Early detection and correlation of tear fluid inflammatory factors that influence angiogenesis in premature infants with and without retinopathy of prematurity.

Purpose: To measure the levels of inflammatory factors in tear fluid of pre-term infants with and without retinopathy of prematurity (ROP). Methods: The cross-sectional pilot study included 29 pre-term infants undergoing routine ROP screening. Pre-term infants were grouped as those without ROP (no ROP; n = 14) and with ROP (ROP; n = 15). Sterile Schirmer's strips were used to collect the tear fluid from pre-term infants. Inflammatory factors such as interleukin (IL)-6, IL-8, MCP1 (Monocyte Chemoattractant Protein 1; CCL2), RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted; CCL5), and soluble L-selectin (sL-selectin) were measured by cytometric bead array using a flow cytometer. Results: Birth weight (BW) and gestation age (GA) were significantly (P < 0.05) lower in pre-term infants with ROP compared with those without ROP. Higher levels of RANTES (P < 0.05) and IL-8 (P = 0.09) were observed in the tear fluid of pre-term infants with ROP compared with those without ROP. Lower levels of tear fluid IL-6 (P = 0.14) and sL-selectin (P = 0.18) were measured in pre-term infants with ROP compared with those without ROP. IL-8 and RANTES were significantly (P < 0.05) higher in the tear fluid of pre-term infants with stage 3 ROP compared with those without ROP. Tear fluid RANTES level was observed to be inversely associated with GA and BW of pre-term infants with ROP and not in those without ROP. Furthermore, the area under the curve and odds ratio analysis demonstrated the relevance of RANTES/BW (AUC = 0.798; OR-7.2) and RANTES/MCP1 (AUC = 0.824; OR-6.8) ratios in ROP. Conclusions: Distinct changes were observed in the levels of tear inflammatory factors in ROP infants. The status of RANTES in ROP suggests its possible role in pathobiology and warrants further mechanistic studies to harness it in ROP screening and management.

Correlation between tear levels of vascular endothelial growth factor and vitamin D at retinopathy of prematurity stages in preterm infants.

Deregulation of vascular endothelial growth factor (VEGF) levels leads to retinopathy of prematurity (ROP). Vitamin D (VIT-D) is known to regulate VEGF in an oxygen dependent manner. The purpose of this study was to correlate tear levels of VEGF and VIT-D with different ROP stages in preterm infants. In this prospective cross-sectional study, we enrolled 104 pre-term infants. They were grouped into: Group-1 (Classical ROP) and Group-2 (Aggressive ROP), which were further subdivided into Group-1A (progressing), Group-1B (regressing), Group-2A (pre-treatment), and Group-2B (post-treatment). Tear VEGF and VIT-D levels and their association with different ROP stages were assessed. Stage 1 and stage 2 had higher whereas stage 3 had lower VEGF levels in Group-1B compared to Group-1A. Stage 1 and stage 3 showed higher levels of VIT-D with no difference in stage 2 in Group-1B compared to Group-1A., Group-2B showed higher VEGF and lower VIT-D levels compared to Group-2A. Presence of a positive correlation at an early stage (stage 1) of ROP and a negative correlation at a more advanced stage (stage 3) of ROP with VIT-D and VEGF implies stage-specific distinct signaling crosstalk. These findings suggest that VIT-D supplementation may have the potential to modify the course and outcome of ROP.

Retinopathy of prematurity and neurodevelopmental outcomes in preterm infants: A systematic review and meta-analysis.

Background: Retinopathy of prematurity (ROP) and abnormal brain development share similar risk factors and mechanisms. There has been contrasting evidence on the association of ROP with adverse neurodevelopmental outcomes. Objective: We analysed the association between ROP at levels of severity and treatment with all neurodevelopmental outcomes until adolescence. Data source: We followed PRISMA guidelines and searched Medline and Embase between 1 August 1990 and 31 March 2022. Study selection and participants: Randomised or quasi-randomised clinical trials and observational studies on preterm infants (<37 weeks) with ROP [type 1 or severe ROP, type 2 or milder ROP, laser or anti-vascular endothelial growth factor (VEGF) treated] were included. Data extraction and synthesis: We included studies on ROP and any neurocognitive or neuropsychiatric outcomes. Outcomes: The primary outcomes were as follows: cognitive composite scores evaluated between the ages of 18 and 48 months by the Bayley Scales of Infant and Toddler Development (BSID) or equivalent; neurodevelopmental impairment (NDI; moderate to severe NDI or severe NDI), cerebral palsy, cognitive impairment; and neuropsychiatric or behavioural problems. The secondary outcomes were as follows: motor and language composite scores evaluated between the ages of 18 and 48 months by BSID or equivalent; motor/language impairment; and moderate/severe NDI as defined by the authors. Results: In preterm infants, "any ROP" was associated with an increased risk of cognitive impairment or intellectual disability [n = 83,506; odds ratio (OR): 2.56; 95% CI: 1.40-4.69; p = 0.002], cerebral palsy (n = 3,706; OR: 2.26; 95% CI: 1.72-2.96; p < 0.001), behavioural problems (n = 81,439; OR: 2.45; 95% CI: 1.03-5.83; p = 0.04), or NDI as defined by authors (n = 1,930; OR: 3.83; 95% CI: 1.61-9.12; p = 0.002). Type 1 or severe ROP increased the risk of cerebral palsy (OR: 2.19; 95% CI: 1.23-3.88; p = 0.07), cognitive impairment or intellectual disability (n = 5,167; OR: 3.56; 95% CI: 2.6-4.86; p < 0.001), and behavioural problems (n = 5,500; OR: 2.76; 95% CI: 2.11-3.60; p < 0.001) more than type 2 ROP at 18-24 months. Infants treated with anti-VEGF had higher odds of moderate cognitive impairment than the laser surgery group if adjusted data (gestational age, sex severe intraventricular haemorrhage, bronchopulmonary dysplasia, sepsis, surgical necrotising enterocolitis, and maternal education) were analysed [adjusted OR (aOR): 1.93; 95% CI: 1.23-3.03; p = 0.04], but not for cerebral palsy (aOR: 1.29; 95% CI: 0.65-2.56; p = 0.45). All outcomes were adjudged with a "very low" certainty of evidence. Conclusion and relevance: Infants with "any ROP" had higher risks of cognitive impairment or intellectual disability, cerebral palsy, and behavioural problems. Anti-VEGF treatment increased the risk of moderate cognitive impairment. These results support the association of ROP and anti-VEGF treatment with adverse neurodevelopmental outcomes. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42022326009.

Anti-vascular endothelial growth factor in the management of retinopathy of prematurity: A survey among the members of Indian Retinopathy of Prematurity Society.

Purpose: To report the results of the survey for the role of anti-VEGF in the management of retinopathy of prematurity (ROP) among the members of Indian ROP (iROP) society. Methods: A questionnaire was designed in English using Google forms and its link was circulated to the members of the iROP society on their mobile numbers. The survey included questions pertaining to demographics, anti-VEGF agents, injection technique, post-injection follow-up, and documentation pertaining to their ROP practice. Anonymous responses were obtained and analyzed for individual questions. Results: 226 members of the society were contacted and 157 responded (69.4%) to the survey. 137 (87.2%) respondents used anti-VEGF in the management of ROP. Aggressive posterior ROP (APROP) was the most common indication (78, 52.7%). The procedure was carried out in the main operation room (102, 70.3%) simultaneously for both the eyes (97; 68%) under topical anesthesia (134; 86.4%) by most of the respondents. One-hundred thirteen (77.9%) respondents used half of the adult dose, irrespective of the agent used; however, more than half of them preferred bevacizumab (85, 54%). 53 (36.3%) respondents followed up infants as per disease severity rather than a fixed schedule while only 33 (23%) performed photo documentation. 151 (96.2%) respondents felt the need for guidelines regarding the usage of anti-VEGF in ROP. Conclusion: There is an increase in the trend towards the use of anti-VEGF in the management of severe ROP, particularly APROP. However, there are considerable variations among the ROP practitioners regarding the agent, dosage, follow-up schedule, and documentation, suggesting the need for uniform guidelines.

Tear Fluid Angiogenic Factors: Potential Noninvasive Biomarkers for Retinopathy of Prematurity Screening in Preterm Infants.

Purpose: To determine the status of proangiogenic factors in the tear fluid of preterm infants with and without retinopathy of prematurity (ROP). Methods: Preterm infants (n = 36) undergoing routine ROP screening included in the prospective study were categorized as No-ROP (n = 13, no ROP at any visits), ROP (if ROP was present at first visit; n = 18), or No-ROP to ROP (no disease at first visit, but developed ROP subsequently; n = 5). Infants with ROP were also grouped as progressing (n = 7) and regressing (n = 16) based on ROP evolution between the first and subsequent visits. Schirmer's strips were used to collect tear fluid and proangiogenic factors (VEGF, angiogenin, soluble vascular cell adhesion molecule, and fractalkine) levels (in picograms per milliliter) in tear fluid were measured by multiplex ELISA. Results: Lower levels of VEGF (135 ± 69; mean ± standard deviation) and higher levels of angiogenin (6568 ± 4975) were observed in infants with ROP compared with infants without ROP (172.5 ± 54.0; 4139 ± 3909) at the first visit. Significantly lower levels of VEGF were observed in the No-ROP to ROP group compared with the No-ROP and ROP groups. The VEGF and angiogenin levels at the first visit were significantly lower in infants with ROP with progressing disease. Angiogenin levels negatively correlated with birth weight and gestational age in ROP. The area under the curve (AUC) and odds ratio (OR) analysis demonstrated that angiogenin/birth weight (AUC = 0.776; OR, 8.6); angiogenin/gestational age (AUC = 0.706; OR, 7.3) and Angiogenin/VEGF (AUC = 0.806; OR, 14.3) ratios were able to differentiated preterm infants with and without ROP. Conclusions: The association between angiogenin and ROP suggests its possible role in ROP. The ratio of angiogenin level with birth weight, gestational age, and/or VEGF could serve as a potential noninvasive screening biomarker for ROP.

Imaging the pediatric retina: An overview.

Recent decade has seen a shift in the causes of childhood blinding diseases from anterior segment to retinal disease in both developed and developing countries. The common retinal disorders are retinopathy of prematurity and vitreoretinal infections in neonates, congenital anomalies in infants, and vascular retinopathies including type 1 diabetes, tumors, and inherited retinal diseases in children (up to 12 years). Retinal imaging helps in diagnosis, management, follow up and prognostication in all these disorders. These imaging modalities include fundus photography, fluorescein angiography, ultrasonography, retinal vascular and structural studies, and electrodiagnosis. Over the decades there has been tremendous advances both in design (compact, multifunctional, tele-consult capable) and technology (wide- and ultra-wide field and noninvasive retinal angiography). These new advances have application in most of the pediatric retinal diseases though at most times the designs of new devices have remained confined to use in adults. Poor patient cooperation and insufficient attention span in children demand careful crafting of the devices. The newer attempts of hand-held retinal diagnostic devices are welcome additions in this direction. While much has been done, there is still much to do in the coming years. One of the compelling and immediate needs is the pediatric version of optical coherence tomography angiography. These needs and demands would increase many folds in future. A sound policy could be the simultaneous development of adult and pediatric version of all ophthalmic diagnostic devices, coupled with capacity building of trained medical personnel.

Foveal cyst: Unknown etiology and unexplained response to treatment.

BACKGROUND: Foveal cysts have been associated with vitreous traction due to a taut posterior hyaloid. These eyes may progress to become a full-thickness macular hole, remain stable, or resolve after a posterior vitreous detachment. A foveal cyst in an eye with a complete posterior vitreous detachment and no other obvious pathology is unusual. CASE PRESENTATION: A 21-year-old male presented with blurred vision in the left eye of 1-month duration. On examination his left-eye vision was 20/60, and anterior segment examination was normal. Fundus examination showed internal limiting membrane folds with a suspected lamellar macular hole. A spectral domain optical coherence scan showed a thin dome-like cyst in the sub foveal region involving the outer retinal layer with a detached posterior hyaloid face. A trial of intravitreal dexamethasone implant was given, following which there was improvement in vision and resolution of the foveal cyst. At the third-month follow-up, the patient presented with a stellate pattern of hyporeflectivity in the macular area both on spectral domain optical coherence scan and multicolor imaging with no change in visual acuity. CONCLUSION: The presence of a foveal cyst in a young male without any risk factors is peculiar, and the rapid response to intravitreal dexamethasone implant raises questions about the pathogenesis. The stellate pattern of hyporeflectivity on spectral domain optical coherence scan imaging with an intraretinal "filling defect"-like picture on fluorescein angiography suggests a possible ongoing ischemic pathology.

Tele-consultations in the wake of COVID-19 - Suggested guidelines for clinical ophthalmology.

While telemedicine has been around for a few decades, it has taken great importance and prominence in recent times. With the fear of the virus being transmitted, patients and physicians across specialties are using consultation via a telephone call or video from the safety of their homes. Though tele-ophthalmology has been popular for screening, there are no clear guidelines on how to comprehensively manage patients seeking advice and treatment for a particular eye condition. Some major barriers to diagnosis and management are compromised detailed examination, no measurement of the visual acuity or intraocular pressure and a retinal evaluation not being feasible. Despite these limitations, we do need to help those patients who need immediate care or attention. Hence, this article has put together some guidelines to follow during such consultations. They are important and timely due to the medicolegal and financial implications.

Vitamin-D3 (α-1, 25(OH) 2D3) Protects Retinal Pigment Epithelium From Hyperoxic Insults.

Purpose: Oxidative stress affects the retinal pigment epithelium (RPE) leading to development of vascular eye diseases. Cholecalciferol (VIT-D) is a known modulator of oxidative stress and angiogenesis. This in vitro study was carried out to evaluate the protective role of VIT-D on RPE cells incubated under hyperoxic conditions. Methods: Cadaver primary RPE (PRPE) cells were cultured in hyperoxia (40% O2) with or without VIT-D (α-1, 25(OH) 2D3). The functional and physiological effects of PRPE cells with VIT-D treatment were analyzed using molecular and biochemical tools. Results: Vascular signaling modulators, such as vascular endothelial growth factor (VEGF) and Notch, were reduced in hyperoxic conditions but significantly upregulated in the presence of VIT-D. Additionally, PRPE conditioned medium with VIT-D induced the tubulogenesis in primary human umbilical vein endothelial cells (HUVEC) cells. VIT-D supplementation restored phagocytosis and transmembrane potential in PRPE cells cultured under hyperoxia. Conclusions: VIT-D protects RPE cells and promotes angiogenesis under hyperoxic insult. These findings may give impetus to the potential of VIT-D as a therapeutic agent in hyperoxia induced retinal vascular diseases.

Retinopathy of prematurity treatment: Asian perspectives.

Retinopathy of prematurity (ROP) is a vasoproliferative disease of developing retinal vessels that affects premature infants and can lead to severe and irreversible visual loss if left untreated. India and some other Asian countries are in the middle of a 'third ROP epidemic'. Blindness due to ROP is largely preventable if appropriate, adequate and accessible screening programmes are available. Screening of the premature babies is the first step in ROP management. With the increase in use of tele-screening techniques, more premature babies have been brought under the screening network both from urban and rural regions. Laser photocoagulation to the avascular retina using indirect ophthalmoscopy delivery system is the gold standard for ROP treatment and is usually done under topical anaesthesia in the Asian region in contrast to the western world. Use of intravitreal anti-vascular endothelial growth factors (VEGF) although controversial in management of ROP has been found to be effective in various Asian studies as well. ROP surgery in India and other middle-income Asian countries is largely performed only in few tertiary eye care centres. Poor visual prognosis, late presentation with advanced retinal detachments, lack of adequate number of trained paediatric retinal surgeons and paediatric anaesthetists also contribute to this problem. This current paper summarizes the Asian experience of ROP management.

The use of handheld spectral domain optical coherence tomography in pediatric ophthalmology practice: Our experience of 975 infants and children.

PURPOSE: Optical coherence tomography (OCT) is an important imaging tool assessing retinal architecture. In this article, we report a single centers experience of using handheld spectral domain (SD)-OCT in a pediatric population using the Envisu 2300 (Bioptigen Inc., Research Triangle Park, NC, USA). METHODS: We studied SD-OCT images from 975 patients imaged from January 2011 to December 2014. The variety of cases that underwent an SD-OCT was analyzed. Cases examples from different case scenarios were selected to showcase unique examples of many diseases. RESULTS: Three hundred and sixty-eight infants (37.7%) were imaged for retinopathy of prematurity, 362 children (37.1%) underwent the test for evaluation of suboptimal vision or an unexplained vision loss, 126 children (12.9%) for evaluation of nystagmus or night blindness, 54 children (5.5%) for an intraocular tumor or a mass lesion such as retinoblastoma, and 65 children (6.7%) for other diseases of the pediatric retina. The unique findings in the retinal morphology seen with some of these diseases are discussed. CONCLUSION: The handheld SD-OCT is useful in the evaluation of the pediatric retinal diseases. The test is useful in the assessment of vision development in premature children, evaluation of unexplained vision loss and amblyopia, nystagmus and night blindness, and intraocular tumors (including retinoblastoma).

Look what else we found--clinically significant abnormalities detected during routine ROP screening.

PURPOSE: The purpose of this study was to report the spectrum of anterior and posterior segment diagnoses in Asian Indian premature infants detected serendipitously during routine retinopathy of prematurity (ROP) screening during a 1 year period. METHODS: A retrospective review of all Retcam (Clarity MSI, USA) imaging sessions during the year 2011 performed on infants born either <2001 g at birth and/or <34.1 weeks of gestation recruited for ROP screening was performed. All infants had a minimum of seven images at each session, which included the dilated anterior segment, disc, and macula center and the four quadrants using the 130° lens. RESULTS: Of the 8954 imaging sessions of 1450 new infants recruited in 2011, there were 111 (7.66%) with a diagnosis other than ROP. Anterior segment diagnoses seen in 31 (27.9%) cases included clinically significant cataract, lid abnormalities, anophthalmos, microphthalmos, and corneal diseases. Posterior segment diagnoses in 80 (72.1%) cases included retinal hemorrhages, cherry red spots, and neonatal uveitis of infective etiologies. Of the 111 cases, 15 (13.5%) underwent surgical procedures and 24 (21.6%) underwent medical procedures; importantly, two eyes with retinoblastoma were detected which were managed timely. CONCLUSIONS: This study emphasizes the importance of ocular digital imaging in premature infants. Visually significant, potentially life-threatening, and even treatable conditions were detected serendipitously during routine ROP screening that may be missed or detected late otherwise. This pilot data may be used to advocate for a possible universal infant eye screening program using digital imaging.

Microscope-integrated optical coherence tomography: A new surgical tool in vitreoretinal surgery.

Optical coherence tomography (OCT) has revolutionized imaging of ocular structures and various disease conditions. Though it has been used in the clinic for some decades, the OCT has only recently found its way into the operating theater. Early attempts at intraoperative OCT, hand-held and microscope mounted, have already improved our understanding of the surgical pathology and the role it might play in surgical decision-making. The microscope-integrated OCT now allows seamless, high-resolution, real-time imaging of surgical maneuvers from the incision to wound closure. Visualization of instruments and intraoperative tissue manipulation are possible with this in vivo modality and, therefore, help improve the outcome of surgery. In this article, we describe the advantages it offers during various vitreoretinal procedures.

Macular edema in Asian Indian premature infants with retinopathy of prematurity: Impact on visual acuity and refractive status after 1-year.

PURPOSE: To report the impact of transient, self-resolving, untreated "macular edema" detected on spectral domain optical coherence tomography in Asian Indian premature infants with retinopathy of prematurity (ROP) on visual acuity (VA) and refraction at 1-year of corrected age. MATERIALS AND METHODS: Visual acuity and refraction of 11 infants with bilateral macular edema (Group A) was compared with gestational age-matched 16 infants with ROP without edema (Group B) and 17 preterms infants without ROP and without edema (Group C) at 3, 6, 9 and 12 months of corrected age using Teller Acuity Cards and cycloplegic retinoscopy. Sub-group analysis of the previously described pattern A and B macular edema was performed. RESULTS: Visual acuity was lower in infants with macular edema compared with the other two control groups throughout the study period, but statistically significant only at 3 months. Visual improvement in these infants was highest between the 3 rd and 6 th month and plateaued by the end of the 1 st year with acuity comparable to the other two groups. The edema cohort was more hyperopic compared to the other two groups between 3 and 12 months of age. Pattern A edema had worse VA compared to pattern B, although not statistically significant. CONCLUSION: Macular edema, although transient, caused reduced VA as early as 3 months of corrected age in Asian Indian premature infants weighing <2000 g at birth. The higher hyperopia in these infants is possibly due to visual disturbances caused at a critical time of fovealization. We hypothesize a recovery and feedback mechanism based on the principles of active emmetropization to explain our findings.

Retinal Imaging of Infants on Spectral Domain Optical Coherence Tomography.

Spectral domain coherence tomography (SD OCT) has become an important tool in the management of pediatric retinal diseases. It is a noncontact imaging device that provides detailed assessment of the microanatomy and pathology of the infant retina with a short acquisition time allowing office examination without the requirement of anesthesia. Our understanding of the development and maturation of the infant fovea has been enhanced by SD OCT allowing an in vivo assessment that correlates with histopathology. This has helped us understand the critical correlation of foveal development with visual potential in the first year of life and beyond. In this review, we summarize the recent literature on the clinical applications of SD OCT in studying the pathoanatomy of the infant macula, its ability to detect subclinical features, and its correlation with disease and vision. Retinopathy of prematurity and macular edema have been discussed in detail. The review also summarizes the current status of SD OCT in other infant retinal conditions, imaging the optic nerve, the choroid, and the retinal nerve fibre in infants and children, and suggests future areas of research.

Correlation of spectral-domain optical coherence tomography with fundus fluorescein angiography in an infant with retinal hamartomas.

PURPOSE: To describe the correlation between the surface morphology on spectral-domain optical coherence tomography (SD-OCT) and leakage pattern on fundus fluorescein angiography (FFA) in an infant with multiple retinal hamartomas. METHODS: An Asian Indian female infant was found to have 2 retinal lesions in the right eye and 1 in the left eye during Retcam (Clarity MSI, CA, USA) screening for retinopathy of prematurity at 45 weeks postmenstrual age. Spectral-domain optical coherence tomography on the hand-held OCT (Envisu 2300, Bioptigen, NC, USA) and FFA on the Retcam 3 were performed under monitoring in the office. RESULTS: Spectral-domain OCT detected all 3 lesions but only 1 lesion was detected on FFA. While this lesion had an irregular surface with overlying vitreoretinal (VR) traction on SD-OCT, the other 2 lesions not detected on FFA were smooth and had no VR traction. After a follow-up to 18 months corrected age, there was no change in the morphology of any of the lesions. CONCLUSIONS: It is possible to characterize retinal hamartomas in infants using SD-OCT and correlate them with FFA. Spectral-domain OCT examination can be used to diagnose and monitor lesions even if they are not detectable on angiography.

Universal ocular screening of 1021 term infants using wide-field digital imaging in a single public hospital in India - a pilot study.

PURPOSE: Universal eye screening of neonates is currently not standard of care. Early detection of abnormalities could offer prompt management and a reduction in visual morbidity. We report a pilot study using wide-field digital imaging to screen all infants at birth to explore its feasibility as a tool for universal screening. METHODS: Consecutively enrolled 1021 term infants in a public hospital were imaged within 72 hr of birth using the Retcam shuttle (Clarity MSI, USA). Anterior and dilated posterior segment images were obtained. Infants with abnormal images were examined clinically, and medical or surgical treatment was given when needed, at no cost to the family. RESULTS: Of the 1021 healthy full-term newborns, 48 babies had abnormal findings (4.7%). Retinal haemorrhages were the most common (52.1%) abnormality of which 24% were macular. A 'ridge' resembling retinopathy of prematurity in both eyes constituted 18.8% of all abnormalities. Nine infants (18.8% of abnormalities and 0.9% overall) had conditions meriting medical or surgical intervention and would have been missed otherwise. Seven of these nine babies (0.7%) needed medical attention with a systemic work-up for conditions such as posterior uveitis with linear perivasculitis, salt and pepper retinopathy or posterior synechia. Two of nine babies (0.2%) required surgical intervention for unilateral cataract and retinoblastoma. CONCLUSION: Universal eye screening of all neonates using wide-field digital imaging is possible and safe. Extrapolating our results to the national scenario, we estimate that 226 950 infants requiring treatment would go undiagnosed annually. Universal infant eye imaging strategies must receive serious national consideration.