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Background/AimsTo analyse the long-term anatomic and visual outcomes of patients with peripapillary pachychoroid syndrome (PPS), a recently described entity in the pachychoroid disease spectrum.MethodsThis study retrospectively included patients from several retina centres worldwide. Visual acuity (VA), retinal thickness and choroidal thickness at baseline, 6 months and final follow-up were assessed. Temporal trends in VA and anatomic characteristics were evaluated. Visual and anatomic outcomes in eyes that were observed versus those that were treated were analysed.ResultsFifty-six eyes of 35 patients were included with mean follow-up of 27±17 months. Median VA was 20/36 at baseline and remained stable through follow-up (p=0.77). Retinal thickness significantly decreased subfoveally (p=0.012), 1.5 mm nasal to the fovea (p=0.002) and 3.0 mm nasal to the fovea (p=0.0035) corresponding to areas of increased thickening at baseline. Choroidal thickness significantly decreased subfoveally (p=0.0030) and 1.5 mm nasal to the fovea (p=0.0030). Forty-three eyes were treated with modalities including antivascular endothelial growth factor injection, photodynamic therapy, and others. VA remained stable in treated eyes over follow-up (p=0.67). An isolated peripapillary fluid pocket in the outer nuclear layer was characteristic of PPS.ConclusionPatients with PPS experienced decreased retinal oedema and decreased choroidal thickening throughout the course of disease. While some patients experienced visual decline, the overall visual outcome was relatively favourable and independent of trends in retinal or choroidal thickening.

Contains fulltext : 244044.pdf (Publisher’s version ) (Open Access) PURPOSE: Perifoveal exudative vascular anomalous complex (PEVAC) was initially described as an isolated aneurysmal lesion in healthy eyes. Similar aneurysmal abnormalities may occur in association with retinal vascular diseases such as diabetic retinopathy or retinal vein occlusions (PEVAC-resembling). The aim of this study was to compare several imaging characteristics of PEVAC and PEVAC-resembling lesions. METHODS: Ten eyes with a PEVAC and 27 eyes with a PEVAC-resembling lesion were included in this cross-sectional study. They were all imaged with optical coherence tomography (OCT), OCT angiography (OCT-A) and colour fundus photography (CFP). Several clinical, morphological and vascular characteristics were assessed and compared between both PEVAC types. RESULTS: All PEVAC lesions were unilateral, while PEVAC-resembling lesions appeared bilateral in 23% of patients (p > 0.05). Unilateral multifocal PEVAC-resembling lesions were more frequently observed (56%) than unilateral multifocal PEVAC lesions (10%, p 0.05). No notable differences were observed in other studied characteristics. CONCLUSIONS: The clinical, morphological and vascular features of PEVAC and PEVAC-resembling lesions are similar based on multimodal imaging. Given the bilaterality and multifocality seen in PEVAC-resembling lesions, an underlying retinal vascular disease may stimulate the quantity of aneurysmal abnormalities. Due to the similarities with PEVAC-resembling lesions, PEVAC may also be considered a microangiopathy but with an unknown origin.

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Purpose: To study the risk of recurrence in acute central serous chorioretinopathy (aCSC) and to evaluate the risk of transitioning to chronic CSC. Patients and Methods: The medical records and multimodal imaging data of 295 aCSC cases were reviewed. Typical aCSC was defined as the presence of serous subretinal fluid (SRF), one focal leakage spot on fluorescein angiography (FA), retinal pigment epithelium (RPE) alterations limited in area to less than one optic disc diameter, and complete recovery from this first CSC episode. An increase in RPE alterations combined with persistent SRF was considered a sign of chronicity, which was determined in cases with >12 months follow-up. The main outcome measures included final visual acuity, percentage of disease recurrence, and percentage of cases moving toward a chronic phenotype. Treatment strategies and their efficacy were also reviewed. Results: A total of 295 eyes in 291 patients with aCSC were included. Spontaneous recovery was awaited in 154 eyes (52%), whereas 141 eyes (48%) recovered following treatment. SRF recurrence occurred in 24% of untreated cases and in 4% of treated cases (p

Item does not contain fulltext 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.

Purpose: To increase insight into the myopic presentation of central serous chorioretinopathy (CSC) by comparing a large group of myopic patients with CSC with reference groups with only one of the diagnoses. Methods: Myopic patients with CSC (spherical equivalent

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.

Central serous chorioretinopathy (CSCR) is characterised by retinal serous detachment usually localised in the macular region. CSCR predominantly affects men between 30 and 50 years of age. Traditional classification differentiates between acute (duration shorter than 4 to 6 months) and chronic disease (duration longer than 4 to 6 months). The pathogenesis is multifactorial and current thinking assumes the presence of localised choroidal hyperpermeability with subsequent secondary changes in the retinal pigment epithelium (RPE). The symptoms of acute CSCR include central blurred vision, often with deterioration in visual acuity. Optical coherence tomography (OCT) reveals subretinal fluid (SRF) and/or single retinal pigment epithelial detachments. Fluorescein angiography (FA) usually shows a leaking point with absent or only minor RPE changes in the acute phase and indocyanine green angiography (ICG) highlights circumscribed areas of thickened and hyperpermeable choroid. Acute cases may show spontaneous resolution of SRF, but may also recur and/or become chronic. After the initial diagnosis, spontaneous remission is seen in about 70 to 80% of cases, with a recurrence rate of about 50%. Due to the favourable spontaneous course, it is recommended to wait for 4 to 6 months after the first symptoms manifest. Steroid therapy is considered as a major risk factor. Chronic cases are characterised by slow deterioration in visual acuity with reduced contrast and colour perception. There are extensive RPE changes, with secondary degenerative changes of the photoreceptors. The disease can by complicated by choroidal neovascularisation (CNV), especially in elderly patients. The literature lists a number of treatments: The leakage point (visible in the FA) can be treated by focal laser therapy, either micropulse laser or, if sufficiently distant from the fovea, by argon laser coagulation. Randomised trials in chronic CSCR demonstrated good outcomes with photodynamic therapy. With observation periods ranging from 3 to 6 months, several case series reports found improvement after systemic administration of mineralocorticoid receptor antagonists, carbonic anhydrase inhibitors or non-steroidal anti-inflammatory drugs. In the presence of secondary CNV, anti-VEGF treatment should be initiated. It is unclear whether the combination with PDT might be useful.Die Chorioretinopathia centralis serosa (CCS) ist durch eine seröse Abhebung der Netzhaut in der Makula charakterisiert. Es sind meist Männer zwischen 30 und 50 Jahren betroffen. Es wird eine akute Form (Krankheitsdauer kürzer als 4 – 6 Monate) von einer chronischen Form (länger als 4 – 6 Monate) unterschieden. Die Pathogenese ist multifaktoriell, es wird aktuell von einer lokalen Hyperpermeabilität der Chorioidea mit sekundären Veränderungen der Photorezeptoren und des retinalen Pigmentepithels (RPE) ausgegangen. Symptome einer akuten CCS sind ein zentrales Verschwommensehen bei häufig geringer Visusverschlechterung. Die optische Kohärenztomografie (OCT) zeigt subretinale Flüssigkeit mit oder ohne einzelne Pigmentepithelabhebungen, in der Fluoresceinangiografie (FAG) findet man meist einen Quellpunkt, die Indocyaningrünangiografie (ICG) zeigt umschriebene Areale verdickter chorioidaler Gefäße. Die akute Form kann spontan abheilen, aber auch rezidivieren und/oder in eine chronische Form übergehen. Nach Erstdiagnose zeigt sich in ca. 70 – 80% der Fälle eine spontane Remission, in ca. 50% kommt es zu einem Rezidiv. Aufgrund des guten Spontanverlaufes sollte bei Erstmanifestation in den ersten 4 – 6 Monaten zugewartet werden. Steroidtherapie gilt als Hauptrisikofaktor. Bei der chronischen Form tritt eine langsame Visusverschlechterung mit vermindertem Kontrastsehen und Farbsehen ein. Es imponieren flächige Veränderungen im RPE mit sekundären degenerativen Veränderungen der Photorezeptoren. Als Komplikation, besonders bei älteren Patienten, kann eine chorioidale Neovaskularisation (CNV) auftreten. Mögliche Therapien sind: Eine fokale Lasertherapie des in der FAG sichtbaren Quellpunktes kann mit Mikropulslaser- oder bei ausreichender Entfernung zur Fovea mit Argonlaserkoagulation behandelt werden. Bei der chronischen CCS belegen Studien, dass die photodynamische Therapie (PDT) gute Resultate zeigt. Für die Therapie mit Mineralkortikoid-Antagonisten gibt es Fallserienberichte mit einer Evidenz der Behandlung für einen Beobachtungszeitraum von 3 – 6 Monaten. Bei Vorliegen einer sekundären CNV sollte eine Anti-VEGF-Therapie erfolgen. Es ist unklar, ob dabei eine Kombinationstherapie mit PDT sinnvoll ist.

Item does not contain fulltext 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.

Item does not contain fulltext 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.

Supplemental Digital Content is Available in the Text. Posterior cystoid retinal degeneration in chronic central serous chorioretinopathy is often accompanied by active subretinal fluid leakage and associated diffuse atrophic retinal pigment epithelium alterations. Treatment results in posterior cystoid retinal degeneration resolution in less than half of the cases, and final visual outcome remains poor even after posterior cystoid retinal degeneration resolution. A degenerative process may underlie posterior cystoid retinal degeneration development, causing retinal tissue loss, and irreversible vision loss., 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.

Contains fulltext : 229749.pdf (Publisher’s version ) (Open Access) No systemic biomarker of Central Serous Chorioretinopathy (CSCR) has been identified. Lipocalin 2 (LCN2 or NGAL), alone or complexed with MMP-9 (NGAL/MMP-9), is increased in several retinal disorders. Serum levels of LCN2 and NGAL/MMP-9 were measured in CSCR patients (n = 147) with chronic (n = 76) or acute/recurrent disease (n = 71) and in age- and sex-matched healthy controls (n = 130). Samples with CRP > 5 mg/L, creatinine > 100 µmol/L, and/or urea > 7.5 mmol/L were excluded. Serum LCN2 was lower in CSCR patients than controls (81.4 ± 48.7 vs 107.3 ± 44.5 ng/ml, p

Danial Mohabati,1,2 Thomas J van Rijssen,1 Elon HC van Dijk,1 Gregorius PM Luyten,1 Tom O Missotten,3 Carel B Hoyng,4 Suzanne Yzer,3 Camiel JF Boon1,5 1Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands; 2Department of Ophthalmology, Rotterdam Ophthalmic Institute, Rotterdam, the Netherlands; 3Department of Ophthalmology, The Rotterdam Eye Hospital, Rotterdam, the Netherlands; 4Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; 5Department of Ophthalmology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 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 >6months 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. Keywords: chronic central serous chorioretinopathy, long-term outcome, severity, treatment, photodynamic therapy, posterior cystoid retinal degeneration

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Extraction of image-based biomarkers, such as the presence, visibility, or thickness of a certain layer, from 3-D optical coherence tomography data provides relevant clinical information. We present a method to simultaneously determine the number of visible layers in the outer retina and segment them. The method is based on a model selection approach with special attention given to the balance between the quality of a fit and model complexity. This will ensure that a more complex model is selected only if this is sufficiently supported by the data. The performance of the method was evaluated on healthy and retinitis pigmentosa (RP) affected eyes. In addition, the reproducibility of automatic method and manual annotations was evaluated on healthy eyes. Good agreement between the segmentation performed manually by amedical doctor and results obtained fromthe automatic segmentation was found. The mean unsigned deviation for all outer retinal layers in healthy and RP affected eyes varied between 2.6 and $4.9~\mu \text{m}$ . The reproducibility of the automatic method was similar to the reproducibility of the manual segmentation. Overall, the method provides a flexible and accurate solution for determining the visibility and location of outer retinal layers and could be used as an aid for the disease diagnosis and monitoring.

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.

Contains fulltext : 215584.pdf (Publisher’s version ) (Open Access) Central serous chorioretinopathy (CSC) is a common cause of central vision loss, primarily affecting men 20-60 years of age. To date, no consensus has been reached regarding the classification of CSC, and a wide variety of interventions have been proposed, reflecting the controversy associated with treating this disease. The recent publication of appropriately powered randomised controlled trials such as the PLACE trial, as well as large retrospective, non-randomised treatment studies regarding the treatment of CSC suggest the feasibility of a more evidence-based approach when considering treatment options. The aim of this review is to provide a comprehensive overview of the current rationale and evidence with respect to the variety of interventions available for treating CSC, including pharmacology, laser treatment, and photodynamic therapy. In addition, we describe the complexity of CSC, the challenges associated with treating CSC, and currently ongoing studies. Many treatment strategies such as photodynamic therapy using verteporfin, oral mineralocorticoid antagonists, and micropulse laser treatment have been reported as being effective. Currently, however, the available evidence suggests that half-dose (or half-fluence) photodynamic therapy should be the treatment of choice in chronic CSC, whereas observation may be the preferred approach in acute CSC. Nevertheless, exceptions can be considered based upon patient-specific characteristics.

Item does not contain fulltext PURPOSE: To assess ophthalmologic characteristics in patients and unaffected individuals in families with multiple members affected by central serous chorioretinopathy (CSC), both at presentation and long-term follow-up. METHODS: In 103 subjects from 23 families with at least 2 affected patients with CSC per family, prospective extensive ophthalmologic examination was performed, including best-corrected visual acuity, indirect ophthalmoscopy, digital color fundus photography, optical coherence tomography, fundus autofluorescence, and fluorescein angiography imaging. From these, 24 individuals from 6 families had undergone extensive ophthalmologic examination in either 1994 or 1995 and were followed up in this study. RESULTS: Subretinal fluid accumulation on optical coherence tomography and/or "hot spots" of leakage on fluorescein angiography indicative of CSC were detected in 45 of 103 phenotyped subjects (44%). Findings suggestive of CSC, but without the presence of subretinal fluid on optical coherence tomography and/or "hot spots" of leakage on fluorescein angiography, were observed in an additional 27 family members (26%). In 4 of 17 previously nonaffected subjects (24%) from the 24 individuals that were followed up after more than 20 years, we found more severe abnormalities. CONCLUSION: Extensive ophthalmologic phenotyping resulted in the detection of (suggestive) CSC in 52% of family members of patients with CSC. Genetic factors may play an important role in these specific CSC cases. Moreover, during follow-up, progressive disease can occur in a noteworthy number of patients.

The goal of treatment in CSC should be a complete and durable resolution of SRF. PDT is able to achieve this goal by targeting the choroidal congestion and leakage that appears to lie at the basis of SRF leakage in CSC. Based on the findings of the PLACE trial, half-dose PDT with reduced settings appears to be the most effective treatment to achieve this anatomical end point in cCSC, while also achieving functional improvement, with a favorable safety profile. PDT also might be the treatment of choice in selected aCSC cases in which treatment is desired to achieve fast SRF resolution, visual improvement, and minimization of the recurrence risk.

AimTo report the discordance in central serous chorioretinopathy (CSCR) classification among practising retina specialists.MethodsThe study conducted was a multicentre survey. Multimodal retinal images along with relevant clinical details of 100 cases diagnosed as CSCR (from six centres) were circulated among six retina specialists across the globe. The image sets included colour fundus photographs, fundus autofluorescence images, optical coherence tomography b-scans, fluorescein and indocyanine green angiography of the study and fellow eyes. The graders were asked to classify the disease of study eye, according to their own criteria. The graders were masked to the responses of other graders. The final analysis of the pooled response data was done based on the diagnosis of study eye only. The main outcome measure was degree of agreement between six independent observers using Fleiss Kappa statistics.ResultsGrading for 100 eyes of 100 patients (men, 93%) was included in the analysis. 20 patients had a history of steroid use. The graders provided 36 different terms to classify the disease, with poor agreement among graders (Fleiss Kappa=0.134). The consistency in diagnosing acute CSCR was statistically higher than for either chronic (p=0.012) or recurrent CSCR (pConclusionThe high discordance among experienced retina specialists in describing CSCR clinical subtypes is highlighted. The current work demonstrates the limitations of current empirical CSCR classification methods and the need for a more objective and refined system to bring uniformity in diagnosis and prognostication of the disease.

Danial Mohabati,1,2 Elon HC van Dijk,1 Thomas J van Rijssen,1 Eiko K de Jong,3 Myrte B Breukink,3 Jose P Martinez-Ciriano,4 Greet Dijkman,1 Carel B Hoyng,3 Sascha Fauser,5 Suzanne Yzer,4 Camiel JF Boon1,6 1Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands; 2Department of Ophthalmology, Rotterdam Ophthalmic Institute, Rotterdam, the Netherlands; 3Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; 4Department of Ophthalmology, The Rotterdam Eye Hospital, Rotterdam, the Netherlands; 5Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany; 6Department of Ophthalmology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 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

Purpose To describe cases presenting with features of idiopathic macular telangiectasia (MacTel) Type 2 and central serous chorioretinopathy (CSC). Methods Databases from four tertiary retina centers were searched for cases copresenting CSC and MacTel Type 2. Results Five cases were identified (4 men, 1 woman; mean age: 67.2 years). Four patients were referred for chronic or nonresolving CSC, and the diagnosis of MacTel Type 2 was made based on multimodal imaging findings. One patient had advanced MacTel Type 2, and developed acute CSC. Regarding the MacTel Type 2 findings, all subjects presented perifoveal telangiectasia on fluorescein angiography, and four subjects showed intraretinal cavitations typical of MacTel Type 2 on optical coherence tomography, in one or both eyes. Regarding the CSC findings, fluorescein angiography identified focal or extended retinal pigment epithelium alteration in all eyes, and an active leakage in two eyes. Indocyanine green angiography showed choroidal vascular hyperpermeability in four subjects. On optical coherence tomography, pigment epithelial detachments were detected in five eyes (four subjects), and foveal detachments were present in five eyes (three subjects), which spontaneously resolved (two eyes), responded to photodynamic therapy (two eyes), or persisted (one eye). Mean choroidal thickness was 402 ± 99 μm. Conclusion The codiagnosis of CSC and MacTel Type 2 should be considered in atypical presentations associating features from both disorders.

Wing H Chung,1 Elon H C van Dijk,1 Danial Mohabati,1 Greet Dijkman,1 Suzanne Yzer,2 Eiko K de Jong,3 Sascha Fauser,4 Reinier O Schlingemann,5–7 Carel B Hoyng,3 Camiel J F Boon1,5 1Department of Ophthalmology, Leiden University Medical Center, Leiden, 2Rotterdam Eye Hospital, Rotterdam, 3Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; 4Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany; 5Department of Ophthalmology, 6Ocular Angiogenesis Group, Departments of Ophthalmology and Cell Biology and Histology, Academic Medical Center, 7Netherlands Institute for Neuroscience, Amsterdam, the Netherlands 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

BEST1 (VMD2) is a gene located on the long arm of chromosome 11 (11q12.3) that encodes for the 585 amino acid transmembrane protein bestrophin 1, located on the basolateral aspect of retinal pigment epithelial (RPE) cells.1 The exact function of bestrophin 1 is still not unequivocally characterized, but it is linked to transepithelial chloride flow possibly by controlling Ca2+ channels in the RPE.1–3 Mutations in BEST1 therefore affect RPE metabolism, and by consequence outer retinal function with which the RPE is intimately associated. Over 200 mutations in BEST1 have been identified and published.1,3,4 Mutations are associated with Best vitelliform macular dystrophy (VMD, MIM 153700), adult-onset vitelliform macular dystrophy (MIM 608161), retinitis pigmentosa 50 (RP50, MIM 613194), and autosomal dominant vitreoretinochoroidopathy (MIM 193220). These diseases are all caused by autosomal dominant mutations. Recently, a phenotype caused by autosomal recessive mutations in BEST1 was described: autosomal recessive bestrophinopathy (ARB, OMIM 611809). Autosomal recessive bestrophinopathy is a rare ocular disease. It was defined by Burgess et al1 in 2008, although the same condition with compound heterozygous mutations in VMD2 had been described 2 years earlier.5 It results from biallelic mutations in BEST1 and is characterized by a multifocal vitelliform dystrophy with subretinal fluid. An association with hypermetropia and angle closure has been described.1 Herein, we review the clinical features and mutation analysis of four families with ARB.

Contains fulltext : 50306.pdf (Publisher’s version ) (Closed access) PURPOSE: To test human CRB1 heterozygotes for possible clinical or functional retinal changes and to evaluate whether a patient with Leber congenital amaurosis (LCA) with CRB1 mutations not consistent with previously described CRB1 phenotypes carried a modifier allele in another LCA gene. METHODS: Seven unrelated heterozygous carriers of CRB1 mutations underwent phenotyping by full eye examinations (indirect ophthalmoscopy and slit lamp biomicroscopy) and functional testing (standard full-field electroretinography [ERG] and multifocal ERG). For genotyping of the LCA patients and their parents, denaturing high-performance liquid chromatography (dHPLC) analyses were performed, followed by sequence analysis of CRB1, followed by sequence analysis of the AIPL1 and CRX genes to identify a putative modifier effect in a patient with an atypical CRB1 phenotype. RESULTS: Reduced full-field ERG b-wave amplitudes were observed with scotopic -2 dB flash (140 microV; P < 0.05), normal full-field cone ERGs, and significant regional retinal dysfunction on mfERG in five of seven carriers of CRB1 mutations. A known AIPL1 mutation (p. R302L) was identified as a potential modifier allele in a patient with LCA carrying two CRB1 mutations and with a prominent maculopathy. CONCLUSIONS: In human heterozygotes of CRB1 mutations (parents of offspring with LCA), distinctive regional retinal dysfunctions were found by multifocal ERG measurements that were consistent with the focal histologic abnormalities reported for the two CRB1 knockout mice models. This phenotypic finding may identify CRB1 carriers and point to the causal gene defect in affected LCA offspring, significantly facilitating the molecular diagnostic process. Evidence suggests a modifier allele in AIPL1 in a patient with LCA with prominent atrophic macular lesions and homozygous defects in CRB1.

Contains fulltext : 57320.pdf (Publisher’s version ) (Closed access) Mutations in the ABCA4 gene have been associated with autosomal recessive Stargardt disease (STGD1), cone-rod dystrophy (CRD), and retinitis pigmentosa (RP). We employed a recently developed genotyping microarray, the ABCR400-chip, to search for known ABCA4 mutations in patients with isolated or autosomal recessive CRD (54 cases) or RP (90 cases). We performed detailed ophthalmologic examinations and identified at least one ABCA4 mutation in 18 patients (33%) with CRD and in five patients (5.6%) with RP. Single-strand conformation polymorphism (SSCP) analysis and subsequent DNA sequencing revealed four novel missense mutations (R24C, E161K, P597S, G618E) and a novel 1-bp deletion (5888delG). Ophthalmoscopic abnormalities in CRD patients ranged from minor granular pigmentary changes in the posterior pole to widespread atrophy. In 12 patients with recordable electroretinogram (ERG) tracings, a cone-rod pattern was detected. Three patients demonstrated progression from a retinal dystrophy resembling STGD1 to a more widespread degeneration, and were subsequently diagnosed as CRD. In addition to a variable degree of atrophy, all RP patients displayed ophthalmologic characteristics of classic RP. When detectable, ERG recordings in these patients demonstrated rod-cone patterns of photoreceptor degeneration. In conclusion, in this study, we show that the ABCA4 mutation chip is an efficient first screening tool for arCRD.

Autosomal recessive retinal dystrophies cause visual impairment in approximately 1 in 4000 individuals worldwide.1 The non-syndromic forms are highly heterogeneous and can be classified into clinical subgroups, the most frequent ones being retinitis pigmentosa, cone and cone-rod dystrophies, and Leber congenital amaurosis (LCA). LCA represents the most severe phenotype with an onset of symptoms before the age of six months, visual acuity below 20/400, a searching nystagmus, sluggish pupillary reactions, and a non-detectable electroretinogram (ERG). Visual fields are usually not measurable.1 Photophobia is only occasionally reported in LCA.2 Patients with juvenile and early onset retinitis pigmentosa present with night blindness in early childhood, usually before the age of two years. They do not show searching nystagmus3 and have a relatively well preserved macular function. Central vision is often lost in the second or third decade of life.4 The cloning of more than 20 genes allows the molecular characterisation of approximately 50% of the autosomal recessive inherited retinal dystrophy cases (http://www.sph.uth.tmc.edu/Retnet5,6 ). To establish a useful clinical prognosis for patients a well defined genotype–phenotype correlation is required. Although the general population in the Netherlands is relatively outbred, there are a few examples of autosomal recessive diseases caused by Dutch founder mutations. Batten disease was found to be due to identity-by-descent in a highly inbred family.7 A frequent LDL receptor mutation originating from Dutch 17th century settlers causes familial hypercholesterolaemia in South Africa and Canada.8 The RP12 locus was mapped through linkage analysis in a genetic isolate from the northwest of the Netherlands,9 which was followed by the cloning of the underlying gene, CRB1 .10 In 1959 Schappert-Kimmijser et al described an isolated Dutch population living on a former island with a relatively high frequency of LCA.11 In 1637 this …

Stargardt disease (STGD1) is caused by mutations in the ABCA4 gene. It has previously been reported that abnormalities in STGD1 may be detectable in the photoreceptors using spectral domain-optical coherence tomography (SD-OCT) prior to the detection of retinal pigment epithelium abnormalities. We present a 5-year-old asymptomatic girl with normal appearing fundi who possessed pathogenic ABCA4 variants on both chromosomes and where thickening of the external limiting membrane was the only abnormality detected on SD-OCT.

Purpose Choroidal thinning has been associated with reticular pseudodrusen (RPD) and β-peripapillary atrophy (β-PPA), which have been linked to normal-tension glaucoma (NTG). This analysis sought to determine whether RPD are independently associated with β-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. β-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 β-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 β-PPA, but choroidal thickness is a confounder in this relationship. Because β-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.

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.

Objective To report a new phenotype caused by mutations in the CRB1 gene in a family with 2 affected siblings. Design Molecular genetics and observational case studies. Participants Two affected siblings and 3 unaffected family members. Methods Each subject received a complete ophthalmic examination together with color fundus photography, fundus autofluorescence (FAF), and spectral-domain optical coherence tomography (SD-OCT). Microperimetry 1 (MP-1) mapping and electroretinogram (ERG) analysis were performed on the proband. Screening for disease-causing mutations was performed by whole exome sequencing in 3 family members followed by segregation analyses in the entire family. Main Outcome Measures Appearance of the macula as examined by clinical examination, fundus photography, FAF imaging, SD-OCT, and visual function by MP-1 and ERG. Results The proband and her affected brother exhibited unusual, previously unreported, findings of a macular dystrophy with relative sparing of the retinal periphery beyond the vascular arcades. The FAF imaging showed severely affected areas of hypoautofluorescence that extended nasally beyond the optic disc in both eyes. A central macular patch of retinal pigment epithelium (RPE) sparing was evident in both eyes on FAF, whereas photoreceptor sparing was documented in the right eye only using SD-OCT. The affected brother presented with irregular patterns of autofluorescence in both eyes characterized by concentric rings of alternating hyper- and hypoautofluorescence, and foveal sparing of photoreceptors and RPE, as seen on SD-OCT, bilaterally. After negative results in screening for mutations in candidate genes including ABCA4 and PRPH2 , DNA from 3 members of the family, including both affected siblings and their mother, was screened by whole exome sequencing resulting in identification of 2 CRB1 missense mutations, c.C3991T:p.R1331C and c.C4142T:p.P1381L, which segregated with the disease in the family. Of the 2, the p.R1331C CRB1 mutation has not been described before and the p.P1381L variant has been described in 1 patient with Leber congenital amaurosis. Conclusions This report illustrates a novel presentation of a macular dystrophy caused by CRB1 mutations. Both affected siblings exhibited a relatively well-developed retinal structure and preservation of generalized retinal function. An unusual 5-year progression of macular atrophy alone was observed that has not been described in any other CRB1 -associated phenotypes.

Enhanced S-cone syndrome is an orphan disease caused by mutations in the NR2E3 gene which result in an increased number of S-cones overpopulating the retina. Although the characteristic onset of enhanced S-cone syndrome can be well-documented by current ophthalmic imaging modalities, techniques such as spectral-domain optical coherence tomography (SD-OCT) and scanning laser ophthalmoscopy (SLO) fail to provide sufficient details regarding the microstructure of photoreceptors in retinal diseases. Adaptive optics (AO) provides a unique opportunity to analyze the effects of genetic mutations on photoreceptors by compensating aberrations of human eyes.Three eyes of three young adults with enhanced S-cone syndrome were studied by clinical examination, genetic screening, fundus autofluorescence (FAF) imaging, SD-OCT, and electroretinography (ERG). Cone mosaic imaging was accomplished by an AO-SLO equipped with a dual crystal on silicon spatial light modulator. Qualitative image analyses and genetic findings were investigated in each patient.The diagnosis of patients was confirmed by ERG finding. Genetic screening confirmed the presence of two disease-causing mutations in the NR2E3 gene in each study patient, as well as identified a novel mutation (202 AG, S68G). Fundus photograph, FAF, and SD-OCT found rosette-like lesion within the mid-periphery along the vascular arcades of the retina. In all AO-SLO images of patients, sparse distribution and asymmetric size of cone mosaic pattern were found within central retina. There were regions of dark space between groups of photoreceptors, distinguishable from shadowing and artifacts.AO-SLO provided an in-depth window into the retina of live enhanced S-cone syndrome patients beyond the ability of other current imaging modalities. Dark lesions within the central retina in each patient contain structurally dysfunctional cones which account for retinal mosaic disorganization, and may predispose affected areas to other abnormalities such as rosette lesions. AO-SLO can be an efficient diagnostic tool in clinics for examining cellular-level pathologies in various retinal dystrophies.

Acute macular neuroretinopathy (AMN) is a rare condition that was first described by Bos and Deutman in 1975.1 To date, 67 cases are reported in the English medical literature, all of which have been as single case reports or small case series. When AMN was first described, it was considered an excl

Contains fulltext : 51579.pdf (Publisher’s version ) (Closed access) PURPOSE: Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP) cause severe visual impairment early in life. Thus far, mutations in 13 genes have been associated with autosomal recessive LCA and juvenile RP. The purpose of this study was to use homozygosity mapping to identify mutations in known LCA and juvenile RP genes. METHODS: The genomes of 93 consanguineous and nonconsanguineous patients with LCA and juvenile RP were analyzed for homozygous chromosomal regions by using SNP microarrays. This patient cohort was highly selected, as mutations in the known genes had been excluded with the LCA mutation chip, or a significant number of LCA genes had been excluded by comprehensive mutation analysis. Known LCA and juvenile RP genes residing in the identified homozygous regions were analyzed by sequencing. Detailed ophthalmic examinations were performed on the genotyped patients. RESULTS: Ten homozygous mutations, including seven novel mutations, were identified in the CRB1, LRAT, RPE65, and TULP1 genes in 12 patients. Ten patients were from consanguineous marriages, but in two patients no consanguinity was reported. In 10 of the 12 patients, the causative mutation was present in the largest or second largest homozygous segment of the patient's genome. CONCLUSIONS: Homozygosity mapping using SNP microarrays identified mutations in a significant proportion (30%) of consanguineous patients with LCA and juvenile RP and in a small number (3%) of nonconsanguineous patients. Significant homozygous regions which did not map to known LCA or juvenile RP genes and may be instrumental in identifying novel disease genes were detected in 33 patients.

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-naive 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.

Contains fulltext : 50025.pdf (Publisher’s version ) (Closed access) 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.

Contains fulltext : 34408.pdf ( ) (Closed access) Retinoid dehydrogenases/reductases catalyze key oxidation-reduction reactions in the visual cycle that converts vitamin A to 11-cis retinal, the chromophore of the rod and cone photoreceptors. It has recently been shown that mutations in RDH12, encoding a retinol dehydrogenase, result in severe and early-onset autosomal recessive retinal dystrophy (arRD). In a cohort of 1011 individuals diagnosed with arRD, we have now identified 20 different disease-associated RDH12 mutations, of which 16 are novel, in a total of 22 individuals (2.2%). Haplotype analysis suggested a founder mutation for each of the three common mutations: p.L99I, p.T155I and c.806_810delCCCTG. Patients typically presented with early disease that affected the function of both rods and cones and progressed to legal blindness in early adulthood. Eleven of the missense variants identified in our study exhibited profound loss of catalytic activity when expressed in transiently transfected COS-7 cells and assayed for ability to convert all-trans retinal to all-trans retinol. Loss-of-function appeared to result from decreased protein stability, as expression levels were significantly reduced. For the p.T49M variant, differing activity profiles were associated with each of the alleles of the common p.R161Q RDH12 polymorphism, suggesting that genetic background may act as a modifier of mutation effect. A locus (LCA3) for Leber congenital amaurosis, a severe, early-onset form of arRD, maps close to RDH12 on chromosome 14q24. Haplotype analysis in the family in which LCA3 was mapped excluded RDH12 as the LCA3 gene and thus suggests the presence of a novel arRD gene in this region.

To compare choroidal thickness (CT) measurements in early AMD between patients with and without reticular pseudodrusen (RPD) using spectral-domain optical coherence tomography (SD-OCT).This cross-sectional study examined 84 age- and sex-matched AMD patients (40 RPD [63 eyes], 44 non-RPD [75 eyes]). Fundus photographs and scanning laser ophthalmoscopy images were graded to identify RPD and non-RPD groups by three retinal specialists (MO, SY, SB) who were masked to corresponding SD-OCTs. CT at the fovea and 2400 to 3000 μm superior and inferior to the fovea was measured on SD-OCT by a grader (AG) and reviewed by a retinal specialist (SB). Only images with a clear posterior choroidal margin were analyzed (six eyes excluded due to poor image quality), and enhanced depth imaging SD-OCT was used when available (20 of 138 eyes). Greatest retinal thickness (RT) on horizontal foveal SD-OCT was also recorded.Mean CTs in the superior, foveal, and inferior macula in RPD (191.3 μm ± 57.9 SD, 176.3 μm ± 60.5 SD, 179.7 μm ± 56.24 SD) were significantly less than that of non-RPD (228.0 μm ± 66.1 SD, 216.5 μm ± 70.3 SD, 224.4 μm ± 71.9 SD; P = 0.0010, P = 0.0005, P = 0.0001, respectively), as was greatest RT (P = 0.0301).CT was thinner throughout the macula in the RPD group as compared with the non-RPD group. The current analysis supports an association between RPD and a thinned choroidal layer and is consistent with a choroidal etiology of RPD. CT may be integral to understanding RPD, and may be helpful in stratifying AMD progression risk.

Contains fulltext : 50548.pdf (Publisher’s version ) (Open Access) PURPOSE: To test the efficiency of a microarray chip as a diagnostic tool in a cohort of northwestern European patients with Leber congenital amaurosis (LCA) and to perform a genotype-phenotype analysis in patients in whom pathologic mutations were identified. METHODS: DNAs from 58 patients with LCA were analyzed using a microarray chip containing previously identified disease-associated sequence variants in six LCA genes. Mutations identified by chip analysis were confirmed by sequence analysis. On identification of one mutation, all protein coding exons of the relevant genes were sequenced. In addition, sequence analysis of the RDH12 gene was performed in 22 patients. Patients with mutations were phenotyped. RESULTS: Pathogenic mutations were identified in 19 of the 58 patients with LCA (32.8%). Four novel sequence variants were identified. Mutations were most frequently found in CRB1 (15.5%), followed by GUCY2D (10.3%). The p.R768W mutation was found in 8 of 10 GUCY2D alleles, suggesting that it is a founder mutation in the northwest of Europe. In early childhood, patients with AIPL1 or GUCY2D mutations show normal fundi. Those with AIPL1-associated LCA progress to an RP-like fundus before the age of 8, whereas patients with GUCY2D-associated LCA still have relatively normal fundi in their mid-20s. Patients with CRB1 mutations present with distinct fundus abnormalities at birth and consistently show characteristics of RP12. Pathogenic GUCY2D mutations result in the most severe form of LCA. CONCLUSIONS: Microarray-based mutation detection allowed the identification of 32% of LCA sequence variants and represents an efficient first-pass screening tool. Mutations in CRB1, and to a lesser extent, in GUCY2D, underlie most LCA cases in this cohort. The present study establishes a genotype-phenotype correlation for AIPL1, CRB1, and GUCY2D.