Disease quiescence in endophthalmitis patients treated with anti-VEGF injections for retinal pathologies.

BACKGROUND: The most feared complication of intravitreal injections is the development of endophthalmitis, which could lead to irreversible visual loss. The aim of this study was to characterize the clinical profiles, causative pathogens, and clinical outcome of patients post-endophthalmitis. METHODS: Retrospective, single center case series study. Clinical records, causative pathogens and management of all cases of endophthalmitis post intravitreal anti-vascular endothelial growth factor (VEGF) injections recorded between January 1st, 2006 and May 30th, 2022; were retrieved. The visual and anatomic changes prior to the episode of endophthalmitis and up to 2 years post-treatment were compared. RESULTS: Eleven post-injection endophthalmitis eyes of 10 patients (n = 3 females; 30%) were recruited at mean age of 64.5 ± 20.4 years. The median last recorded BCVA, up to 3 months prior to the episode of endophthalmitis was 60 (Interquartile range (IQR) 55-75) ETDRS letters. Then, it dropped to 30 (IQR 0-57.5), 35 (IQR 0-52.5) and 35 (IQR 0-57.5) ETDRS letters at presentation, 6- and 12-months follow-up; respectively (p = 0.027, p = 0.017 and p = 0.012). However, at 24 months, the median BCVA returned to similar baseline values prior to the episode of endophthalmitis; BCVA 50 (IQR 0-60) ETDRS letters, p = 0.062. Interestingly, two eyes with neovascular age-related macular degeneration (NVAMD), 1 with myopic choroidal neovascularization (CNV) and 1 with retinal vein occlusion (RVO), experienced disease quiescence and did not require additional anti-VEGF injections up to 2 years of follow-up. CONCLUSION: This study demonstrates long-term recovery of vision loss due to endophthalmitis post anti-VEGF injections, regained up to 2 years later. It also indicates that disease quiescence post endophthalmitis may not only occur in eyes treated for NVAMD, but also with myopic CNV and RVO.

Prevalence and associated factors of cystoid macular edema in children with early onset inherited retinal dystrophies.

PURPOSE: To assess the prevalence of Cystoid macular edema (CME) in children with early onset retinal dystrophies (EORD) and to evaluate if there are associated factors and/or response to early treatment. METHODS: Consecutive, retrospective case series. Medical records of patients, 18 years or younger, diagnosed with EORD were included in the study. Optic coherence tomography (OCT) scans, clinical and genetic characteristics as well as other associated factors were analyzed. Main outcome was the presence of CME on OCT scans. RESULTS: One hundred and two children with EORD (aged 1-18 years, mean 9.7 ± 4.2) were recruited. OCT was performed in 60/102 and among them, 19/60 had CME (31.7%). The disease-causing gene was identified in 13 children with CME; autosomal-recessive inheritance was found in 88.3% of those with an identified genotype. Children with Usher syndrome had CME in 44.4% of the cases. Early treatment of CME resulted in variable response. CONCLUSIONS: Our results show that 31.7% of children with EORD who underwent OCT have macular edema. CME prevalence was found to be relatively higher in children with Usher syndrome. Autosomal recessive was the most prevalent inheritance identified in the EORD group as well as in the CME group. Additional prospective research is needed to assess the efficacy of early CME treatment in pediatric EORD patients.

Retinal Degeneration Associated With RPGRIP1: A Review of Natural History, Mutation Spectrum, and Genotype-Phenotype Correlation in 228 Patients.

Purpose: RPGRIP1 encodes a ciliary protein expressed in the photoreceptor connecting cilium. Mutations in this gene cause ∼5% of Leber congenital amaurosis (LCA) worldwide, but are also associated with cone-rod dystrophy (CRD) and retinitis pigmentosa (RP) phenotypes. Our purpose was to clinically characterize RPGRIP1 patients from our cohort, collect clinical data of additional RPGRIP1 patients reported previously in the literature, identify common clinical features, and seek genotype-phenotype correlations. Methods: Clinical data were collected from 16 patients of our cohort and 212 previously reported RPGRIP1 patients and included (when available) family history, best corrected visual acuity (BCVA), refraction, comprehensive ocular examination, optical coherence tomography (OCT) imaging, visual fields (VF), and full-field electroretinography (ffERG). Results: Out of 228 patients, the majority (197, 86%) were diagnosed with LCA, 18 (7%) with RP, and 13 (5%) with CRD. Age of onset was during early childhood (n = 133, average of 1.7 years). All patients but 6 had moderate hyperopia (n = 59, mean of 4.8D), and average BCVA was 0.06 Snellen (n = 124; only 10 patients had visual acuity [VA] > 0.10 Snellen). On funduscopy, narrowing of blood vessels was noted early in life. Most patients had mild bone spicule-like pigmentation starting in the midperiphery and later encroaching upon the posterior pole. OCT showed thinning of the outer nuclear layer (ONL), while cystoid changes and edema were relatively rare. VF were usually very constricted from early on. ffERG responses were non-detectable in the vast majority of cases. Most of the mutations are predicted to be null (363 alleles), and 93 alleles harbored missense mutations. Missense mutations were identified only in two regions: the RPGR-interacting domain and the C2 domains. Biallelic null mutations are mostly associated with a severe form of the disease, whereas biallelic missense mutations usually cause a milder disease (mostly CRD). Conclusion: Our results indicate that RPGRIP1 biallelic mutations usually cause severe retinal degeneration at an early age with a cone-rod pattern. However, most of the patients exhibit preservation of some (usually low) BCVA for a long period and can potentially benefit from gene therapy. Missense changes appear only in the conserved domains and are associated with a milder phenotype.

Postoperative Macular Proliferative Vitreoretinopathy: A Case Series and Literature Review.

Premacular membranes developing following pars plana vitrectomy (PPV) can cause significant anatomical and functional deficits to the macula. Recent reports showed that postoperative premacular membranes are a localized presentation of macular proliferative vitreoretinopathy (mPVR). Here, we report retrospectively a case series of 5 patients with severe mPVR which developed following uneventful PPV and were followed up to 32 months in the Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, between October 2016 and February 2020. All patients underwent primary repair of rhegmatogenous retinal detachment (RRD) before mPVR developed. Mean best-corrected visual acuity (BCVA) at presentation was 20/76 Snellen (0.58 LogMAR). Median duration of the retinal detachment time until surgery was 1.5 days (range 1-21 days). Mean interval time from last normal follow-up exam to diagnosis of mPVR was 19 days (range 10-28). BCVA dropped from a mean of 20/38 Snellen (0.28 LogMAR) prior to mPVR development to 20/166 Snellen (0.92 LogMAR) following its development, recovering to 20/57 Snellen (0.45 LogMAR) after peeling of membranes. Mean central macular thickness measured by optical coherence tomography decreased from 711 to 354 µm postsurgery. In conclusion, short-term mPVR is a different entity from macular pucker in terms of rapid development, structural distortion, and visual compromise. Surgical treatment significantly restores macular function and anatomy.

Cell-Based Therapies for Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. The pathogenesis of AMD involves dysfunction and loss of the retinal pigment epithelium (RPE), a monolayer of cells that provide nourishment and functional support for the overlying photoreceptors. RPE cells in mammals are not known to divide, renew or regenerate in vivo, and in advanced AMD, RPE loss leads to degeneration of the photoreceptors and impairment of vision. One possible therapeutic approach would be to support and replace the failing RPE cells of affected patients, and indeed moderate success of surgical procedures in which relatively healthy autologous RPE from the peripheral retina of the same eye was transplanted under the retina in the macular area suggested that RPE replacement could be a means to attenuate photoreceptor cell loss. This prompted exploration of the possibility to use pluripotent stem cells (PSCs) as a potential source for "healthy and young" RPE cells for such cell-based therapy of AMD. Various approaches ranging from the use of allogeneic embryonic stem cells to autologous induced pluripotent stem cells are now being tested within early clinical trials. Such PSC-derived RPE cells are either injected into the subretinal space as a suspension, or transplanted as a monolayer patch upon scaffold support. Although most of these approaches are at early clinical stages, safety of the RPE product has been demonstrated by several of these studies. Here, we review the concept of cell-based therapy of AMD and provide an update on current progress in the field of RPE transplantation.

Outcomes of primary rhegmatogenous retinal detachment repair among young adult patients.

PURPOSE: To evaluate the functional and anatomical outcomes of primary rhegmatogenous retinal detachment (RRD) repair in young adults. METHODS: A retrospective, comparative case series study. Patients between the ages of 18 and 40 years who underwent surgical repair of primary RRD between the years 2006 and 2013 were included. Patients were divided into three groups according to the surgical technique used: scleral buckle (SB), pars plana vitrectomy (PPV) or combined surgery (SB-PPV). RESULTS: Ninety eyes (90 patients) were included. The mean age (SD) was 31.5 ± 5.1 years (range 22-40). Sixty-seven patients underwent SB, 10 had PPV and 13 had SB-PPV. Anatomical success rates were similar between the three groups (87%, 90% and 85% for SB, PPV and SB-PPV groups, respectively; p-value = 0.9). Mean (SD) preoperative LogMAR visual acuity (VA) was 0.46 ± 0.6, 1.73 ± 1.1, 1.1 ± 1.1 for SB, PPV and SB-PPV groups, respectively (p < 0.0001). The VA improved at last follow-up to 0.23 ± 0.4, 0.7 ± 1.5 and 1.09 ± 1.08 in SB, PPV and SB-PPV groups, respectively (p < 0.0001). Macula-off was diagnosed in 19.4% of SB, 80% of PPV and 53.9% of SB-PPV groups (p < 0.0001). In the SB group one phakic patient (1.5%) needed cataract extraction, while following PPV, all phakic eyes (100%) underwent cataract extraction eventually (p-value < 0.0001). CONCLUSIONS: The study emphasizes the efficacy of SB as a primary procedure for the repair of retinal detachment in young adults in terms of anatomical and functional success. Furthermore, preservation of the lens as a result of using SB rather than PPV when possible is of great importance in this age group.

SENIOR-LØKEN SYNDROME: A Case Series and Review of the Renoretinal Phenotype and Advances of Molecular Diagnosis.

PURPOSE: To report genetic and clinical findings in a case series of 10 patients from eight unrelated families diagnosed with Senior-Løken syndrome. METHODS: A retrospective study of patients with Senior-Løken syndrome. Data collected included clinical findings electroretinography and ocular imaging. Genetic analysis was based on molecular inversion probes, whole-exome sequencing (WES), and Sanger sequencing. RESULTS: All patients who underwent electrophysiology (8/10) had widespread photoreceptor degeneration. Genetic analysis revealed two mutations in NPHP1, two mutations in NPHP4, and two mutations in IQCB1 (NPHP5). Five of the six mutations identified in the current study were found in a single family each in our cohort. The IQCB1-p.R461* mutation has been identified in 3 families. Patients harboring mutations in IQCB1 were diagnosed with Leber congenital amaurosis, while patients with NPHP4 and NPHP1 mutations showed early and sector retinitis pigmentosa, respectively. Full-field electroretinography was extinct for 6 of 10 patients, moderately decreased for two, and unavailable for another 2 subjects. Renal involvement was evident in 7/10 patients at the time of diagnosis. Kidney function was normal (based on serum creatinine) in patients younger than 10 years. Mutations in IQCB1 were associated with high hypermetropia, whereas mutations in NPHP4 were associated with high myopia. CONCLUSION: Patients presenting with infantile inherited retinal degeneration are not universally screened for renal dysfunction. Modern genetic tests can provide molecular diagnosis at an early age and therefore facilitate early diagnosis of renal disease with recommended periodic screening beyond childhood and family planning.

Unique combination of clinical features in a large cohort of 100 patients with retinitis pigmentosa caused by FAM161A mutations.

FAM161A mutations are the most common cause of autosomal recessive retinitis pigmentosa in the Israeli-Jewish population. We aimed to characterize the spectrum of FAM161A-associated phenotypes and identify characteristic clinical features. We identified 114 bi-allelic FAM161A patients and obtained clinical records of 100 of these patients. The most frequent initial symptom was night blindness. Best-corrected visual acuity was largely preserved through the first three decades of life and severely deteriorated during the 4th-5th decades. Most patients manifest moderate-high myopia. Visual fields were markedly constricted from early ages, but maintained for decades. Bone spicule-like pigmentary changes appeared relatively late, accompanied by nummular pigmentation. Full-field electroretinography responses were usually non-detectable at first testing. Fundus autofluorescence showed a hyper-autofluorescent ring around the fovea in all patients already at young ages. Macular ocular coherence tomography showed relative preservation of the outer nuclear layer and ellipsoid zone in the fovea, and frank cystoid macular changes were very rare. Interestingly, patients with a homozygous nonsense mutation manifest somewhat more severe disease. Our clinical analysis is one of the largest ever reported for RP caused by a single gene allowing identification of characteristic clinical features and may be relevant for future application of novel therapies.

PHENOTYPIC CHARACTERISTICS OF ROD-CONE DYSTROPHY ASSOCIATED WITH MYO7A MUTATIONS IN A LARGE FRENCH COHORT.

PURPOSE: To document the rod-cone dystrophy phenotype of patients with Usher syndrome type 1 (USH1) harboring MYO7A mutations. METHODS: Retrospective cohort study of 53 patients (42 families) with biallelic MYO7A mutations who underwent comprehensive examination, including functional visual tests and multimodal retinal imaging. Genetic analysis was performed either using a multiplex amplicon panel or through direct sequencing. Data were analyzed with IBM SPSS Statistics software v. 21.0. RESULTS: Fifty different genetic variations including 4 novel were identified. Most patients showed a typical rod-cone dystrophy phenotype, with best-corrected visual acuity and central visual field deteriorating linearly with age. At age 29, binocular visual field demonstrated an average preservation of 50 central degrees, constricting by 50% within 5 years. Structural changes based on spectral domain optical coherence tomography, short wavelength autofluorescence, and near-infrared autofluorescence measurements did not however correlate with age. Our study revealed a higher percentage of epiretinal membranes and cystoid macular edema in patients with MYO7A mutations compared with rod-cone dystrophy patients with other mutations. Subgroup analyses did not reveal substantial genotype-phenotype correlations. CONCLUSION: To the best of our knowledge, this is the largest French cohort of patients with MYO7A mutations reported to date. Functional visual characteristics of this subset of patients followed a linear decline as in other typical rod-cone dystrophy, but structural changes were variable indicating the need for a case-by-case evaluation for prognostic prediction and choice of potential therapies.

The Genetics of Usher Syndrome in the Israeli and Palestinian Populations.

Purpose: Usher syndrome (USH) is the most common cause for deaf-blindness. It is genetically and clinically heterogeneous and prevalent in populations with high consanguinity rate. We aim to characterize the set of genes and mutations that cause USH in the Israeli and Palestinian populations. Methods: Seventy-four families with USH were recruited (23 with USH type 1 [USH1], 33 with USH2, seven with USH3, four with atypical USH, and seven families with an undetermined USH type). All affected subjects underwent a full ocular evaluation. A comprehensive genetic analysis, including Sanger sequencing for the detection of founder mutations, homozygosity mapping, and whole exome sequencing in large families was performed. Results: In 79% of the families (59 out of 74), an autosomal recessive inheritance pattern could be determined. Mutation detection analysis led to the identification of biallelic causative mutations in 51 (69%) of the families, including 21 families with mutations in USH2A, 17 in MYO7A, and seven in CLRN1. Our analysis revealed 28 mutations, 11 of which are novel (including c.802G>A, c.8558+1G>T, c.10211del, and c.14023A>T in USH2A; c.285+2T>G, c.2187+1G>T, c.3892G>A, c.5069_5070insC, c.5101C>T, and c.6196C>T in MYO7A; and c.15494del in GPR98). Conclusions: We report here novel homozygous mutations in various genes causing USH, extending the spectrum of causative mutations. We also prove combined sequencing techniques as useful tools to identify novel disease-causing mutations. To the best of our knowledge, this is the largest report of a genetic analysis of Israeli and Palestinian families (n = 74) with different USH subtypes.

A homozygous founder missense variant in arylsulfatase G abolishes its enzymatic activity causing atypical Usher syndrome in humans.

PURPOSE: We aimed to identify the cause of disease in patients suffering from a distinctive, atypical form of Usher syndrome. METHODS: Whole-exome and genome sequencing were performed in five patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and sensorineural hearing loss. Functional analysis of the wild-type and mutant proteins was performed in human fibrosarcoma cells. RESULTS: We identified a homozygous founder missense variant, c.133G>T (p.D45Y) in arylsulfatase G (ARSG). All patients shared a distinctive retinal phenotype with ring-shaped atrophy along the arcades engirdling the fovea, resulting in ring scotoma. In addition, patients developed moderate to severe sensorineural hearing loss. Both vision and hearing loss appeared around the age of 40 years. The identified variant affected a fully conserved amino acid that is part of the catalytic site of the enzyme. Functional analysis of the wild-type and mutant proteins showed no basal activity of p.D45Y. CONCLUSION: Homozygosity for ARSG-p.D45Y in humans leads to protein dysfunction, causing an atypical combination of late-onset Usher syndrome. Although there is no evidence for generalized clinical manifestations of lysosomal storage diseases in this set of patients, we cannot rule out the possibility that mild and late-onset symptoms may appear.

Destabilization of tetraplex structures of the fragile X repeat sequence (CGG)n is mediated by homolog-conserved domains in three members of the hnRNP family.

Hairpin or tetrahelical structures formed by a d(CGG)n sequence in the FMR1 gene are thought to promote expansion of the repeat tract. Subsequent to this expansion FMR1 is silenced and fragile X syndrome ensues. The injurious effects of d(CGG)n secondary structures may potentially be countered by agents that act to decrease their stability. We showed previously that the hnRNP-related protein CBF-A destabilized G'2 bimolecular tetraplex structures of d(CGG)n. Analysis of mutant proteins revealed that the CBF-A-conserved domains RNP11 and ATP/GTP binding box were sufficient and necessary for G'2 d(CGG)n disruption while the RNP21 motif inhibited the destabilization activity. Here, we report that a C-terminal fragment of CBF-A whose only remaining conserved domain was the ATP/GTP binding motif, disrupted G'2 d(CGG)n more selectively than wild-type CBF-A. Further, two additional members of the hnRNP family, hnRNP A2 and mutant hnRNP A1 effectively destabilized G'2 d(CGG)n. Examination of mutant hnRNP A2 proteins revealed that, similar to CBF-A, their RNP11 element and ATP/GTP binding motif mediated G'2 d(CGG)n disruption, while the RNP21 element blocked their action. Similarly, the RNP11 and RNP21 domains of hnRNP A1 were, respectively, positive and negative mediators of G'2 d(CGG)n destabilization. Last, employing the same conserved motifs that mediated disruption of the DNA tetraplex G'2 d(CGG)n, hnRNP A2 destabilized r(CGG)n RNA tetraplex.