PURPOSE: To evaluate scotopic retinal organization in retinopathy of prematurity (ROP) through a study of spatial summation. METHODS: Thresholds for a range of stimulus diameters (0.4°-10°) were measured using a two alternative, spatial, forced choice psychophysical procedure. The critical diameter (DCRIT) for complete summation was estimated in subjects with a history of severe ROP (N = 7) and mild ROP (N = 17). Subjects who were born preterm and never had ROP (N = 16) and term-born subjects (N = 7) were also tested. The subjects ranged in age from 9 to 17 (median 13.5) years. RESULTS: Critical diameter for complete spatial summation was significantly larger in ROP subjects than in subjects who never had ROP and in term-born control subjects. Critical diameter varied significantly with severity of ROP. CONCLUSIONS: The larger DCRIT values in ROP are consistent with altered organization of the post receptor retina. This may offer the ROP retina a strategy for achieving noise reduction and good dark-adapted visual sensitivity.
Retinopathy of prematurity (ROP) is a neurovascular disease that affects prematurely born infants and is known to have significant long term effects on vision. We conducted the studies described herein not only to learn more about vision but also about the pathogenesis of ROP. The coincidence of ROP onset and rapid developmental elongation of the rod photoreceptor outer segments motivated us to consider the role of the rods in this disease. We used noninvasive electroretinographic (ERG), psychophysical, and retinal imaging procedures to study the function and structure of the neurosensory retina. Rod photoreceptor and post-receptor responses are significantly altered years after the preterm days during which ROP is an active disease. The alterations include persistent rod dysfunction, and evidence of compensatory remodeling of the post-receptor retina is found in ERG responses to full-field stimuli and in psychophysical thresholds that probe small retinal regions. In the central retina, both Mild and Severe ROP delay maturation of parafoveal scotopic thresholds and are associated with attenuation of cone mediated multifocal ERG responses, significant thickening of post-receptor retinal laminae, and dysmorphic cone photoreceptors. These results have implications for vision and control of eye growth and refractive development and suggest future research directions. These results also lead to a proposal for noninvasive management using light that may add to the currently invasive therapeutic armamentarium against ROP.
AIM: This nonsystematic review examined differences in the composition of raw maternal breastmilk and pasteurised donor milk and possible health effects on preterm infants. METHODS: We searched PubMed up to July 2018 for studies published in English that focused on four comparisons as follows: raw maternal milk versus donor milk, human milk before and after Holder pasteurisation, milk from mothers who delivered preterm and at term and milk collected during early and late lactation. We also searched for possible effects of the milk components, as well as the effects of maternal and donor milk on preterm infants' health. RESULTS: Raw maternal milk contained factors involved in antioxidant and anti-inflammatory defence, gut microbiome establishment and the maturation of immune defences, food tolerability and metabolism. Many of these factors were reduced or abolished in processed donor milk. Both maternal milk and donor milk have been associated with a reduced incidence of necrotising enterocolitis. High-dose feeding with maternal milk during the neonatal period reportedly reduced the risk of other morbidities and promoted growth and neurodevelopment. CONCLUSION: Many of the components in raw maternal breastmilk were lacking in pasteurised donor milk, which was inferior in promoting the growth and development of very preterm infants.
The topic of pediatric neurodegenerative disease is broad and ever expanding. Children who suffer from neurodegenerative disease often have concomitant visual dysfunction. Neuro-ophthalmologists may become involved in clinical care to identify corroborating eye findings when a specific condition is suspected, to monitor for disease progression, and in some cases, to assess treatment efficacy. Ophthalmic findings also may be the harbinger of a neurodegenerative process so a keen awareness of the possible manifestations of these conditions is important. The purpose of this review is to highlight common examples of the neuro-ophthalmic manifestations of pediatric neurodegenerative disease using a case-based approach in an effort to provide a framework for approaching these complex patients.
BACKGROUND: The role of VEGF in the pathogenesis of retinopathy of prematurity (ROP) has been clearly established. However, little is known about temporal changes in circulating VEGF concentrations in the preterm infant. The objective was to determine the longitudinal serum concentrations of VEGF in relation to ROP. METHODS: This study included 52 infants born at <31 weeks gestational age (non-ROP n=33, non-proliferative ROP n=10, treated for ROP n=9). VEGF concentrations were analyzed in blood samples collected at birth, at 3 days postnatal age, and then weekly until at least a gestational age of 35 weeks. RESULTS: VEGF concentrations at birth did not differ between groups, independent of later ROP status. In contrast, VEGF serum concentrations were significantly higher at first detection of ROP in infants who were later treated for ROP compared to infants without ROP. At the time of laser therapy, serum VEGF concentrations did not differ between groups. CONCLUSION: Circulatory concentrations of VEGF, in infants who later developed severe ROP, were elevated at the time when ROP first was detected but not at the time when current treatment most often occurred. This supports the need for further studies of circulating VEGF in relation to the timing of ROP treatment.Pediatric Research (2015); doi:10.1038/pr.2015.181.
INTRODUCTION: Thrombocytopenia has been identified as an independent risk factor for retinopathy of prematurity (ROP), although underlying mechanisms are unknown. In this study, the association of platelet count and serum platelet-derived factors with ROP was investigated. METHODS: Data for 78 infants born at gestational age (GA) <28 weeks were included. Infants were classified as having no/mild ROP or severe ROP. Serum levels of vascular endothelial growth factor A, platelet-derived growth factor BB, and brain-derived neurotrophic factor were measured in serum samples collected from birth until postmenstrual age (PMA) 40 weeks. Platelet counts were obtained from samples taken for clinical indication. RESULTS: Postnatal platelet counts and serum concentrations of the 3 growth factors followed the same postnatal pattern, with lower levels in infants developing severe ROP at PMA 32 and 36 weeks (p < 0.05-0.001). With adjustment for GA, low platelet counts and low serum concentrations of all 3 factors at PMA 32 weeks were significantly associated with severe ROP. Serum concentrations of all 3 factors also strongly correlated with platelet count (p < 0.001). CONCLUSION: In this article, we show that ROP, platelet counts, and specific pro-angiogenic factors correlate. These data suggest that platelet-released factors might be involved in the regulation of retinal and systemic angiogenesis after extremely preterm birth. Further investigations are needed.
The neonatal period of very preterm infants is often characterized by a difficult adjustment to extrauterine life, with an inadequate nutrient supply and insufficient levels of growth factors, resulting in poor growth and a high morbidity rate. Long-term multisystem complications include cognitive, behavioral, and motor dysfunction as a result of brain damage as well as visual and hearing deficits and metabolic disorders that persist into adulthood. Insulinlike growth factor 1 (IGF-1) is a major regulator of fetal growth and development of most organs especially the central nervous system including the retina. Glucose metabolism in the developing brain is controlled by IGF-1 which also stimulates differentiation and prevents apoptosis. Serum concentrations of IGF-1 decrease to very low levels after very preterm birth and remain low for most of the perinatal development. Strong correlations have been found between low neonatal serum concentrations of IGF-1 and poor brain and retinal growth as well as poor general growth with multiorgan morbidities, such as intraventricular hemorrhage, retinopathy of prematurity, bronchopulmonary dysplasia, and necrotizing enterocolitis. Experimental and clinical studies indicate that early supplementation with IGF-1 can improve growth in catabolic states and reduce brain injury after hypoxic/ischemic events. A multicenter phase II study is currently underway to determine whether intravenous replacement of human recombinant IGF-1 up to normal intrauterine serum concentrations can improve growth and development and reduce prematurity-associated morbidities.
BACKGROUND: Insulin-like growth factor 1 (IGF-1) is a mitogenic hormone involved in many processes such as growth, metabolism, angiogenesis and differentiation. After very preterm birth, energy demands increase while maternal supplies of nutrients and other factors are lost and the infant may become dependent on parenteral nutrition for weeks. Low postnatal IGF-1 concentrations in preterm infants are associated with poor weight gain, retinopathy of prematurity (ROP) and other morbidities. We will describe the process by which we aim to develop supplementation with recombinant human (rh) IGF-1 and its binding protein rhIGFBP-3 as a possible therapy to promote growth and maturation and reduce morbidities in extremely preterm infants. METHODS: In order to calculate a dose of IGF-1 tolerated by neonates, a pharmacokinetic study of transfusion with fresh frozen plasma was performed, which provided a relatively low dose of IGF-1, (on average 1.4 μg/kg), that increased serum IGF-1 to levels close to those observed in fetuses and preterm infants of similar GAs. Thereafter, a Phase I 3 hours IV infusion of rhIGF-1/rhIGFBP-3 was conducted in 5 infants, followed by a Phase II study with four sections (A-D). In the Phase II, sections A-D studies, time on infusion increased and younger gestational ages were included. RESULTS: IV infusion increased IGF-1 but with short half-life (0.5h) implying a need for continuous infusion. In order to obtain in utero levels of IGF-I, the dose was increased from 100 to 250 μg/kg/24 h and the infusion was prolonged from 3 weeks postnatal age until a postmenstrual age of 29 weeks and 6 days. CONCLUSION: The purpose has been to ensure high-quality research into the development of a new drug for preterm infants. We hope that our work will help to establish a new standard for the testing of medications for preterm infants.
Importance: Lack of arachidonic acid (AA) and docosahexaenoic acid (DHA) after extremely preterm birth may contribute to preterm morbidity, including retinopathy of prematurity (ROP). Objective: To determine whether enteral supplementation with fatty acids from birth to 40 weeks' postmenstrual age reduces ROP in extremely preterm infants. Design, Setting, and Participants: The Mega Donna Mega trial, a randomized clinical trial, was a multicenter study performed at 3 university hospitals in Sweden from December 15, 2016, to December 15, 2019. The screening pediatric ophthalmologists were masked to patient groupings. A total of 209 infants born at less than 28 weeks' gestation were tested for eligibility, and 206 infants were included. Efficacy analyses were performed on as-randomized groups on the intention-to-treat population and on the per-protocol population using as-treated groups. Statistical analyses were performed from February to April 2020. Interventions: Infants received either supplementation with an enteral oil providing AA (100 mg/kg/d) and DHA (50 mg/kg/d) (AA:DHA group) or no supplementation within 3 days after birth until 40 weeks' postmenstrual age. Main Outcomes and Measures: The primary outcome was severe ROP (stage 3 and/or type 1). The secondary outcomes were AA and DHA serum levels and rates of other complications of preterm birth. Results: A total of 101 infants (58 boys [57.4%]; mean [SD] gestational age, 25.5 [1.5] weeks) were included in the AA:DHA group, and 105 infants (59 boys [56.2%]; mean [SD] gestational age, 25.5 [1.4] weeks) were included in the control group. Treatment with AA and DHA reduced severe ROP compared with the standard of care (16 of 101 [15.8%] in the AA:DHA group vs 35 of 105 [33.3%] in the control group; adjusted relative risk, 0.50 [95% CI, 0.28-0.91]; P = .02). The AA:DHA group had significantly higher fractions of AA and DHA in serum phospholipids compared with controls (overall mean difference in AA:DHA group, 0.82 mol% [95% CI, 0.46-1.18 mol%]; P < .001; overall mean difference in control group, 0.13 mol% [95% CI, 0.01-0.24 mol%]; P = .03). There were no significant differences between the AA:DHA group and the control group in the rates of bronchopulmonary dysplasia (48 of 101 [47.5%] vs 48 of 105 [45.7%]) and of any grade of intraventricular hemorrhage (43 of 101 [42.6%] vs 42 of 105 [40.0%]). In the AA:DHA group and control group, respectively, sepsis occurred in 42 of 101 infants (41.6%) and 53 of 105 infants (50.5%), serious adverse events occurred in 26 of 101 infants (25.7%) and 26 of 105 infants (24.8%), and 16 of 101 infants (15.8%) and 13 of 106 infants (12.3%) died. Conclusions and Relevance: This study found that, compared with standard of care, enteral AA:DHA supplementation lowered the risk of severe ROP by 50% and showed overall higher serum levels of both AA and DHA. Enteral lipid supplementation with AA:DHA is a novel preventive strategy to decrease severe ROP in extremely preterm infants. Trial Registration: ClinicalTrials.gov Identifier: NCT03201588.
Fetal and early postnatal inflammation have been associated with increased morbidity in extremely preterm infants. This study aimed to demonstrate if postpartum levels of docosahexaenoic acid (DHA) and arachidonic acid (AA) were associated with early inflammation. In a cohort of 90 extremely preterm infants, DHA and AA in cord blood, on the first postnatal day and on postnatal day 7 were examined in relation to early systemic inflammation, defined as elevated C-reactive protein (CRP) and/or interleukin-6 (IL-6) within 72 h from birth, with or without positive blood culture. Median serum level of DHA was 0.5 mol% (95% CI (confidence interval) 0.2-0.9, = 0.006) lower than the first postnatal day in infants with early systemic inflammation, compared to infants without signs of inflammation, whereas levels of AA were not statistically different between infants with and without signs of inflammation. In cord blood, lower serum levels of both DHA (correlation coefficient -0.40; = 0.010) and AA (correlation coefficient -0.54; < 0.001) correlated with higher levels of IL-6. Levels of DHA or AA did not differ between infants with and without histological signs of chorioamnionitis or fetal inflammation. In conclusion, serum levels of DHA at birth were associated with the inflammatory response during the early postnatal period in extremely preterm infants.
UNLABELLED: Poor postnatal growth after preterm birth does not match the normal rapid growth in utero and is associated with preterm morbidities. Insulin-like growth factor 1 (IGF-1) axis is the major hormonal mediator of growth in utero, and levels of IGF-1 are often very low after preterm birth. We reviewed the role of IGF-1 in foetal development and the corresponding preterm perinatal period to highlight the potential clinical importance of IGF-1 deficiency in preterm morbidities. CONCLUSION: There is a rationale for clinical trials to evaluate the potential benefits of IGF-1 replacement in very preterm infants.
PURPOSE: To evaluate the Childhood Glaucoma Research Network (CGRN) classification system and describe the prevalence of each subtype according to this classification. MATERIALS AND METHODS: Retrospectively, the medical records of 205 consecutive childhood glaucoma and glaucoma suspect patients at an urban tertiary care center were reviewed. The initial diagnosis and new diagnosis according to CGRN classification were recorded. RESULTS: All patients fit one of the seven categories of the new classification. Seventy-one percent of diagnoses were changed upon reclassification. Twenty-three percent of patients had primary glaucoma (juvenile open-angle glaucoma and primary congenital glaucoma [PCG]); 36% had secondary glaucoma (glaucoma associated with nonacquired ocular anomalies; glaucoma associated with nonacquired systemic disease or syndrome; glaucoma associated with acquired condition; and glaucoma following cataract surgery); and 39% were glaucoma suspect. Of the patients diagnosed with glaucoma, PCG was the most common diagnosis, seen in 32% of patients. CONCLUSION: The CGRN classification provides a useful method of classifying childhood glaucoma.
The aim of this study is to investigate the nationwide incidence and treatment pattern of retinopathy of prematurity (ROP) in South Korea. Using the population-based National Health Insurance database (2007-2018), the nationwide incidence of ROP among premature infants with a gestational age (GA) < 37 weeks (GA < 28 weeks, GA28; 28 weeks ≤ GA < 37 weeks; GA28-37) and the percentage of ROP infants who underwent treatment [surgery (vitrectomy, encircling/buckling); retinal ablation (laser photocoagulation, cryotherapy)] were evaluated. We identified 141,964 premature infants, 42,300 of whom had ROP, with a nationwide incidence of 29.8%. The incidence of ROP in GA28 group was 4.3 times higher than in GA28-37 group (63.6% [2240/3522] vs 28.9% [40,060/138,442], p < 0.001). As for the 12-year trends, the incidence of ROP decreased from 39.5% (3308/8366) in 2007 to 23.5% (2943/12,539) in 2018. 3.0% of ROP infants underwent treatment (25.0% in GA28; 1.7% in GA28-37); 0.2% (84/42,300) and 2.9% (1214/42,300) underwent surgery and retinal ablation, respectively. The overall percentage of ROP infants who underwent treatment has decreased from 4.7% in 2007 to 1.8% in 2018. This first Korean nationwide epidemiological study of ROP revealed a decreased incidence of ROP and a decreased percentage of ROP infants undergoing conventional treatment during a 12-year period.
PURPOSE: To present in vivo anterior segment optical coherence tomography (OCT) features of infants with Peters' anomaly obtained during presurgical examination under general anaesthesia, and to evaluate the impact of OCT features on surgical decision making. METHODS: This is a single-centre, consecutive, observational case series including 44 eyes of 27 infants with Peters' anomaly (5-18 months) undergoing keratoplasty. Medical records of patients were reviewed retrospectively. Clinical features and OCT findings, along with their impact on surgical decision-making were analysed. RESULTS: Of 27 patients, 10 had unilateral and 17 had bilateral disease. Two patients with mild disease (three eyes) had a posterior corneal defect with leukoma (2/27, 7.4%). Twenty patients (32 eyes) with iridocorneal adhesions were classified as having moderate Peters' anomaly (20/27, 74.1%) and five patients (nine eyes) with lenticulocorneal adhesions were classified as having severe Peters' anomaly (5/27, 18.5%). The range of angle closure, anterior chamber depth and maximum iridocorneal adhesion length (all p<0.001) were significantly different among groups, indicating that they might serve as novel OCT parameters for assessing the severity of Peters' anomaly. The surgical approach in seven patients (21.2%) was altered in response to intraoperative OCT findings, which provided information regarding the anatomical structure of the anterior chamber not provided by the surgical microscope. The use of OCT prevented unnecessary cataract surgeries in five patients. CONCLUSIONS: Our study showed that information gained from OCT under anaesthesia allows surgeons to classify type and severity of Peters' anomaly and supports surgical decision making.
BACKGROUND: Sturge-Weber syndrome is a disorder marked by a distinctive facial capillary malformation, neurological abnormalities, and ocular abnormalities such as glaucoma and choroidal hemangioma. CASE PRESENTATION: We report a case of progressively formed retinal vessel malformation in a premature male infant with Sturge-Weber syndrome and retinopathy of prematurity, after treatment with intravitreal anti-vascular endothelial growth factor (VEGF). The baby was born at 30 weeks gestation with a nevus flammeus involving his left eyelids and maxillary area. On postmenstrual age week 39, he received intravitreal anti-VEGF. Diffuse choroidal hemangioma became evident at 40 weeks, with the classic "tomato catsup fundus" appearance. These clinical findings characterized Sturge-weber syndrome. He presented with posterior retinal vessel tortuosity and vein-to-vein anastomoses at 44 weeks. CONCLUSION: This is a rare case of documented progression of retinal vessel malformations in a patient with Sturge-Weber syndrome and retinopathy of prematurity.
PURPOSE: To review the published literature assessing the efficacy of β-blockers for the treatment of periocular hemangioma in infants. METHODS: Literature searches were conducted in May 2018 in PubMed with no date restrictions and limited to studies published in English and in the Cochrane Library database without any restrictions. The combined searches yielded 437 citations. Of these,16 articles were deemed appropriate for inclusion in this assessment and assigned a level of evidence rating by the panel methodologist. RESULTS: None of the 16 studies included in this assessment were rated level I, 3 were rated level II, and 13 were rated level III. The most common treatment regimen was 2 mg/kg daily oral propranolol, but intralesional and topical β-blockers were also used. Treatment effect was most often measured in terms of reduction in the size of the lesions, which occurred in the majority of patients. β-Blockers were consistently shown to reduce astigmatism, but this reduction was shown to be statistically significant in only 2 series. The effect of β-blockers on amblyopia was not adequately documented. β-Blockers were generally well tolerated and had mild side effects (fatigue, gastrointestinal upset/diarrhea, restlessness/sleep disturbances, minor wheezing, and cold extremities). Complications severe enough to require cessation of treatment occurred in only 2 patients out of a total of 229 who received β-blockers. CONCLUSIONS: There is limited evidence to support the safety and efficacy of both topical and systemic β-blockers to promote regression of periocular hemangiomas. Additional research may confirm the best dosage and route of administration to maximize efficacy in reducing induced astigmatism and amblyopia associated with periocular hemangiomas while minimizing side effects.
OBJECTIVE: To assess the accuracy with which available retinopathy of prematurity (ROP) predictive models detect clinically significant ROP and to what extent and at what risk these models allow for the reduction of screening examinations for ROP. METHODS: A literature search of the PubMed and Cochrane Library databases was conducted last on May 1, 2015, and yielded 305 citations. After screening the abstracts of all 305 citations and reviewing the full text of 30 potentially eligible articles, the panel members determined that 22 met the inclusion criteria. One article included 2 studies, for a total of 23 studies reviewed. The panel extracted information about study design, study population, the screening algorithm tested, interventions, outcomes, and study quality. The methodologist divided the studies into 2 categories-model development and model validation-and assigned a level of evidence rating to each study. One study was rated level I evidence, 3 studies were rated level II evidence, and 19 studies were rated level III evidence. RESULTS: In some cohorts, some models would have allowed reductions in the number of infants screened for ROP without failing to identify infants requiring treatment. However, the small sample size and limited generalizability of the ROP predictive models included in this review preclude their widespread use to make all-or-none decisions about whether to screen individual infants for ROP. As an alternative, some studies proposed approaches to apply the models to reduce the number of examinations performed in low-risk infants. CONCLUSIONS: Additional research is needed to optimize ROP predictive model development, validation, and application before such models can be used widely to reduce the burdensome number of ROP screening examinations.