Puerarin Attenuates Iron Overload-Induced Ferroptosis in Retina through a Nrf2-Mediated Mechanism.

SCOPE: Age-related increases in retinal iron are involved in the development of retinal degeneration. The recently discovered iron-dependent mechanism of cell death known as ferroptosis has been linked to a wide range of pathologies. However, its role in iron overload-induced retinal degeneration is still uncertain. Puerarin has been associated with retinal protection. The purpose of this research is to determine how puerarin prevents retinal ferroptosis under iron overload conditions. METHODS AND RESULTS: Models of iron overload in Kunming mice, 661W cell, and ARPE-19 cell are established. Increased iron deposition significantly worsens retinal pathology, decreases cell viability, and induces ferroptotic changes. Puerarin mitigates iron overload-induced ferroptosis by decreasing excessive iron through the regulation of iron handling proteins and lowering lipid peroxidation through the inhibition of cyclooxygenase 2 expression and activation of the nuclear factor-E2-related factor 2 (Nrf2) signaling pathway and downstream ferroptosis-related proteins (solute carrier family 7 member 11, glutathione peroxidase 4 and heme oxygenase-1). The protective effect of puerarin on ferroptosis is diminished by the Nrf2-specific inhibitor ML385. CONCLUSION: These findings suggest targeting ferroptosis may be a novel strategy for the management of retinal degeneration. Puerarin may exert some of its ocular benefits by attenuating ferroptosis.

Rate and associations of inner retinal thinning in eyes with retinal vein occlusion and regressed macular oedema.

PURPOSE: To investigate the associations between visual acuity (VA) and structural optical coherence tomography (OCT) features in retinal vein occlusion (RVO) eyes after cystoid macular oedema (CMO) regression and to assess whether inner retinal thinning is progressive. METHODS: Retrospective observational study of RVO eyes with regressed CMO for at least 6 months. OCT scans at CMO regression were analysed, and features were correlated with VA at that visit. The inner retinal thickness was longitudinally compared between RVO and unaffected fellow eyes (controls) with linear mixed models. The rate of inner retinal thinning was obtained as the interaction term between disease status and time. Associations between inner retinal thinning and clinical characteristics were explored. RESULTS: Thirty-six RVO eyes were followed for 34.2 ± 21.1 months after CMO regression. The presence of ellipsoid zone disruption (regression estimate[standard error(SE)] = 0.16[0.04] LogMAR vs. intact, p < 0.001) and lower inner retinal thickness (regression estimate[SE] = -0.25[0.12] LogMAR for 100-µm increase, p = 0.01) were associated with worse VA. The inner retinal thickness decreased faster in RVO than controls (rate of retinal thinning -0.27 ± 0.09 µm/month vs. -0.08 ± 0.11 µm/month, p = 0.01). Macular ischaemia was associated with a faster rate of retinal thinning (interaction term macular ischaemia*follow-up time, p = 0.04). CONCLUSION: Inner retinal and photoreceptors' layers integrity are associated with better visual acuity once CMO resolves. RVO eyes undergo progressive inner retinal thinning after CMO regression, faster in eyes with macular ischaemia.

PROPHYLACTIC TREATMENT OF LATTICE DEGENERATION IN FELLOW EYES AFTER REPAIR OF UNCOMPLICATED PRIMARY RHEGMATOGENOUS RETINAL DETACHMENT.

PURPOSE: To evaluate prophylactic treatment (PTx) of lattice degeneration (LD) on retinal tear (RT) and rhegmatogenous retinal detachment (RRD) risk in fellow eyes of patients after primary RRD repair in the first eye. METHODS: This was a consecutive case series with cohort control involving patients with RRD repair from January 1, 2013, through December 31, 2017. Patients received PTx (PTx cohort) or no PTx (No-PTx cohort) in fellow eye with 5-year follow-up. Primary outcome measure was proportion with new fellow eye RT/RRD. Secondary outcomes included logarithm of minimum angle of resolution (logMAR) best-corrected visual acuity (BCVA) and status of myopia, posterior vitreous detachment, and pseudophakia. RESULTS: Four hundred ninety-eight patients were divided into 146 and 352 in PTx and No-PTx cohorts, respectively. PTx cohort developed significantly ( P < 0.05) fewer RT/RRD (17%) than No-PTx cohort (41%). PTx significantly ( P < 0.05) lowered RT/RRD irrespective of posterior vitreous detachment and myopia status. PTx patients undergoing phacoemulsification demonstrated significantly ( P < 0.05) less RT/RRD (22%) than No-PTx cohort (31%). There was no significant ( P = 0.96) final BCVA difference between PTx (median = 0 logMAR) and No-PTx (median = 0 logMAR) cohorts. CONCLUSION: PTx of asymptomatic fellow eye LD reduced RT/RRD risk.

Macular neovascularization in inherited retinal diseases: A review.

Inherited retinal diseases (IRDs) are the most common cause of blindness in working-age adults. Macular neovascularization (MNV) may be a presenting feature or occurs as a late-stage complication in several IRDs. We performed an extensive literature review on MNV associated with IRDs. MNV is a well-known complication of Sorsby fundus dystrophy and pseudoxanthoma elasticum. Those with late-onset Stargardt disease may masquerade as exudative age-related macular degeneration (AMD) when MNV is the presenting feature. Peripherinopathies may develop MNV that responds well to a short course of anti-vascular endothelial growth factor (anti-VEGF) therapy, while bestrophinopathies tend to develop MNV in the early stages of the disease without vision loss. Enhanced S-cone syndrome manifests type 3 MNV that typically regresses into a subfoveal fibrotic nodule. MNV is only a rare complication in choroideraemia and rod-cone dystrophies. Most IRD-related MNVs exhibit a favorable visual prognosis requiring less intensive regimens of anti-vascular endothelial growth factor therapy compared to age-related macular degeneration. We discuss the role of key imaging modalities in the diagnosis of MNV across a wide spectrum of IRDs and highlight the gaps in our knowledge with respect to the natural history and prognosis to pave the way for future directions of research.

Risk Factors for the Development of Fellow Eye Horseshoe Retinal Tears Following Horseshoe Retinal Tear in the Presenting Eye.

BACKGROUND: This study investigated factors associated with fellow eye horseshoe retinal tear (HST) development in consecutive patients with a presenting eye HST. MATERIALS AND METHODS: Medical records were reviewed for patients with initial HSTs between 2015 and 2017 and 24 factors were analyzed. Logistic regression was used to assess factors associated with fellow eye HST development. RESULTS: In total, 242 patients with an HST were identified with mean follow-up of 68.3 months. Four associations with fellow eye HST development were identified: (1) presence of fellow eye lattice degeneration, (2) subsequent presenting eye HSTs, (3) fellow eye vitreous hemorrhage at presenting eye HST occurrence, (4) OCT-determined stage 3 fellow eye posterior vitreous detachment at presenting eye HST occurrence. CONCLUSION: Four clinical findings associated with fellow eye HST development following presenting eye HST were identified. These factors may be important considerations during management patients with HST. [Ophthalmic Surg Lasers Imaging Retina 2023;54:338-345.].

Retinal detachment in a pediatric patient with enhanced S-cone syndrome.

Enhanced S-cone syndrome (ESCS), also known as Goldmann-Favre syndrome, is a retinal degeneration that presents in childhood and leads to progressive nyctalopia and visual field loss. In advanced cases, this degeneration can result in loss of central visual acuity. We describe the case of a 15-year-old boy with ESCS who presented with retinal detachment, a rare complication.

Stickler and Wagner Syndrome in African Americans.

BACKGROUND: Stickler (STL) and Wagner (WGN) syndromes are rare inherited vitreoretinopathies associated with retinal detachments (RD). There is a paucity of case reports describing these diseases in African American patients. METHODS: An IRB-approved, retrospective chart review of African American patients with genetically proven ocular-only STL or WGN was performed, and 6 patients were identified. RESULTS: Three patients had a COL2A1 mutation, two had a COL11A1 mutation, and one had a VCAN mutation. None had Pierre Robin facies. All were myopes with lattice degeneration and five had RD. Three underwent RD repair with vitrectomy (PPV), scleral buckle (SB), endolaser (EL), and silicone oil (SO). Two received laser retinopexy for localized RD and one received a prophylactic SB with 360° peripheral laser retinopexy. CONCLUSION: STL and WGN should be considered in myopic African American patients with lattice degeneration, giant retinal tears, abnormal vitreous, or spontaneous RD. Prophylactic laser treatment and aggressive surgical treatment of RD should be considered. [Ophthalmic Surg Lasers Imaging Retina 2023;54:97-101.].

Analysis of Posterior Vitreous Detachment and Development of Complications Using a Large Database of Retina Specialists.

PURPOSE: To examine the incidence of complications after posterior vitreous detachment (PVD) through an extended follow-up period and to identify patient-specific factors associated with a greater incidence of complication. DESIGN: Multicenter, retrospective observational study. PARTICIPANTS: Eyes with acute PVDs between 2015 and 2019 were identified through the Vestrum Health database. METHODS: Complications (vitreous hemorrhage, retinal break, and retinal detachment) were evaluated after acute PVD at presentation and throughout the 6-month follow-up period. MAIN OUTCOME MEASURES: Rate of complications throughout the 6 month follow-up period after PVD and odds of complications by patient-specific factors. RESULTS: A total of 9635 eyes were included. The rate of any complication was 25.0%, isolated vitreous hemorrhage was 13.1%, retinal breaks without detachment was 16.0%, and retinal detachment was 4.2%. The majority of each complication was noted at presentation; however, 8.0% of isolated vitreous hemorrhages, 19.2% of retinal breaks without detachment, and 25.8% of retinal detachments were first noted within the 6-month follow-up period. Men experienced a significantly higher rate of any complication than women (30.0% versus 21.7%, P < 0.001), as well as retinal breaks and retinal detachments at both presentation and within 6-month follow-up. Patients with pseudophakia experienced significantly higher rates of delayed retinal detachment than phakic eyes (odds ratio, 1.85 [1.13, 3.04], P = 0.01). Among eyes with lattice/peripheral retinal degeneration, 44.2% experienced any complication throughout the clinical course. The presence of a retinal break in the fellow eye and retinal detachment in the fellow eye was associated with a significantly increased rate of any complication at any time point (retinal break: P < 0.0001; retinal detachment: P = 0.02), as well as each individual complication within the 6 month follow-up period. Among eyes with vitreous hemorrhage at presentation, 42.0% had a concurrent or delayed retinal break and 10.5% had concurrent or delayed retinal detachments. CONCLUSIONS: A clinically significant proportion of PVD-related complications are detected late, warranting extended follow-up, especially in higher-risk groups such as men, pseudophakic eyes, eyes with lattice/peripheral retinal degeneration, and eyes with a history of retinal breaks or detachment in the fellow eye. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Incidence and Risk Factors for Delayed Retinal Tears after an Acute, Symptomatic Posterior Vitreous Detachment.

PURPOSE: To determine the long-term incidence of and risk factors for delayed retinal tears after acute, symptomatic posterior vitreous detachment (PVD) without concurrent retinal tears. DESIGN: Retrospective, observational case series. SUBJECTS: Patients diagnosed with an acute, symptomatic PVD without concurrent retinal tears at a tertiary eye center between 2013 and 2018. METHODS: This is a retrospective, consecutive, and observational case series. Acute and symptomatic PVD was defined as experiencing flashes or floaters for 1 month or less at the time of diagnosis. Patients with a retinal tear or detachment at or before the time of diagnosis were not included. The occurrence and timing of subsequent retinal tears after initial PVD diagnosis were recorded. The age, sex, race, refractive error, lens status, lattice degeneration status, and type of physician (retina specialist vs. nonretina specialist) who saw the patient were also recorded. MAIN OUTCOME MEASURES: Time to the development of a delayed retinal tear. RESULTS: A total of 389 eyes from 389 patients had acute and symptomatic PVDs without concurrent retinal tears or detachments at diagnosis. Kaplan-Meier analysis showed that 7.39% of eyes developed delayed retinal tears by 6.24 years after initial PVD diagnosis. Of these tears, 50% occurred within 4.63 months of PVD diagnosis, and 63.46% occurred within 1 year of PVD diagnosis. Cox-Mantel log-rank analysis showed that those who were younger (age < 60 years), myopic, or had lattice degeneration were more likely to develop tears. A multivariate Cox proportional-hazards models controlling for other significant risk factors supported lattice degeneration as a likely risk factor for delayed retinal tear. CONCLUSIONS: This study demonstrates that 7.39% of patients with acute, symptomatic PVD without concurrent retinal tears develop delayed retinal tears by 6.24 years after PVD diagnosis, with many developing tears well after a typical 6-week follow-up time for PVD. Lattice degeneration is a significant risk factor for delayed tears. These findings can guide clinicians in establishing optimal follow-up protocols for patients with acute, symptomatic PVD. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Ongoing retinal degeneration despite intraventricular enzyme replacement therapy with cerliponase alfa in late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2 disease).

BACKGROUND/AIMS: Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) is a neurodegenerative, blinding lysosomal storage disorder. The purpose of the current study was to characterise the progression of CLN2-associated retinal degeneration in patients under intraventricular enzyme replacement therapy (ERT) with cerliponase alfa. METHODS: We analysed visual function, retinal morphology and neuropaediatric data using preferential looking test (PLT), Weill Cornell Batten Scale (WCBS), optical coherence tomography (OCT) imaging and the Hamburg Motor-Language late-infantile neuronal ceroid lipofuscinosis (LINCL) Scale (M-L scale). RESULTS: Fifty-six eyes of 28 patients had baseline PLT, WCBS and OCT. 15 patients underwent serial examinations, resulting in a total of 132 OCT scans and WCBS results, 66 Hamburg M-L scores and 49 PLT results during a mean follow-up time of 18.2 months (range 5-40). A negative correlation (r=-0.69, p<0.001) was found between central retinal thickness (CRT) values and age at examination with a maximal annual decrease of 23 µm between 56 and 80 months of age. A significant correlation was observed between PLT results and the age at examination (r=0.46, p=0.001), the WCBS scores (r=0.62; p<0.001) and CRT values (r=-0.64; p<0.001). The M-L score correlated with the ocular measurements (CRT: r=0.58, p<0.001; WCBS r=-0.64, p<0.001; PLT score: r=-0.57, p<0.001). CONCLUSION: Despite intraventricular ERT, retinal degeneration progressed in patients with CLN2 and was particularly pronounced between 56 and 80 months of age. Retina-directed therapies should therefore be initiated before or as early as possible during the phase of rapid retinal degeneration. PLT and WCBS were identified as valuable outcome measures to monitor disease progression. TRIAL REGISTRATION NUMBER: NCT04613089.

Risk of Normal Tension Glaucoma Progression From Automated Baseline Retinal-Vessel Caliber Analysis: A Prospective Cohort Study.

PURPOSE: To determine the relationship between baseline retinal-vessel calibers computed by a deep-learning system and the risk of normal tension glaucoma (NTG) progression. DESIGN: Prospective cohort study. METHODS: Three hundred and ninety eyes from 197 patients with NTG were followed up for at least 24 months. Retinal-vessel calibers (central retinal arteriolar equivalent [CRAE] and central retinal venular equivalent [CRVE]) were computed from fundus photographs at baseline using a previously validated deep-learning system. Retinal nerve fiber layer (RNFL) thickness and visual field (VF) were evaluated semiannually. The Cox proportional-hazards model was used to evaluate the relationship of baseline retinal-vessel calibers to the risk of glaucoma progression. RESULTS: Over a mean follow-up period of 34.36 ± 5.88 months, 69 NTG eyes (17.69%) developed progressive RNFL thinning and 22 eyes (5.64%) developed VF deterioration. In the multivariable Cox regression analysis adjusting for age, gender, intraocular pressure, mean ocular perfusion pressure, systolic blood pressure, axial length, standard automated perimetry mean deviation, and RNFL thickness, narrower baseline CRAE (hazard ratio per SD decrease [95% confidence interval], 1.36 [1.01-1.82]) and CRVE (1.35 [1.01-1.80]) were associated with progressive RNFL thinning and narrower baseline CRAE (1.98 [1.17-3.35]) was associated with VF deterioration. CONCLUSION: In this study, each SD decrease in the baseline CRAE or CRVE was associated with a more than 30% increase in the risk of progressive RNFL thinning and a more than 90% increase in the risk of VF deterioration during the follow-up period. Baseline attenuation of retinal vasculature in NTG eyes was associated with subsequent glaucoma progression. High-throughput deep-learning-based retinal vasculature analysis demonstrated its clinical utility for NTG risk assessment.

Inner retinal degeneration associated with optic nerve head drusen in pseudoxanthoma elasticum.

BACKGROUND/AIMS: To determine the association of age, presence of optic nerve head drusen (ONHD) and number of previous intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections with inner retinal layer thicknesses in patients with pseudoxanthoma elasticum (PXE). METHODS: In this retrospective case-control study, longitudinal spectral-domain optical coherence tomography imaging data from patients with PXE were compared with controls. A custom deep-learning-based segmentation algorithm was trained and validated to quantify the retinal nerve fibre layer (RNFL) and ganglion cell layer (GCL). The association of age, number of anti-VEGF injections and ONHD with the RNFL and GCL thickness in the outer ETDRS subfields as dependent variables was investigated using mixed model regression. RESULTS: Fourty-eight eyes of 30 patients with PXE were compared with 100 healthy eyes. The mean age was 52.5±12.9 years (range 21.3-68.2) for patients and 54.2±18.7 years (range 18.0-84.5) for controls. In patients, ONHD were visible in 15 eyes from 13 patients and 31 eyes had received anti-VEGF injections. In the multivariable analysis, age (-0.10 µm/year, p<0.001), the diagnosis of PXE (-2.03 µm, p=0.005) and an interaction term between age and the presence of ONHD (-0.20 µm/year, p=0.001) were significantly associated with the GCL thickness. Including the number of intravitreal injections did not improve the model fit. The RNFL thickness was not significantly associated with any of these parameters. CONCLUSIONS: This study demonstrates a significant association of ageing and ONHD with GCL thinning in patients with PXE, but not with the number of anti-VEGF injections. Given the severity of inner retinal degeneration in PXE, a clinical trial investigating neuroprotective therapy warrants consideration.

In vivo base editing rescues cone photoreceptors in a mouse model of early-onset inherited retinal degeneration.

Leber congenital amaurosis (LCA) is the most common cause of inherited retinal degeneration in children. LCA patients with RPE65 mutations show accelerated cone photoreceptor dysfunction and death, resulting in early visual impairment. It is therefore crucial to develop a robust therapy that not only compensates for lost RPE65 function but also protects photoreceptors from further degeneration. Here, we show that in vivo correction of an Rpe65 mutation by adenine base editor (ABE) prolongs the survival of cones in an LCA mouse model. In vitro screening of ABEs and sgRNAs enables the identification of a variant that enhances in vivo correction efficiency. Subretinal delivery of ABE and sgRNA corrects up to 40% of Rpe65 transcripts, restores cone-mediated visual function, and preserves cones in LCA mice. Single-cell RNA-seq reveals upregulation of genes associated with cone phototransduction and survival. Our findings demonstrate base editing as a potential gene therapy that confers long-lasting retinal protection.

Lateral gain is impaired in macular degeneration and can be targeted to restore vision in mice.

Macular degeneration is a leading cause of blindness. Treatments to rescue vision are currently limited. Here, we study how loss of central vision affects lateral feedback to spared areas of the human retina. We identify a cone-driven gain control mechanism that reduces visual function beyond the atrophic area in macular degeneration. This finding provides an insight into the negative effects of geographic atrophy on vision. Therefore, we develop a strategy to restore this feedback mechanism, through activation of laterally projecting cells. This results in improved vision in Cnga3-/- mice, which lack cone function, as well as a mouse model of geographic atrophy. Our work shows that a loss of lateral gain control contributes to the vision deficit in macular degeneration. Furthermore, in mouse models we show that lateral feedback can be harnessed to improve vision following retinal degeneration.

Clinical profile and distribution of peripheral retinal changes in myopic population in a hospital-based study in North India.

Purpose: To evaluate the prevalence of different types of peripheral retinal changes in a myopic population in North India and correlate them with axial length. Methods: This cross-sectional, hospital-based survey included 600 eyes of 300 myopic individuals, aged between 10 and 40 years, attending the outdoor ophthalmology clinic of a tertiary eye care hospital in North India were examined from July 2019 to July 2020. They were divided into mild, moderate, high, and severe myopia according to the spherical equivalent of refraction. Axial length was recorded. Peripheral retinal changes were examined by scleral indentation binocular indirect ophthalmoscopy. Standardized findings considered with their fundus location were lattice degeneration, white without pressure and white with pressure, snail-track degenerations, peripheral chorioretinal atrophy, retinal holes, tears, and detachment. The study was approved by the institutional ethics committee, and all participants provided informed consent. Results: Peripheral retinal degenerations were found in almost half (53%) of all myopes included in the study. The most common peripheral retinal degeneration found was lattice degeneration, followed by white without pressure, white with pressure, and chorioretinal atrophy. Most of the peripheral retinal degenerations were seen in the temporal quadrant of the fundus, either superotemporal or inferotemporal. There was a significant positive association between the prevalence of peripheral retinal degeneration with age, increased axial length, and severity of myopia. Conclusion: The results of our study indicate the necessity for careful peripheral fundus examinations of all myopes, irrespective of age and degree of myopia, for early diagnosis and better management of visual-threatening complications like retinal detachment.

The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention.

Norrie disease is caused by mutation of the NDP gene, presenting as congenital blindness followed by later onset of hearing loss. Protecting patients from hearing loss is critical for maintaining their quality of life. This study aimed to understand the onset of pathology in cochlear structure and function. By investigating patients and juvenile Ndp-mutant mice, we elucidated the sequence of onset of physiological changes (in auditory brainstem responses, distortion product otoacoustic emissions, endocochlear potential, blood-labyrinth barrier integrity) and determined the cellular, histological, and ultrastructural events leading to hearing loss. We found that cochlear vascular pathology occurs earlier than previously reported and precedes sensorineural hearing loss. The work defines a disease mechanism whereby early malformation of the cochlear microvasculature precedes loss of vessel integrity and decline of endocochlear potential, leading to hearing loss and hair cell death while sparing spiral ganglion cells. This provides essential information on events defining the optimal therapeutic window and indicates that early intervention is needed. In an era of advancing gene therapy and small-molecule technologies, this study establishes Ndp-mutant mice as a platform to test such interventions and has important implications for understanding the progression of hearing loss in Norrie disease.

Protection against light-induced retinal degeneration via dual anti-inflammatory and anti-angiogenic functions of thrombospondin-1.

BACKGROUND AND PURPOSE: Retinal photodamage is a high-risk factor for age-related macular degeneration (AMD), the leading cause of irreversible blindness worldwide. However, both the pathogenesis and effective therapies for retinal photodamage are still unclear and debated. EXPERIMENTAL APPROACH: The anti-inflammatory effects of thrombospondin-1 on blue light-induced inflammation in ARPE-19 cells and in retinal inflammation were evaluated. Furthermore, the anti-angiogenic effects of thrombospondin-1 on human microvascular endothelial cells (hMEC-1 cells) and a laser-induced choroidal neovascularisation (CNV) mouse model were evaluated. in vitro experiments, including western blotting, immunocytochemistry, migration assays and tube formation assays, as well as in vivo experiments, including immunofluorescence, visual electrophysiology, spectral-domain optical coherence tomography, and fluorescein angiography, were employed to evaluate the anti-inflammatory and anti-angiogenic effects of thrombospondin-1. KEY RESULTS: Specific effects of blue light-induced retinal inflammation and pathological angiogenesis were reflected by up-regulation of pro-inflammatory factors and activation of angiogenic responses, predominantly regulated by the NF-κB and VEGFR2 pathways respectively. During the blue light-induced pathological progress, THBS-1 derived from retinal pigment epithelium down-regulated proteomics and biological assays. Thrombospondin-1 treatment also suppressed inflammatory infiltration and neovascular leakage. The protective effect of Thrombospondin-1 was additionally demonstrated by a substantial rescue of visual function. Mechanistically, thrombospondin-1 reversed blue light-induced retinal inflammation and angiogenesis by blocking the activated NF-κB and VEGFR2 pathways, respectively. CONCLUSION AND IMPLICATIONS: Thrombospondin-1, with dual anti-inflammatory and anti-neovascularisation properties, is a promising agent for protection against blue light-induced retinal damage and retinal degenerative disorders which are pathologically associated with inflammatory and angiogenic progress. LINKED ARTICLES: This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc.

Wolfram syndrome with vitelliform retinal deposits.

BACKGROUND: : Wolfram Syndrome is a rare genetic disorder usually inherited in an autosomal recessive manner. The acronym DIDMOAD characterizes the classic constellation of findings: diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. However, other ocular and systemic manifestations may also be present. The aim of this report is to present a patient with Wolfram Syndrome presenting with vitelliform changes in the retina - an association that has not been previously reported. MATERIALS AND METHODS: : Case Report. RESULTS: : Ophthalmologic examination and imaging studies showed bilateral optic neuropathy and scattered bilateral subretinal vitelliform deposits. Genetic testing was positive for Wolfram Syndrome. CONCLUSION: : This patient showed optic atrophy with associated vitelliform retinal changes. The previously unreported association of these findings present possible associations in the molecular pathophysiology underlying both Wolfram syndrome and the spectrum of retinal disorders associated with vitelliform changes.

Transcriptional Profiling Identifies Upregulation of Neuroprotective Pathways in Retinitis Pigmentosa.

Hereditary retinal degenerations like retinitis pigmentosa (RP) are among the leading causes of blindness in younger patients. To enable in vivo investigation of cellular and molecular mechanisms responsible for photoreceptor cell death and to allow testing of therapeutic strategies that could prevent retinal degeneration, animal models have been created. In this study, we deeply characterized the transcriptional profile of mice carrying the transgene rhodopsin V20G/P23H/P27L (VPP), which is a model for autosomal dominant RP. We examined the degree of photoreceptor degeneration and studied the impact of the VPP transgene-induced retinal degeneration on the transcriptome level of the retina using next generation RNA sequencing (RNASeq) analyses followed by weighted correlation network analysis (WGCNA). We furthermore identified cellular subpopulations responsible for some of the observed dysregulations using in situ hybridizations, immunofluorescence staining, and 3D reconstruction. Using RNASeq analysis, we identified 9256 dysregulated genes and six significantly associated gene modules in the subsequently performed WGCNA. Gene ontology enrichment showed, among others, dysregulation of genes involved in TGF-ß regulated extracellular matrix organization, the (ocular) immune system/response, and cellular homeostasis. Moreover, heatmaps confirmed clustering of significantly dysregulated genes coding for components of the TGF-ß, G-protein activated, and VEGF signaling pathway. 3D reconstructions of immunostained/in situ hybridized sections revealed retinal neurons and Müller cells as the major cellular population expressing representative components of these signaling pathways. The predominant effect of VPP-induced photoreceptor degeneration pointed towards induction of neuroinflammation and the upregulation of neuroprotective pathways like TGF-ß, G-protein activated, and VEGF signaling. Thus, modulation of these processes and signaling pathways might represent new therapeutic options to delay the degeneration of photoreceptors in diseases like RP.

Resolution of cystoid macular edema with topical carbonic anhydrase inhibitor in a patient with retinal dystrophy associated with Cohen syndrome.

Background: Cohen Syndrome (CS) is an autosomal recessive multisystemic disorder characterized by various ophthalmologic findings, including retinal dystrophy and associated cystoid macular edema (CME), in which there was no known effective treatment approach.Material and Methods: We describe a CS patient with a homozygous c.62 T > G, p.(Leu21*) mutation in the VPS13B gene with a topical carbonic anhydrase inhibitor (CAI; brinzolamide %1, thrice daily) responding CME.Case Description: A seven-year-old girl with an established diagnosis of CS was referred with a primary complaint of nyctalopia. On ophthalmologic examination, bilateral decreased visual acuity and normal-appearing macula with mild optic disc pallor were present. However, the detailed evaluation revealed bilateral blunted foveal reflexes, barely visible foveal pigmentation, and slightly attenuated retinal vessels without any peripheral retinal pigmentary changes in dilated fundus examination, and CME on optical coherence tomography. Bilateral topical brinzolamide thrice daily was initiated for CME. Visual acuity increased, and CME was resolved except for minimal schisis at the inner nuclear layer level at the third-month follow-up visit and remained stable up to one-year follow-up. CME reappeared after five months of self-discontinuation of the patient's therapy but resolved again with treatment resumption.Conclusion: We report the first case of CME secondary to rod-cone dystrophy associated with CS showing improvement in anatomy and visual acuity with a topical CAI.