Screening for Impaired Visual Acuity in Older Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: A 2016 review for the US Preventive Services Task Force (USPSTF) found that effective treatments are available for refractive errors, cataracts, and wet (advanced neovascular) or dry (atrophic) age-related macular degeneration (AMD), but there were no differences between visual screening vs no screening on visual acuity or other outcomes. Objective: To update the 2016 review on screening for impaired visual acuity in older adults, to inform the USPSTF. Data Sources: Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews (to February 2021); surveillance through January 21, 2022. Study Selection: Randomized clinical trials and controlled observational studies on screening, vascular endothelial growth factor (VEGF) inhibitors (wet AMD), and antioxidant vitamins and minerals (dry AMD); studies on screening diagnostic accuracy. Data Extraction and Synthesis: One investigator abstracted data and a second checked accuracy. Two investigators independently assessed study quality. Results: Twenty-five studies (N = 33 586) were included (13 trials, 11 diagnostic accuracy studies, and 1 systematic review [19 trials]). Four trials (n = 4819) found no significant differences between screening vs no screening in visual acuity or other outcomes. Visual acuity tests (3 studies; n = 6493) and screening question (3 studies; n = 5203) were associated with suboptimal diagnostic accuracy. For wet AMD, 4 trials (n = 2086) found VEGF inhibitors significantly associated with greater likelihood of 15 or more letters visual acuity gain (risk ratio [RR], 2.92 [95% CI, 1.20-7.12]; I2 = 76%; absolute risk difference [ARD], 10%) and less than 15 letters visual acuity loss (RR, 1.46 [95% CI, 1.22-1.75]; I2 = 80%; ARD, 27%) vs sham treatment, with no increased risk of serious harms. For dry AMD, a systematic review (19 trials) found antioxidant multivitamins significantly associated with decreased risk of progression to late AMD (3 trials, n = 2445; odds ratio [OR], 0.72 [95% CI, 0.58-0.90]) and 3 lines or more visual acuity loss (1 trial, n = 1791; OR, 0.77 [95% CI, 0.62-0.96]) vs placebo. Zinc was significantly associated with increased risk of genitourinary events and beta carotene with increased risk of lung cancer in former smokers; other serious harms were infrequent. Conclusions and Relevance: This review found that effective treatments are available for common causes of impaired visual acuity in older adults. However, direct evidence found no significant association between vision screening vs no screening in primary care and improved visual outcomes.

Screening for Glaucoma in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Two 2013 systematic reviews to inform the US Preventive Services Task Force (USPSTF) found insufficient evidence to assess benefits and harms of screening for primary open-angle glaucoma (OAG) in adults. Objective: To update the 2013 reviews on screening for glaucoma, to inform the USPSTF. Data Sources: Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews (to February 2021); surveillance through January 21, 2022. Study Selection: Randomized clinical trials (RCTs) of screening, referral, and treatment; and studies of screening test diagnostic accuracy. Data Extraction and Synthesis: One investigator abstracted data and a second checked accuracy. Two investigators independently assessed study quality. Results: Eighty-three studies (N = 75 887) were included (30 trials and 53 diagnostic accuracy studies). One RCT (n = 616) found screening of frail elderly persons associated with no difference in vision outcomes vs no screening but with significantly greater falls risk (relative risk [RR], 1.31 [95% CI, 1.13-1.50]). No study evaluated referral to an eye health professional. For glaucoma diagnosis, spectral domain optical coherence tomography (providing high-resolution cross-sectional imaging; 15 studies, n = 4242) was associated with sensitivity of 0.79 (95% CI, 0.75-0.83) and specificity of 0.92 (95% CI, 0.87-0.96) and the Humphrey Visual Field Analyzer (for perimetry, or measurement of visual fields; 6 studies, n = 11 244) with sensitivity of 0.87 (95% CI, 0.69-0.95) and specificity 0.82 (95% CI, 0.66-0.92); tonometry (for measurement of intraocular pressure; 13 studies, n = 32 892) had low sensitivity (0.48 [95% CI, 0.31-0.66]). Medical therapy for ocular hypertension and untreated glaucoma was significantly associated with decreased intraocular pressure and decreased likelihood of glaucoma progression (7 trials, n = 3771; RR, 0.68 [95% CI, 0.49-0.96]; absolute risk difference -4.2%) vs placebo, but 1 trial (n = 461) found no differences in visual acuity, quality of life, or function. Selective laser trabeculoplasty and medical therapy had similar outcomes (4 trials, n = 957). Conclusions and Relevance: This review found limited direct evidence on glaucoma screening, showing no association with benefits. Screening tests can identify persons with glaucoma and treatment was associated with a lower risk of glaucoma progression, but evidence of improvement in visual outcomes, quality of life, and function remains lacking.

Projection-Resolved Optical Coherence Tomography Angiography of Macular Retinal Circulation in Glaucoma.

PURPOSE: To detect macular perfusion defects in glaucoma using projection-resolved optical coherence tomography (OCT) angiography. DESIGN: Prospective observation study. PARTICIPANTS: A total of 30 perimetric glaucoma and 30 age-matched normal participants were included. METHODS: One eye of each participant was imaged using 6×6-mm macular OCT angiography (OCTA) scan pattern by 70-kHz 840-nm spectral-domain OCT. Flow signal was calculated by the split-spectrum amplitude-decorrelation angiography algorithm. A projection-resolved OCTA (PR-OCTA) algorithm was used to remove flow projection artifacts. Four en face OCTA slabs were analyzed: the superficial vascular complex (SVC), intermediate capillary plexus (ICP), deep capillary plexus (DCP), and all-plexus retina (SVC + ICP + DCP). The vessel density (VD), defined as the percentage area occupied by flow pixels, was calculated from en face OCTA. A novel algorithm was used to adjust the vessel density to compensate for local variations in OCT signal strength. MAIN OUTCOME MEASURES: Macular retinal VD, ganglion cell complex (GCC) thickness, and visual field (VF) sensitivity. RESULTS: Focal capillary dropout could be visualized in the SVC, but not the ICP and DVP, in glaucomatous eyes. In the glaucoma group, the SVC and all-plexus retinal VD (mean ± standard deviation: 47.2%±7.1% and 73.5%±6.6%) were lower than in the normal group (60.5%±4.0% and 83.2%±4.2%, both P < 0.001, t test). The ICP and DCP VD were not significantly lower in the glaucoma group. Among the overall macular VD parameters, the SVC VD had the best diagnostic accuracy as measured by the area under the receiver operating characteristic curve (AROC). The accuracy was even better when the worse hemisphere (inferior or superior) was used, achieving an AROC of 0.983 and a sensitivity of 96.7% at a specificity of 95%. Among the glaucoma participants, the hemispheric SVC VD values were highly correlated with the corresponding GCC thickness and VF sensitivity (P < 0.003). The reflectance compensation step in VD calculation significantly improved repeatability, normal population variation, and correlation with VF and GCC thickness. CONCLUSIONS: On the basis of PR-OCTA, glaucoma preferentially affects perfusion in the SVC in the macula more than the deeper plexuses. Reflectance-compensated SVC VD measurement by PR-OCTA detected glaucoma with high accuracy and could be useful in the clinical evaluation of glaucoma.

Optic Nerve Head Gene Transcription Sequelae to a Single Elevated IOP Exposure Provides Insights Into Known Responses to Chronically Elevated IOP.

Purpose: To clarify the optic nerve head (ONH) gene expression responses associated with a single, axon-damaging exposure to elevated IOP in relation to the composite cellular events previously identified in models of chronically elevated IOP. Methods: Anesthetized rats were exposed unilaterally to an 8-hour pulse-train controlled elevation of IOP (PT-CEI) at 60 mm Hg, while others received normotensive CEI at 20 mm Hg. ONH RNA was harvested at 0 hours and 1, 2, 3, 7, and 10 days after either CEI and from naïve animals. RNA sequencing was performed to analyze ONH gene expression. DAVID Bioinformatics tools were used to identify significant functional annotation clusters. Gene function was compared between PT-CEI and two models of chronic ocular hypertension from the literature. Results: The number of significantly changed genes peaked immediately (n = 1354) after PT-CEI (0 hours). This was followed by a lull (<4 genes per time point) at 1 and 2 days after PT-CEI. Gene activity increased again at 3 days (136 genes) and persisted at 7 (78 genes) and 10 (339 genes) days. Significant gene functional categories included an immediate upregulation of Defense Response at 0 hours, followed by upregulation in Cell Cycle, a reduction in Axonal-related genes at 3 to 10 days, and upregulation of Immune Response-related genes at 10 days following PT-CEI. The most commonly upregulated gene expression across our PT-CEI study and two chronic models of ocular hypertension were cell cycle related. Conclusions: The PT-CEI model places in sequence ONH gene expression responses previously reported in models with chronically elevated IOP and may provide insights into their role in optic nerve damage.

Case Series of Stickler Syndrome Presenting With Acute Angle Closure.

PURPOSE: Stickler syndrome is associated with open-angle glaucoma, but no reports exist of adults presenting with acute angle closure. Here, we report the clinical associations and short-term outcomes in 2 patients with Stickler syndrome who presented with acute angle closure at a single tertiary referral center. OBSERVATIONS: A 36-year-old female with Stickler syndrome presented with acute onset of red and painful left eye with cloudy vision. Initial intraocular pressure (IOP) was measured to be 54 mm Hg. Gonioscopy revealed no angle structures or peripheral anterior synechiae in the left eye. Two laser peripheral iridotomies were created 5 days apart without adequate IOP lowering. Left eye cataract extraction with intraocular lens implantation and Ahmed glaucoma drainage device implantation were performed with resolution of ocular hypertension.A 35-year-old male with Stickler syndrome presented with intermittent right eye pain and blurry vision. IOP was 42 mm Hg and gonioscopy revealed 270 degrees of angle closure in the right eye. The patient underwent laser peripheral iridotomy in the right eye with resolution of ocular hypertension by the next day. CONCLUSIONS: Recognizing angle closure as a potential feature of Stickler syndrome can help providers adequately screen and manage patients with Stickler syndrome presenting with acutely elevated IOP.

Cortactin has an essential and specific role in osteoclast actin assembly.

Osteoclasts are essential for bone dynamics and calcium homeostasis. The cells form a tight seal on the bone surface, onto which they secrete acid and proteases to resorb bone. The seal is associated with a ring of actin filaments. Cortactin, a c-Src substrate known to promote Arp2/3-mediated actin assembly in vitro, is expressed in osteoclasts and localizes to the sealing ring. To address the role of cortactin and actin assembly in osteoclasts, we depleted cortactin by RNA interference. Cortactin-depleted osteoclasts displayed a complete loss of bone resorption with no formation of sealing zones. On nonosteoid surfaces, osteoclasts flatten with a dynamic, actin-rich peripheral edge that contains podosomes, filopodia, and lamellipodia. Cortactin depletion led to a specific loss of podosomes, revealing a tight spatial compartmentalization of actin assembly. Podosome formation was restored in cortactin-depleted cells by expression of wild-type cortactin or a Src homology 3 point mutant of cortactin. In contrast, expression of a cortactin mutant lacking tyrosine residues phosphorylated by Src did not restore podosome formation. Cortactin was found to be an early component of the nascent podosome belt, along with dynamin, supporting a role for cortactin in actin assembly.

Endogenous hypercortisolism inducing reversible ocular hypertension.

PURPOSE: To describe the clinical findings of two patients with reversible ocular hypertension secondary to endogenous hypercortisolism. DESIGN: Retrospective, observational case series. SUBJECTS: A 65-year-old man (patient 1) and a 21-year-old woman (patient 2) were both found to have Cushing's syndrome after presentation to our clinic with elevated intraocular pressures (IOP). METHODS: Clinical histories, ophthalmic examinations including IOP measurements, optical coherence tomography of the retinal nerve fiber layer, visual field testing, magnetic resonance imaging and computerized tomography of two patients were reviewed between 2007 and 2019. OBSERVATIONS: Patient 1 demonstrated elevated IOP (maximum 26 mmHg OD and 22 mmHg OS) and bilateral disc edema. Following diagnosis of Cushing's syndrome, the patient underwent two pituitary resections and bilateral adrenalectomy, with subsequent resolution of his hypercortisolism and ocular hypertension (OHT). Patient 2 presented with blurred vision and found to have OHT (maximum 32 mmHg OU). Following diagnosis of Cushing's disease and two resections of her adrenocorticotropic hormone (ACTH) producing pituitary adenoma, her IOPs normalized. Both patients maintained normal IOPs after resolution of their endogenous hypercortisolism and discontinuation of topical IOP-lowering medication. CONCLUSIONS AND IMPORTANCE: Ocular hypertension induced by endogenous hypercortisolism is, in some cases, fully reversible following normalization of cortisol levels. These findings suggest that the physiologic changes to the trabecular meshwork induced by endogenous hypercortisolism may be fully reversible.

Projection-Resolved Optical Coherence Tomography Angiography of the Peripapillary Retina in Glaucoma.

PURPOSE: To detect plexus-specific peripapillary retinal perfusion defects in glaucoma, using projection-resolved optical coherence tomography angiography (PR-OCTA). DESIGN: Prospective cross-sectional study. METHODS: One eye each of 45 perimetric glaucoma participants and 37 age-matched normal participants were scanned using 4.5-mm OCTA scans centered on the disc. The PR-OCTA algorithm removed flow projection artifacts in OCT angiograms. Five en face OCTA slabs were analyzed: nerve fiber layer plexus (NFLP), ganglion cell layer plexus (GCLP), superficial vascular complex (SVC [NFLP + GCLP]), deep vascular complex (DVC), and all plexi combined. Peripapillary retinal capillary density (CD) and vessel density (VD) were calculated using a reflectance-compensated algorithm. RESULTS: Focal capillary dropout could be visualized more clearly in the NFLP than in the other slabs. The NFLP, SVC, and all-plexus CD in the glaucoma group were significantly lower (P < 0.001) than in the normal group, but no significant differences in GCLP-CD and DVC-CD appeared between the 2 groups. Both NFLP-CD and SVC-CD had excellent diagnostic accuracy, as measured by the area under the receiver operating characteristic curve (AROC = 0.981 and 0.976), correlation with visual field mean deviation (Pearson r = 0.819 and 0.831), and repeatability (intraclass correlation coefficients = 0.947 and 0.942). Performances of NFLP-VD and SVC-VD were similar to the corresponding CD parameters. CONCLUSIONS: In this glaucoma group, reduction in perfusion was more pronounced in superficial layers of the peripapillary retina (NFLP and SVC) than in the deeper layers. Reflectance-compensated CD and VD parameters for both NFLP and SVC could be useful in the clinical management of glaucoma.

Optic Nerve Head Astrocytes Display Axon-Dependent and -Independent Reactivity in Response to Acutely Elevated Intraocular Pressure.

Purpose: Optic nerve head (ONH) astrocytes provide support for axons, but exhibit structural and functional changes (termed reactivity) in a number of glaucoma models. The purpose of this study was to determine if ONH astrocyte structural reactivity is axon-dependent. Methods: Using rats, we combine retrobulbar optic nerve transection (ONT) with acute controlled elevation of intraocular pressure (CEI), to induce total optic nerve axon loss and ONH astrocyte reactivity, respectively. Animals were euthanized immediately or 1 day post CEI, in the presence or absence of ONT. ONH sections were labeled with fluorescent-tagged phalloidin and antibodies against ß3 tubulin, phosphorylated cortactin, phosphorylated paxillin, or complement C3. ONH label intensities were quantified after confocal microscopy. Retrobulbar nerves were assessed for axon injury by light microscopy. Results: While ONT alone had no effect on ONH astrocyte structural orientation, astrocytes demonstrated significant reorganization of cellular extensions within hours after CEI, even when combined with ONT. However, ONH astrocytes displayed differential intensities of actin (phosphorylated cortactin) and focal adhesion (phosphorylated paxillin) mediators in response to CEI alone, ONT alone, or the combination of CEI and ONT. Lastly, label intensities of complement C3 within the ONH were unchanged in eyes subjected to CEI alone, ONT alone, or the combination of CEI and ONT, relative to controls. Conclusions: Early ONH astrocyte structural reactivity to elevated IOP is multifaceted, displaying both axon dependent and independent responses. These findings have important implications for pursuing astrocytes as diagnostic and therapeutic targets in neurodegenerative disorders with fluctuating levels of axon injury.

Electron Beam Irradiated Corneal Versus Gamma-Irradiated Scleral Patch Graft Erosion Rates in Glaucoma Drainage Device Surgery.

INTRODUCTION: Patch graft erosion and implant exposure is a known complication of glaucoma drainage device (GDD) surgery. Recently, electron beam (e-beam) irradiated corneal tissue ha s become available; however, limited data exist on the rates of erosion for e-beam irradiated corneal grafts compared to traditional scleral grafts after GDD surgery. METHODS: This retrospective study examines the records of 253 eyes from 225 adult subjects who underwent GDD surgery with either e-beam irradiated corneal or scleral grafts at the Casey Eye Institute by five surgeons between April 22, 2014 and October 11, 2017. Surgical procedures and the occurrence of graft erosion were determined using billing codes and verified by manual review of electronic health records. RESULTS: The average age at the time of surgery was 61.3 ± 17.5 years (n = 200) and 60.8 ± 16.8 years (n = 53) for the e-beam irradiated cornea and sclera groups, respectively. The average follow-up time post-surgery was 416 ± 345 days and 495 ± 343 days for the e-beam irradiated cornea and sclera groups, respectively. There were no statistically significant differences in sex, age, follow-up time, and glaucoma diagnosis between the groups; however, the e-beam irradiated cornea group was statistically more likely to have an Ahmed implant as compared to the sclera group. No erosion events were noted in either group. CONCLUSION: e-Beam irradiated corneal grafts were used 3.8 times more frequently relative to scleral grafts, yet there were no cases of graft erosion in either group during the follow-up period.

In Vivo Small Molecule Delivery to the Optic Nerve in a Rodent Model.

Small molecule delivery to the optic nerve would allow for exploration of molecular and cellular pathways involved in normal physiology and optic neuropathies such as glaucoma, and provide a tool for screening therapeutics in animal models. We report a novel surgical method for small molecule drug delivery to the optic nerve head (ONH) in a rodent model. In proof-of-principle experiments, we delivered cytochalasin D (Cyt D; a filamentous actin inhibitor) to the junction of the superior optic nerve and globe in rats to target the actin-rich astrocytic cytoskeleton of the ONH. Cyt D delivery was quantified by liquid chromatography and mass spectrometry of isolated optic nerve tissue. One day after Cyt D delivery, anterior ONH filamentous actin bundle content was significantly reduced as assessed by fluorescent-tagged phalloidin labeling, relative to sham delivery. Anterior ONH nuclear counts and axon-specific beta-3 tubulin levels, as well as peripapillary retinal ganglion cell layer nuclear counts were not significantly altered after Cyt D delivery relative to sham delivery. Lastly, the surgical delivery technique caused minimal observable axon degeneration up to 10 days post-surgery. This small molecule delivery technique provides a new approach to studying optic neuropathies in in vivo rodent models.

Combined Glaucoma Tube Shunt (Ahmed) and Fluocinolone Acetonide (Retisert™) Implantation Compared to Ahmed Alone in Uveitic Glaucoma.

INTRODUCTION: Glaucoma is a known complication of uveitis, and may require glaucoma tube shunt implantation for intraocular pressure (IOP) control. The success of glaucoma tube shunt implantation in the setting of a local ocular steroid depot in uveitic glaucoma remains unknown. The purpose of this study was to determine whether patients who underwent combined glaucoma tube shunt (Ahmed) and fluocinolone acetonide (Retisert™, Bausch + Lomb, Bridgewater, NJ, USA) implantation have superior outcomes compared to patients with Ahmed implants only in the setting of uveitic glaucoma. METHODS: All participants were studied retrospectively and underwent Ahmed implantation alone or with existing/concurrent Retisert implantation (combined group) at a single academic institution. The main outcome measures were IOP, visual acuity (VA), number of IOP-lowering medications, and adverse events at 6 months after Ahmed implantation. Secondary outcome measures included adverse events and surgical success at 6 months after Ahmed implantation. RESULTS: Mean IOP at 6 months after Ahmed implantation was 15.3 ± 4.8 and 15.1 ± 4.9 mm Hg in the Ahmed only group (n = 17) and the combined group (n = 17), respectively (p = 0.89). The mean number of IOP-lowering medications at 6 months after Ahmed implantation was 1.7 ± 1.0 and 1.8 ± 1.0 in the Ahmed only group and the combined group, respectively (p = 0.86). Mean VA at 6 months after Ahmed implantation was 0.35 ± 0.29 and 0.42 ± 0.33 log mean angle of resolution in the Ahmed only group and the combined group, respectively (p = 0.50). No significant differences in surgical success or adverse events were noted between the two groups. CONCLUSION: At 6 months, no significant differences in mean IOP, mean number of IOP-lowering medications, VA, surgical success, or adverse events were noted between Ahmed implantation alone or combined Ahmed and Retisert implantation in patients with uveitic glaucoma.

The Utility of Diaton Tonometer Measurements in Patients With Ocular Hypertension, Glaucoma, and Glaucoma Tube Shunts: A Preliminary Study for its Potential Use in Keratoprosthesis Patients.

PURPOSE: Glaucoma is common in patients with the Boston type 1 keratoprosthesis (KPro). Because of the inability to perform corneal applanation in KPro patients, digital palpation is currently the mainstay for assessment of intraocular pressure (IOP). The purpose of this study was to determine whether the Diaton tonometer, which estimates IOP through transpalpebral scleral indentation, can reasonably detect high IOP when compared with Goldmann applanation tonometry (GAT) in patients with ocular hypertension, glaucoma, or glaucoma tube shunts. If reliable in these patients, it may be helpful in patients with KPros. MATERIALS AND METHODS: We prospectively measured IOP using GAT and Diaton transpalpebral tonometry (DTT) on the upper and lower eyelids in 87 eyes of 57 adult participants with ocular hypertension and glaucoma, several of whom had glaucoma tube shunts. RESULTS: The correlation coefficient between GAT and DTT on the upper eyelid was 0.64 (P<0.0001). For detecting an IOP of >21 mm Hg as measured by GAT, DTT on the upper eyelid had a sensitivity and specificity of 65% and 81%, respectively. The positive and negative predictive values were 74% and 73%, respectively. Bland-Altman analysis demonstrated limits of agreement of 2.0±19.5 mm Hg for GAT versus DTT on the upper eyelid. The presence of a tube shunt did not significantly affect the results. CONCLUSIONS: Diaton tonometry has a large margin of error compared with GAT in patients with ocular hypertension, glaucoma, and glaucoma tube shunts. However, given the current lack of an objective and quantitative method of IOP measurement in KPro patients, Diaton tonometry may be useful in this population as a supplement to digital palpation.

A Period of Controlled Elevation of IOP (CEI) Produces the Specific Gene Expression Responses and Focal Injury Pattern of Experimental Rat Glaucoma.

Purpose: We determine if several hours of controlled elevation of IOP (CEI) will produce the optic nerve head (ONH) gene expression changes and optic nerve (ON) damage pattern associated with early experimental glaucoma in rats. Methods: The anterior chambers of anesthetized rats were cannulated and connected to a reservoir to elevate IOP. Physiologic parameters were monitored. Following CEI at various recovery times, ON cross-sections were graded for axonal injury. Anterior ONHs were collected at 0 hours to 10 days following CEI and RNA extracted for quantitative PCR measurement of selected messages. The functional impact of CEI was assessed by electroretinography (ERG). Results: During CEI, mean arterial pressure (99 ± 6 mm Hg) and other physiologic parameters remained stable. An 8-hour CEI at 60 mm Hg produced significant focal axonal degeneration 10 days after exposure, with superior lesions in 83% of ON. Message analysis in CEI ONH demonstrated expression responses previously identified in minimally injured ONH following chronic IOP elevation, as well as their sequential patterns. Anesthesia with cannulation at 20 mm Hg did not alter these message levels. Electroretinographic A- and B-waves, following a significant reduction at 2 days after CEI, were fully recovered at 2 weeks, while peak scotopic threshold response (pSTR) remained mildly but significantly depressed. Conclusions: A single CEI reproduces ONH message changes and patterns of ON injury previously observed with chronic IOP elevation. Controlled elevation of IOP can allow detailed determination of ONH cellular and functional responses to an injurious IOP insult and provide a platform for developing future therapeutic interventions.

Astrocyte Structural and Molecular Response to Elevated Intraocular Pressure Occurs Rapidly and Precedes Axonal Tubulin Rearrangement within the Optic Nerve Head in a Rat Model.

Glaucomatous axon injury occurs at the level of the optic nerve head (ONH) in response to uncontrolled intraocular pressure (IOP). The temporal response of ONH astrocytes (glial cells responsible for axonal support) to elevated IOP remains unknown. Here, we evaluate the response of actin-based astrocyte extensions and integrin-based signaling within the ONH to 8 hours of IOP elevation in a rat model. IOP elevation of 60 mm Hg was achieved under isoflurane anesthesia using anterior chamber cannulation connected to a saline reservoir. ONH astrocytic extension orientation was significantly and regionally rearranged immediately after IOP elevation (inferior ONH, 43.2° ± 13.3° with respect to the anterior-posterior axis versus 84.1° ± 1.3° in controls, p<0.05), and re-orientated back to baseline orientation 1 day post IOP normalization. ONH axonal microtubule filament label intensity was significantly reduced 1 and 3 days post IOP normalization, and returned to control levels on day 5. Phosphorylated focal adhesion kinase (FAK) levels steadily decreased after IOP normalization, while levels of phosphorylated paxillin (a downstream target of FAK involved in focal adhesion dynamics) were significantly elevated 5 days post IOP normalization. The levels of phosphorylated cortactin (a downstream target of Src kinase involved in actin polymerization) were significantly elevated 1 and 3 days post IOP normalization and returned to control levels by day 5. No significant axon degeneration was noted by morphologic assessment up to 5 days post IOP normalization. Actin-based astrocyte structure and signaling within the ONH are significantly altered within hours after IOP elevation and prior to axonal cytoskeletal rearrangement, producing some responses that recover rapidly and others that persist for days despite IOP normalization.

Gender difference in the pathophysiology and treatment of glaucoma.

Glaucoma is the principal cause of irreversible blindness in the world, the second leading cause of blindness in the United States, and it results in optic nerve head axonal degeneration and corresponding visual field deficits. Intraocular pressure (IOP) is the only known modifiable risk factor in glaucoma. Non-modifiable risk factors for glaucoma include age, ethnicity, central corneal thickness, and family history. While our understanding of the role of gender as a risk factor in glaucoma development and progression remains nascent, multiple observations have shown gender differences in the incidence and prevalence of glaucoma. Depending on the type of glaucoma, hormone therapy, oral contraceptive use and menopausal status have also been associated with glaucoma. In addition, pregnancy leads to changes in IOP, while the treatment of glaucoma must be tailored based on the systemic effects of topical therapeutics on the mother and fetus. This review will focus on the epidemiologic, anatomic and endocrinologic differences in male and female glaucoma patients. In addition, this review will discuss treatment modalities that may be more appropriate for one gender than the other, especially with respect to a woman's pregnancy status.

Astrocyte processes label for filamentous actin and reorient early within the optic nerve head in a rat glaucoma model.

PURPOSE: To determine if astrocyte processes label for actin and to quantify the orientation of astrocytic processes within the optic nerve head (ONH) in a rat glaucoma model. METHODS: Chronic intraocular pressure (IOP) elevation was produced by episcleral hypertonic saline injection and tissues were collected after 5 weeks. For comparison, eyes with optic nerve transection were collected at 2 weeks. Fellow eyes served as controls. Axonal degeneration in retrobulbar optic nerves was graded on a scale of 1 to 5. Optic nerve head sections (n ≥ 4 eyes per group) were colabeled with phalloidin (actin marker) and antibodies to astrocytic glial fibrillary acidic protein and aquaporin 4, or axonal tubulin ßIII. Confocal microscopy and FIJI software were used to quantify the orientation of actin bundles. RESULTS: Control ONHs showed stereotypically arranged actin bundles within astrocyte processes. Optic nerve head actin bundle orientation was nearly perpendicular to axons (82.9° ± 6.3° relative to axonal axis), unlike the retrobulbar optic nerve (45.4° ± 28.7°, P < 0.05). With IOP elevation, ONH actin bundle orientation became less perpendicular to axons, even in eyes with no perceivable axonal injury (i.e., 38.8° ± 15.1° in grade 1, P < 0.05 in comparison to control ONHs). With severe injury, ONH actin bundle orientation became more parallel to the axonal axis (24.1° ± 28.4°, P < 0.05 in comparison to control ONHs). Optic nerve head actin bundle orientation in transected optic nerves was unchanged. CONCLUSIONS: Actin labeling identifies fine astrocyte processes within the ONH. Optic nerve head astrocyte process reorientation occurs early in response to elevated IOP.

Scotoma formation after exposure of retinal pigmented epithelium to indocyanine green.

PURPOSE: To describe objective, clinical evidence of retinal pigmented epithelial (RPE) cell toxicity after exposure to indocyanine green (ICG) in two patients. METHODS: Using color photos, we show the physical changes in the retina after RPE exposure to ICG. In addition, we present Humphrey visual field examination results, which correlate precisely with sites of ICG contact with the RPE layer. PATIENTS: A case series of two patients who underwent vitrectomy and membrane stripping with ICG use by a single surgeon. RESULTS: Visual examination, color photos, and Humphrey visual field examination results postoperatively reveal scotoma formation corresponding precisely to the size and location of ICG contact with the RPE layer. CONCLUSION: Our two case reports support the theory of ICG solution toxicity to RPE cells, while emphasizing that exposure of RPE to ICG should be avoided in retinal surgery.