Outcomes of intravitreal anti-VEGF injections and panretinal photocoagulation in preretinal hemorrhage secondary to proliferative diabetic retinopathy involving the fovea.

PURPOSE: To evaluate the outcome of intravitreal anti-vascular endothelial growth factor (VEGF) injections and panretinal photocoagulation (PRP) in fovea involving preretinal hemorrhage (PRH) secondary to proliferative diabetic retinopathy (PDR). METHODS: Retrospective non-comparative cross-sectional series of patients diagnosed with fovea involving PRH secondary to PDR at our institute from March 2019 to October 2021 who were treated with combination treatments of intravitreal anti-VEGF and PRP and have completed a minimum 6-month follow-up. The primary outcome measure was serial changes in the visual acuity (VA) and PRH regression from the fovea. Secondary outcome measures were the quantitative assessment of the size of PRH, its association with VA improvement and time to regression, and the proportion of patients who underwent surgery for poor response. RESULTS: In total, 22 eyes of 21 patients showed regression of PRH from the foveal center at 33.6 days, and complete regression was seen at 140.7 days. The average number of anti-VEGF injections required for clearance of PRH from the fovea was 1.6. Mean LogMAR visual acuity improved from 0.54 at baseline to 0.32 at 4 weeks and 0.18 at 6 months ( P < 0.01). Three eyes (13.6%) required vitrectomy surgery during follow-up. The mean area of PRH as measured by Image J analysis was 14.78 mm 2 at baseline, 8.97 mm 2 at 4 weeks, and 1.25 mm 2 at 3 months ( P < 0.01). No statistically significant difference was seen between the size of PRH and PRH clearance time and VA improvement. No systemic side effects were observed following the intravitreal injections during follow-up. CONCLUSION: Intravitreal anti-VEGF injections and PRP were found to be effective and safe treatment methods for fovea involving PRH secondary to PDR. Long-term studies are warranted to assess the long-term efficacy.

Rapid regression of idiopathic multifocal choroiditis with intravitreal methotrexate-wide-field optical coherence tomography angiography-based study.

Wide-field optical coherence tomography angiography (OCTA) results in a patient of idiopathic multifocal choroiditis successfully treated with intravitreal methotrexate injections.

Role of Anti-Vascular Endothelial Growth Factor (Anti-VEGF) in the Treatment of Retinopathy of Prematurity: A Narrative Review in the Context of Middle-Income Countries.

The rise in preterm births and higher survival rates of premature infants have led to a global increase in retinopathy of prematurity (ROP), a vasoproliferative retinal disorder common in premature infants. ROP is one of the leading causes of childhood blindness. Clinical manifestation of ROP ranges from mild abnormal retinal neovascularization to bilateral retinal detachment and vision loss. The incidence of ROP is higher in middle income countries, including India, which has the highest number of global preterm births. Low birth weight and low gestational age are the primary risk factors for ROP; however, anemia, cardiac defects, blood transfusion, apnea, sepsis, respiratory distress syndrome, high exposure to oxygen and poor postnatal weight gain may also contribute to its development. India has stringent ROP screening guidelines revised in 2018, and screening of infants with either birth weight <2000 grams or gestational age <34 weeks is mandated. With an improved understanding of the pathogenesis of ROP in the past decades and advances in clinical research, treatment for ROP has evolved from cryotherapy to laser retinal ablation. Most recently, anti-vascular endothelial growth factor (anti-VEGF) drugs have emerged as a favorable treatment option for zone-I and II ROP. This article reviews the current approaches for ROP treatment in India with a particular focus on anti-VEGF drugs. The article also integrates the understanding of safety and risk-benefit evaluation of the current approaches in ROP management. The review concluded that there is a need to increase the ROP screening not only for preterm and low birth weight but also for optimal gestational age infants with healthy birth weight. Anti-VEGF therapies have shown improved efficacy, although studies are required to establish the long-term safety.

Topical glycerine for corneal clouding during retinal laser photocoagulation for retinopathy of prematurity.

AIM: To document the use of topical glycerine to reduce corneal edema in cases of retinopathy of prematurity (ROP) undergoing laser photocoagulation (PHC). METHODS: Thirty-two eyes of 16 babies (9 males) with a mean gestational age of 30 weeks, mean gestational weight of 1242 grams underwent PHC for Type 1 (zone 1 disease) retinopathy of prematurity. All babies received a single PHC session. Twenty eyes of 10 babies received intravitreal anti-VEGF injection, 1-3 weeks before PHC session. All patients received a single drop of glycerine during the PHC session to clear the corneal clouding. All patients underwent PHC to the avascular area right up to the ora serrata. Patients were seen at one week and one month to assess the adequacy of laser PHC. RESULTS: We were able to complete the PHC for all babies in a single session without any ocular or systemic adverse events. We did not find any skip lesions at follow-up, and the second session of laser PHC was not required in any eyes. CONCLUSION: Topical glycerine is safe and effective to clear corneal clouding in eyes undergoing laser PHC for retinopathy of prematurity.

A Novel Method to Improve Inter-Clinician Variation in the Diagnosis of Retinopathy of Prematurity Using Machine Learning.

PURPOSE: Inter-clinician variation could cause uncertainty in disease management. This is reported to be high in Retinopathy of Prematurity (ROP), a potentially blinding retinal disease affecting premature infants. Machine learning has the potential to quantify the differences in decision-making between ROP specialists and trainees and may improve the accuracy of diagnosis. METHODS: An anonymized survey of ROP images was administered to the expert(s) and the trainee(s) using a study-designed user interface. The results were analyzed for repeatability as well as to identify the level of agreement in the classification. "Ground truth" was prepared for each individual and a unique classifier was built for each individual using the same. The classifier allowed the identification of the most important features used by each individual. RESULTS: Correlation and disagreement between the expert and the trainees were visualized using the Dipstick™ diagram. Intra-clinician repeatability and reclassification statistics were assessed for all. The repeatability was 88.4% and 86.2% for two trainees and 92.1% for the expert, respectively. Commonly used features differed for the expert and the trainees and accounted for the variability. CONCLUSION: This novel, automated algorithm quantifies the differences using machine learning techniques. This will help audit the training process by objectively measuring differences between experts and trainees. TRANSLATIONAL RELEVANCE: Training for image-based ROP diagnosis can be more objectively performed using this novel, machine learning-based automated image analyzer and classifier.

Impact of COVID-19-related lockdown on retinal disorders treated with intravitreal injections.

PURPOSE: To study functional changes in vision and morphological changes on optical coherence tomography (OCT) scans in patients where intravitreal therapy (IVT) with injections has been delayed due to COVID-19 pandemic lockdown. METHODS: Retrospective cross-sectional study included 77 eyes with the diagnosis of exudative age-related macular degeneration (eAMD), diabetic macular edema (DME), and retinal vein occlusion (RVO), regularly receiving IVT with anti-vascular endothelial growth factor (Anti-VEGF) injections or dexamethasone implant and were not able to receive the injections as intended due to lockdown. Best-corrected visual acuity (BCVA), central foveal thickness (CFT), and qualitative morphological features on OCT were analyzed pre- and post-therapy break off. RESULTS: The mean duration of IVT break-off was 57 days. Mean BCVA logarithm of minimum angle of resolution (logMAR) worsened from 0.33 (20/42) to 0.35 (40/44) (P = 0.02) and mean CFT increased from 297.90 µm to 402.16 µm (P < 0.01), from pretherapy break-off to return visit. Worsening of the visual acuity was seen across all the three disease cohorts, significantly more in the eyes with eAMD. CONCLUSION: Marginal decline in the visual acuity and worsening of the OCT features were observed as a result of delay in the IVT injections of DME, eAMD and RVO patients.

Preferred practice guidelines for retinopathy of prematurity screening during the COVID-19 pandemic.

Retinopathy of prematurity (ROP) is the leading cause of preventable infant blindness in the world and predominantly affects babies who are born low birth weight and premature. India has the largest number of surviving preterm births born annually. ROP blindness can be largely prevented if there is a robust screening program which detects treatment requiring disease in time. ROP treatment must be provided within 48 h of reaching this threshold of treatment making it a relative emergency. During the severe acute respiratory syndrome-coronavirus disease 2019 pandemic in 2020 ROP screening was disrupted throughout the world due to lockdowns and restriction of movement of these infants, their families, specialists and healthcare workers. The Indian ROP Society issued guidelines for ROP screening and treatment in March 2020, which was aimed at preserving the chain-of-care despite the potential limitations and hazards during the (ongoing) pandemic. This preferred practice guideline is summarized in this manuscript.

Efficacy of 0.01% low dose atropine and its correlation with various factors in myopia control in the Indian population.

We aimed to evaluate the efficacy and safety of low-dose atropine compared to placebo in the Indian population and also to study the impact of various modifiable and non-modifiable factors on myopia progression (MP) and drug efficacy (DE). It was a single-centre prospective placebo-controlled interventional study. 43 participants aged 6-16 years with progressive myopia received 0.01% atropine in the right eyes (treatment) and placebo in the left eyes (control) for 1-year. The main outcome measures were annual MP and axial length elongation (ALE) in treatment and control eyes and their percentage difference between two eyes (drug efficacy). Secondary outcome measures were the occurrence of any adverse events and the correlation of MP, ALE, and DE with various factors. 40 participants (80 eyes) completed the follow-up. After 1-year, MP was 0.25 D (IQR 0.13-0.44) and 0.69 D (IQR 0.50-1.0) (p < 0.001) in treatment and control respectively (63.89% reduction) with respective ALE of 0.14 mm (IQR 0.05-0.35) and 0.32 mm (IQR 0.19-0.46) (p < 0.001) (44.44% reduction). No adverse events were noted. Reduction in MP and ALE was statistically significant in all children irrespective of age-group, baseline MP, family history, screen-time, near and outdoor-time. The strongest determinants of annual MP were age (Treatment: r = - 0.418, p = 0.007; Control: r = - 0.452, p = 0.003) and baseline MP (Treatment: r = 0.64, p = 0.000; Control: r = 0.79, p = 0.000). Screen-time in control eyes was associated with greater ALE (r = 0.620, p = 0.042). DE was higher when outdoor time exceeded 2 h/day (p = 0.035) while the efficacy was lower with prolonged near activities (p = 0.03), baseline fast-progressors (p < 0.05) and history of parental myopia (p < 0.05). 0.01% atropine is effective and safe in retarding MP and ALE in Indian eyes.

Longitudinal study of serpiginous choroiditis and serpiginous like choroiditis using wide field OCT angiography.

PURPOSE: To assess the ability of wide field Swept Source OCTA (SS-OCTA) imaging to detect morphological variations in Serpiginous Choroiditis (SC) and Serpiginous Like Choroiditis (SLC) in response to treatment and also analyze these findings quantitatively using Image J software. METHODS: Retrospective observational case series of nine eyes with clinical diagnosis of active SC and SLC, who underwent SS-OCTA and fundus autofluorescence (FAF) imaging at baseline and each follow up visit till 6 months. Morphological analysis was done by two independent graders and quantitative analysis to measure the size and intensity of lesion was done using publicly available Image J software at baseline and each follow up visit. DESIGN: Retrospective observational case series. RESULTS: Using SS-OCTA, all the active lesions followed a characteristic healing pattern. Active lesions appear well defined hypo flow void patches and as healing progressed, lesion became more ill-defined and iso-hyper- intense. Significant increase in mean intensity of the lesion could be apparent after 1 and 6 month of treatment. There was reduction in the size of lesions during follow up however this difference was not statistically significant. CONCLUSION: SS-OCTA could be a useful noninvasive tool to study the treatment response in SC/SLC both morphologically as well as quantitatively. Quantitative parameters need to be designed in further research studies to aid in uniform management and follow up of uveitis cases.

Effect of sustained-release long-acting intravitreal dexamethasone implant in patients of non-proliferative diabetic retinopathy undergoing phacoemulsification: A randomized controlled trial.

PURPOSE: Cataract and diabetes, both being a major health care problem, an intervention evaluated for the combination of the two attains paramount importance. The purpose of the study was to determine the role of intraoperative intravitreal dexamethasone implant in patients with diabetic retinopathy with/without macula edema undergoing phacoemulsification. METHODS: The study was a two-arm, single-center, randomized, assessor-blinded trial of 151 patients with type-2 diabetes mellitus and cataract. It had two groups: dexamethasone group (DEX) versus standard of care (SOC) group, i.e. phacoemulsification and intraocular lens (IOL) implantation without injection of dexamethasone drug delivery system (DDS). The number of rescue interventions required, central macular thickness by optical coherence tomography (OCT), Early Treatment Diabetic Retinopathy Study (ETDRS) score, laser flare meter (LFM) values, intraocular pressure (IOP), and grade of diabetic retinopathy (DR) were recorded until three months follow up. Macular thickness and number of rescue medications between the treatment groups were the co-primary outcomes. RESULTS: A statistically significant interaction was present between treatment and time on OCT score (P < 0.001). The requirement of rescue interventions in the dexamethasone DDS group [40.2% (33/82)] was lesser as compared to the SOC group [49.3% (34/69)] at the end of 12 weeks [odds ratio (OR), 0.70 (0.36-1.33)] follow up although not statistically significant (P = 0.343). A statistically significant interaction was present between treatment and time on LFM score (P = 0.003). No statistically significant interaction was present between the treatment and time on visual acuity score (P = 0.08) and IOP score (P = 0.375). CONCLUSION: Dexamethasone implant may have potential as a valuable therapy for patients undergoing cataract surgery with DR with/without macular edema with effects lasting for at least three months.

Screening for obstructive sleep apnea in a diabetic retinopathy clinic in a tertiary care center.

PURPOSE: : To screen for obstructive sleep apnea (OSA) in patients presenting to diabetic retinopathy (DR) clinic and to correlate its presence with the severity of DR. METHODS: : A prospective, cross-sectional study of diabetes mellitus patients in retina clinic of a tertiary care referral center, North India (January 2019-March 2020). All were subjected to STOP-Bang Questionnaire and Epworth Sleepiness Scale (ESS) score. Patients at high OSA risk (STOP-Bang score ≥5 and ESS score ≥10) were referred to Department of Otorhinolaryngology (sleep clinic) for polysomnography. Based on Apnea Hypopnea Index (AHI), OSA was graded as mild (AHI = 5-14/h), moderate (AHI = 15-30/h), and severe (AHI >30/h). Statistical analysis was done using three models of outcome measures: (1) "No DR" versus "any DR," (2) "Less severe DR" versus "More severe DR," and (3) "No diabetic macular edema (DME)" versus "DME." RESULTS: : Of 362 patients screened, 18 (4.97%) had OSA (11 mild, 5 moderate, and 2 severe). Though OSA did not show a significant association with various outcome measures, patients with moderate-severe OSA had higher odds in developing "any DR" (OR = 7.408; 95% CI = 0.533-102.898), "more severe DR" (OR = 1.961; 95% CI = 0.153-25.215), and "DME" (OR = 2.263; 95% CI = 0.357-14.355), on multiple logistic regression. CONCLUSION: : Ours is the first screening study of OSA in DR patients in India, the diabetes capital of the world. We detected OSA in 4.97% of patients in a DR clinic, with an increased risk of "any DR," "more severe DR," and "DME" in the presence of moderate-severe OSA.

Preterm refraction and ocular biometry in children with and without retinopathy of prematurity in the first year of life.

PURPOSE: To determine ocular biometric and refractive profiles of premature children at risk of retinopathy of prematurity (ROP), comparing those who did and did not require laser treatment. METHODS: In this prospective study, premature infants underwent biometry and refraction with their first ROP examination. Study parameters were assessed again at 3 months, 6 months, and 1 year. The main outcome measures were spherical equivalent, axial length, and keratometry. RESULTS: A total of 122 infants (243 eyes) were included. At baseline, infants without ROP, those with ROP who never needed treatment, and those who later needed treatment had overall comparable axial length (P = 0.53) and myopia (P = 0.05); the highest severity group had higher corneal steepness and more myopia at baseline. At 1 year, children with laser-treated ROP had the shortest axial lengths, with the least decrease in keratometry, and the greatest increase in myopia (-2.0 D; P = 0.001). Anisometropia, if present initially, persisted through the 1-year examination. Mean refractive error was more myopic in zone 1 disease (P = 0.3) and in aggressive posterior ROP (P = 0.15). CONCLUSIONS: Severe ROP is associated with disruption of emmetropization, and steeper corneas and more myopia at the first ROP examination, before any intervention. In our study cohort, these differences became more marked over the course of 1 year after laser therapy. The myopia in these cases was not axial. Laser therapy did not induce new anisometropia.

Five-year demographic profile of retinopathy of prematurity at a tertiary care institute in North India.

Purpose: The purpose of this study is to study the demographic profile and pattern of retinopathy of prematurity (ROP) at a tertiary care institute in India. Methods: An ambispective study from January 2013 to December 2017. Infants with birth weights (BWs) <1750 g and gestational ages <34 weeks were screened for ROP. Demographic details and ROP severity were recorded. Results: Data of 2595 of the 3697 infants screened were analyzed. The number of infants screened and treated for ROP increased from 190 and 29, respectively (2013), to 818 and 132, respectively (2017). The overall incidence of "any ROP" was 32.3%, and severe ROP was 17.7%. Though 39.5% of all infants were outborns (not born in the study center), severe ROP was present in 69.7% of these compared to 18.8% among inborns. Outborns with ROP had a higher mean BW (1308 g) compared to inborns (1202 g) (P < 0.01). ROP Stage 1 was seen in 12%, Stage 2 in 34%, Stage 3 in 13%, Stage 4 in 6%, Stage 5 in 14%, and aggressive posterior ROP (APROP) in 20%. APROP was seen in 16% of infants in 2013, 10% in 2014, 15% in 2015, 22% in 2016, and 28% in 2017. Infants with Stage 4B/Stage5 (15.6% of all ROP) were presented at a mean age of 7.5 months and all had no/delayed screening. Conclusion: Incidence of any ROP was 32.3% and was more common in outborns than inborns. The proportion of infants with APROP showed a rising trend over the years. Nearly 15.6% of infants were presented with stage4B/5 ROP due to delayed/absent screening.

Enzymatic vitreolysis using reengineered Vibrio mimicus-derived collagenase.

Purpose: Collagen is a key player contributing to vitreoelasticity and vitreoretinal adhesions. Molecular reorganization causes spontaneous weakening of these adhesions with age, resulting in the separation of the posterior hyaloid membrane (PHM) from the retina in what is called complete posterior vitreous detachment (PVD). Incomplete separation of the posterior hyaloid or tight adherence or both can lead to retinal detachment, vitreomacular traction syndrome, or epiretinal membrane formation, which requires surgical intervention. Pharmacological vitrectomy has the potential of avoiding surgical vitrectomy; it is also useful as an adjunct during retinal surgery to induce PVD. Previously studied enzymatic reagents, such as collagenase derived from Clostridium histolyticum, are nonspecific and potentially toxic. We studied a novel collagenase from Vibrio mimicus (VMC) which remains active (VMA), even after deletion of 51 C-terminal amino acids. To limit the activity of VMA to the vitreous cavity, a fusion construct (inhibitor of hyaluronic acid-VMA [iHA-VMA]) was made in which a 12-mer peptide (iHA, which binds to HA) was fused to the N-terminus of VMA. The construct was evaluated in the context of PVD. Methods: VMA and iHA-VMA were expressed in Escherichia coli, purified, and characterized with gelatin zymography, collagen degradation assay, fluorescamine-based assay, and cell-based assays. Two sets of experiments were performed in New Zealand albino rabbits. Group A (n = 10) received iHA-VMA, while group B (n = 5) received the equivalent dose of VMA. In both groups, saline was injected as a control in the contralateral eyes. Animals were monitored with indirect ophthalmoscopy, optical coherence tomography (OCT), and B-scan ultrasonography. Retinal toxicity was assessed with hematoxylin and eosin (H&E) staining of retinal tissue. Results: The activity of iHA-VMA and VMA was comparable and 65-fold lower than that of C. histolyticum collagenase Type IV. In the iHA-VMA group, all the rabbits (n = 10) developed PVD, with complete PVD seen in six animals. No statistically significant histomorphological changes were seen. In the VMA group, four of the five rabbits developed complete PVD; however, retinal morphological changes were seen in two animals. Conclusions: iHA-VMA displays targeted action confined to the vitreous and shows potential for safe pharmacologic vitreolysis.