Peripapillary retinal nerve fibre layer thinning in patients with X-linked retinoschisis.

AIMS: To assess peripapillary retinal nerve fibre layer (pRNFL) thickness in patients with X-linked retinoschisis (XLRS), as pRNFL thinning may limit functional improvements in gene therapy trials. METHODS: This retrospective multicentre study included 49 eyes from 25 patients diagnosed with XLRS. Data collected with multimodal imaging at baseline and last follow-up (when available) included age, best-recorded visual acuity (BRVA), central retinal thickness, macular volume (MV), presence and location of peripheral retinoschisis and pRNFL thickness in the global (G), superotemporal (TS), superonasal (NS), inferotemporal (TI), inferonasal (NI), nasal (N) and temporal (T) sectors. Retinal sensitivity, assessed by microperimetry, was also recorded for seven patients at baseline. RESULTS: pRNFL was thinner (below the fifth percentile) in at least one sector in 72% of right eyes and 79% of left eyes, with thinning across three or more sectors in 20% of right and 17% of left eyes. In 44% of cases, thinning occurred in the temporal sectors of both eyes, with no nasal sectoral thinning. Number of peripheral retinoschisis quadrants matched thinned pRNFL sectors. A strong positive correlation was found between MV and temporal pRNFL thickness (r=0.71, p<0.01), while weak negative correlation trends were noted with age (p=0.05) and BRVA (logMAR; p=0.12) related to temporal thickness of pRNFL sectors. CONCLUSION: pRNFL thinning, predominantly sectoral and linked to macular or peripheral retinoschisis, occurs in about three-quarters of patients with XLRS, while diffuse thinning occurs in one-fifth. Temporal pRNFL thinning might occur only after the collapse of intraretinal cystoid cavities in the macula.

Trends in Shoulder Arthroplasty in Germany: A 10-Year Epidemiological Analysis of Patients with Primary Osteoarthritis of the Shoulder.

Shoulder arthroplasty has significantly gained popularity in orthopedic surgery, driven by progress in prosthesis design and surgical techniques. This study explored the epidemiology of shoulder arthroplasty, analyzing healthcare data from 2012 to 2022 for primary osteoarthritis of the shoulder. The data included patient demographics and types of surgical procedures. Data analysis indicates a higher utilization rate of reverse total shoulder arthroplasty (RTSA; n = 41,251) over total- (TSA; n = 18,679) and hemiarthroplasty (HSA; n = 12,827) for primary shoulder osteoarthritis. Overall, a significant increase in RTSA procedures from n = 2237 (2012) to n = 5415 (2022) was observed, representing more than a two-fold increase of 121.1%. The relative proportion of RTSA among all types of shoulder arthroplasty increased from 39% (2012) to 68.6% (2022), while HSA decreased and TSA essentially remained constant. Age analysis identified the following peaks: RTSA, 77 ± 7 y; HSA, 68 ± 12 y; and TSA, 67 ± 10 y. Among the over 60s, significantly more women were treated with any type of prosthesis, whereas in young patients (45 to 59 y), more men received HSA or TSA. Our study confirms that RTSA has become the preferred choice for elderly patients in Germany, reflecting the prevailing preference despite varying patient ages and conditions, with a noted difference in sex in treatment prevalence.

Anti-VEGF Treatment for Secondary Neovascularization in Pseudoxanthoma Elasticum - Age of Onset, Treatment Frequency, and Visual Outcome.

PURPOSE: To assess the onset, treatment frequency, and visual outcome of anti-vascular endothelial growth factor (anti-VEGF) treatment due to secondary choroidal neovascularization (CNV) in patients with pseudoxanthoma elasticum (PXE). DESIGN: Retrospective cohort study METHODS: One-hundred six eyes of 53 patients with PXE were analyzed. The assessment of CNV activity relied on hemorrhage visible on funduscopy and intra- / subretinal fluid on optical coherence tomography (OCT), individually defining a shortening or extension of treatment interval. Best-corrected visual acuity (BCVA) at baseline, age at anti-VEGF therapy initiation, and BCVA-drop events at exudation onset (worsening of BCVA of 2 or more lines) were documented. Further, we assessed the number of injections during the first year and the total number of injections, the time to treatment initiation of the fellow eye, and BCVA over time. RESULTS: During a median observation period of 77 months (IQR 49; 126) patients received a median number of 28.0 anti-VEGF-injections (IQR 9.8; 43.5). Eight patients received no injection (median age at baseline 38.1 years), 11 patients underwent anti-VEGF treatment in one eye (median age 47.2 years) and 34 patients in both eyes (median age 51.8 years). The median age at the first anti-VEGF treatment was 52.80 years (IQR 47.2-57.6). Applying Cox regression models, the median "survival" time of fellow eye until treatment initiation was 16.8 months. In the group of bilateral treated patients, the median time difference was 9.6 months (IQR 2.1- 32.4, range 0-122) The median number of injections was 5.5 per eye in the first year of treatment (IQR 3-7) and was associated with the total number of injections in the observation period (2.33, CI 1.22-3.44, P < .001). A better BCVA at the last follow-up visit was associated with a better baseline BCVA (P < .001, R2 = 0.318) and with the absence of a BCVA drop at the onset of exudation (P = 0.035, R2 = 0.339). CONCLUSIONS: The results of this study indicate that anti-VEGF treatment is required for most PXE patients at a relatively young age. Once treatment in one eye is initiated, the time to fellow eye treatment is relatively short. A BCVA drop before treatment initiation is a risk factor for worse visual outcomes, suggesting that treatment is prudent before exudation affects the central retina. Given the young age of onset and intensive treatment needs, patients with PXE might particularly benefit from longer-acting anti-VEGF therapeutics.

Early Vitrectomy with Silicone Oil Tamponade in the Management of Postoperative Endophthalmitis.

Background: Early vitrectomy for postsurgical endophthalmitis may improve visual acuity outcomes. Silicone oil as a tamponade has some potential benefits in the management of endophthalmitis. This study aims to evaluate the use of a silicone oil tamponade in the surgical management of endophthalmitis. Material and Methods: All patients with a pars plana vitrectomy with silicone oil tamponade for postsurgical endophthalmitis at the Department of Ophthalmology, University of Bonn, Germany, between 2017 and 2021 were retrospectively reviewed. We included all preoperative data, including BCVA at diagnosis, clinical findings, and symptoms. For every follow-up visit, we looked at BCVA and complications. Results: In total, 82 patients were included in this study. The mean follow-up was 13.1 months (range 1-58 months). An intravitreal injection was the cause in 42 patients (51.2%) and cataract surgery in 29 patients (35.4%). The mean interval between the causing event and the date of onset was 8.8 days (range, 1-59 days). The most prevalent pathogen was Staphylococcus epidermidis in 16 patients (19.5%). In 47 patients (57.3%), no pathogen was found. The initial best-corrected visual acuity was 2.1 logMAR and improved significantly to 1.0 logMAR after six months (p < 0.001) and 1.1 logMAR after 1 year (p < 0.001). In a multivariate analysis, a low BCVA at diagnosis (p = 0.041) was a significant predictor for poor visual acuity outcomes. A total of 17 patients (20.1%) developed postoperative complications. Five patients (6.1%) needed an anterior chamber washout with repeated injections of antibiotics. Two patients (2.4%) had persistent fibrin and were treated with YAG-laser treatment. Three patients (6.7%) developed a retinal detachment. Two patients (2.4%) had persistent corneal decompensation with endothelial cell loss and received perforating keratoplasty. We performed a matched-pair analysis (n = 30, each group n = 15) to compare a silicone oil tamponade with BSS at the end of surgery. The visual acuity outcome showed no significant differences (BCVA after one year: 1.17 logMAR in eyes with silicone oil and 0.90 logMAR in eyes with BSS; p = 0.684). Conclusions: In our study, a vitrectomy with silicone oil tamponade in the surgical management of postoperative endophthalmitis led to a significant improvement in visual acuity and had a low complication rate. Low BCVA at diagnosis was significantly associated with poor visual acuity outcomes. A comparison of silicone oil and BSS at the end of surgery showed similar results.

Mitochondrial Retinopathy.

PURPOSE: To report the retinal phenotype and the associated genetic and systemic findings in patients with mitochondrial disease. DESIGN: Retrospective case series. PARTICIPANTS: Twenty-three patients with retinopathy and mitochondrial disease, including chronic progressive external ophthalmoplegia (CPEO), maternally inherited diabetes and deafness (MIDD), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Kearns-Sayre syndrome, neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome, and other systemic manifestations. METHODS: Review of case notes, retinal imaging, electrophysiologic assessment, molecular genetic testing including protein modeling, and histologic analysis of muscle biopsy. MAIN OUTCOME MEASURES: Phenotypic characteristics of mitochondrial retinopathy. RESULTS: Genetic testing identified sporadic large-scale mitochondrial DNA deletions and variants in MT-TL1, MT-ATP6, MT-TK, MT-RNR1, or RRM2B. Based on retinal imaging, 3 phenotypes could be differentiated: type 1 with mild, focal pigmentary abnormalities; type 2 characterized by multifocal white-yellowish subretinal deposits and pigment changes limited to the posterior pole; and type 3 with widespread granular pigment alterations. Advanced type 2 and 3 retinopathy presented with chorioretinal atrophy that typically started in the peripapillary and paracentral areas with foveal sparing. Two patients exhibited a different phenotype: 1 revealed an occult retinopathy, and the patient with RRM2B-associated retinopathy showed no foveal sparing, no severe peripapillary involvement, and substantial photoreceptor atrophy before loss of the retinal pigment epithelium. Two patients with type 1 disease showed additional characteristics of mild macular telangiectasia type 2. Patients with type 1 and mild type 2 or 3 disease demonstrated good visual acuity and no symptoms associated with the retinopathy. In contrast, patients with advanced type 2 or 3 disease often reported vision problems in dim light conditions, reduced visual acuity, or both. Short-wavelength autofluorescence usually revealed a distinct pattern, and near-infrared autofluorescence may be severely reduced in type 3 disease. The retinal phenotype was key to suspecting mitochondrial disease in 11 patients, whereas 12 patients were diagnosed before retinal examination. CONCLUSIONS: Different types of mitochondrial retinopathy show characteristic features. Even in absence of visual symptoms, their recognition may facilitate the often challenging and delayed diagnosis of mitochondrial disease, in particular in patients with mild or nebulous multisystem disease.

NPHP1 gene-associated nephronophthisis is associated with an occult retinopathy.

Biallelic deletions in the NPHP1 gene are the most frequent molecular defect of nephronophthisis, a kidney ciliopathy and leading cause of hereditary end-stage kidney disease. Nephrocystin 1, the gene product of NPHP1, is also expressed in photoreceptors where it plays an important role in intra-flagellar transport between the inner and outer segments. However, the human retinal phenotype has never been investigated in detail. Here, we characterized retinal features of 16 patients with homozygous deletions of the entire NPHP1 gene. Retinal assessment included multimodal imaging (optical coherence tomography, fundus autofluorescence) and visual function testing (visual acuity, full-field electroretinography, color vision, visual field). Fifteen patients had a mild retinal phenotype that predominantly affected cones, but with relative sparing of the fovea. Despite a predominant cone dysfunction, night vision problems were an early symptom in some cases. The consistent retinal phenotype on optical coherence tomography images included reduced reflectivity and often a granular appearance of the ellipsoid zone, fading or loss of the interdigitation zone, and mild outer retinal thinning. However, there were usually no obvious structural changes visible upon clinical examination and fundus autofluorescence imaging (occult retinopathy). More advanced retinal degeneration might occur with ageing. An identified additional CEP290 variant in one patient with a more severe retinal degeneration may indicate a potential role for genetic modifiers, although this requires further investigation. Thus, diagnostic awareness about this distinct retinal phenotype has implications for the differential diagnosis of nephronophthisis and for individual prognosis of visual function.

Surgical Aspects in Gene Therapy for Inherited Retinal Diseases. / Chirurgische Aspekte der Gentherapie von Netzhautdystrophien.

Inherited retinal dystrophies (IRD) have been studied since their recognition by Franz Donders and Albrecht von Graefe. It nevertheless took 100 years for a causal therapy to take shape in the form of gene therapy: The approval of Voretigen Neparvovec (VN) for the treatment of hereditary retinal dystrophies due to RPE65 mutations was thus a significant milestone - for the era of personalised medicine in general and ophthalmology in particular. The clinical management around gene therapy applications is complex and requires the cooperation of various experts as a multidisciplinary team. This article describes the requirements, challenges, approaches, and open questions regarding the surgical aspects of gene therapy for retinal dystrophies. The first part outlines the standard surgical treatment. Based on this standard, alternative approaches are indicated for each individual step and their value discussed. Knowledge gaps are defined and in the outlook we speculate on future developments.

MINIMAL OPTICAL COHERENCE TOMOGRAPHY B-SCAN DENSITY FOR RELIABLE DETECTION OF INTRARETINAL AND SUBRETINAL FLUID IN MACULAR DISEASES.

PURPOSE: To determine the minimal optical coherence tomography B-scan density for reliable detection of intraretinal and subretinal fluid. METHODS: Spectral domain optical coherence tomography raster scanning (Spectralis; Heidelberg Engineering, Heidelberg, Germany) using a scan field of 20° × 20° of 97 B-scans with an interscan distance (ISD) of 60 µm was performed in 150 eyes of 150 consecutive patients at monitoring visits for intravitreal anti-vascular endothelial growth factor therapy. Using custom software, every other B-scan was repeatedly deleted to generate additional data sets with an ISD of 120 µm (49 B-scans), 240 µm (25 B-scans), and 480 µm (13 B-scans). Two independent reviewers evaluated the data sets for the presence of cystoid spaces of intraretinal fluid and subretinal fluid. RESULTS: Treatment diagnoses were neovascular age-related macular degeneration (68.0%), macular edema secondary to retinal vein occlusion (20.7%), diabetic macular edema (10.7%), and other retinal diseases (4.0%). Using the source data sets with an ISD of 60 µm, intraretinal fluid was detected in 56.0%, subretinal fluid in 19.3%, and either/both in 68.7%. Compared with these results, the sensitivity of detection of intraretinal fluid and/or subretinal fluid using an ISD of 120 µm, 240 µm, and 480 µm was 99.0% (95% confidence interval, 94.7-100.0; P = 0.5), 97.1% (91.7-99.4; P = 0.1), and 87.4% (79.4-93.1; P = 0.0001), respectively. CONCLUSION: An increase of ISD up to 240 µm does not significantly impair the detection of treatment-relevant exudative retinal changes in monitoring during intravitreal therapy of macular diseases. These findings are relevant for the choice of optical coherence tomography B-scan density in both routine clinical care and interventional clinical studies.

Optical Coherence Tomography Angiography for Evaluation of Sattler's Layer in Vogt-Koyanagi-Harada Disease.

The authors report a case of acute Vogt-Koyanagi-Harada syndrome with massively impaired perfusion in the Sattler's layer on optical coherence tomography angiography (OCTA). The hypoperfusion fully resolved during a period of 4 weeks and correlated well with hypofluorescent spots on indocyanine green angiography. This is the first time reduced perfusion in Sattler's layer has been observed on OCTA. This finding may aid further understanding of the pathology underlying VKH syndrome and indicates that evaluation of deeper choroidal layers like Sattler's layer may be of importance for disease monitoring and predicting prognosis in choroidal diseases. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:639-642.].

Cd59a deficiency in mice leads to preferential innate immune activation in the retinal pigment epithelium-choroid with age.

Dysregulation of the complement system has been implicated in the pathogenesis of age-related macular degeneration. To investigate consequences of altered complement regulation in the eye with age, we examined Cd59a complement regulator deficient (Cd59a(-/-)) mice between 4 and 15 months. In vivo imaging revealed an increased age-related accumulation of autofluorescent spots in Cd59a(-/-) mice, a feature that reflects accumulation of subretinal macrophages and/or microglia. Despite this activation of myeloid cells in the eye, Cd59a(-/-) mice showed normal retinal histology and function as well as normal choroidal microvasculature. With age, they revealed increased expression of activators of the alternative complement pathway (C3, Cfb, Cfd), in particular in the retinal pigment epithelium (RPE)-choroid but less in the retina. This molecular response was not altered by moderately-enhanced light exposure. Cd59a deficiency therefore leads to a preferential age-related dysregulation of the complement system in the RPE-choroid, that alone or in combination with light as a trigger, is not sufficient to cause choroidal vascular changes or retinal degeneration and dysfunction. This data emphasizes the particular vulnerability of the RPE-choroidal complex to dysregulation of the alternative complement pathway during aging.

The role of the complement system in age-related macular degeneration.

BACKGROUND: Age-related macular degeneration (AMD) is a common retinal disease in older people. In Europe, about 1.6% of persons over age 65 and more than 13% of persons over age 85 have late-stage AMD, which can severely impair vision. The development of AMD is influenced both by environmental factors and by a strong hereditary component. METHOD: We selectively searched the PubMed database for articles published between April 2001 and November 2013 with the key words "age-related macular degeneration," "risk factor," "complement," and "therapy." The website www.clinicaltrials.gov was also used to search for relevant clinical trials. RESULTS: Old age and smoking are confirmed risk factors for AMD. Moreover, genetic association studies have pointed to signaling pathways in which the complement system, a part of the individual's innate immune system, takes on a central role in the pathogenesis of the disease. Several clinical trials designed to interfere specifically with these pathomechanisms have yielded rather disappointing results, although a phase II study of the monoclonal antibody lampalizumab showed that blocking complement factor D lessened the progression of geographic atrophy. A risk model based on 13 genetic markers was found to have positive predictive values in predisposed individuals that ranged from 5.1% (in persons aged 65 to 69) to 91.7% (in persons aged 85 or older). It should be borne in mind that 50% of patients with AMD are not carriers of risk-associated markers. CONCLUSION: There is no rationale at present for genetic testing to estimate the individual risk of developing AMD. Several recent clinical trials have incorporated current pathophysiological knowledge, but nearly all of these trials have yielded negative findings, with only one exception.