Perivascular neurons instruct 3D vascular lattice formation via neurovascular contact.

The vasculature of the central nervous system is a 3D lattice composed of laminar vascular beds interconnected by penetrating vessels. The mechanisms controlling 3D lattice network formation remain largely unknown. Combining viral labeling, genetic marking, and single-cell profiling in the mouse retina, we discovered a perivascular neuronal subset, annotated as Fam19a4/Nts-positive retinal ganglion cells (Fam19a4/Nts-RGCs), directly contacting the vasculature with perisomatic endfeet. Developmental ablation of Fam19a4/Nts-RGCs led to disoriented growth of penetrating vessels near the ganglion cell layer (GCL), leading to a disorganized 3D vascular lattice. We identified enriched PIEZO2 expression in Fam19a4/Nts-RGCs. Piezo2 loss from all retinal neurons or Fam19a4/Nts-RGCs abolished the direct neurovascular contacts and phenocopied the Fam19a4/Nts-RGC ablation deficits. The defective vascular structure led to reduced capillary perfusion and sensitized the retina to ischemic insults. Furthermore, we uncovered a Piezo2-dependent perivascular granule cell subset for cerebellar vascular patterning, indicating neuronal Piezo2-dependent 3D vascular patterning in the brain.

Therapeutic benefit of idebenone in patients with Leber hereditary optic neuropathy: The LEROS nonrandomized controlled trial.

Leber hereditary optic neuropathy (LHON) is a mitochondrial disease leading to rapid and severe bilateral vision loss. Idebenone has been shown to be effective in stabilizing and restoring vision in patients treated within 1 year of onset of vision loss. The open-label, international, multicenter, natural history-controlled LEROS study (ClinicalTrials.gov NCT02774005) assesses the efficacy and safety of idebenone treatment (900 mg/day) in patients with LHON up to 5 years after symptom onset (N = 199) and over a treatment period of 24 months, compared to an external natural history control cohort (N = 372), matched by time since symptom onset. LEROS meets its primary endpoint and confirms the long-term efficacy of idebenone in the subacute/dynamic and chronic phases; the treatment effect varies depending on disease phase and the causative mtDNA mutation. The findings of the LEROS study will help guide the clinical management of patients with LHON.

Compartmentalized ciliation changes of oligodendrocytes in aged mouse optic nerve.

Primary cilia are microtubule-based sensory organelles that project from the apical surface of most mammalian cells, including oligodendrocytes, which are myelinating cells of the central nervous system (CNS) that support critical axonal function. Dysfunction of CNS glia is associated with aging-related white matter diseases and neurodegeneration, and ciliopathies are known to affect CNS white matter. To investigate age-related changes in ciliary profile, we examined ciliary length and frequency in the retinogeniculate pathway, a white matter tract commonly affected by diseases of aging but in which expression of cilia has not been characterized. We found expression of Arl13b, a marker of primary cilia, in a small group of Olig2-positive oligodendrocytes in the optic nerve, optic chiasm, and optic tract in young and aged C57BL/6 wild-type mice. While the ciliary length and ciliated oligodendrocyte cells were constant in young mice in the retinogeniculate pathway, there was a significant increase in ciliary length in the anterior optic nerve as compared to the aged animals. Morphometric analysis confirmed a specific increase in the ciliation rate of CC1+ /Olig2+ oligodendrocytes in aged mice compared with young mice. Thus, the prevalence of primary cilia in oligodendrocytes in the visual pathway and the age-related changes in ciliation suggest that they may play important roles in white matter and age-associated optic neuropathies.

Osteopontin drives retinal ganglion cell resiliency in glaucomatous optic neuropathy.

Chronic neurodegeneration and acute injuries lead to neuron losses via diverse processes. We compared retinal ganglion cell (RGC) responses between chronic glaucomatous conditions and the acute injury model. Among major RGC subclasses, αRGCs and intrinsically photosensitive RGCs (ipRGCs) preferentially survive glaucomatous conditions, similar to findings in the retina subject to axotomy. Focusing on an αRGC intrinsic factor, Osteopontin (secreted phosphoprotein 1 [Spp1]), we found an ectopic neuronal expression of Osteopontin (Spp1) in other RGCs subject to glaucomatous conditions. This contrasted with the Spp1 downregulation subject to axotomy. αRGC-specific Spp1 elimination led to significant αRGC loss, diminishing their resiliency. Spp1 overexpression led to robust neuroprotection of susceptible RGC subclasses under glaucomatous conditions. In contrast, Spp1 overexpression did not significantly protect RGCs subject to axotomy. Additionally, SPP1 marked adult human RGC subsets with large somata and SPP1 expression in the aqueous humor correlated with glaucoma severity. Our study reveals Spp1's role in mediating neuronal resiliency in glaucoma.

High Altitude as a Risk Factor for the Development of Nonarteritic Anterior Ischemic Optic Neuropathy.

BACKGROUND: Episodic high-altitude exposure leads to optic disc edema and retinopathy. It is uncertain whether high-altitude exposure is a risk factor for nonarteritic anterior ischemic optic neuropathy (NAION). METHODS: We performed a single-center, retrospective, cross-sectional case study of 5 patients with high-altitude-associated NAION (HA-NAION) from April 2014 to April 2019. Main study parameters included known vascular risk factors for NAION, evolution of visual acuity, visual field, optic disc, and macula measurements. RESULTS: We studied 5 eyes of 5 patients with HA-NAION that occurred at 7,000-9,000 ft above sea level, 28 patients with classic NAION that developed at sea level (normal altitude NAION or NA-NAION), and 40 controls. All 5 patients with HA-NAION had clinically confirmed NAION by a neuro-ophthalmologist within 3-21 days of onset and comprehensive follow-up evaluations (average follow-up of 23 months). Other than high-altitude exposure, 4 of 5 patients had undiagnosed obstructive sleep apnea (OSA, apnea-hypopnea index 5.4-22.2) and 1 had systemic vascular risk factors. All patients had disc-at-risk in the contralateral eye. The best-corrected distance visual acuity was 20/20 to 20/70 (median logMAR 0) at presentation and 20/70 to counting finger (median logMAR 0) at ≥6 months. Automated static perimetry revealed average mean deviation of -18.6 dB at presentation and -22.1 dB at ≥6 months. The average retinal nerve fiber layer was 244 µm (80-348 µm) at onset and 59 µm (55-80 µm) at ≥6 months. The average ganglion cell complex thickness was 50 µm (43-54 µm) at onset and 52 µm (50-55 µm) at ≥6 months. The patients with OSA were started on home continuous positive airway pressure treatment. Visual outcomes were similar in patients with HA-NAION and NA-NAION. - After addressing all NAION risk factors, no new events occurred in the HA-NAION group within 2-8 years with or without repeat high-altitude exposure. CONCLUSIONS: NAION can occur under high-altitude conditions. HA-NAION is associated with relatively younger age at onset, disc-at-risk, and OSA. These patients exhibit a relatively progressive course of vision loss after initial onset and severe thinning of optic nerves on optical coherence tomography. Treatment for OSA is recommended, especially with repeated high-altitude exposure.

Association of left ventricular diastolic function with coronary artery calcium score: A Project Baseline Health Study.

BACKGROUND: Coronary artery calcium (CAC) and left ventricular diastolic dysfunction (LVDD) are strong predictors of cardiovascular events and share common risk factors. However, their independent association remains unclear. METHODS: In the Project Baseline Health Study (PBHS), 2082 participants underwent cardiac-gated, non-contrast chest computed tomography (CT) and echocardiography. The association between left ventricular (LV) diastolic function and CAC was assessed using multidimensional network and multivariable-adjusted regression analyses. Multivariable analysis was conducted on continuous LV diastolic parameters and categorical classification of LVDD and adjusted for traditional cardiometabolic risk factors. LVDD was defined using reference limits from a low-risk reference group without established cardiovascular disease, cardiovascular risk factors or evidence of CAC, (n â€‹= â€‹560). We also classified LVDD using the American Society of Echocardiography recommendations. RESULTS: The mean age of the participants was 51 â€‹± â€‹17 years with 56.6% female and 62.6% non-Hispanic White. Overall, 38.1% had hypertension; 13.7% had diabetes; and 39.9% had CAC >0. An intertwined network was observed between diastolic parameters, CAC score, age, LV mass index, and pulse pressure. In the multivariable-adjusted analysis, e', E/e', and LV mass index were independently associated with CAC after adjustment for traditional risk factors. For both e' and E/e', the effect size and statistical significance were higher across increasing CAC tertiles. Other independent correlates of e' and E/e' included age, female sex, Black race, height, weight, pulse pressure, hemoglobin A1C, and HDL cholesterol. The independent association with CAC was confirmed using categorical analysis of LVDD, which occurred in 554 participants (26.6%) using population-derived thresholds. CONCLUSION: In the PBHS study, the subclinical coronary atherosclerotic disease burden detected using CAC scoring was independently associated with diastolic function. GOV IDENTIFIER: NCT03154346.

Upregulation of retinal VEGF and connexin 43 in murine nonarteritic anterior ischemic optic neuropathy induced with 577 nm laser.

Nonarteritic anterior ischemic optic neuropathy (NAION) is a common acute optic neuropathy and cause of irreversible vision loss in those older than 50 years of age. There is currently no effective treatment for NAION and the biological mechanisms leading to neuronal loss are not fully understood. Promising novel targets include glial cells activation and intercellular communication mediated by molecules such as gap junction protein Connexin 43 (Cx43), which modulate neuronal fate in central nervous system disorders. In this study, we investigated retinal glial changes and neuronal loss following a novel NAION animal model using a 577 nm yellow laser. We induced unilateral photochemical thrombosis using rose bengal at the optic nerve head vasculature in adult C57BL/6 mice using a 577 nm laser and performed morphometric analysis of the retinal structure using serial in vivo optical coherence tomography (OCT) and histology for glial and neuronal markers. One day after experimental NAION, in acute phase, OCT imaging revealed peripapillary thickening of the retinal ganglion cell complex (GCC, baseline: 79.5 ±â€¯1.0 µm, n = 8; NAION: 93.0 ±â€¯2.5 µm, n = 8, P < 0.01) and total retina (baseline: 202.9 ±â€¯2.4 µm, n = 8; NAION: 228.1 ±â€¯6.8 µm, n = 8, P < 0.01). Twenty-one days after ischemia, at a chronic phase, there was significant GCC thinning (baseline 78.3 ±â€¯2.1 µm, n = 6; NAION: 72.2 ±â€¯1.9 µm, n = 5, P < 0.05), mimicking human disease. Examination of molecular changes in the retina one day after ischemia revealed that NAION induced a significant increase in retinal VEGF levels (control: 2319 ±â€¯195, n = 5; NAION: 4549 ±â€¯683 gray mean value, n = 5, P < 0.05), which highly correlated with retinal thickness (r = 0.89, P < 0.05). NAION also led to significant increase in mRNA level for Cx43 (Gj1a) at day 1 (control: 1.291 ±â€¯0.38; NAION: 3.360 ±â€¯0.58 puncta/mm2, n = 5, P < 0.05), but not of glial fibrillary acidic protein (Gfap) at the same time (control: 2,800 ±â€¯0.59; NAION: 4,690 ±â€¯0.90 puncta/mm2 n = 5, P = 0.19). Retinal ganglion cell loss at day 21 was confirmed by a 30% decrease in Brn3a+ cells (control: 2,844 ±â€¯235; NAION: 2,001 ±â€¯264 cells/mm2, n = 4, P < 0.05). We described a novel protocol of NAION induction by photochemical thrombosis using a 577 nm laser, leading to retinal edema and VEGF increase at day 1 and RGCs loss at day 21 after injury, consistent with the pathophysiology of human NAION. Early changes in glial cells intercommunication revealed by increased Cx43+ gap junctions are consistent with a retinal glial role in mediating cell-to-cell signaling after an ischemic insult. Our study demonstrates an early glial response in a novel NAION animal model and reveals glial intercommunication molecules such as Cx43 as a promising therapeutic target in acute NAION.

Multicolor Imaging of Optic Disc Drusen.

ABSTRACT: Optic disc drusen (ODD) are calcified deposits at the anterior optic nerve that are often detectable by ophthalmic imaging, including optical coherence tomography and fundus autofluorescence imaging. Multicolor (MC) imaging is a novel modality that captures reflectance of blue, green, and near-infrared laser lights with confocal scanning laser ophthalmoscopy to rapidly acquire high-resolution reflectance images of the optic disc and retina. Here, we show an eye with 3 MC imaging features of ODD, including prominent green hyperreflectance of the optic disc, green sheathing of the papillary and peripapillary vasculature (arterioles > venules), and presence of orange superficial ODD. MC imaging can provide rapid high-resolution assessment of eyes with optic nerve head elevation to help distinguish pseudopapilledema vs papilledema in children and adults without dilation, and future large studies incorporating MC imaging will help determine its contribution in the diagnosis and monitoring of ODD and assessment of other causes of optic nerve head elevation.

Predicting Visuo-Motor Diseases From Eye Tracking Data.

Eye tracking, or oculography, provides insight into where a person is looking. Recent advances in camera technology and machine learning have enabled prevalent devices like smart-phones to track gaze and visuo-motor behavior at near clinical-quality resolution. A critical gap in using oculography to diagnose visuo-motor dysfunction on a large scale is in the design of visual task paradigms, algorithms for diagnosis, and sufficiently large datasets. In this study, we used a 500 Hz infrared oculography dataset in healthy controls and patients with various neurological diseases causing visuo-motor abnormality due to eye movement disorder or vision loss. We used novel visuo-motor tasks involving rapid reading of 40 single-digit numbers per page and developed a machine learning algorithm for predicting disease state. We show that oculography data acquired while a person reads one page of 40 single-digit numbers (15-30 seconds duration) is predictive of of visuo-motor dysfunction (ROC-AUC = 0:973). Remarkably, we also find that short recordings of about 2.5 seconds (6-12× reduction in time) are sufficient for disease detection (ROC-AUC = 0:831). We identify which tasks are most informative for identifying visuo-motor dysfunction (those with the most visual crowding), and more specifically, which aspects of the task are most predictive (the recording segments where gaze moves vertically across lines). In addition to segregating disease and controls, our novel visuo-motor paradigms can discriminate among diseases impacting eye movement, diseases associated with vision loss, and healthy controls (81% accuracy compared with baseline of 33%).

Peripapillary and macular microvasculature features of non-arteritic anterior ischemic optic neuropathy.

Purpose: The hallmark of non-arteritic anterior ischemic optic neuropathy (NAION) is vascular compromise to the anterior optic nerve and thinning of the retinal nerve fiber layer (RNFL) and secondary degeneration of the retinal ganglion cell body or thinning of the ganglion cell complex (GCC). This study investigates optical coherence tomography (OCT) and OCT Angiography (OCTA) changes in chronic NAION and identifies imaging biomarkers that best predict disease. Methods: We performed a retrospective case-control study of 24 chronic NAION eyes (18 patients) and 70 control eyes (45 patients) to compare both whole-eye and regional OCT, OCTA, static perimetry measurements. OCT measurements were quantified automatically using commercial software, and OCTA was analyzed using custom MATLAB script with large vessel removal to measure 154 total parameters per eye. Results: We confirmed that static perimetry mean deviation (MD) was significantly worse in chronic NAION (-13.53 ± 2.36) than control (-0.47 ± 0.72; P < 0.001) eyes, and NAION eyes had 31 µm thinner RNFL (control: 95.9 ± 25.8 µm; NAION: 64.5 ± 18.0, P < 0.001), and 21.8 µm thinner GCC compared with controls (control: 81.5 ± 4.4 µm; NAION: 59.7 ± 10.5, P < 0.001). Spearman correlation analysis of OCTA parameters reveal that vessel area density (VAD) and flux are highly correlated with visual field MD and OCT measurements. Hierarchical clustering two distinct groups (NAION and control), where standardized measurements of NAION eyes were generally lower than controls. Two-way mixed ANOVAs showed significant interaction between patient status (control and chronic NAION) and structure (optic disk and macula) for annulus VAD and flux values and mean RNFL and GCC thickness. Post-hoc tests showed this effect stems from lower peripapillary values in NAION compared to controls. Separate logistic regression models with LASSO regularization identified VAD and flux are one of the best OCTA parameters for predicting NAION. Conclusion: Ischemic insult to the optic disk is more severe likely from primary degeneration of the affected peripapillary region while macula is affected by secondary retrograde degeneration and loss of retinal ganglion cells. In addition to OCT measurements, peripapillary and macular vascular parameters such as VAD and flux are good predictors of optic nerve and retinal changes in NAION.

Immunoprofiling of Nonarteritic Anterior Ischemic Optic Neuropathy.

Purpose: Nonarteritic anterior ischemic optic neuropathy (NAION) is a common acute optic neuropathy in those older than 50 years. There is no blood diagnostic test or efficient treatment for NAION. We investigated the suitability of blood inflammatory proteins as biomarkers and therapeutic targets of NAION. Methods: We conducted an exploratory, cross-sectional case-control study including 18 patients with NAION (n = 5 acute, and n = 13 chronic) and 9 controls. NAION was confirmed by clinical examination and optical coherence tomography. Subjects underwent peripheral blood collection; plasma was isolated within 2 hours and analyzed using a 76-plex array of cytokines, chemokines, and growth factors. Results: In acute NAION, there was increased peripapillary retinal thickness on optical coherence tomography consistent with optic disc edema. Plasma profiling revealed dramatic changes in inflammatory proteins in NAION. Statistical analysis generated a list of 20 top-ranked molecules in NAION, with 15% overlap in acute and chronic NAION. Principal component analysis, hierarchical clustering, and Spearman correlation generally segregated controls, acute and chronic NAION, with some overlap. Longitudinal data from one patient demonstrated an evolving inflammatory pattern from acute to chronic NAION. In acute NAION, Eotaxin-3, MCP-2, TPO, and TRAIL were the top biomarker candidates. In chronic NAION, IL-1α and CXCL10 emerged as the strongest therapeutic targets. Conclusions: Post-NAION inflammation occurs in both acute and chronic NAION. Statistical analysis of plasma profile changes generated a list of 20 potential biomarker and therapeutic targets of NAION. Translational Relevance: We identified blood molecular targets to improve NAION diagnosis and treatment.

Topographic Quadrant Analysis of Peripapillary Superficial Microvasculature in Optic Disc Drusen.

Background: Limited information is known about the topographic effect of optic disc drusen (ODD) on peripapillary retinal nerve fibers and microvasculature. Objective: This study aims to understand the structural and functional impact of ODD in different quadrants of the optic disc. Methods: We performed a retrospective case-control study of 22 ODD patients (34 eyes) and 26 controls (33 eyes) to compare optical coherence tomography (OCT) retinal nerve fiber layer (RNFL), OCT angiography (OCTA), and corresponding static perimetry mean deviation (MD) calculated using the modified Garway-Heath map in different quadrants of the optic disc. OCTA was analyzed using custom MATLAB script to measure six parameters in a peripapillary annulus with large vessel removal: vessel area density (VAD), vessel skeleton density (VSD), vessel perimeter index (VPI), vessel complexity index (VCI), flux, and vessel diameter index (VDI). Results: Quadrant analysis revealed that OCTA VAD and VCI were significantly decreased in superior, nasal, and inferior but not temporal quadrant. RNFL, VSD, and VPI were significantly impacted only in the superior and nasal quadrants. Corresponding visual field MDs in all ODD eyes were not different in the four quadrants, although eyes with MD equal or worse than -5 dB (32%) had worst visual field corresponding to the superior quadrant of the optic disc (inferior arcuate visual field). Structure-structure comparison of OCT and OCTA showed high correlation of RNFL with multiple OCTA measurements in the superior, nasal, and inferior quadrants but not temporal quadrant. Structure-function analysis revealed significant correlation of VAD and VCI and visual field MD in every quadrant, but RNFL was only significantly correlated in the superior and inferior quadrants. Conclusions: Peripapillary VAD and VCI are decreased in more quadrants than RNFL, supporting the clinical utility of performing OCTA in addition to OCT. Consistent with the most common locations of ODD, five OCT/OCTA measurements (VAD, VCI, RNFL, VSD, VPI) are decreased in the superior and nasal quadrants. OCT/OCTA measurements were significantly impacted in contrast to the relatively mild effect on corresponding visual field MD, consistent with the idea that a decrease in objective structural and vascular measurements occurs without parallel change in subjective visual function in ODD.

Freezing of saccades in dopa-responsive parkinsonian syndrome.

PURPOSE: Ocular motor abnormalities such as abnormal saccades are common in idiopathic Parkinson's disease (PD) and atypical parkinsonian syndrome, such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). In this study, we describe a case of patient with PD and show a video illustrating severe delay of reflexive saccades. OBSERVATIONS: A 68-year-old Caucasian woman with diagnosis of PD presented for evaluation of diplopia. Neuro-ophthalmic examination revealed good visual acuity in both eyes and normal optic nerves but prominent ocular motor abnormalities, including hypometric saccades, impaired smooth pursuit, and convergence insufficiency causing diplopia at near. Despite treatment with carbidopa-levodopa three times per day, she exhibited episodic, severe delay of reflexive saccades. During these episodes, the patient appeared frozen and unable to initiate reflexive saccades for 20 s or longer. This freezing of reflexive saccades was variable and occurred suddenly during exam but could be interrupted by smooth pursuit. There was no gait freezing, eyelid apraxia, or prominent exacerbation of other motor symptoms. Freezing of saccades dramatically resolved after increasing dosage of carbidopa-levodopa. CONCLUSIONS AND IMPORTANCE: We describe a patient with dopa-responsive parkinsonian syndrome with intermittent difficulty initiating reflexive saccades mimicking ocular motor apraxia. Resolution of saccadic freezing with higher carbidopa-levodopa is consistent with ocular motor impairment as a result of degeneration and dysfunction of the dopaminergic pathways in supranuclear ocular motor control.

Hypoxia-induced inflammation: Profiling the first 24-hour posthypoxic plasma and central nervous system changes.

Central nervous system and visual dysfunction is an unfortunate consequence of systemic hypoxia in the setting of cardiopulmonary disease, including infection with SARS-CoV-2, high-altitude cerebral edema and retinopathy and other conditions. Hypoxia-induced inflammatory signaling may lead to retinal inflammation, gliosis and visual disturbances. We investigated the consequences of systemic hypoxia using serial retinal optical coherence tomography and by assessing the earliest changes within 24h after hypoxia by measuring a proteomics panel of 39 cytokines, chemokines and growth factors in the plasma and retina, as well as using retinal histology. We induced severe systemic hypoxia in adult C57BL/6 mice using a hypoxia chamber (10% O2) for 1 week and rapidly assessed measurements within 1h compared with 18h after hypoxia. Optical coherence tomography revealed retinal tissue edema at 18h after hypoxia. Hierarchical clustering of plasma and retinal immune molecules revealed obvious segregation of the 1h posthypoxia group away from that of controls. One hour after hypoxia, there were 10 significantly increased molecules in plasma and 4 in retina. Interleukin-1ß and vascular endothelial growth factor were increased in both tissues. Concomitantly, there was significantly increased aquaporin-4, decreased Kir4.1, and increased gliosis in retinal histology. In summary, the immediate posthypoxic period is characterized by molecular changes consistent with systemic and retinal inflammation and retinal glial changes important in water transport, leading to tissue edema. This posthypoxic inflammation rapidly improves within 24h, consistent with the typically mild and transient visual disturbance in hypoxia, such as in high-altitude retinopathy. Given hypoxia increases risk of vision loss, more studies in at-risk patients, such as plasma immune profiling and in vivo retinal imaging, are needed in order to identify novel diagnostic or prognostic biomarkers of visual impairment in systemic hypoxia.

Multimodal Imaging Features of Optic Disc Drusen.

PURPOSE: To identify key en face multimodal imaging features of optic disc drusen (ODD). DESIGN: Retrospective cross-sectional study. METHODS: Setting: a single academic center. Patient orStudyPopulation: 786 patients (10-82 years of age) with diagnostic codes for optic disc drusen (ODD) in clinical notes extracted using natural language processing. Intervention orObservationProcedures: color fundus imaging, green-light and blue-light fundus autofluorescence (FAF), near-infrared reflectance (NIR), and enhanced-depth imaging optical coherence tomography (EDI-OCT). MainOutcomeMeasurements: Ophthalmic imaging characteristics and sensitivity of en face imaging compared with EDI-OCT. RESULTS: A total of 38 patients (61 eyes) had high-quality EDI-OCT scans and en face multimodal imaging. Green-light FAF imaging had the highest diagnostic sensitivity (96.8%) for ODD and showed homogeneous hyperautofluorescence, whereas blue-light FAF imaging had heterogeneous brightness, which helped differentiate superficial from deep ODD. Blue-light FAF (93.5%) and NIR (91.8%) imaging were also sensitive tests and revealed papillary and peripapillary features that were not well seen on green-light FAF, including the size and depth of ODD, morphology of the optic disc, and common ODD-associated structures such as horizontal hyper-reflective lines and peripapillary hyper-reflective ovoid mass-like structures (PHOMS). Color fundus imaging had the lowest sensitivity (82%). There was good inter-rater reliability for all en face imaging modalities (P < .0001 for all). CONCLUSIONS: In en face imaging, green-light FAF had the highest sensitivity for the diagnosis of ODD, whereas blue-light FAF and NIR images provided more information regarding the severity, location, depth, and size of ODD. In eyes that are negative on green-light FAF, EDI-OCT should be performed and provides the highest-resolution characterization of the entire optic disc to assess or rule out ODD.

Dual Specific Phosphatase 14 Deletion Rescues Retinal Ganglion Cells and Optic Nerve Axons after Experimental Anterior Ischemic Optic Neuropathy.

PURPOSE: Understanding molecular changes is essential for designing effective treatments for nonarteritic anterior ischemic optic neuropathy (AION), the most common acute optic neuropathy in adults older than 50 years. We investigated changes in the mitogen-activated protein kinase (MAPK) pathway after experimental AION and focused on dual specificity phosphatase 14 (Dusp14), an atypical MAPK phosphatase that is downstream of Krüppel-like transcription factor (KLF) 9-mediated inhibition of retinal ganglion cell (RGC) survival and axonal regeneration. MATERIALS AND METHODS: We induced severe AION in a photochemical thrombosis model in adult C57BL/6 wild-type and Dusp14 knockout mice. For comparison, some studies were performed using an optic nerve crush model. We assessed changes in MAPK pathway molecules using Western blot and immunohistochemistry, measured retinal thickness using optical coherence tomography (OCT), and quantified RGCs and axons using histologic methods. RESULTS: Three days after severe AION, there was no change in the retinal protein levels of MAPK ERK1/2, phosphorylated-ERK1/2 (pERK1/2), downstream effector Elk-1 and phosphatase Dusp14 on Western blot. Western blot analysis of purified RGCs after a more severe model using optic nerve crush also showed no change in Dusp14 protein expression. Because of the known importance of the Dusp14 and MAPK pathway in RGCs, we examined changes after AION in Dusp14 knockout mice. Three days after AION, Dusp14 knockout mice had significantly increased pERK1/2+, Brn3A+ RGCs on immunohistochemistry. Three weeks after AION, Dusp14 knockout mice had significantly greater preservation of retinal thickness, increased number of Brn3A+ RGCs on whole mount preparation, and increased number of optic nerve axons compared with wild-type mice. CONCLUSIONS: Genetic deletion of Dusp14, a MAPK phosphatase important in KFL9-mediated inhibition of RGC survival, led to increased activation of MAPK ERK1/2 and greater RGC and axonal survival after experimental AION. Inhibiting Dusp14 or activating the MAPK pathway should be examined further as a potential therapeutic approach to treatment of AION.Abbreviations: AION: anterior ischemic optic neuropathy; Dusp14: dual specific phosphatase 14; ERK1/2: extracellular signal-regulated kinases 1/2; Elk-1: ETS Like-1 protein; GCC: ganglion cell complex; GCL: ganglion cell layer; inner nuclear layer; KO: knockout; MAPK: mitogen-activated phosphokinase; OCT: optical coherence tomography; RGC: retinal ganglion cell; RNFL: retinal nerve fiber layer.

Updates on ophthalmic imaging features of optic disc drusen, papilledema, and optic disc edema.

PURPOSE OF REVIEW: Optic nerve head elevation can be associated with vision loss. This review provides an update regarding key features of optic disc drusen (ODD) compared with papilledema from increased intracranial pressure and optic disc edema from other causes. RECENT FINDINGS: Clinical history and funduscopic examination are not sufficient to correctly diagnose different causes of optic nerve head elevation. Multimodal ophthalmic imaging is noninvasive and should be used as first-line diagnostic testing to distinguish optic disc edema or papilledema from pseudoedema. Advanced ophthalmic imaging, including enhanced depth imaging optical coherence tomography (EDI-OCT) and autofluorescence imaging, can visualize ODD at high resolution and determine whether there is optic disc edema. OCT angiography does not require contrast and can rapidly visualize papillary, peripapillary, and macular microvasculature and identify important vascular biomarker of ischemia and, potentially, visual prognosis. SUMMARY: Multimodal ophthalmic imaging can help in the diagnosis of ODD and optic disc edema and identify patients at high risk of vision loss and neurological issues in order to ensure appropriate diagnosis and treatment.

Vision Loss in Optic Disc Drusen Correlates With Increased Macular Vessel Diameter and Flux and Reduced Peripapillary Vascular Density.

PURPOSE: To determine the key optical coherence tomography (OCT) and OCT angiography (OCTA) parameters that correlate with visual field loss in optic disc drusen (ODD). DESIGN: Retrospective cross-sectional study. METHODS: Single academic center. Seventeen patients with ODD (29 eyes) and 35 age-matched controls (53 eyes). Static perimetry, OCT, and OCTA imaging of optic disc and macula. Static perimetry, OCT, and OCTA measurements. RESULTS: We investigated the relationship between static perimetry and 14 OCT/OCTA measurements in patients with ODD vs age-matched controls and found 5 key measurements that most correlated with visual field loss included: peripapillary retinal nerve fiber layer (RNFL), macular ganglion cell complex (GCC), peripapillary vessel area density (VAD), macular vessel diameter (VD), and flux. Hierarchical clustering of these 5 measurements vs all clinical characteristics revealed 3 distinct clusters. ODD and control eyes with no visual field loss (mean deviation [MD] > -2.0 dB) had high RNFL and GCC, and low macular VD and flux. ODD eyes with mild visual field loss (MD -2.0 to -5.0 dB) had high RNFL, GCC, and increased macular VD and flux. ODD eyes with moderate/severe visual field loss (MD < -5.0 dB) had decreased RNFL, GCC, peripapillary VAD, and increased macular VD and flux. CONCLUSIONS: OCT and OCTA provided objective measurements that can help predict visual field loss in ODD. Our data suggest that increased macular flow may be an early biomarker of visual field loss in ODD, while decreased peripapillary vessel density and RNFL thickness are late biomarkers of visual field loss in ODD.