Fred K. Chen

Description:Objective: To determine the long-term functional and structural outcomes of intravitreal anti-VEGF therapy for macular neovascularization (MNV) in PRPH2-associated retinopathy. Methods: Multicenter retrospective case series including patients with molecularly confirmed PRPH2-associated retinopathy complicated by unilateral MNV. Best-corrected visual acuity (BCVA) and central subfield thickness (CST) were selected as outcome measures and compared between eyes with MNV undergoing anti-VEGF therapy and fellow eyes. Results: Six patients affected by PRPH2-associated retinopathy had MNV at a median age of 55 years. Two novel PRPH2 variants were found [c.499del p.(Cys150Phefs*3), c.660dup p.(Pro221Alafs*80)]. In all patients the phenotype was characterized by a pattern dystrophy with multifocal flecks. At baseline, eyes with MNV had a median (range) BCVA (logMAR) of 0.2 (0.2 to 0.7), corresponding to 20/32 Snellen, while the median (range) CST was 320 μm (228 to 362). After a median follow-up of 6.2 years and 5.5 injections per patient, 5 (83%) eyes retained a BCVA of at least 20/32 Snellen, while CST decreased by a median (range) of -69 μm (-117 to +15). No additional CST thinning was observed in eyes with MNV compared to their fellow eyes. In 4 (67%) eyes, OCT angiography revealed large neovascular networks growing below the retinal pigment epithelium (RPE) that persisted after resolution of exudation. Conclusions: A favorable long-term outcome can be obtained in PRPH2-associated retinopathy complicated by MNV when timely intravitreal anti-VEGF therapy is administered. Further research is needed to understand the significance of sub-RPE neovascular networks.

Description:Geographic atrophy is a leading cause of severe vision loss and is estimated to affect around 100,000 people in Australia alone. This survey is topical for clinical optometrists as the first treatment for geographic atrophy has just been approved by the Australian Therapeutics Goods Administration and may soon become available in Australia. Considering that treatments for geographic atrophy secondary to age-related macular degeneration are likely imminent, a survey of Australian optometrists was conducted to gauge their readiness in caring for people with geographic atrophy. The Royal Australian and New Zealand College of Ophthalmologists age-related macular degeneration referral guidelines working group determined 26 survey questions relating to management of geographic atrophy. Strength of agreement questions utilised a 5-point Likert scale. Optometrists answered anonymously during January to March 2024. There were 101 survey responses. Almost all (97%) respondents have access to colour fundus photography, three-quarters (74%) to optical coherence tomography, and almost half (44%) to fundus autofluorescence. Almost all (97%) see patients with GA regularly, with 73% seeing at least two geographic atrophy patients per month and the majority reviewing them every 6 months. Around half were confident in differentiating geographic atrophy from inherited retinal disease (49%) and confident in identifying early signs of atrophy (44%). Around half (46%) nominated that they would refer over 50% of their current geographic atrophy patients to ophthalmology for assessment of their suitability for new treatments. Eighty-three percent would refer a patient with good vision (6/12 or better) to initiate treatment to save encroachment on the fovea. Respondents were keen to receive more education about diagnosis (88%) and new treatments (93%). Optometrists are preparing for changes in the clinical management of geographic atrophy and are keen to receive further education to ensure optimal patient-centric care as new treatments become available.

Description:ROSAH syndrome is an autosomal dominant systemic disease featuring retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis and migrainous headache. Ocular manifestation of ROSAH syndrome can simulate posterior uveitis, vasculitis, generalized retinal dystrophy and neuroretinitis. To report a case of a 17-year-old female presenting with recurrent vitreous hemorrhage on a background of dental anomalies and anhidrosis. This case report illustrates the clinical findings and multimodal imaging features including spectral domain optical coherence tomography (OCT), OCT angiography (OCTA), fundus autofluorescence (FAF), ultrawide-field Optos fluorescein angiography (FA) and electrophysiology. A retinal dystrophy panel detected the c.710C>T p.Thr237Met variant, confirming genetic diagnosis of ROSAH syndrome. This case further elaborates, by way of multimodal imaging, on two striking features recently described in the literature-preretinal neovascularisation around the disc and along the vascular arcades, as well as an isolated expanding hyperautofluorescent ring around the disc. The use of widefield OCTA complemented the findings of FA in demonstrating the lack of retinal capillary closure. The macular edema was responsive to anti-vascular endothelium growth factor (anti-VEGF) injection, however only for a period of 6-weeks before reoccurrence. This report provides new insights into ROSAH phenotype. Anti-VEGF can be considered as a short-term treatment for ROSAH-associated macular edema.

Description:To determine the profile of inflammation-related proteins and complement system factors in the plasma of CRB1-associated inherited retinal dystrophies (CRB1-IRDs). We used the Olink Explore 384 Inflammation II panel for targeted proteomics in 30 cases and 29 controls (cohort I) to identify immune pathways involved in CRB1-IRDs. Genotyping was performed in cohort I and a second cohort of 123 patients from 14 countries and 1292 controls (cohort II). A significant shift in complement cascade factors was observed in plasma proteomes of CRB1-IRD patients (enrichment for complement cascade, Padj = 3.03 × 10-15). We detected higher plasma levels of complement factor I and complement factor H [CFH] (q = 0.008 and q = 0.046, respectively, adjusted for age and sex), inhibitors of complement component 3 (C3), which correlated significantly (Pearson's coefficient >0.6) with elevated levels of C3 (q = 0.064). The CRB1 missense variants frequently found in patients showed a strong linkage disequilibrium with the common CFH variant rs7535263 (D' = 0.97 for p.(Cys948Tyr); D' = 1.0 for p.(Arg764Cys)), known to be linked with altered plasma CFH-related protein levels. Correction for the CFH genotype revealed significantly elevated plasma levels of CFH-related 2 (CFHR2) in CRB1-IRD patients (q = 0.041). CRB1-IRDs are characterized by changes in plasma levels of complement factors and proteins of the innate immune system, and linkage between CRB1 and CFH genes implicates functional variants of the CFH-CFHR locus with specific pathogenic variants of CRB1.

Description:Inherited retinal disease (IRD) refers to a heterogeneous group of genetic eye disease that causes progressive vision loss and was once regarded untreatable. However, regulatory approval for Luxturna (voretigene neparvovec-rzyl) for patients with biallelic mutation in the RPE65 gene has heralded new optimism for patients with the disease. One critical question in designing clinical trial in patients with IRD is choosing appropriate outcome measures to assess the retina, taking into consideration the slow disease progression and the inherent low vision associated with the disease. In this review, the functional and structural endpoints that have been utilised in human retinal gene therapy clinical trials in patient selection as well as measures of safety and efficacy are described. For clinicians, an appreciation of these specialised measures of eye health in a patient with IRD will enhance understanding of retinal health assessments, disease prognosis as well as facilitating discussions with patients potentially eligible for retinal gene therapy clinical trial.