Phase I Study of Intravitreal Injection of Autologous CD34+ Stem Cells from Bone Marrow in Eyes with Vision Loss from Retinitis Pigmentosa.

Purpose: To evaluate the feasibility and safety of intravitreal injection of autologous CD34+ stem cells from bone marrow (BMSCs) in eyes with vision loss from retinitis pigmentosa (RP). Design: Phase I prospective, open-label, single-center study. Participants: Seven eyes (7 patients) with RP with best-corrected visual acuity (BCVA) of 20/60 to 20/400 or visual field constriction to within 10°. Methods: A comprehensive examination with ETDRS BCVA, macular OCT, perimetry, and fluorescein angiography was performed at baseline, 1 to 3 months, and 6 months after study treatment. Bone marrow aspiration, isolation of CD34+ BMSCs under good manufacturing practice conditions, and intravitreal cell injection were performed on the same day. The CD34+ cells were isolated from bone marrow using a Ficoll gradient and the Miltenyi CliniMACS system. Isolated CD34+ cells were released for clinical use if viability, sterility, and purity met the release criteria accepted by the United States Food and Drug Administration for this clinical study. Main Outcome Measures: Number of CD34+ cells isolated for injection and adverse events associated with study treatment during follow-up. Secondary outcome measures are changes in BCVA and perimetry. Results: All isolated CD34+ cells passed the release criteria. A mean of 3.26 ± 0.66 million viable CD34+ cells (range 1.6 to 7.05 million) were injected intravitreally per eye. No adverse event was noted during the study follow-up except for 1 participant who was noted with transient cells in the anterior chamber with mild elevation in intraocular pressure at 18 hours after study injection which normalized by 24 hours. Best-corrected visual acuity remained within 2 lines of baseline or improved in all participants at 6 months follow-up. Perimetry was stable or improved in all eyes during study follow-up except 1 eye with transient improvement at 1 month and worsening of both eyes at 6 months. Conclusions: Intravitreal injection of autologous CD34+ BMSCs is feasible and appears to be well tolerated in eyes with vision loss from RP. A larger randomized prospective study would be needed to evaluate further the safety and potential efficacy of this cell therapy for vision loss associated with RP. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

International Classification System for Ocular Complications of Anti-VEGF Agents in Clinical Trials.

PURPOSE: Complications associated with intravitreal anti-VEGF therapies are reported inconsistently in the literature, thus limiting an accurate evaluation and comparison of safety between studies. This study aimed to develop a standardized classification system for anti-VEGF ocular complications using the Delphi consensus process. DESIGN: Systematic review and Delphi consensus process. PARTICIPANTS: Twenty-five international retinal specialists participated in the Delphi consensus survey. METHODS: A systematic literature search was conducted to identify complications of intravitreal anti-VEGF agent administration based on randomized controlled trials (RCTs) of anti-VEGF therapy. A comprehensive list of complications was derived from these studies, and this list was subjected to iterative Delphi consensus surveys involving international retinal specialists who voted on inclusion, exclusion, rephrasing, and addition of complications. Furthermore, surveys determined specifiers for the selected complications. This iterative process helped to refine the final classification system. MAIN OUTCOME MEASURES: The proportion of retinal specialists who choose to include or exclude complications associated with anti-VEGF administration. RESULTS: After screening 18 229 articles, 130 complications were categorized from 145 included RCTs. Participant consensus via the Delphi method resulted in the inclusion of 91 complications (70%) after 3 rounds. After incorporating further modifications made based on participant suggestions, such as rewording certain phrases and combining similar terms, 24 redundant complications were removed, leaving a total of 67 complications (52%) in the final list. A total of 14 complications (11%) met exclusion thresholds and were eliminated by participants across both rounds. All other remaining complications not meeting inclusion or exclusion thresholds also were excluded from the final classification system after the Delphi process terminated. In addition, 47 of 75 proposed complication specifiers (63%) were included based on participant agreement. CONCLUSIONS: Using the Delphi consensus process, a comprehensive, standardized classification system consisting of 67 ocular complications and 47 unique specifiers was established for intravitreal anti-VEGF agents in clinical trials. The adoption of this system in future trials could improve consistency and quality of adverse event reporting, potentially facilitating more accurate risk-benefit analyses. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Intravitreal Anti-Vascular Endothelial Growth Factor Therapies for Retinal Disorders.

Vascular endothelial growth factors (VEGFs) are key mediator of retinal and choroidal neovascularization as well as retinal vascular leakage leading to macular edema. As such, VEGF plays an important role in mediating visually significant complications associated with common retinal disorders such as diabetic retinopathy, retinal vein occlusion, and age-related macular degeneration. Various drugs that inhibit vascular endothelial growth factors (anti-VEGF therapies) have been developed to minimize vision loss associated with these disorders. These drugs are injected into the vitreous cavity in a clinic setting at regular intervals. This article provides an overview of the various anti-VEGF drugs used in ophthalmology and the common retinal conditions that benefit from this therapy.

Fungal Endophthalmitis Masquerading as Sympathetic Ophthalmia.

PURPOSE: To describe the ocular pathology of a patient with fungal endophthalmitis with features mimicking sympathetic ophthalmia. METHODS: Review of medical records and histopathology of a single patient. RESULTS: A 72-year-old male who sustained penetrating injury to the left eye with an agave plant presented to our clinic 16 months after the initial injury. Prior to presentation, the patient had developed endophthalmitis and had undergone anterior chamber washout, vitrectomy, and intravitreal steroids, antibiotics, antifungals, and anti-vascular endothelial growth factor (VEGF) therapy. At presentation, the patient had a blind, painful eye and subsequently underwent enucleation. Histopathology demonstrated granulomatous inflammation with multinucleated giant cells in the iris and Dalen Fuchs nodules with CD68 positive epithelioid histiocytes associated with the retinal pigment epithelium (RPE) sparing the choriocapillaris. These findings were initially attributed to sympathetic ophthalmia. The fellow eye did not have any signs of inflammation, and additional fungal PAS stains were positive for filamentous fungal elements, leading to a diagnosis of fungal endophthalmitis. CONCLUSIONS: Fungal endophthalmitis may develop histopathologic features that are similar to those seen in sympathetic ophthalmia. Recognition of the overlap between the histopathologic features of these diseases may reduce the possibility of misdiagnosis and unnecessary treatment of the fellow eye.

Real-World Experience Using Intravitreal Brolucizumab Alone or in Combination with Aflibercept in the Management of Neovascular Age-Related Macular Degeneration.

Purpose: To evaluate real-world experience using intravitreal brolucizumab (IVBr), alone or in combination with aflibercept, in eyes with neovascular age-related macular degeneration (nAMD) treated previously with other inhibitors of VEGF (anti-VEGF). Methods: This was a retrospective study of all eyes with nAMD treated with IVBr on a treat-and-extend protocol at a single center. Best-corrected visual acuity (BCVA), optical coherence tomography (OCT) at baseline and final visit, and drug-related adverse events were analyzed. Eyes with recurrent macular fluid on IVBr every 8 weeks were treated with a combination therapy alternating between IVBr and aflibercept every month. Results: Among 52 eyes (40 patients) on IVBr, all had been previously treated with other anti-VEGF therapy, with 73% having persistent macular fluid. After a mean follow-up of 46.2±27.4 weeks on IVBr, the mean treatment interval for intravitreal therapy increased to 8.8±2.1 weeks on IVBr from a baseline of 6.1±3.1 weeks (p<0.001). Macular fluid decreased and BCVA was stable/improved in 61.5% of eyes on IVBr. Ten eyes with increased macular fluid on IVBr monotherapy when extended to every 8 weeks were treated with combination therapy alternating between IVBr and aflibercept every 4 weeks. In these eyes, 80% had improved macular fluid on OCT and 70% stable or improved BCVA after a median follow-up of 53 weeks on combination therapy. Mild intraocular inflammation developed in four eyes, all occurring on IVBr monotherapy, and none had associated vision loss. Conclusion: In the real world, IVBr used to treat eyes with nAMD previously treated with other anti-VEGF therapies appears to be well tolerated and associated with an improvement in macular fluid, stabilization of BCVA, and/or increase in intravitreal treatment interval. Combination therapy alternating between IVBr and aflibercept monthly appears to be well tolerated and can be considered for eyes with macular fluid on IVBr every 8 weeks.

Long-Term Retinal Vascular Changes in Age-Related Macular Degeneration Measured Using Optical Coherence Tomography Angiography.

BACKGROUND AND OBJECTIVE: To determine if age-related macular degeneration (AMD) status affects longitudinal retinal vessel changes. PATIENTS AND METHODS: Retrospective, cohort study of 125 eyes (75 patients) with AMD, following retinal vessel density (VD) and foveal avascular zone (FAZ) measurements using optical coherence tomography angiography (OCT-A) over 24 months. RESULTS: FAZ area (P < .001) and perimeter (P < .001) increased over 2 years, with no difference between nonexudative and exudative AMD (P = .134-.976). Eyes with geographic atrophy (GA) showed greater progressive VD loss (P = .023-.038), and greater increase in FAZ area (P = .044) and perimeter (P = .040) compared to eyes without GA. Neither baseline nor 2-year change in vascular parameters were associated with choroidal neovascularization (CNV) or GA incidence in nonexudative AMD, or anti-VEGF injection frequency in exudative AMD (P = .070-.952). CONCLUSION: AMD eyes with GA undergo more rapid loss of retinal vessel density and FAZ enlargement over 2 years, suggesting a relationship between the retinal vasculature and AMD pathophysiology. [Ophthalmic Surg Lasers Imaging Retina 2022;53:529-536.].

Prospective Cross-Sectional Study of Repeatability of Peripapillary Capillary Density Measurement Using Optical Coherence Tomography Angiography in Eyes With Optic Nerve and Retinal Vascular Pathology.

BACKGROUND: Optical coherence tomography angiography (OCTA) is a new noninvasive imaging modality that provides high resolution images of the optic nerve head and peripapillary retinal capillary vasculature which can be affected by optic nerve or retinal pathologies. High repeatability of peripapillary capillary density measurement using OCTA has been demonstrated in normal eyes and eyes with glaucoma. The purpose of our study was to quantify the repeatability of peripapillary capillary density measurement using OCTA in both normal eyes and eyes with optic atrophy, optic disc edema, and retinal vasculopathy. METHODS: This prospective cross-sectional study enrolled 31 patients (59 eyes) including 16 eyes with optic nerve pathology (7 with disc edema from papilledema and 9 with optic atrophy), 35 eyes with retinal vascular disease, and 8 normal eyes. All eyes were imaged twice (30 minutes apart) with the Optovue AngioVue OCTA instrument to obtain 4.5 × 4.5 mm peripapillary scans. Scans were considered good quality if signal strength was 6 or greater. The OCTA parameters obtained include the radial peripapillary capillary (RPC) density of the whole disc, inside the disc, peripapillary region, and the 4 quadrants of the disc (superior, nasal, inferior, and temporal). A Student's t test was used to compare means. Intraclass correlation coefficient (ICC) was calculated to measure repeatability. RESULTS: Repeatability of RPC density measurements for all regions analyzed demonstrated good to excellent repeatability for the whole cohort {ICC for the whole image was 0.915 (95% confidence interval [CI] = 0.855-0.951)}; ICC for the peripapillary region was 0.945 (95% CI = 0.905-0.969). In the subset of eyes with good image quality (i.e., signal strength ≥ 6), ICC was slightly higher for all regions, with excellent repeatability of the peripapillary region (ICC was 0.971 [95% CI = 0.943-0.986]). Conversely, for eyes with poor image quality scans (i.e., signal strength < 6), ICC was lower, corresponding to moderate to good repeatability for most parameters. For the subset of eyes with optic atrophy, disc edema from papilledema or retinal vasculopathy, all had good to excellent repeatability of the vessel density of the entire disc (ICC values were 0.954 [95% CI = 0.804-0.990], 0.921 [95% CI = 0.711-0.982], and 0.895 [95% CI = 0.788-0.951, respectively]) and of the peripapillary region (ICC values were 0.980 [95% CI = 0.904-0.996], 0.966 [95% CI = 0.854-0.993], and 0.916 [95% CI = 0.827-0.961], respectively). CONCLUSIONS: The peripapillary capillary density measurement obtained using a commercial OCTA instrument is highly repeatable in eyes with optic nerve atrophy, disc edema from papilledema, or retinal vasculopathy.

Analysis of the retinal capillary plexus layers in a murine model with diabetic retinopathy: effect of intravitreal injection of human CD34+ bone marrow stem cells.

BACKGROUND: Diabetic retinopathy is a retinal vasculopathy involving all three retinal capillary plexus layers. Since human CD34+ bone marrow stem cells (BMSCs) have the potential to promote revascularization of ischemic tissue, this study tests the hypothesis that intravitreal injection of human CD34+ BMSCs can have protective effects on all layers of the retinal vasculature in eyes with diabetic retinopathy. METHODS: Streptozotocin (STZ)-induced diabetic mice were injected intravitreally with 50,000 human CD34+ BMSCs or phosphate-buffered saline (PBS) into the right eye. Systemic immunosuppression with rapamycin and tacrolimus was started 5 days before the injection and maintained for study duration to prevent rejection of human cells. All mice were euthanized 4 weeks after intravitreal injection; both eyes were enucleated for retinal flat mount immunohistochemistry. The retinal vasculature was stained with Isolectin-GS-IB4. Confocal microscopy was used to image four circular areas of interest of retina, 1-mm diameter around the optic disc. Images of superficial, intermediate, and deep retinal capillary plexus layers within the areas of interest were obtained and analyzed using ImageJ software with the Vessel Analysis plugin to quantitate the retinal vascular density and vascular length density in the three plexus layers. RESULTS: Three distinct retinal capillary plexus layers were visualized and imaged using confocal microscopy. Eyes that received intravitreal injection of CD34+ BMSCs (N=9) had significantly higher vascular density and vascular length density in the superficial retinal capillary plexus when compared to the untreated contralateral eyes (N=9) or PBS treated control eyes (N=12; P values <0.05 using ANOVA followed by post-hoc tests). For the intermediate and deep plexus layers, the difference was not statistically significant. CONCLUSIONS: The protective effect of intravitreal injection of the human CD34+ BMSCs on the superficial retinal capillary plexus layers is demonstrated using confocal microscopy in this murine model of diabetic retinopathy.

Subretinal versus intravitreal administration of human CD34+ bone marrow-derived stem cells in a rat model of inherited retinal degeneration.

BACKGROUND: To evaluate whether subretinal or intravitreal injection of human CD34+ bone marrow-derived stem cells (BMSC) can have protective effects on retinal degeneration that may be enhanced by coadministration of exosomes harvested from human bone marrow mesenchymal stem cells (MSCs). METHODS: Human CD34+ cells were harvested from the mononuclear cell fraction of bone marrow using magnetic beads and labeled with EGFP. Exosomes were harvested from cultured human MSCs under hypoxic conditions. Royal College of Surgeons (RCS) 3-weeks-old rats, immunosuppressed with cyclosporine A, received subretinal or intravitreal injection of CD34+ cells (50,000 cells), CD34+ cells with exosomes (50,000 cells+10 µg), exosomes alone (10 µg), or PBS. Retinal function was examined using electroretinography (ERG), and the eyes were harvested for histologic and immunohistochemical analysis. RESULTS: The b-wave amplitude of ERG at 2 weeks after injection was significantly higher in eyes with subretinal or intravitreal CD34+ BMSC alone or in combination with exosomes when compared to PBS injected eyes or untreated contralateral eyes. At 4 weeks after injection, the ERG signal decreased in all groups but eyes with subretinal CD34+ BMSCs alone or combined with exosomes showed partially preserved ERG signal and preservation of the outer nuclear layer of the retina near the injection site on histology when compared to eyes with PBS injection. Immunohistochemical analysis identified the human cells in the outer retina. Subretinal or intravitreal exosome injection had no effect on retinal degeneration when administered alone or in combination with CD34+ cells. CONCLUSIONS: Both subretinal and intravitreal injection of human CD34+ BMSCs can provide functional rescue of degenerating retina, although the effects were attenuated over time in this rat model. Regional preservation of the outer retina can occur near the subretinal injection site of CD34+ cells. These results suggest that CD34+ cells may have therapeutic potential in retinal degeneration.

Intraoperative Retinal Changes May Predict Surgical Outcomes After Epiretinal Membrane Peeling.

Purpose: To investigate whether intraoperative retinal changes during epiretinal membrane (ERM) peeling affect anatomic or functional outcomes after surgery. Methods: We measured retinal thickness using an intraoperative optical coherence tomography (iOCT) device in patients undergoing pars plana vitrectomy with membrane peeling for idiopathic ERM. Changes in intraoperative central macular thickness (iCMT) were compared with postoperative improvements in CMT and best-corrected visual acuity (VA). Results: Twenty-seven eyes from 27 patients (mean age 68 years) underwent iOCT-assisted ERM peeling surgery. Before surgery, mean VA was logMAR 0.50 ± 0.36 (Snellen 20/63), and mean baseline CMT was 489 ± 82 µm. Mean iCMT before peeling was 477 ± 87 µm, which correlated well with preoperative CMT (P < 0.001). Mean change in iCMT was -39.6 ± 37 µm (range -116 to +77 µm). After surgery, VA improved to logMAR 0.40 ± 0.38 (Snellen 20/50) at month 1 and logMAR 0.27 ± 0.23 (Snellen 20/37) at month 3, whereas CMT decreased to 397 ± 44 µm and 396 ± 51 µm at months 1 and 3. Eyes that underwent greater amount of iCMT change (absolute value of iCMT change) were associated with greater CMT reduction at month 1 (P < 0.001) and month 3 (P = 0.010), whereas those with greater intraoperative thinning (actual iCMT change) showed a trend toward better VA outcomes at months 1 (P = 0.054) and 3 (P = 0.036). Conclusions: Intraoperative changes in retinal thickness may predict anatomic and visual outcomes after idiopathic ERM peeling surgery. Translational Relevance: Our study suggests that intraoperative retinal tissue response to ERM peeling surgery measured by iOCT may be a prognostic indicator for restoration of retinal architecture and for visual acuity outcomes.

Ocular Outcomes after Treatment of Cytomegalovirus Retinitis Using Adoptive Immunotherapy with Cytomegalovirus-Specific Cytotoxic T Lymphocytes.

PURPOSE: To describe ocular outcomes in eyes with cytomegalovirus (CMV) retinitis treated with adoptive immunotherapy using systemic administration of CMV-specific cytotoxic Tlymphocytes (CMV-specific CTLs). DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with active CMV retinitis evaluated at a tertiary care academic center. METHODS: Treatment of CMV retinitis with standard-of-care therapy (systemic or intravitreal antivirals) or CMV-specific CTLs (with or without concurrent standard-of-care therapies). MAIN OUTCOME MEASURES: The electronic medical record was reviewed to determine baseline characteristics, treatment course, and ocular outcomes, including best-corrected visual acuity (BCVA), treatments administered (CMV-specific CTLs, systemic antivirals, intravitreal antivirals), resolution of CMV retinitis, any occurrence of immune recovery uveitis, cystoid macular edema, retinal detachment, or a combination thereof. RESULTS: Seven patients (3 of whom had bilateral disease [n = 10 eyes]) were treated with CMV-specific CTLs, whereas 20 patients (6 of whom had bilateral disease [n = 26 eyes]) received standard-of-care treatment. Indications for CMV-specific CTL therapy included persistent or progressive CMV retinitis (71.4% of patients); CMV UL54 or UL97 antiviral resistance mutations (42.9%); side effects or toxicity from antiviral agents (57.1%); patient intolerance to longstanding, frequent antiviral therapy for persistent retinitis (28.6%); or a combination thereof. Two patients (28.6%; 4 eyes [40%]) received CMV-specific CTL therapy without concurrent systemic or intravitreal antiviral therapy for active CMV retinitis, whereas 5 patients (71.4%; 6 eyes [60%]) continued to receive concurrent antiviral therapies. Resolution of CMV retinitis was achieved in 9 eyes (90%) treated with CMV-specific CTLs, with BCVA stabilizing (4 eyes [40%]) or improving (4 eyes [40%]) in 80% of eyes over an average follow-up of 33.4 months. Rates of immune recovery uveitis, new-onset cystoid macular edema, and retinal detachment were 0%, 10% (1 eye), and 20% (2 eyes), respectively. These outcomes compared favorably with a nonrandomized cohort of eyes treated with standard-of-care therapy alone, despite potentially worse baseline characteristics. CONCLUSIONS: CMV-specific CTL therapy may represent a novel monotherapy or adjunctive therapy, or both, for CMV retinitis, especially in eyes that are resistant, refractory, or intolerant of standard-of-care antiviral therapies. More generally, adoptive cell transfer and adoptive immunotherapy may have a role in refractory CMV retinitis. Larger prospective, randomized trials are necessary.

NATURAL HISTORY AND PREDICTORS OF VISION LOSS IN EYES WITH DIABETIC MACULAR EDEMA AND GOOD INITIAL VISUAL ACUITY.

PURPOSE: To identify clinical and anatomic factor-associated vision loss in eyes with treatment-naïve diabetic macular edema and good initial visual acuity. METHODS: Retrospective cohort study after long-term history of eyes with untreated center-involving diabetic macular edema and baseline visual acuity ≥ 20/25 seen at the University of California, Davis Eye Center between March 2007 and March 2018. We collected characteristics including diabetes type, hemoglobin A1c, presence of visual symptoms, visual acuity, and diabetic retinopathy severity; and spectral-domain optical coherence tomography biomarkers including central subfield thickness, intraretinal cyst size, intraretinal hyperreflective foci, disorganization of retinal inner layers, and outer layer disruptions to determine factors associated with vision loss as defined by DRCR Protocol V as threshold for initiating aflibercept therapy. RESULTS: Fifty-six eyes (48 patients) with untreated diabetic macular edema and mean baseline visual acuity of logMAR 0.05 ± 0.05 (Snellen 20/22) were followed for an average of 5.1 ± 3.3 years, with a median time to vision loss of 465 days (15 months). Older age (hazard ratio [HR] 1.04/year, P = 0.0195) and eyes with severe NPDR (HR 3.0, P = 0.0353) or proliferative diabetic retinopathy (HR 7.7, P = 0.0008) had a higher risk of a vision loss event. None of the spectral-domain optical coherence tomography biomarkers were associated with vision loss except central subfield thickness (HR 0.98, P = 0.0470) and cyst diameter (HR 1.0, P = 0.0094). CONCLUSION: In eyes with diabetic macular edema and good initial vision, those with older age and worse diabetic retinopathy severity should be monitored closely for prompt treatment initiation when vision loss occurs.

Repeatability of Vascular Density Measurement of the Three Retinal Plexus Layers Using OCT Angiography in Pathologic Eyes (OCTA Vascular Density Repeatability of Three Plexus Layers).

PURPOSE: Although commercial optical coherence tomography angiography (OCTA) machines quantitate retinal vascular density (VD) by dividing the vasculature into superficial and deep capillary plexus (SCP, DCP), histology reveals three distinct plexus layers. This study tested the hypothesis that the VD measurement of three distinct retinal plexus layers obtained using custom segmentation has high repeatability comparable to that of automatically segmented SCP and DCP layers. MATERIALS AND METHODS: Forty-four participants (86 eyes) were enrolled - 54 eyes with retinal vasculopathy and 25 eyes with macular edema. Macular OCTA images (3x3 mm and 6x6 mm) were obtained twice within 30 minutes by the same personnel using the same instrument (AngioVue, Optovue, version 2018.0.0.18). The intraclass correlation coefficient (ICC) was calculated to access repeatability. RESULTS: The repeatability of VD for SCP and DCP was good-to-moderate (ICC=0.65-0.85) and minimally affected by image quality, retinal vasculopathy, or macular edema. The repeatability of the VD of the custom-segmented intermediate and deep plexus layers (cICP and cDCP) was poor/moderate (ICC=0.40-0.74) but better in the subset without macular edema using 3x3 mm scans with good images quality (ICC=0.58-0.93). Repeatability of cICP and cDCP VD measurement for 6x6 mm scans was poor (ICC≤0.5) in eyes with retinal vasculopathy and/or macular edema. CONCLUSION: Although repeatability of the VD measurement is high for the automatically segmented SCP and DCP, repeatability of VD is poor for the cICP and cDCP using larger scans in eyes with retinal vasculopathy and/or macular edema.

Factors Affecting Repeatability of Foveal Avascular Zone Measurement Using Optical Coherence Tomography Angiography in Pathologic Eyes.

PURPOSE: To determine factors that may affect the repeatability of the foveal avascular zone (FAZ) measurement obtained using optical coherence tomography angiography (OCTA) including instrument type, image segmentation, image quality, and fundus pathology. PATIENTS AND METHODS: This prospective single-center study enrolled 43 subjects (85 eyes) with retinal vasculopathy, macular edema, optic pathology or normal contralateral eye. The macula was imaged twice using Optovue Angiovue and once using Cirrus Angioplex to obtain 3x3mm OCTA images centered on the fovea. Images were generated by the same operator within 30 mins. The FAZ size for the entire retinal thickness ("overall FAZ") was measured automatically using the OCTA software. The FAZ size of the superficial and deep retinal vascular plexus layers was measured manually using the enface OCTA images of the segmented layers and Image J analysis. Intraclass correlations coefficient (ICC) was calculated to determine repeatability. RESULTS: For the overall FAZ measurement, repeatability was excellent (ICC 0.953 right eye, 0.938, left eye) using the same machine (intra-instrument) and somewhat lower but still good to excellent (ICC 0.803 right eye, 0.917 left eye) using machines made by different vendors (inter-instrument). For the segmented layers, intra-instrument repeatability of FAZ measurement was excellent (ICC > 0.95) for both plexus layers. Inter-instrument repeatability was good for the superficial plexus layer (ICC 0.86 right eye, 0.88 left eye) but reduced for the deep plexus layer (ICC 0.63 right eye, 0.57 left eye). Suboptimal image quality and presence of retinal vasculopathy and macular edema tended to reduce FAZ repeatability but to a lesser degree. CONCLUSION: Inter- and intra-instrument repeatability of the overall FAZ measurement was high using commercial OCTA instruments and only mildly reduced by suboptimal image quality and fundus pathology. For segmented layers, intra-instrument repeatability remained high but inter-instrument repeatability was reduced for the deep plexus layer.

Phase I/II randomized study of proton beam with anti-VEGF for exudative age-related macular degeneration: long-term results.

BACKGROUND/OBJECTIVE: To determine if treatment of exudative age-related macular degeneration (eAMD) using proton beam therapy (PBT) combined with intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is safe and effective long term. SUBJECT/METHODS: Thirty eyes with newly diagnosed eAMD were enrolled in a phase I/II prospective, sham-controlled double-masked university study. Eyes were randomized 1:1:1-24 GyE, 16 GyE or sham radiation, and treated with three initial monthly intravitreal ranibizumab or bevacizumab. Subsequent anti-VEGF reinjection was based on monthly optical coherence tomography and examination for 2 years and standard of care thereafter. RESULTS: A total of 23 eyes completed 2-year study follow-up, of which 16 maintained monthly follow-up. Mean best-correct visual acuity (BCVA) at 2 years was similar among treatment groups (p > 0.05). The 24 GyE group required fewer anti-VEGF injections when compared with the sham group at 2 years (4.67 ± 1.9 vs 9.67 ± 3.5; p = 0.017). Extended follow-up (mean 4 years) available in 22 eyes showed persistent reduced need for anti-VEGF therapy among eyes treated with 24 GyE compared with sham radiation (2.0 ± 1.6 vs 4.84 ± 2.4 per year, p = 0.008). New and increasing geographic atrophy (GA), noted in some eyes in all treatment groups, resulted in decreased mean BCVA from baseline for the 24 GyE group on extended follow-up (p = 0.009). Possible mild radiation retinopathy noted in 15% of eyes was not visually significant. CONCLUSIONS: Initial treatment combining PBT (24 GyE) with intravitreal anti-VEGF therapy appears to decrease the need for anti-VEGF reinjection in eyes with newly diagnosed eAMD. Radiation retinopathy risk was low and does not appear visually significant. Long-term vision was limited by GA development especially in the 24 GyE group.

Identification of Patients with Pentosan Polysulfate Sodium-Associated Maculopathy through Screening of the Electronic Medical Record at an Academic Center.

AIMS: This chart review of a quaternary academic medical center electronic medical record (EMR) aimed to identify patients at risk of development of maculopathy with exposure to pentosan polysulfate sodium (PPS). METHODS: A review of electronic medical records of a quaternary medical center of patients with either documented exposure to PPS or diagnosis of interstitial cystitis (IC) from 2007 to 2019 was performed for retinal imaging and visual acuity; the study was conducted in August of 2019. RESULTS: 216 charts were included for analysis, of which 96 had documented eye exams and 24 had retinal imaging done. We identified three patients with maculopathy in the context of long-term exposure to PPS via chart review, and one additional patient was identified by referral. The median PPS exposure duration was 11 years (range 7 to 19 years). Median logMAR BCVA OD 0.6 range was 0.0-1.9 (approximate Snellen equivalent 20/80 range (20/20-20/1600)) and OS 0.7 range was 0.1-1.9 (approximate Snellen equivalent 20/100 range (20/25-20/1600)). Ultrawidefield color fundus imaging and fundus autofluorescence revealed findings of pigmentary changes and patchy macular atrophy. Optical coherence tomography (OCT) demonstrated outer retinal thinning and increased choroidal transmission coincident with areas of atrophy seen on fundus imaging. CONCLUSIONS: Less than half of patients at risk for development of maculopathy due to exposure to PPS had received eye examinations, suggesting that those at risk are not receiving adequate screening. We found two patients with PPS maculopathy who had relatively preserved central vision, one patient with bitemporal vision loss, and one patient who developed vision loss in both eyes.

Retinal Vessel Density in Exudative and Nonexudative Age-Related Macular Degeneration on Optical Coherence Tomography Angiography.

PURPOSE: Although the choroid contributes to the pathogenesis of age-related macular degeneration (AMD), the role of retinal perfusion is unclear. We sought to compare retinal vascular measurements between eyes with nonexudative and exudative AMD using optical coherence tomography angiography (OCT-A). DESIGN: Retrospective, cross-sectional study. METHODS: OCT-A images were analyzed from 310 eyes of 182 patients (mean age ± standard deviation [SD], 78.8 ± 8.8 years) with nonexudative (54.2%) and exudative (45.8%) AMD to measure retinal vessel density (VD) from the superficial capillary plexus in the foveal, parafoveal, and full macular regions and foveal avascular zone (FAZ) area, perimeter, and circularity. Multivariate regressions were used to compare nonexudative and exudative AMD eyes and the impact of anti-vascular endothelial growth factor (anti-VEGF) treatments or geographic atrophy (GA). RESULTS: In eyes with AMD, VD decreases with age in the foveal (ß = -0.211, P < .001), parafoveal (ß = -0.305, P < .001), and full macular regions (ß = -0.295, P < .001). Eyes with exudative AMD demonstrated lower VD, especially in the parafoveal (29.8% ± 6.3% vs 33.0% ± 5.7%, P < .001) and full regions (27.9% ± 6.2% vs 31.2% ± 5.5%, P < .001) compared with nonexudative AMD. There were no differences in FAZ area, perimeter, or circularity between the 2 groups (P = .503-.907). In eyes with exudative AMD, previous anti-VEGF treatments did not impact retinal vascular measurements (P = .324-.986). Nonexudative AMD severity and presence of central GA also impacted retinal VD and FAZ morphology. CONCLUSIONS: Retinal VD is decreased in eyes with exudative AMD compared with nonexudative AMD but is unaffected by anti-VEGF treatments, suggesting a retinal vascular contribution to the pathogenesis of AMD.