A clinical and molecular characterisation of CRB1-associated maculopathy.

To date, over 150 disease-associated variants in CRB1 have been described, resulting in a range of retinal disease phenotypes including Leber congenital amaurosis and retinitis pigmentosa. Despite this, no genotype-phenotype correlations are currently recognised. We performed a retrospective review of electronic patient records to identify patients with macular dystrophy due to bi-allelic variants in CRB1. In total, seven unrelated individuals were identified. The median age at presentation was 21 years, with a median acuity of 0.55 decimalised Snellen units (IQR = 0.43). The follow-up period ranged from 0 to 19 years (median = 2.0 years), with a median final decimalised Snellen acuity of 0.65 (IQR = 0.70). Fundoscopy revealed only a subtly altered foveal reflex, which evolved into a bull's-eye pattern of outer retinal atrophy. Optical coherence tomography identified structural changes-intraretinal cysts in the early stages of disease, and later outer retinal atrophy. Genetic testing revealed that one rare allele (c.498_506del, p.(Ile167_Gly169del)) was present in all patients, with one patient being homozygous for the variant and six being heterozygous. In trans with this, one variant recurred twice (p.(Cys896Ter)), while the four remaining alleles were each observed once (p.(Pro1381Thr), p.(Ser478ProfsTer24), p.(Cys195Phe) and p.(Arg764Cys)). These findings show that the rare CRB1 variant, c.498_506del, is strongly associated with localised retinal dysfunction. The clinical findings are much milder than those observed with bi-allelic, loss-of-function variants in CRB1, suggesting this in-frame deletion acts as a hypomorphic allele. This is the most prevalent disease-causing CRB1 variant identified in the non-Asian population to date.

Early Patterns of Macular Degeneration in ABCA4-Associated Retinopathy.

PURPOSE: To describe the earliest features of ABCA4-associated retinopathy. DESIGN: Case series. PARTICIPANTS: Children with a clinical and molecular diagnosis of ABCA4-associated retinopathy without evidence of macular atrophy. METHODS: The retinal phenotype was characterized by color fundus photography, OCT, fundus autofluorescence (FAF) imaging, electroretinography, and in 2 patients, adaptive optics scanning laser ophthalmoscopy (AOSLO). Sequencing of the ABCA4 gene was performed in all patients. MAIN OUTCOME MEASURES: Visual acuity, OCT, FAF, electroretinography, and AOSLO results. RESULTS: Eight children with ABCA4-associated retinopathy without macular atrophy were identified. Biallelic variants in ABCA4 were identified in all patients. Four children were asymptomatic, and 4 reported loss of VA. Patients were young (median age, 8.5 years; interquartile range, 6.8 years) with good visual acuity (median, 0.155 logarithm of the minimum angle of resolution [logMAR]; interquartile range, 0.29 logMAR). At presentation, the macula appeared normal (n = 3), had a subtly altered foveal reflex (n = 4), or demonstrated manifest fine yellow dots (n = 1). Fundus autofluorescence identified hyperautofluorescent dots in the central macula in 3 patients, 2 of whom showed a normal fundus appearance. Only 1 child had widespread hyperautofluorescent retinal flecks at presentation. OCT imaging identified hyperreflectivity at the base of the outer nuclear layer in all 8 patients. Where loss of outer nuclear volume was evident, this appeared to occur preferentially at a perifoveal locus. Longitudinal split-detector AOSLO imaging in 2 individuals confirmed that the greatest change in cone spacing occurred in the perifoveal, and not foveolar, photoreceptors. Electroretinography showed a reduced B-wave-to-A-wave ratio in 3 of 5 patients tested; in 2 children, recordings clearly showed electronegative results. CONCLUSIONS: In childhood-onset ABCA4-associated retinopathy, the earliest stages of macular atrophy involve the parafovea and spare the foveola. In some cases, these changes are predated by tiny, foveal, yellow, hyperautofluorescent dots. Hyperreflectivity at the base of the outer nuclear layer, previously described as thickening of the external limiting membrane, is likely to represent a structural change at the level of the foveal cone nuclei. Electroretinography suggests that the initial site of retinal dysfunction may occur after phototransduction.

Slowed recovery of human photopic ERG a-wave amplitude following intense bleaches: a slowing of cone pigment regeneration?

We have used the post-bleach recovery of the ERG a-wave to estimate the time-course of regeneration of cone pigment, following bleaching exposures far stronger than in a previous study. We recorded the photopic electroretinogram a-wave from two subjects, in response to dim red flashes delivered following 1-min exposures to intensities ranging from 1.1 × 10(4) to 1.3 × 10(5) photopic cd m(-2). The measured response amplitudes were "linearized" to derive estimates of pigment level. These estimated pigment levels were found to increase at an initially linear rate, consistent with a "rate-limited" model of photopigment regeneration. The extracted time-course was similar to that previously reported in densitometric studies of cone pigment regeneration after similarly intense exposures. On the other hand, the rate of regeneration was slower than measured in the same subjects following less intense bleaches. These results are consistent with the notion that cone pigment regeneration is slowed following very strong bleaching exposures, possibly as a result of depletion of a pool of retinoid.

Modelling the initial phase of the human rod photoreceptor response to the onset of steady illumination.

The initial time course of the change in photoreceptor outer segment membrane conductance in response to light flashes has been modelled using biochemical analysis of phototransduction, and the model has been successfully applied to a range of in vitro recordings and has also been shown to provide a good fit to the leading edge of the electroretinogram a-wave recorded in vivo. We investigated whether a simple modification of the model's equation would predict responses to the onset of steady illumination and tested this against electroretinogram recordings. Scotopic electroretinograms were recorded from three normal human subjects, using conductive fibre electrodes, in response to light flashes (0.30-740 scotopic cd m(-2) s) and to the onset of steady light (11-1,900 scotopic cd m(-2)). Subjects' pupils were dilated pharmacologically. The standard form of the model was applied to flash responses, as in previous studies, to obtain values for the three parameters: maximal response amplitude r (max), sensitivity S and effective delay time t (eff). A new "step response" equation was derived, and this equation provided a good fit to rod responses to steps of light using the same parameter values as for the flash responses. The results support the applicability of the model to the leading edge of electroretinogram responses: in each subject, the model could be used to fit responses both to flashes of light and to the onset of backgrounds with a single set of parameter values.

Case report: retinopathy in a patient with cold hemagglutinin disease.

PURPOSE: We describe abnormalities of retinal vasculature and blood flow in a patient with cold hemagglutinin disease. METHOD: Case report and literature review using the PubMed database. RESULTS: A man with cold hemagglutinin disease and no visual symptoms was referred to the Eye Department with retinal abnormalities found during a routine optometrist examination. He was found to have scattered retinal hemorrhages, abnormal retinal vasculature resembling neovascularization (but that did not show leakage on fundus fluorescein angiography), and aggregated material flowing visibly in the retinal vessels. CONCLUSION: No specific descriptions of retinopathy related to cold hemagglutinin disease have been previously published. We suggest that the abnormalities are secondary to areas of retinal ischemia, resulting in the development of a form of collateral circulation.

Complications of cataract surgery.

Modern cataract surgery is safe in more than 95 per cent of patients. In the small number of cases where a serious complication occurs, the most common is an intra-operative posterior capsular rupture. This can lead to vitreous loss or a dropped nucleus and can increase the risk of post-operative cystoid macular oedema or retinal detachment. Post-operatively, posterior capsular opacification is the most common complication and can be readily treated with a YAG capsulotomy. The most devastating complication is endophthalmitis, the rate of which is now significantly decreased through the use of intracameral antibiotics. As a clinician, the most important step is to assess the patient pre-operatively to predict higher risk individuals and to counsel them appropriately. In these patients, various pre- or intra-operative management steps can be taken in addition to routine phacoemulsification to optimise their visual outcome.