GSK3 inhibition reduces ECM production and prevents age-related macular degeneration-like pathology.

Malattia Leventinese/Doyne honeycomb retinal dystrophy (ML/DHRD) is an age-related macular degeneration-like (AMD-like) retinal dystrophy caused by an autosomal dominant R345W mutation in the secreted glycoprotein, fibulin-3 (F3). To identify new small molecules that reduce F3 production in retinal pigmented epithelium (RPE) cells, we knocked-in a luminescent peptide tag (HiBiT) into the endogenous F3 locus that enabled simple, sensitive, and high-throughput detection of the protein. The GSK3 inhibitor, CHIR99021 (CHIR), significantly reduced F3 burden (expression, secretion, and intracellular levels) in immortalized RPE and non-RPE cells. Low-level, long-term CHIR treatment promoted remodeling of the RPE extracellular matrix, reducing sub-RPE deposit-associated proteins (e.g., amelotin, complement component 3, collagen IV, and fibronectin), while increasing RPE differentiation factors (e.g., tyrosinase, and pigment epithelium-derived factor). In vivo, treatment of 8-month-old R345W+/+ knockin mice with CHIR (25 mg/kg i.p., 1 mo) was well tolerated and significantly reduced R345W F3-associated AMD-like basal laminar deposit number and size, thereby preventing the main pathological feature in these mice. This is an important demonstration of small molecule-based prevention of AMD-like pathology in ML/DHRD mice and may herald a rejuvenation of interest in GSK3 inhibition for the treatment of retinal degenerative diseases, including potentially AMD itself.

Prevalence, time course, and visual impact of peripapillary hyperreflective ovoid mass-like structures (PHOMS) in pediatric patients with optic nerve pathologies.

BACKGROUND: Peripapillary hyperreflective ovoid mass-like structures (PHOMS) are a recently defined optical coherence tomography (OCT) finding. The purpose of this study was to characterize the presence of PHOMS and their visual significance in pediatric patients with and without optic nerve pathologies. METHODS: This retrospective study evaluated 400 patients (<18 years of age) including normal control subjects and patients with optic neuritis, papillitis, optic nerve head drusen (ONHD), and papilledema. Information on demographics, visual function, and structural parameters were obtained. RESULTS: PHOMS were found in 7 of 258 normal control eyes (2.7%), 9 of 59 eyes with optic neuritis (15.3%), 58 of 76 eyes with ONHD (76.3%), 3 of 11 eyes with papillitis (27.3%), and 180 of 308 eyes with papilledema (58.4%). PHOMS were more prevalent in the papilledema (P < 0.001), ONHD (P < 0.001), and optic neuritis (P = 0.028) eyes than in control eyes. We identified 5 cases where PHOMS developed de novo. This occurred over an average of 2.3 years (range, 0.2-7.4 years). Sixteen cases of PHOMS resolved over an average of 1.1 years (range, 0.3-4.0 years). Cross-sectionally, PHOMS were not associated with visual acuity (P = 0.551), retinal nerve fiber layer thickness (P = 0.068), ganglion cell volume (P = 0.375), or visual field mean deviation (P = 0.795). CONCLUSIONS: PHOMS are present in a majority of children with papilledema or ONHD. PHOMS are dynamic and may form de novo over time with optic nerve pathology and may resolve either through treatment or atrophy. There was no relationship between the presence of PHOMS and poor visual function in our study cohort.

Diagnostic dilemma of papilledema and pseudopapilledema.

BACKGROUND: Papilledema is the optic disc swelling caused by increased intracranial pressure (ICP) that can damage the optic nerve and cause subsequent vision loss. Pseudopapilledema refers to optic disc elevation without peripapillary fluid that can arise from several optic disc disorders, with optic disc drusen (ODD) being the most frequent cause. Occasionally, pseudopapilledema patients are mistakenly diagnosed as papilledema, leading to the possibility of unneeded procedures. We aim to thoroughly examine the most current evidence on papilledema and pseudopapilledema causes and several methods for distinguishing between both conditions. METHODS: An extensive literature search was conducted on electronic databases including PubMed and google scholar using keywords that were relevant to the assessed pathologies. Data were collected and then summarized in comprehensive form. RESULTS: Various techniques are employed to distinguish between papilledema and pseudopapilledema. These techniques include Fundus fluorescein angiography, optical coherence tomography, ultrasonography, and magnetic resonance imaging. Lumbar puncture and other invasive procedures may be needed if results are suspicious. CONCLUSION: Papilledema is a sight-threatening condition that may lead to visual affection. Many disc conditions may mimic papilledema. Accordingly, differentiation between papilledema and pseudopailledema is crucial and can be conducted through many modalities.

Imagen en retromodo para el diagnóstico de drusas del disco óptico: una serie de casos / Retro-mode imaging for the diagnosis of optic disc drusen: A case series

Objetivo: Nuestro principal objetivo es el de comparar la capacidad para detectar las drusas del disco óptico (DDO) utilizando diversas técnicas de imágenes no-invasivas, incluida la novedosa técnica de imagen de retromodo (RMI). Como segundo objetivo analizamos las características morfológicas de las DDO bajo esta última técnica. Materiales y métodos: Este estudio incluyó un total de 7 pacientes con DDO bilaterales, obteniendo un total de 14 ojos analizados. Se utilizaron técnicas no invasivas de imágenes multimodales, que incluyeron fotografía multicolor del fondo de ojo (MC), reflectancia en infrarrojo (NIR), autofluorescencia en luz verde y en luz azul (G-FAF y B-FAF, respectivamente) y RMI. La FAF se utilizó como el método principal para el diagnóstico de DDO. Dos observadores realizaron las comparaciones, obteniendo las tasas de detección de cada uno de los métodos. Las mediciones cuantitativas de las DDO incluyeron el número, el perímetro (P) y el área (A) de las DDO identificadas mediante la técnica de RMI. Resultado: La edad promedio de los pacientes incluidos fue de 49,28±23,16 años; 5 de los 7 pacientes fueron de sexo masculino. La técnica de RMI pudo detectar DDO en todos los casos, con una sensibilidad del 100%, en comparación con MC (sensibilidad del 60,71%), NIR (sensibilidad del 60,71%), B-FAF (sensibilidad del 100%), G-FAF (sensibilidad del 100%). RMI fue la única técnica de imagen capaz de evaluar morfológica y cuantitativamente las DDO. Conclusiones: RMI es una prometedora modalidad no-invasiva de imagen para diagnosticar DDO superficiales, proporcionando información valiosa sobre la distribución, la ubicación y el tamaño de estas. Por lo tanto, mediante nuestros resultados sugerimos la incorporación de la novedosa técnica de RMI como una herramienta complementaria para el diagnóstico y el seguimiento de DDO en combinación con los otros métodos de imagen multimodales.(AU)

Objective: We aimed to compare the detectability of optic disc drusen (ODD), using various non-invasive imaging techniques, including the novel retro-mode imaging (RMI), as well as to analyze the morphological characteristics of ODD on RMI. Methods: This study involved 7 patients with bilateral ODD, totaling 14 eyes. Multimodal imaging techniques, including multicolor fundus photography (MC), near-infrared reflectance (NIR), green and blue light fundus autofluorescence (G-FAF and B-FAF, respectively), and RMI were used to examine the eyes. FAF was used as the primary method of identifying ODD, and each method's detection rate was compared by two observers. Quantitative measurements of ODD included the number of ODD visualized by the RMI technique, the perimeter (P) and area (A) of ODD were identified. Results: The average age of the patients included was 49.28±23.16 years, with 5 of the 7 being men. RMI was able to detect ODD in all cases, with a sensitivity of 100%, compared to MC (sensitivity 60.71%), NIR (sensitivity 60.71%), B-FAF (sensitivity 100%), G-FAF (sensitivity 100%). RMI was the only imaging technique capable of assessing ODD morphology and quantifying ODD. Conclusions: RMI is a promising imaging modality for diagnosing superficial ODD, providing valuable information on the distribution, location, and size of ODD. We suggest the incorporation of RMI as a complementary tool for diagnosing and monitoring ODD in combination with other multimodal imaging methods.(AU)

Optic disc drusen: Dystrophic calcification, a potential target for treatment.

Optic disc drusen (ODD) are calcified, acellular bodies, seen in the optic nerve head of up to 2% of the population. Although seldomly affecting visual acuity, visual field defects are common, and severe, ischemic complications causing irreversible vision loss are known to occur. Different treatment strategies for ODD have been explored, but so far without success. This review focuses on the unique, calcified property of ODD, describing what we know about ODD pathogenesis and previously tried treatment strategies. In this context, we discuss current knowledge about calcium and pathological calcifications, including intracranial and ocular calcifications. We also explore some of the obstacles that must be addressed to develop a therapy centred on the concept of calcification, should calcification be identified as a pathogenic factor contributing to vision loss.

Validation of retinal oximetry vessel selection using fluorescein angiography in patients with optic disc drusen.

Retinal oximetry could provide insights into the pathophysiology of optic nerve disease, including optic disc drusen (ODD). Vessel selection for oximetry analysis is based on morphological characteristics of arterioles and venules and supported by an overlay of estimated blood oxygen saturations. The purpose of this cross-sectional study was to determine the validity of this vessel selection procedure by comparing it with vessel selection supported by video fluorescein angiography (FA). The study included 36 eyes of 36 patients with ODD who underwent retinal oximetry (Oxymap retinal oximeter T1) followed by FA (Heidelberg Spectralis). Two trained graders selected vessel segments in a pre-defined measurement area around the optic disc. One of these graders additionally performed the vessel segment selection with the support of FA images. When performed by the same grader, FA-supported and non-FA-supported vessel selection did not lead to significant differences in total vessel segment length, estimated oxygen saturations or vessel diameters (all p > 0.05). Inter-grader differences were found for arterial and venous segment lengths and arterial saturation (p < 0.05). A similar tendency was found for the arteriovenous saturation difference (p = 0.10). In conclusion, identifying vessel segments for retinal oximetry analysis based on vessel morphology and supported by a color-coded saturation overlay appears to be a valid method without the need for invasive angiography. A numerically small inter-grader variation may influence oximetry results. Further studies of retinal oximetry in ODD are warranted.

Drusen in the macula and parapapillary region.

PURPOSE: To examine histological characteristics and differences between drusen beneath the retinal pigment epithelium (small hard drusen) located in the macula and located in the parapapillary region. METHODS: We histomorphometrically examined human eyes enucleated due to uveal melanomas or secondary angle-closure glaucoma. RESULTS: The study included 106 eyes (age, 62.6 ± 15.2 years) with macular drusen (n = 7 globes) or parapapillary drusen (n = 29 eyes) and 70 eyes without drusen. In all drusen, periodic-acid-Schiff-positive material was located between the RPE basal membrane and the inner collagenous layer of Bruch's membrane (BM). Macular drusen as compared with parapapillary drusen had lower height (15.2 ± 10.1 µm versus 34.3 ± 19.8 µm; P = 0.003), while both groups did not differ significantly in basal drusen width (74.0 ± 36.3 µm versus 108.7 ± 101.0 µm; P = 0.95). Eyes with macular drusen and eyes without drusen did not differ significantly in BM thickness (2.74 ± 0.44 µm versus 2.55 ± 0.88 µm; P = 0.57) or in RPE cell density (35.4 ± 10.4 cells/480 µm versus 32.8 ± 7.5 cells/480 µm; P = 0.53), neither in the drusen region nor in the drusen vicinity, while BM thickness (4.60 ± 1.490 µm; P < 0.001) and RPE cell density (56.9 ± 26.8 cells/480 µm; P = 0.005) were higher at the parapapillary drusen. Eyes with macular drusen, eyes with parapapillary drusen, and eyes without drusen did not differ significantly in choriocapillaris density (all P > 0.10) and thickness (all P > 0.35). Limitations of the study, among others, were a small number and size of drusen examined, diseases leading to enucleation, lack of serial sections, limited resolution of light microscopy, and enucleation-related and histological preparation-associated artefacts. CONCLUSIONS: The findings of this study, also taking into account its methodological limitations, suggest that macular drusen and parapapillary drusen shared the morphological feature of periodic-acid-Schiff-positive material between the RPE basal membrane and BM and that they did not vary significantly in choriocapillaris thickness and density. RPE cell density and BM thickness were higher in parapapillary drusen than in macular drusen.

Retro-mode imaging for the diagnosis of optic disc drusen: a case series.

OBJECTIVE: We aimed to compare the detectability of optic disc drusen (ODD), using various non-invasive imaging techniques, including the novel retro-mode imaging (RMI), as well as to analyze the morphological characteristics of ODD on RMI. METHODS: This study involved seven patients with bilateral ODD, totaling 14 eyes. Multimodal imaging techniques, including multicolor fundus photography (MC), near-infrared reflectance (NIR), green and blue light fundus autofluorescence (G-FAF and B-FAF, respectively), and RMI were used to examine the eyes. FAF was used as the primary method of identifying ODD, and each method's detection rate was compared by two observers. Quantitative measurements of ODD included the number of ODD visualized by the RMI technique, the perimeter (P) and area (A) of ODD were identified. RESULTS: The average age of the patients included was 49.28 ±â€¯23.16 years, with five of the seven being men. RMI was able to detect ODD in all cases, with a sensitivity of 100%, compared to MC (sensitivity 60.71%), NIR (sensitivity 60.71%), B-FAF (sensitivity 100%), G-FAF (sensitivity 100%). RMI was the only imaging technique capable of assessing ODD morphology and quantifying ODD. CONCLUSIONS: RMI is a promising imaging modality for diagnosing superficial ODD, providing valuable information on the distribution, location, and size of ODD. We suggest the incorporation of RMI as a complementary tool for diagnosing and monitoring ODD in combination with other multimodal imaging methods.

Concomitant optic disk drusen and papilledema due to idiopathic intracranial hypertension in a pediatric cohort.

BACKGROUND: Optic disk drusen (ODD) in pediatric patients typically presents with pseudopapilledema. Diagnosing concomitant papilledema due to idiopathic intracranial hypertension (IIH) in these patients can be challenging. The purpose of this study was to evaluate the incidence and clinical features of papilledema due to IIH among pediatric patients with a new diagnosis of ODD and to discuss the clinical and paraclinical findings that helped diagnose this group. METHODS: The medical records of children <15 years of age with ODD confirmed by B-scan ultrasound at their first visit over a 4-year period (2019-2022) were reviewed retrospectively. Patients with concurrent IIH were identified, and the demographic and clinical characteristics were reviewed. RESULTS: A total of 83 children with confirmed ODD at the initial presentation were included, of whom 4 (4.8%) were diagnosed with concomitant IIH. Patients ranged in age from 7 to 15 years; 3 of the 4 were female, and 3 had IIH-related symptoms at presentation (1 was asymptomatic). None of the 4 patients had papilledema greater than Frisen grade 2. CONCLUSIONS: We recommend that clinicians review pertinent IIH symptoms and risk factors in children with ODD and follow the standard workup for IIH in suspicious cases. In asymptomatic patients with a new diagnosis of ODD, we recommend obtaining a follow-up optic nerve evaluation and optical coherence tomography scan to detect any significant interval change that might serve as a possible indicator of concomitant papilledema.

Optical coherence tomography angiography findings in optic disc drusen and idiopathic intracranial hypertension.

PURPOSE: To evaluate the changes in peripapillary microvascularity in idiopathic intracranial hypertension (IIH) and optic disc drusen (ODD) patients, by comparing them with those in healthy individuals, via optical coherence tomography angiography (OCTA). METHODS: Sixty-two eyes of 33 patients with ODD, 58 eyes of 30 patients with IIH, and 70 eyes of 70 healthy people were imaged for 6 × 6-mm optic disc scans on a spectral-domain OCTA. Vascular densities in superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris (CC) of ODD, IIH, and healthy eyes were compared with a one-way analysis of variance. Post-hoc analysis was performed with the Gabriel test. RESULTS: There was a significant decrease in peripapillary vessel density in SCP, DCP, and CC in patients with IIH compared to the control group (p < 0.05). In ODD patients, especially peripapillary vessel density in DCP was significantly reduced compared to the control group (p < 0.05). Peripapillary vessel density in DCP was significantly lower in the IIH group than ODD group (p < 0.05). CONCLUSIONS: Peripapillary vascular density may be affected during the course of the disease in both IIH and ODD. Compared to healthy individuals, the decrease in vascular density in these patients and the consequent decrease in perfusion in the peripapillary region may guide the pathogenesis of the complications in the course of these two diseases. Although vascular density in DCP and CC differs significantly between IIH and ODD, case-controlled studies are needed to evaluate the role of OCTA in the differential diagnosis of IHH and ODD.

Prevalence of optic disc drusen: A systematic review, meta-analysis and forecasting study.

Optic disc drusen (ODD) are calcium-containing deposits in the optic nerve head, capable of causing visual field defects and sudden visual loss. The underlying pathophysiology remains inadequately understood and treatment options are missing. In this paper, we systematically reviewed prevalence studies of ODD in non-selected populations to provide an overview of its prevalence, conducted meta-analyses to determine modality-specific prevalence estimates and performed a forecasting study to estimate current and future global population number of individuals with ODD. We searched 11 literature databases on 25 October 2022 for prevalence studies of ODD in non-selected populations. Eight eligible studies provided data from a total of 27 463 individuals. Prevalence estimates were stratified according to diagnostic modalities: ophthalmoscopy 0.37% (95% CI: 0.10-0.95%), fundus photography 0.12% (95% CI: 0.03-0.24%), spectral domain optical coherence tomography with enhanced depth imaging 2.21% (95% CI: 1.25-3.42%) and histopathology 1.82% (95% CI: 1.32-2.38%). Using histopathology-based summary prevalence estimate, we forecast 145 million individuals with ODD currently, a number expected to increase further due to world population growth. These numbers underscore the importance of including ODD in health education and highlight the necessity of continuing research in ODD.

Understanding pseudopapilledema on spectral domain optical coherence tomography.

Purpose: Optic nerve head drusen (ONHD), peripapillary hyperreflective ovoid mass-like structures (PHOMS), and horizontal hyperreflective lines (HHL) are commonly seen in eyes with pseudopapilledema on enhanced depth imaging (EDI) spectral domain optical coherence tomography (SDOCT). The objective of this study is to assess the frequency of ONHD, PHOMS, and HHL on spectral domain OCT in the eyes diagnosed to have pseudopapilledema. Methods: A retrospective case-control study included patients diagnosed as pseudopapilledema and had EDI SD OCT imaging of the optic nerve head (n = 48 eyes) and controls (n = 20 eyes). OCT scans through the optic nerve head were studied to diagnose ONHD, HHL, and PHOMS. One proportion z test was used to find the difference in proportions. Results: Forty eight eyes of 27 subjects were studied. ONHD as described by the optic disc drusen Studies consortium was noted in 19 eyes (39.48%), P value-0.032, PHOMS in 31 eyes (64.6%), P value 0.043, HL in 19 eyes (39.48%), P value 0.032, and none of the normals had ONHD, PHOMS, and HHL. Conclusions: PHOMS are more frequently seen than ONHD and HHL in eyes with pseudopapilledema.

Radial peripapillary capillary network in optic disc anomalies with abnormal tissues on disc surface.

Background: Optic disc anomalies with abnormal tissue on the disc surface includes, myelinated nerve fiber, optic disc drusen, and Bergmeister papillae. Imaging the radial peripapillary capillary (RPC) network in optic disc anomalies with optical coherence tomography-angiography (OCTA) can give information on the RPC network in these conditions. Purpose: This video describes the OCTA of optic nerve head and RPC network using the angio disc mode in cases of optic disc anomalies with abnormal tissue on the disc surface. Synopsis: This video presents characteristic features of RPC network in one eye each of myelinated nerve fiber, optic disc drusen, and Bergmeister papillae. Highlights: OCTA in optic disc anomalies with abnormal tissue on the disc surface show a dense RPC microvascular network. OCTA is an effective imaging modality to study vascular plexus/RPC and their alteration in these disc anomalies. Video link: https://youtu.be/zlflgijy56c.

The Presence of Optic Disc Drusen in Eyes with Uveitis.

PURPOSE: To evaluate the coexistence of optic disc drusen (ODD) in eyes with uveitis. METHODS: In this retrospective, observational study, patients followed up in a uvea clinic with all types of uveitis were evaluated. ODD were confirmed by ocular ultrasonography, optic nerve head enhanced-depth imaging optical coherence tomography, fundus autofluorescence, and fundus photography. RESULTS: ODD were detected in 17 of 545 (3.1%) uveitis patients. The mean age was 18.9 ± 10.4 years, and 76.5% were female. 45.5% were anterior, 42.4% were panuveitis, 6.1% were intermediate, and 6.1% were posterior uveitis. ODD were found bilaterally in all 17 patients; uveitis was unilateral in one patient. 58.8% were under the age of 18, and in this group, the rate of buried ODD was 78.9% (p = 0.039). In adults (seven patients), ODD were buried in 42.9%. CONCLUSION: ODD can be detected in eyes with uveitis and may clinically mimic optic disc edema, lead to misdiagnosis and/or overtreatment.

The extracellular microenvironment in immune dysregulation and inflammation in retinal disorders.

Inherited retinal dystrophies (IRDs) as well as genetically complex retinal phenotypes represent a heterogenous group of ocular diseases, both on account of their phenotypic and genotypic characteristics. Therefore, overlaps in clinical features often complicate or even impede their correct clinical diagnosis. Deciphering the molecular basis of retinal diseases has not only aided in their disease classification but also helped in our understanding of how different molecular pathologies may share common pathomechanisms. In particular, these relate to dysregulation of two key processes that contribute to cellular integrity, namely extracellular matrix (ECM) homeostasis and inflammation. Pathological changes in the ECM of Bruch's membrane have been described in both monogenic IRDs, such as Sorsby fundus dystrophy (SFD) and Doyne honeycomb retinal dystrophy (DHRD), as well as in the genetically complex age-related macular degeneration (AMD) or diabetic retinopathy (DR). Additionally, complement system dysfunction and distorted immune regulation may also represent a common connection between some IRDs and complex retinal degenerations. Through highlighting such overlaps in molecular pathology, this review aims to illuminate how inflammatory processes and ECM homeostasis are linked in the healthy retina and how their interplay may be disturbed in aging as well as in disease.