Longer-Term Anti-VEGF Therapy Outcomes in Neovascular Age-Related Macular Degeneration, Diabetic Macular Edema, and Vein Occlusion-Related Macular Edema: Clinical Outcomes in 130 247 Eyes.

PURPOSE: The clinical practice visual acuity (VA) outcomes of anti-VEGF therapy for up to 5 years were assessed in patients with neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), branch retinal vein occlusion-related macular edema (BRVO-ME), and central retinal vein occlusion-related macular edema (CRVO-ME). DESIGN: A retrospective analysis was performed using the Vestrum Health Retina Database. PARTICIPANTS: Treatment-naive patients with nAMD, DME, BRVO-ME, or CRVO-ME who received anti-VEGF injections between 2014 and 2019 and had follow-up data for ≥12 months. METHODS: Data on age, sex, the number of anti-VEGF treatments, and VA were analyzed. MAIN OUTCOME MEASURES: Mean VA change up to 3 years (BRVO-ME and CRVO-ME) and 5 years (nAMD and DME). RESULTS: At 1, 3, and 5 years, in 67 666, 21 305, and 5208 eyes with nAMD, after a mean of 7.6, 19.5, and 32 injections, there was a mean change of +3.1, -0.2, and -2.2 letters, respectively. At 1, 3, and 5 years, in 40 832, 7728, and 1192 eyes with DME, after a mean of 6.2, 15.4, and 26.0 injections, there was a mean change of +4.7, +3.3, and +3.1 letters, respectively. At 1 and 3 years, in 12 451 and 3027 eyes with BRVO-ME, after a mean of 7.1 and 18.2 injections, there was a mean change of +9.5 and +7.7 letters, respectively. At 1 and 3 years, in 9298 and 2264 eyes with CRVO-ME, after a mean of 7.3 and 18.8 injections, there was a mean change of +8.3 and +6.0 letters, respectively (P < 0.01 for all VA changes of > 1 letter). In all 4 conditions, the mean VA increased with the mean number of anti-VEGF injections, eyes with a baseline VA of 20/40 or better tended to lose VA, and eyes with progressively worse baseline VA experienced a progressively greater VA gain at 3 years. CONCLUSIONS: In practice, patients with nAMD, DME, BRVO-ME, and CRVO-ME showed limited visual outcomes, with patients with nAMD tending to lose VA at 3 and 5 years. Across all 4 disorders, the mean change in VA correlated with treatment intensity at 1, 3, and 5 years. Patients with better baseline VA are more vulnerable to vision loss.

KSI-301: an investigational anti-VEGF biopolymer conjugate for retinal diseases.

INTRODUCTION: KSI-301 is an intravitreal anti-vascular endothelial growth factor (VEGF) agent in clinical trials for the treatment of neovascular age-related macular degeneration (nAMD), diabetic retinopathy, diabetic macular edema (DME), and retinal vein occlusion (RVO). Its antibody-biopolymer conjugate structure is designed to decrease clearance from the eye and increase the duration of the effect. AREAS COVERED: This article briefly discusses the impact and mechanisms of nAMD, DME, and RVO and evaluates currently approved anti-VEGF therapies. It progresses to examine a new agent, KSI-301 and the results from numerous clinical trials in these disease areas. EXPERT OPINION: Despite varied results in the phase 2b/3 study for nAMD, there is potential for KSI-301 to serve as a durable therapy for VEGF-mediated retinal disorders. Ongoing phase 3 trials for nAMD, DME, and RVO will provide additional evidence on its efficacy, duration, and safety profiles.

Brolucizumab for persistent macular fluid in neovascular age-related macular degeneration after prior anti-VEGF treatments.

BACKGROUND: Some patients with neovascular age-related macular degeneration (nAMD) have persistent intraretinal/subretinal fluid (IRF/SRF) despite being treated with anti-VEGF agents. There is limited data on efficacy of switching to intravitreal brolucizumab (IVBr) in these patients. PURPOSE: To determine anatomic and visual outcomes of eyes with nAMD treated with for persistent IRF/SRF. METHODS: Retrospective series of eyes with nAMD treated initially with aflibercept (IVA, n = 48) and bevacizumab (IVBe, n = 10), then switched to IVBr for persistent IRF/SRF. RESULTS: In the IVA-IVBr group, a mean of 42 days after one IVBr, mean logMAR changed from 0.50 to 0.49 (p = 0.73) and mean CSFT changed from 340 to 305 µm (p < 0.001); 31% of eyes had no fluid, 42% had persistent but reduced fluid, 25% had stable fluid, and 2% had increased fluid. For a subgroup of 25 eyes that completed a series of 3 IVBr, mean logMAR changed from 0.44 to 0.40 (p = 0.35) and mean CSFT changed from 325 to 277 µm (p = 0.001); 24% of eyes had no fluid at last follow-up, a mean of 54 days after last IVBr. In the IVBe-IVBr group, a mean of 44 days after one IVBr, mean logMAR changed from 0.46 to 0.40 (p = 0.114) and mean CSFT from 401 to 325 µm (p = 0.009); 30% of eyes had no fluid and 70% had persistent but reduced fluid. For a subgroup of four eyes that completed a series of three IVBr, mean logMAR changed from 0.33 to 0.35 (p = 0.391) and mean CSFT improved from 375 to 275 µm (p = 0.001); 50% of eyes had no fluid at last follow-up, a mean of 65 days after last IVBr. CONCLUSION: In nAMD eyes previously treated with IVA and IVBe, switching to IVBr significantly reduced persistent IRF/SRF but did not significantly affect visual outcomes.

Multimodal Imaging Findings in Two Children With Microphthalmos.

Microphthalmos, also called microphthalmia, is a rare developmental disorder of the eye that can be caused by genetic or chromosomal abnormalities or environmental factors. The spectrum of clinical presentation includes nanophthalmia and posterior microphthalmia. It affects approximately one in 1,000 individuals, although there is insufficient literature regarding the clinical and different imaging modalities findings. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:444-446.].

Vascular Endothelial Growth Factor Antagonists: Promising Players in the Treatment of Neovascular Age-Related Macular Degeneration.

Neovascular age-related macular degeneration (nAMD) treatment has been revolutionized by the introduction of vascular endothelial growth factor antagonists (anti-VEGF), but the need for frequent intravitreal injections poses a heavy burden to patients and physicians. Evolving anti-VEGF therapies include longer duration agents, approaches that target multiple pathways, topical anti-VEGF agents, sustained-release, and genetic therapies. Abicipar pegol, a designed ankyrin repeat protein (DARPin), demonstrated the ability to maintain stable visual acuity with 12-week dosing, but was not approved by the FDA due to higher than usual rates of intraocular inflammation. Conbercept, a recombinant anti-VEGF fusion protein, has been approved in China, and is in Phase 3 trials globally. KSI-301 is an anti-VEGF antibody biopolymer conjugate that allowed 66% of nAMD patients to maintain at least a 6-month treatment-free interval in Phase 1b studies. OPT-302, an inhibitor of VEGF-C/D, will be tested in phase 3 studies that compare anti-VEGF-A monotherapy against combination therapy with OPT-302. Faricimab is a bispecific anti-VEGF/Ang-2 antibody that upregulates the Tie-2 signaling pathway and promotes vascular stability; it is undergoing phase 3 trials with potential for 12- or 16-week dosing. PAN-90806 is a topical anti-VEGF agent that showed the ability to reduce injection frequency by 79% compared to ranibizumab monotherapy in a phase 1/2a trial. Sustained-release anti-VEGF therapies include the ranibizumab Port Delivery System (in phase 3 studies), GB-102 (Phase 2b), OTX-TKI (phase 1), and Durasert (preclinical). Suprachoroidal delivery of the tyrosine kinase inhibitor, axitinib, is in preclinical studies. Genetic therapies in phase 1 studies include RGX-314 and ADVM-022, which introduce a viral vector that modifies the retina's cellular apparatus to create an anti-VEGF biofactory, potentially serving as a one-time treatment. Further investigation is warranted for drugs and delivery systems that hope to advance visual outcomes and reduce treatment burden of nAMD.

Comparison Between Graders in Detection of Diabetic Neovascularization With Swept Source Optical Coherence Tomography Angiography and Fluorescein Angiography.

PURPOSE: We compared the ability of ophthalmologists to identify neovascularization (NV) in patients with proliferative diabetic retinopathy using swept-source optical coherence tomography angiography (SS-OCTA) and fluorescein angiography (FA). DESIGN: Retrospective study comparing diagnostic instruments. METHODS: Eyes with proliferative diabetic retinopathy or severe nonproliferative diabetic retinopathy and a high suspicion of NV based on clinical examination were imaged using SS-OCTA and FA at the same visit. Two separate grading sets consisting of scrambled, anonymized SS-OCTA and FA images were created. The ground truth for presence of NV was established by consensus of 2 graders with OCTA experience who did not participate in the subsequent assessment of NV in this study. The 2 anonymized image sets were graded for presence or absence of NV by 12 other graders that included 2 residents, 6 vitreoretinal fellows, and 4 vitreoretinal attending physicians. The percentage of correct grading of NV using SS-OCTA and FA was assessed for each grader and across grader training levels. RESULTS: Forty-seven eyes from 24 patients were included in this study. Overall, the mean percentage of correct NV grading was 87.8% using SS-OCTA with B-scans and 86.2% using FA (P = .92). Assessing each grader individually, there was no statistically significant asymmetry in correct grading using SS-OCTA and FA. CONCLUSIONS: Ophthalmologists across training levels were able to identify diabetic NV with equal accuracy using SS-OCTA and FA. Based on these results, SS-OCTA may be an appropriate standalone modality for diagnosing diabetic NV.

Voretigene Neparvovec in Retinal Diseases: A Review of the Current Clinical Evidence.

Subretinal gene therapy trials began with the discovery of RPE65 variants and their association with Leber congenital amaurosis. The RPE65 protein is critical for the normal functioning of the visual phototransduction cascade. RPE65 gene knockout animal models were developed and showed similar diseased phenotypes to their human counterparts. Proof of concept studies were carried out in these animal models using subretinal RPE65 gene replacement therapy, resulting in improvements in various visual function markers including electroretinograms, pupillary light responses, and object avoidance behaviors. Positive results in animal models led to Phase 1 human studies using adeno-associated viral vectors. Results in these initial human studies also showed positive impact on visual function and acceptable safety. A landmark Phase 3 study was then conducted by Spark Therapeutics using a dose of 1.5 x1011 vector genomes after dose-escalation studies confirmed its efficacy and safety. Multi-luminance mobility testing was used to measure the primary efficacy endpoint due to its excellent reliability in detecting the progression of inherited retinal diseases. After the study met its primary endpoint, the Food and Drug Administration approved voretigene neparvovec (Luxturna®) for use in RPE65-associated inherited retinal diseases.

Complex Combined Tractional and Rhegmatogenous Retinal Detachment in a Twenty-Three-Year-Old Male With Wagner Syndrome.

Wagner syndrome is a rare hereditary vitreoretinopathy that has been reported in only about 300 people worldwide. It is caused by a mutation in the VCAN gene that encodes for the proteoglycan versican, which is a major component of the extracellular matrix of the vitreous gel; retinal detachment is uncommon in these cases. The authors report a case of a 23-year-old male who presented with bilateral combined tractional and rhegmatogenous retinal detachments. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:467-471.].

Abicipar pegol for neovascular age-related macular degeneration.

INTRODUCTION: The development of intravitreal anti-vascular endothelial growth factor (VEGF) therapy has revolutionized management of neovascular age-related macular degeneration (nAMD) and serves as the standard of care for treating this chronic, progressive disease. One shortcoming is the need for frequent intravitreal injections to maintain visual gains, which has led to pursuit of long-acting agents to reduce treatment burden. AREAS COVERED: A literature search was conducted using the keywords 'abicipar pegol' and 'DARPin' on PubMed. EXPERT OPINION: DARPin (Designed Ankyrin Repeat Proteins) molecules such as abicipar pegol offer potential therapeutic advantages over antibodies or antibody fragments, including high affinity, stability, and high molar concentration. The phase III SEQUOIA and CEDAR clinical trials suggest that abicipar allows >90% of patients to maintain stable vision with 12-week dosing intervals, comparable to results achieved with monthly ranibizumab injections. Relative to other anti-VEGF agents, intraocular inflammation has been noted in a concerning percentage of patients, which is hypothesized to be related to the manufacturing process rather than the drug itself. Modifications to reduce pro-inflammatory components resulted in reduced inflammation (8.9%) in the MAPLE study. If this high inflammation rate can be further reduced, abicipar has the potential to decrease treatment burden for nAMD patients.

Voretigene neparvovec-rzyl for treatment of RPE65-mediated inherited retinal diseases: a model for ocular gene therapy development.

Introduction: Over a decade of research and development culminated in the 2017 United States (US) Food and Drug Administration (FDA) approval of voretigene neparvovec-rzyl (VN) for RPE65 mutation-associated inherited retinal disease (IRD), the first approved gene therapy for a hereditary genetic disease in the US, and the first and only pharmacologic treatment for an IRD.Areas covered: VN serves as a model for ocular gene therapy development, while RPE65 mutation-associated IRD serves as an example of a well-suited candidate disorder. This review also discusses development considerations for viral vector gene augmentation, and, studies that led to VN's FDA approval. Subretinal injection of VN resulted in improved performance on the novel multi-luminance mobility test (MLMT), light sensitivity, and visual fields in patients with RPE65 mutation-associated IRD, which predominantly impairs rod function. Additionally, the dosage, administration technique, pharmacokinetics, and safety data of VN are reviewed.Expert Opinion: As a model for development, special challenges associated with the introduction of this first ocular gene therapy include limited genetic testing in clinical practice, novel surgical complexity of ocular gene therapy administration, new functional vision endpoints, as well as unique development, launch, and reimbursement considerations associated with orphan therapies and one-time gene therapies.

Choroidal neovascular membrane associated with primary congenital glaucoma and buphthalmos.

An 18-year-old man with primary congenital glaucoma and buphthalmos in both eyes presented with unilateral, sudden-onset, painless vision loss. He had previously undergone multiple sectoral ab externo rigid-probe trabeculotomy in both eyes and subsequently Baervelt glaucoma implantion in both eyes, with adequate intraocular pressure control. Examination revealed subfoveal choroidal neovascular membrane (CNVM) and associated hemorrhages in the right eye. He was treated with 3 consecutive, monthly, intravitreal injections of bevacizumab and recovered baseline vision.

Visual Acuity Outcomes and Anti-Vascular Endothelial Growth Factor Therapy Intensity in Neovascular Age-Related Macular Degeneration Patients: A Real-World Analysis of 49 485 Eyes.

PURPOSE: This study assessed anti-vascular endothelial growth factor (VEGF) therapy intensity and its relationship with visual acuity (VA) change in real-world neovascular age-related macular degeneration (nAMD) patients. DESIGN: This retrospective analysis was performed on a large database of aggregated, longitudinal, de-identified electronic medical records from a geographically and demographically diverse sample of patients of United States retina specialists (Vestrum Health Retina Database). PARTICIPANTS: Treatment-naïve nAMD patients who underwent anti-VEGF injections between January 1, 2012, and October 31, 2016, were eligible if follow-up data were available before October 31, 2017. METHODS: Age, gender, anti-VEGF treatment type, number of treatments, and VA were extracted from the database. MAIN OUTCOME MEASURE: Mean VA change assessed at 1 year and stratified based on number of anti-VEGF injections received over 1 year. RESULTS: In this analysis, 49 485 eyes were included. The mean age was 80.9 years, and 64% were female. Mean baseline VA was 53.8 letters (Snellen equivalent, 20/80). At 1 year, after a mean of 7.3 anti-VEGF injections, there was a mean gain of 1 letter (0.95 letter; 95% confidence interval [CI] for change in VA, +0.77 to +1.13 letter; P < 0.001). When stratified by anti-VEGF agent, the mean VA changes were nearly identical at 1 year. There was a linear relationship between mean letters gained and mean number of injections, between 4 and 10 injections over 1 year, with 4 or fewer or 10 or more injections associated with loss of vision or a plateau, respectively. Greater mean 1-year change in VA also trended with worse baseline VA; those patients with better VA at presentation tended to be particularly vulnerable to vision loss. Those who received the fewest injections tended to be older and have worse baseline VA. CONCLUSIONS: Real-world nAMD patients receive fewer anti-VEGF injections and experience worse visual outcomes compared with patients receiving fixed, frequent therapy in randomized controlled trials. Mean change in VA correlates with treatment intensity at 1 year, but with ceiling effects related to treatment intensity and baseline VA. Older patients and those with poor baseline VA may be particularly prone to undertreatment.

Subretinal Injection of Voretigene Neparvovec-rzyl in a Patient With RPE65-Associated Leber's Congenital Amaurosis.

Leber's congenital amaurosis (LCA) is a rare inherited retinal degeneration (IRD) that causes severe vision loss, nyctalopia, and nystagmus within the first few years of life. RPE65 gene mutations cause approximately 6% of LCA cases and have become the target for therapy since voretigene neparvovec-rzyl became the first U.S. Food and Drug Administration-approved gene therapy product for IRDs in 2017. The surgery involves pars plana vitrectomy with subretinal injection of a viral vector that carries a functional copy of the RPE65 gene. Intraoperative optical coherence tomography is a useful adjunctive tool to confirm the injection has reached the subretinal space.

Tie-2/Angiopoietin pathway modulation as a therapeutic strategy for retinal disease.

Introduction: The Tie-2/Angiopoietin pathway is a therapeutic target for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Activation of Tie-2 receptor via Ang-1 maintains vascular stability to limit exudation. Ang-2, a competitive antagonist to Ang-1, and VE-PTP, an endothelial-specific phosphatase, interfere with the Tie-2-Ang-1 axis, resulting in vascular leakage. Areas covered: Faricimab, a bispecific antibody that inhibits VEGF-A and Ang-2, is in phase 3 trials for nAMD and DME. Nesvacumab is an Ang-2 inhibitor; when coformulated with aflibercept, it failed to show benefit over aflibercept monotherapy in achieving visual gains in phase 2 studies of nAMD and DME. ARP-1536 is an intravitreally administered VE-PTP inhibitor undergoing preclinical studies. AKB-9778 is a subcutaneously administered VE-PTP inhibitor that, when combined with monthly ranibizumab, reduced DME more effectively than ranibizumab monotherapy in a phase 2 study. AKB-9778 monotherapy did not reduce diabetic retinopathy severity score compared to placebo. AXT107, currently in the preclinical phase, promotes conversion of Ang-2 into a Tie-2 agonist and blocks signaling through VEGFR2 and other receptor tyrosine-kinases. Expert opinion: Tie-2/Angiopoietin pathway modulators show promise to reduce treatment burden and improve visual outcomes in nAMD and DME, with potential to treat cases refractory to current treatment modalities.

Innovative therapies for neovascular age-related macular degeneration.

Introduction: Investigational anti-VEGF treatments for neovascular age-related macular degeneration (nAMD) aim to improve visual outcomes and reduce treatment burden; these include long-acting agents, combination strategies, topical agents, sustained-release, and genetic therapies. Areas covered: The authors provide a comprehensive review of investigational therapies for nAMD, focusing on therapies currently in clinical trial. Expert opinion: Long-acting anti-VEGF agents have demonstrated promising results in phase 3 studies, and include Brolucizumab, a single-chain antibody fragment, and Abicipar, a designed ankyrin repeat protein (DARPin). Other unique anti-VEGF agents in current trials include Conbercept - a fusion protein of the VEGF receptor domains, KSI-301 - an anti-VEGF antibody biopolymer conjugate, and OPT-302 - an inhibitor of VEGF-C/D. Strategies to activate the Tie-2 receptor, some in combination with VEGF inhibition, are of interest, with recent trials of Faricimab, ARP-1536, and nesvacumab. Topical anti-VEGF ± anti-PDGF agents, such as pazopanib, squalamine lactate, regorafenib, and LHA510 have shown limited efficacy and/or have not been advanced, although PAN-90806 continues to advance with promising initial results. Sustained-release anti-VEGF treatments, to address treatment burden, include the ranibizumab Port Delivery System, GB-102, NT-503, hydrogel depot, Durasert, and ENV1305. Similarly, genetic therapies, including RGX-314 and ADVM-022, aim to provide sustained anti-VEGF expression from the retina.

Differentiating Veins From Arteries on Optical Coherence Tomography Angiography by Identifying Deep Capillary Plexus Vortices.

PURPOSE: To introduce a simple method for differentiating retinal veins from arteries on optical coherence tomography angiography (OCTA). DESIGN: Cross-sectional pilot study. METHODS: Four default en face slabs including color depth encoded, grayscale full-thickness retina, superficial plexus, and deep capillary plexus (DCP) from nine 3×3-mm and nine 6×6-mm OCTA scans were exported and aligned. Nine ophthalmologists with minimum OCTA experience from 2 eye institutions were instructed to classify labeled vessels as arteries or veins in 3 stages. Classification was performed based on graders' own assessment at stage 1. Graders were taught that a capillary-free zone was an anatomic feature of arteries at stage 2 and were trained to identify veins originating from vortices within the DCP at stage 3. Grading accuracy was analyzed and correlated with grading time and graders' years in practice. RESULTS: Overall grading accuracy in stages 1, 2, and 3 was (50.4% ± 17.0%), (75.4% ± 6.0%), and (94.7% ± 2.6%), respectively. Grading accuracy for 3×3-mm scans in stages 1, 2, and 3 was (49.9% ± 16.3%), (79.2% ± 9.6%), and (96.9% ± 3.1%), respectively. Accuracy for 6×6-mm scans in stages 1, 2, and 3 was (51.4% ± 20.8%), (72.3% ± 7.9%), and (93.2% ± 3.3%), respectively. Grading performance improved significantly at each stage (all P < .001). No significant correlation was found between accuracy and time spent grading or between accuracy and years in practice (r = -0.164 to 0.617, all P ≥ .077). CONCLUSIONS: We describe a simple method for accurately distinguishing retinal arteries from veins on OCTA, which incorporates the use of vortices in the DCP to identify venous origin.

Pars plana vitrectomy with intraoperative optical coherence tomography for sub-internal limiting membrane fibrosis excision in a child with Terson syndrome: Surgical and pathological correlation.

PURPOSE: To report the intraoperative optical coherence tomography (OCT)-guided surgery of a consolidated sub-internal limiting membrane (ILM) hemorrhage that developed into a sub-ILM fibrotic membrane in a child with a history of Terson syndrome. OBSERVATIONS: A one year-old boy with a history of Terson syndrome due to a motor vehicle accident presented three months after trauma with a white feather-shaped membrane in the left macula. Preoperative OCT showed a preretinal hyperreflective tissue at the foveal center. The patient underwent pars plana vitrectomy. After separation of the posterior hyaloid, intraoperative OCT did not show any change in structural components. After peeling the ILM, the fibrotic membrane persisted. A bent 30-gauged needle was used to create a plane of dissection in the adherent sub-ILM membrane, which was then peeled with ILM forceps without complication. Post-operative OCT confirmed complete excision without evidence of macular edema. Pathology results indicated presence of fibrocellular tissue that contained hemosiderin, consistent with old organized hemorrhage as a component of the membrane. CONCLUSION AND IMPORTANCE: Sub-ILM hemorrhage may persist as a tautly adherent fibrotic membrane that can mimic the appearance of an epiretinal membrane or a chronic subhyaloidal hemorrhage during examination, especially in young children. Intraoperative OCT may aid in select complex macular surgery cases to better delineate the planes of dissection during sub-ILM fibrosis excision.

Circumferential retinal hemorrhages after ophthalmic examination with scleral depression in an infant with anti-VEGF treated retinopathy of prematurity.

We report a case of retinal hemorrhages in a baby with retinopathy of prematurity (ROP) following examination with indirect ophthalmoscopy and scleral depression. There have been rare reports of examination-induced retinal hemorrhages during ROP screening, although those hemorrhages were diffusely scattered in the posterior pole. In this report the hemorrhages were found on the surface of the neovascular ridge. Changes in intraocular pressure caused by scleral depression may result in rupture of the fragile and immature retinal vessels, which have poor autoregulation in these premature babies. Ophthalmologists performing ROP screening examinations should be aware of the possibility of causing retinal hemorrhages with scleral depression, although the hemorrhages will resolve spontaneously.

Clinicopathologic Correlations of Retinal Membranes Associated With Intravitreal 'Stem Cell' Injections.

The histologic findings of a subretinal band and epiretinal membrane (ERM) excised from two patients who developed retinal detachments (RDs) after non-U.S. Food and Drug Administration-regulated intravitreal "stem cell" injections are reported. Both membranes were composed of fibrocellular tissue that stained positively with Smooth Muscle Actin and Masson's trichrome, consistent with collagenous and smooth muscle composition. CD34 immunostain (for hematopoietic cells) was negative for the subretinal band and minimally positive for the ERM. The authors speculate that the "stem cells" may cause RDs by differentiation into myofibroblasts that cause tractional membranes, though further studies are warranted. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:125-131.].