20 ETDRS letters [20/40 and 20/50 in Snellen equivalent respectively], P = 0.354). CONCLUSION: Posterior cystoid retinal degeneration is a relatively common finding in chronic central serous chorioretinopathy, which is often accompanied by active subretinal fluid leakage. Treatment may be beneficial to stop the subretinal fluid leakage component, but is less likely to result in a complete PCRD resolution and/or a best-corrected visual acuity improvement.

Treatment Effects in Retinal Angiomatous Proliferation Imaged with OCT Angiography.

PURPOSE: This prospective case series is aimed at exploring optical coherence tomographic angiography (OCT-A) as a treatment monitoring tool in patients treated for retinal angiomatous proliferation (RAP). METHODS: Twelve treatment-naïve RAP patients were included, with a median age of 79 years (range 65-90). Patients were imaged with an experimental 1,040-nm swept-source phase-resolved OCT-A instrument before and after treatment. Treatment consisted of either intravitreal bevacizumab or triamcinolone injections with or without photodynamic therapy (PDT). Abnormal blood flow after treatment was graded as increased, unchanged, decreased, or resolved. RESULTS: OCT-A images before and after treatment could be obtained in 9 patients. The median follow-up period was 10 weeks (range 5-19). After various treatments, the RAP lesion resolved in 7 patients, in 1 patient the OCT-A depicted decreased flow in the lesion, and 1 patient showed unchanged abnormal blood flow. Monotherapy with intravitreal bevacizumab injections resolved RAP in 1 out of 2 patients. Combined therapy of bevacizumab with PDT resolved RAP in 6 out of 7 patients. CONCLUSIONS: OCT-A visualized resolution of abnormal blood flow in 7 out of 9 RAP patients after various short-term treatment sequences. OCT-A may become an important noninvasive monitoring tool for optimizing treatment strategies in RAP patients.

Clinical spectrum of severe chronic central serous chorioretinopathy and outcome of photodynamic therapy.

PURPOSE: To describe a spectrum of severe chronic central serous chorioretinopathy (cCSC) cases and their response to photodynamic therapy (PDT). PATIENTS AND METHODS: A total of 66 patients (81 eyes) with active severe cCSC were studied, and their response to PDT was compared with a control group consisting of 35 active cCSCs (37 eyes) that did not display characteristics of severity. Best-corrected visual acuity (BCVA) and complete resolution of subretinal fluid (SRF) were considered as main outcome measures. RESULTS: In severe cCSC cases, we found cumulative areas of diffuse atrophic retinal pigment epithelium alterations in 48 eyes (59%), multiple "hot spots" of leakage in 36 eyes (44%), posterior cystoid retinal degeneration in 25 eyes (31%), and 13 eyes (16%) had a diffuse leakage on fluorescein angiography. After PDT treatment, BCVA increased in both groups, from 66 to 72 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters in the case group (P<0.001), and from 78 to 82 ETDRS letters in the control group (P<0.001). SRF had resolved completely in 87% of severe cCSC cases and 95% of controls at final follow-up visit. CONCLUSION: A spectrum of severe cCSC exists, and PDT seems to be an effective treatment in both severe cCSC and nonsevere cCSC in terms of resolution of SRF. Final BCVA shows a significant improvement in both groups after PDT treatment.

Clinical characteristics and long-term visual outcome of severe phenotypes of chronic central serous chorioretinopathy.

PURPOSE: The aim of this study was to investigate disease onset and disease progression in patients with severe chronic central serous chorioretinopathy (cCSC). PATIENTS AND METHODS: The medical records of 143 cCSC patients (199 eyes) were reviewed. All cases had visual complaints for >6 months and showed signs of a severe disease phenotype on optical coherence tomography (OCT) and fluorescein angiography (FA). Clinical presentation at onset was evaluated, together with disease progression on multimodal imaging and final treatment outcome. RESULTS: Twenty-eight cases (14%) had a documented history of an acute episode of CSC, whereas 145 cases (73%) showed pre-existing features of chronicity already at first presentation. The first clinical presentation could not be evaluated in 13% of cases. Best-corrected visual acuity (BCVA) was 70 ± 18 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters at onset and 70 ± 22 ETDRS letters at final visit (p = 0.770). Among all studied cases, 173 eyes (87%) were treated, which resulted in complete resolution of subretinal fluid (SRF) in 76% of eyes at final visit. In eyes with fluorescein angiographic follow-up, the area of diffuse atrophic retinal pigment epithelium (RPE) abnormalities (diffuse atrophic RPE alterations [DARA]) had increased significantly in 43 eyes (68%) at final visit. CONCLUSION: CSC encompasses a clinical spectrum that includes a range of severe phenotypes, in which retinal abnormalities tend to be progressive. Nevertheless, the long-term visual acuity may remain fairly stable with treatment. Few patients with severe chronic CSC have a history of acute CSC, which could indicate that there may be pathogenetic differences between these 2 CSC variants.

Associations Between ß-Peripapillary Atrophy and Reticular Pseudodrusen in Early Age-Related Macular Degeneration.

Purpose: Choroidal thinning has been associated with reticular pseudodrusen (RPD) and ß-peripapillary atrophy (ß-PPA), which have been linked to normal-tension glaucoma (NTG). This analysis sought to determine whether RPD are independently associated with ß-PPA in early AMD patients. Secondary outcomes included the association of RPD and preexisting diagnosis of glaucoma, cup-to-disc ratio (CDR), subfoveal choroidal thickness (SFCT), and IOP. Methods: This prospective cross-sectional study examined 78 age- and sex-matched early AMD patients: 43 RPD patients (63 eyes) and 35 non-RPD patients (64 eyes). Exclusion criteria included advanced AMD, high myopia, and vitreoretinal conditions/surgery. RPD and non-RPD groups were identified by confocal scanning laser ophthalmoscopy. ß-PPA as well as CDR were graded on digital, nonstereoscopic fundus photos. SFCT was measured on spectral-domain optical coherence tomography for 69 patients (35 RPD and 34 non-RPD). IOP and glaucoma diagnosis were extracted from charts. Results: ß-PPA had a greater prevalence in RPD than non-RPD (44% vs. 19%, P = 0.002); however, this relationship was not significant when SFCT was added to the model (P = 0.150). A preexisting diagnosis of glaucoma (P = 0.156), CDR (P = 0.176), and IOP (P = 0.98) was not different between groups. Conclusions: RPD in early AMD are associated with presence of ß-PPA, but choroidal thickness is a confounder in this relationship. Because ß-PPA is a common finding in NTG, focusing on a potential shared pathway between RPD and NTG could improve the understanding of pathophysiology and expand therapies for each condition.

Three Cases of Erdheim-Chester Disease With Intraocular Manifestations: Imaging and Histopathology Findings of a Rare Entity.

PURPOSE: To report intraocular manifestations of Erdheim-Chester Disease (ECD) with multimodal imaging. DESIGN: A retrospective observational case series. METHODS: This was a multicenter case series of 3 patients with confirmed tissue diagnosis of ECD that showed intraocular manifestations and were imaged at baseline and follow-up visits. RESULTS: Intraocular manifestations are rarely observed in association with ECD. Intraocular manifestations of ECD seen on multimodal imaging include histiocytic choroidal infiltration causing choroidal lesions, complicated by recurrent serous retinal detachment (SRD). Short-term resolution of SRD was observed with ocular therapies including intravitreal injections of anti-vascular endothelial growth factor or verteporfin photodynamic therapy in combination with systemic chemotherapy therapies and oral corticosteroids; however, recurrences were common. Chorioretinal biopsy confirmed the diagnosis of ECD in 1 case, with the presence of histiocytic infiltration, fibrosis, and characteristic immunohistologic staining. In another case, with a novel ARAF positive mutation, treatment with sorafenib showed regression of the choroidal lesions and resolution of the SRD on multimodal imaging. These lesions were previously resistant to other forms of therapy. CONCLUSIONS: Rare intraocular manifestations of ECD confirmed on histopathology can be imaged with multimodal imaging. We report 3 cases, including 1 case diagnosed through histology from chorioretinal biopsy and another case associated with a novel ARAF mutation responsive to targeted therapy with sorafenib. The identification of novel somatic mutation associated with ECD enabled treatment with a new-targeted systemic agent. Multimodal imaging in these cases can also be used to monitor response to therapy.

Neovascular age-related macular degeneration without drusen in the fellow eye: clinical spectrum and therapeutic outcome.

PURPOSE: To investigate the clinical characteristics and therapeutic outcome of patients with neovascular age-related macular degeneration (nAMD) in 1 eye, without drusen in the fellow eye. PATIENTS AND METHODS: Medical records of 381 patients were analyzed to identify the cases. The main outcomes included Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) and change in central retinal thickness (CRT). These parameters were reviewed at baseline, first follow-up visit, and after 6, 12, and 24 months. RESULTS: Out of 381 patients, 29 cases (8%) were included (of whom 3 had polypoidal choroidal vasculopathy [PCV]) who were treated with anti-vascular endothelial growth factor (anti-VEGF) therapy which was supplemented by photodynamic therapy (PDT) in the PCV patients. Overall, no statistically significant change in mean BCVA was observed during follow-up. BCVA improved or remained stable (defined as a gain in BCVA, a stable BCVA, or a loss of <5 ETDRS letters) in 22 patients (76%), and 7 patients (23%) had lost ≥5 ETDRS letters at final follow-up. A gain of ≥15 ETDRS letters at final follow-up was seen in 5 patients (17%). Mean CRT had decreased significantly with 99 µm (P<0.001) at 24 months after the initial visit. CONCLUSION: There is a clinical spectrum of nAMD that is not associated with drusen in the fellow eye. Patients with nAMD without drusen in the fellow eye respond to anti-VEGF treatment and, in cases of PCV, to supplemental PDT. The pathophysiology of this spectrum of nAMD may be different from drusen-associated age-related macular degeneration.

Phase-Resolved Doppler Optical Coherence Tomographic Features in Retinal Angiomatous Proliferation.

PURPOSE: To study patients diagnosed with retinal angiomatous proliferation (RAP) based on conventional imaging techniques with phase-resolved Doppler optical coherence tomography (OCT) to detect and localize blood flow in RAP lesions; and to compare these findings to conventional imaging, which are mostly invasive and give limited information concerning intra- and transretinal blood flow. DESIGN: Single-center, consecutive observational case series. METHODS: Twelve treatment-naïve patients diagnosed with RAP based on fundus examination, fluorescein angiography, and indocyanine green angiography were included. Median age was 79 years (range 65-90). Patients were imaged with an experimental 1040 nm swept-source phase-resolved Doppler OCT instrument. Abnormal flow was defined as intraretinal neovascularization or retinal choroidal anastomosis. RESULTS: In 11 patients adequate phase-resolved Doppler OCT images were obtained showing abnormal blood flow in the RAP lesion. In 4 patients a retinal choroidal anastomosis was found, 3 patients showed intraretinal neovascularization connected with a pigment epithelial detachment, 2 patients showed only intraretinal neovascularization, and in 2 patients flow was limited to the subretinal or sub-retinal pigment epithelial space. CONCLUSIONS: Phase-resolved Doppler OCT is able to detect and localize abnormal blood flow within RAP lesions. Blood flow was mostly confined to the intraretinal structures with or without a connecting pigment epithelial detachment; in one-third of patients a retinal choroidal anastomosis was detected. The potential of angiography with phase-resolved Doppler OCT to accurately distinguish between normal and pathologic blood flow in addition to structural OCT data without invasive procedures will help to further elucidate both retinal and choroidal vascular pathologies like RAP.

Long-term effect of gene therapy on Leber's congenital amaurosis.

BACKGROUND: Mutations in RPE65 cause Leber's congenital amaurosis, a progressive retinal degenerative disease that severely impairs sight in children. Gene therapy can result in modest improvements in night vision, but knowledge of its efficacy in humans is limited. METHODS: We performed a phase 1-2 open-label trial involving 12 participants to evaluate the safety and efficacy of gene therapy with a recombinant adeno-associated virus 2/2 (rAAV2/2) vector carrying the RPE65 complementary DNA, and measured visual function over the course of 3 years. Four participants were administered a lower dose of the vector, and 8 were administered a higher dose. In a parallel study in dogs, we investigated the relationship among vector dose, visual function, and electroretinography (ERG) findings. RESULTS: Improvements in retinal sensitivity were evident, to varying extents, in six participants for up to 3 years, peaking at 6 to 12 months after treatment and then declining. No associated improvement in retinal function was detected by means of ERG. Three participants had intraocular inflammation, and two had clinically significant deterioration of visual acuity. The reduction in central retinal thickness varied among participants. In dogs, RPE65 gene therapy with the same vector at lower doses improved vision-guided behavior, but only higher doses resulted in improvements in retinal function that were detectable with the use of ERG. CONCLUSIONS: Gene therapy with rAAV2/2 RPE65 vector improved retinal sensitivity, albeit modestly and temporarily. Comparison with the results obtained in the dog model indicates that there is a species difference in the amount of RPE65 required to drive the visual cycle and that the demand for RPE65 in affected persons was not met to the extent required for a durable, robust effect. (Funded by the National Institute for Health Research and others; ClinicalTrials.gov number, NCT00643747.).

New best1 mutations in autosomal recessive bestrophinopathy.

PURPOSE: To report the ocular phenotype in patients with autosomal recessive bestrophinopathy and carriers, and to describe novel BEST1 mutations. METHODS: Patients with clinically suspected and subsequently genetically proven autosomal recessive bestrophinopathy underwent full ophthalmic examination and investigation with fundus autofluorescence imaging, spectral domain optical coherence tomography, electroretinography, and electrooculography. Mutation analysis of the BEST1 gene was performed through direct Sanger sequencing. RESULTS: Five affected patients from four families were identified. Mean age was 16 years (range, 6-42 years). All affected patients presented with reduced visual acuity and bilateral, hyperautofluorescent subretinal yellowish deposits within the posterior pole. Spectral domain optical coherence tomography demonstrated submacular fluid and subretinal vitelliform material in all patients. A cystoid maculopathy was seen in all but one patient. In 1 patient, the location of the vitelliform material was seen to change over a follow-up period of 3 years despite relatively stable vision. Visual acuity and fundus changes were unresponsive to topical and systemic carbonic anhydrase inhibitors and systemic steroids. Carriers had normal ocular examinations including normal fundus autofluorescence. Three novel mutations were detected. CONCLUSION: Three novel BEST1 mutations are described, suggesting that many deleterious variants in BEST1 resulting in haploinsufficiency are still unknown. Mutations causing autosomal recessive bestrophinopathy are mostly located outside of the exons that usually harbor vitelliform macular dystrophy-associated dominant mutations.

Expanded clinical spectrum of enhanced S-cone syndrome.

IMPORTANCE: New funduscopic findings in patients with enhanced S-cone syndrome (ESCS) may help clinicians in diagnosing this rare autosomal recessive retinal dystrophy. OBJECTIVE: To expand the clinical spectrum of ESCS due to mutations in the NR2E3 gene. DESIGN: Retrospective, noncomparative case series of 31 patients examined between 1983 and 2012. SETTING: Academic and private ophthalmology practices specialized in retinal dystrophies. PARTICIPANTS: A cohort of patients diagnosed with ESCS and harboring known NR2E3 mutations. INTERVENTION: Patients had ophthalmic examinations including visual function testing that led to the original diagnosis. MAIN OUTCOMES AND MEASURES: New fundus features captured with imaging modalities. RESULTS: New clinical observations in ESCS include (1) torpedo-like, deep atrophic lesions with a small hyperpigmented rim, variably sized and predominantly located along the arcades; (2) circumferential fibrotic scars in the posterior pole with a spared center and large fibrotic scars around the optic nerve head; and (3) yellow dots in areas of relatively normal-appearing retina. CONCLUSIONS AND RELEVANCE: Enhanced S-cone syndrome has more pleiotropy than previously appreciated. While the nummular type of pigmentation at the level of the retinal pigment epithelium and cystoid or schisis-like maculopathy with typical functional findings remain classic hallmarks of the disease, changes such as circumferential fibrosis of the macula or peripapillary area and "torpedo-like" lesions along the vascular arcades may also direct the clinical diagnosis and focus on screening the NR2E3 gene for a molecular diagnosis.

Ocular and extra-ocular features of patients with Leber congenital amaurosis and mutations in CEP290.

PURPOSE: This study investigated the centrosomal protein, 290-KD (CEP290) associated genotype and ocular and extra-ocular phenotype in 18 patients with Leber congenital amaurosis (LCA). METHODS: Eighteen patients with LCA from 14 families with mutations in the CEP290 gene were identified with sequencing or with heteroduplex analysis. Ophthalmic examinations were performed on all patients. Scans of the central nervous system were reassessed in three patients and obtained in two. Renal function was evaluated in all patients. Ultrasonography of the kidneys was performed in six patients. RESULTS: Eight patients (from five families) carried the c.2991+1655A>G mutation homozygously. Nine solitary patients carried this variant combined with a nonsense, frameshift, or splice site mutation on the second allele. One new nonsense mutation was identified: c.1078C>T. Fourteen patients (from 12 families) had been completely blind from birth or had light perception. The best-recorded visual acuity was 20/200. Peripheral fundus changes appeared to be progressive with a relatively preserved posterior pole. Novel ophthalmic features for the CEP290 phenotype were Coats-like exudative vasculopathy in two patients, a small chorioretinal coloboma in one patient, and well defined, small, atrophic spots at the level of the retinal pigment epithelium causing a dot-like appearance in five patients. Some CEP290 patients exhibited systemic abnormalities. We found abnormal proprioception in two patients and mild mental retardation in one. One patient was infertile due to immobile spermatozoa. No renal abnormalities were detected. CONCLUSIONS: CEP290-associated LCA has a severe, progressive, and clinically identifiable phenotype. Distinct extra-ocular findings were noted, which may be attributed to ciliary dysfunction.

Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis.

Leber congenital amaurosis (LCA) is one of the main causes of childhood blindness. To date, mutations in eight genes have been described, which together account for approximately 45% of LCA cases. We localized the genetic defect in a consanguineous LCA-affected family from Quebec and identified a splice defect in a gene encoding a centrosomal protein (CEP290). The defect is caused by an intronic mutation (c.2991+1655A-->G) that creates a strong splice-donor site and inserts a cryptic exon in the CEP290 messenger RNA. This mutation was detected in 16 (21%) of 76 unrelated patients with LCA, either homozygously or in combination with a second deleterious mutation on the other allele. CEP290 mutations therefore represent one of the most frequent causes of LCA identified so far.