Use of an Artificial Intelligence-Generated Vascular Severity Score Improved Plus Disease Diagnosis in Retinopathy of Prematurity.

PURPOSE: To evaluate whether providing clinicians with an artificial intelligence (AI)-based vascular severity score (VSS) improves consistency in the diagnosis of plus disease in retinopathy of prematurity (ROP). DESIGN: Multireader diagnostic accuracy imaging study. PARTICIPANTS: Eleven ROP experts, 9 of whom had been in practice for 10 years or more. METHODS: RetCam (Natus Medical Incorporated) fundus images were obtained from premature infants during routine ROP screening as part of the Imaging and Informatics in ROP study between January 2012 and July 2020. From all available examinations, a subset of 150 eye examinations from 110 infants were selected for grading. An AI-based VSS was assigned to each set of images using the i-ROP DL system (Siloam Vision). The clinicians were asked to diagnose plus disease for each examination and to assign an estimated VSS (range, 1-9) at baseline, and then again 1 month later with AI-based VSS assistance. A reference standard diagnosis (RSD) was assigned to each eye examination from the Imaging and Informatics in ROP study based on 3 masked expert labels and the ophthalmoscopic diagnosis. MAIN OUTCOME MEASURES: Mean linearly weighted κ value for plus disease diagnosis compared with RSD. Area under the receiver operating characteristic curve (AUC) and area under the precision-recall curve (AUPR) for labels 1 through 9 compared with RSD for plus disease. RESULTS: Expert agreement improved significantly, from substantial (κ value, 0.69 [0.59, 0.75]) to near perfect (κ value, 0.81 [0.71, 0.86]), when AI-based VSS was integrated. Additionally, a significant improvement in plus disease discrimination was achieved as measured by mean AUC (from 0.94 [95% confidence interval (CI), 0.92-0.96] to 0.98 [95% CI, 0.96-0.99]; difference, 0.04 [95% CI, 0.01-0.06]) and AUPR (from 0.86 [95% CI, 0.81-0.90] to 0.95 [95% CI, 0.91-0.97]; difference, 0.09 [95% CI, 0.03-0.14]). CONCLUSIONS: Providing ROP clinicians with an AI-based measurement of vascular severity in ROP was associated with both improved plus disease diagnosis and improved continuous severity labeling as compared with an RSD for plus disease. If implemented in practice, AI-based VSS could reduce interobserver variability and could standardize treatment for infants with ROP. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Partial CHARGE syndrome with bilateral retinochoroidal colobomas associated with 7q11.23 duplication syndrome: case report.

BACKGROUND: CHARGE syndrome is a relatively common cause of deafness and blindness resulting from failure to form the primordia of specific organs due to deficient contribution of neural crest cell derivatives. The majority of CHARGE syndrome cases are caused by heterozygous mutations in CHD7 on chromosome 8q21. Those with CHARGE syndrome without CHD7 mutation typically do not have an identified genetic defect. 7q11.23 duplication syndrome is associated with mild facial dysmorphism, heart defects, language delay, and autism spectrum disorder. In the current literature, 7q11.23 duplication has not been associated with CHARGE syndrome, retinochoroidal colobomas, or significant ear abnormalities. CASE PRESENTATION: We describe a patient with 7q11.23 duplication syndrome and clinical CHARGE syndrome with no variant in CHARGE-associated genes. CONCLUSIONS: This case highlights the still incomplete understanding of the pathogenesis of CHARGE syndrome and raises the possibility of a dose-sensitive effect of genes in the 7q11.23 critical region on neural crest differentiation and fate.

Angiographic Review of Choroidal Involution in Eyes with Retinopathy of Prematurity Treated with Bevacizumab.

PURPOSE: Retinopathy of prematurity (ROP) is considered a disease of the inner retina; however, there is increasing evidence that demonstrates choroidal vasculature loss in ROP, leading to degeneration of outer retinal function and visual deterioration. Central choroidal thinning is noted in children with history of ROP using optical coherence tomography imaging. This study characterizes the presence and persistence of choroidal loss angiographically in eyes of infants treated with intravitreal bevacizumab (IVB) for stage 3 ROP. METHODS: The fluorescein angiography (FA) images of 62 eyes of 31 infants treated with IVB monotherapy were retrospectively reviewed. The eyes with good quality early-, mid-, and late-phase imaging were included in this study. The presence of choroidal hypofluoresence involving the central and or peripheral retina was noted. In infants with multiple FAs, serial FAs were analyzed for persistence of choroidal hypofluorescence. RESULTS: The mean age and birth weight of infants was 24.4 weeks post-menstrual age and 683 g, respectively. All infants received IVB monotherapy. Twenty-four of 62 angiography images of sufficient quality reviewed showed the presence of choroidal hypofluorescence involving central and peripheral lobular loss in the early phase and its persistence into mid- and late phases. Twelve eyes demonstrated persistent choroidal loss on sequential FA until 3 years chronological age. CONCLUSIONS: The study demonstrates the presence of choroidal vascular loss angiographically both central and peripheral fundus in infants with ROP. It highlights the critical role of choroidal involution in outer retinal function that could affect visual outcomes.

Efficacy of Aflibercept Treatment and Its Effect on the Retinal Perfusion in the Oxygen-Induced Retinopathy Mouse Model of Retinopathy of Prematurity.

INTRODUCTION: Bevacizumab and ranibizumab, which are anti-vascular endothelial growth factor (VEGF) medications, are used frequently in the treatment for retinopathy of prematurity (ROP) in infants. Aflibercept, or VEGF Trap, has been used anecdotally, but translation and clinical studies are lacking. OBJECTIVE: This study investigates the efficacy of aflibercept at reducing areas of non-perfused retina and studies its effect on normal angiogenesis in the oxygen-induced retinopathy mouse model of ROP. METHODS: C57BL/6 J mice were assigned to room air control (n = 21 eyes) or hyperoxia with 75% oxygen (n = 84 eyes). The hyperoxic mice were assigned to 1 of 3 groups: 0 ng (n = 14 eyes), 100 ng (n = 35 eyes), or 1,000 ng (n = 35 eyes) of intravitreal aflibercept administered on postnatal day 14. Eyes were enucleated at PN17 and PN25 postinjection. Retinas were stained with anti-collagen IV antibody and photographed with microscopy. Areas of perfused and non-perfused retina were quantified using ImageJ software. Statistical comparisons were made using ANOVA with Tukey post hoc comparisons. RESULTS: At PN17, there was no significant difference in the area of non-perfused retina between the hyperoxic control and the 100 and 1,000 ng aflibercept groups. At PN25, the 100 ng (p < 0.05) and 1,000 ng (p = 0.008) treatment groups displayed less non-perfusion compared to hyperoxic controls. At the 1,000 ng dose, there was increased non-perfusion compared to the 100 ng dose (p = 0.02). There was reduced non-perfusion by PN25 compared to PN17 for the 100 ng group (p < 0.05), with no difference in the 1,000 ng group. CONCLUSIONS: The study shows that the area of non-perfused retina decreases effectively with aflibercept at PN25 with 100 ng dosage. With the 1,000 ng dosage, there is an inhibition of the physiologic angiogenesis with a higher area of non-perfused retina.

Computed Analysis of Retinal Vascular Growth After Bevacizumab Treatment of Retinopathy of Prematurity Until Age 3 Years.

PURPOSE: Premature infants, after anti-vascular endothelial growth factor injections for retinopathy of prematurity, have persistent peripheral avascular retina (PAR). PAR is ablated with laser; however, physiologic growth of the retinal vasculature in the long term has not been measured. The purposes of this study were to measure retinal vessel growth after treatment with intravitreal bevacizumab (IVB) for retinopathy of prematurity, using serial fluorescein angiography (FA), until age 3 years, and to assess the timing for providing laser ablation in PAR. METHODS: Data from an observational, longitudinal clinical study were collected. Angiographic images of eyes treated with IVB were included; imaging data from laser photocoagulation were excluded. All eyes underwent initial examination under general anesthesia with FA and photographic imaging. The retinal vessel length was measured from the temporal margin of the optic disc passing through the foveal center, and the lengths at subsequent FA were compared. To compare the changes in retinal vessel length over time in individual eyes, a paired-sample t test was performed. FINDINGS: FA images from 70 eyes (35 infants) treated with IVB were available. A total of 150 FA images were available for review; data from 125 images of good quality were used for analysis. The mean postmenstrual ages (PMAs) at first, second, third, and fourth FA were 66.2, 100.9, 135.1, and 180.7 weeks, respectively. The mean retinal vessel length was 14.177 mm at first FA and 13.199 mm at fourth FA (PMA range, 42...234 weeks). Retinal vascular lengths of individual eyes compared over time showed no statistically significant growth from the first FA to age 3 years. The changes in retinal vessel length from first to second FA were -0.117 ± 0.79 mm (p = 0.42; n = 30); from first to third FA, +0.060 ± 0.85 mm (p = 0.79; n = 15); and first to fourth FA, -0.404 ± 1.32 mm (p = 0.45; n = 7). IMPLICATIONS: Beyond 65 weeks' PMA, no meaningful retinal vascular growth occurred after IVB up to age 3 years, guiding the timing for physicians if laser photocoagulation is being considered. Future studies are needed to address retinal growth changes in the growing eyes of infants.

Correlation of central corneal thickness and associated factors in premature infants with and without retinopathy of prematurity.

OBJECTIVE: Central corneal thickness (CCT) in premature infants is described in racially homogenous populations, and factors affecting CCT in infants are relatively unknown. This study describes CCT in premature infants and its association of steroid and oxygen requirements, gestational age (GA), birth weight (BW), race, and their relationship with CCT and corneal haze. METHODS: CCT measurements of 87 infants/174 eyes screened for retinopathy of prematurity were taken between 30 and 44 weeks of GA. CCT was analyzed using a mixed model for its relationship with BW, GA, race, corneal clarity, steroid, and oxygen use. RESULTS: Average CCT decreased at a rate of 12.3 µm/week. Caucasians had the thickest corneas and Hispanics the thinnest (p < 0.01) at baseline, but the rate of CCT decline varied based on racial/ethnic group (p = 0.079). Infants with BW <1000 g had a higher CCT at baseline, but CCT decreased at a faster rate than infants with higher BW (-13. 4 µm/week vs -9.9 µm/week, p = 0.020). Infants born <27 weeks of GA had higher CCT at baseline, but CCT decreased at faster rate compared with patients born later (-13.3 µm/week vs -10.1 µm/week, p = 0.029). Steroid and oxygen use were not statistically significantly associated with CCT or corneal haze (p > 0.05) CONCLUSIONS: CCT varies by racial group in premature infants. Lower BW and GA are associated with increased CCT at baseline but thin at a faster rate. Average, CCT decreases at a rate of 12.3 µm/week between 30 and 44 weeks GA and averages to 550 µm by 44 weeks GA.

Bilateral anterior segment dysgenesis and persistent fetal vasculature associated with terminal 10q26 deletion.

Deletion of the 26q position on chromosome 10 results in a syndrome with well-documented systemic phenotypes. There are few reports of ophthalmic manifestations in terminal 10q26 deletion. We report a 4-week-old boy with terminal 10q26 deletion who had extensive ophthalmic abnormalities, including bilateral anterior segment dysgenesis and bilateral persistent fetal vasculature, with microphthalmia, microcornea, iris corectopia, congenital cataracts, and posterior embryotoxon.

Atypical Bilateral Multifocal Congenital Toxoplasmosis Retinochoroiditis: Case Report With Literature Review.

BACKGROUND: Toxoplasmosis gondii is ubiquitously present on earth and infection, including congenital infection, is common. Neurological, developmental, and ocular effects can be devastating in the congenital toxoplasmosis population. At present, there is no standard, nation-wide neonatal screening for this disease in the United States. CASE PRESENTATION: A 17-month-old Caucasian female presented to our institution by way of referral for macular scarring. She was diagnosed with intrauterine growth retardation and born with low birth weight and microcephaly at an outside institution, but no systemic workup was conducted at that time. On ocular examination, she was found to have nystagmus and extensive multifocal chorioretinal pigmented scars involving the macula and peripheral retina in both eyes with fibrous vitreous strands extending between scars in the right eye. Toxoplasmosis immunoglobulin G was found to be highly positive. Magnetic resonance imaging of the brain showed supratentorial intracranial calcifications. CONCLUSIONS: Our patient presented with severe chorioretinal lesions, microcephaly, and nystagmus with a positive immunoglobulin G toxoplasmosis titer. She did not receive any evaluation, including TORCH infectious panel workup, on being born with low birth weight and microcephaly. There are currently no national programs in place for toxoplasmosis to be included in routine neonatal screening, despite the grave sequelae of congenital infection or that studies in other countries have shown cost-effectiveness in early screening and treatment.

Fluorescein angiographic features post-intravitreal bevacizumab for retinopathy of prematurity: can they support rescue laser photocoagulation to the avascular retina.

OBJECTIVE: To study the fluorescein angiography (FA) features post-intravitreal bevacizumab (post-IVB) monotherapy for retinopathy of prematurity (ROP) that may pose risk for late sight-threatening ROP and support rescue laser to the avascular retina. METHODS: A retrospective review of 26 infants (47 eyes) with type 1 ROP treated with IVB monotherapy. RESULTS: All infants had RetCam and FA performed at an average of 68 weeks postmenstrual age (PMA), 19 at an average 98 weeks PMA, and 10 at an average of 120 weeks PMA. Average gestational age at birth and birth weight were 24.8 weeks (standard deviation [SD] 1.91 weeks) and 683 g (SD 158.85 g), respectively. Average PMA at first IVB was 37 weeks. Eight eyes of 6 infants received repeat IVB for recurrent stage 3 at an average of 46.6 weeks PMA. All infants had inhibited retinal vasculature in zone 2, and 25 of 26 had conventional FA features, which included peripheral leakage, shunts, abnormal branching, and tangles with no late reactivation of ROP until age 3 years. Only 1 infant showed diffuse hyperfluorescence along the regressed proliferation site with a late proliferation necessitating laser to preserve vision. CONCLUSIONS: Conventional FA features seen in 98% post-IVB monotherapy showed no late complications without rescue laser photocoagulation to the avascular retina.

CAT SCRATCH DISEASE IMITATING A TOXOCARA GRANULOMA OF THE OPTIC DISK.

PURPOSE: The study reports an unusual presentation of a young female patient presenting with a granulomatous posterior pole mass and profound vision loss secondary to infection with Bartonella henselae. METHODS: A single case report in a child. RESULTS: An 8-year-old female presented with a recent history of flu-like illness associated with profound vision loss, panuveitis and leukocoria in the left eye. She was found to have a posterior granulomatous mass associated with an exudative retinal detachment presumed as a toxocara granuloma. Magnetic Resonance Imaging ruled out retinoblastoma. Lab work done was negative for toxocariasis and positive for Bartonella henselae titers. She was treated for Cat Scratch Disease (CSD) with steroids and azithromycin. With treatment, the inflammation and exudative retinal detachment resolved, however, the patient had no improvement in visual acuity. CONCLUSIONS: Young patients presenting with leukocoria need a full work up, which includes ruling out retinoblastoma. CSD can present as a granulomatous mass similar to toxocariasis, which can rarely lead to debilitating and irreversible vision loss.

Ocular abnormalities in congenital Zika syndrome: a case report, and review of the literature.

BACKGROUND: As the number of children with Zika virus-related complications grows, the long-term developmental trajectory and its effects on families are unknown. We present the first known case of congenital Zika syndrome seen at our institution with significant fundus findings. CASE PRESENTATION: A 3-day-old Hispanic baby girl presented with severe microcephaly of 24 cm and temperature instability at birth. Her mother had traveled to Honduras early in pregnancy and testing of amniotic fluid was positive for Zika virus via polymerase chain reaction. A dilated fundus examination was significant for bilateral severe colobomatous chorioretinal atrophy of the macula and pigmentary changes. Neonatal magnetic resonance imaging revealed diffuse lissencephaly with decreased brain volume, atrophic corpus callosum and brainstem, periventricular calcifications, and ventriculomegaly of the lateral ventricles. CONCLUSIONS: Our patient, who presented with the first known case of congenital Zika syndrome in Northern Florida, demonstrated profound bilateral colobomatous chorioretinal atrophy of the macula. The ophthalmologic findings along with severe microcephaly emphasize the neurotropism of the Zika virus, and ultimately are indicative of poor developmental and visual prognosis for affected infants. With the increased prevalence of Zika virus, ophthalmologists should be aware of the associated findings and the importance of an eye-screening examination with a dilated fundus examination within 1 month of life of infants in which congenital Zika syndrome is suspected. A multidisciplinary care approach is essential for the care of affected infants and their families.

Möbius syndrome with cardiac rhabdomyomas.

BACKGROUND: Möbius syndrome is a rare congenital condition which presents not merely with 6th and 7th nerve palsies, but involves gaze paresis associated with craniofacial, limb, and other abnormalities. Heterogeneity is well known in patients with Möbius syndrome and rather than being of familial inheritance based on rare cases, it is much more recognized as a sporadic syndrome. We report an infant with features of congenital Möbius syndrome associated with cardiac rhabdomyomas in the absence of tuberous sclerosis. MATERIALS AND METHODS: Observational case report of an infant seen at a tertiary academic center with genetic testing, ophthalmic, neurological, and cardiac clinical examination and imaging. RESULTS: A newborn baby boy at birth was seen with multiple congenital craniofacial malformations, and respiratory distress. He was noted to have micrognathia, retrognathia, wide nasal bridge, low set ears, high arched palate, nonreducing bilateral talipes equinovarus and bilateral large angle esotropia with -4 abduction deficit and facial palsy, findings suggestive of Möbius Syndrome. MRI of the brain was unremarkable except for syringomyelia in the cervical spine. Echocardiography showed two cardiac rhabdomyomas in the right ventricle and ulltrasound of the abdomen showed mild right hydroneprosis. Cytogenetics revealed segmental loss at 21q21.2. Testing for tuberous sclerosis was negative for deletion or duplications of genes TSC1 and TSC2. CONCLUSION: This case highlights the rare co-occurrence of cardiac rhabdomyomas with Möbius syndrome and new segmental loss at 21q21.2 on genetic testing. Findings could indicate not a "suggestion of Möbius", but rather the syndrome itself in association with cardiac defects.

Multiloculated Ciliary Body Cysts and Lenticular Coloboma: A Rare Phenotypic Variation Associated With Persistent Fetal Vasculature.

A case of a 4 year-old boy with persistent fetal vasculature, lenticular coloboma, and a benign, multiloculated ciliary body mass is reviewed. The presence of ciliary body cysts in association with persistent fetal vasculature is sparsely reported. Its presence in a child can cause a diagnostic dilemma and lead to amblyopia. [J Pediatr Ophthalmol Strabismus. 2018;55:e39-e41.].

Achondroplasia With Congenital Onset Glaucoma, and Presumed Axenfeld-Rieger Anomaly.

We report the first case to our knowledge of a 1-week-old female infant with familial inherited achondroplasia associated with bilateral congenital onset glaucoma, posterior embryotoxon and iris hypoplasia suggestive of ocular Axenfeld-Rieger anomaly.