Secondary 12-Month Ocular Outcomes of a Phase 1 Dosing Study of Bevacizumab for Retinopathy of Prematurity.

Importance: Lower bevacizumab dosages are being used for type 1 retinopathy of prematurity, but there are limited data on long-term ocular outcomes with lower doses. Objective: To evaluate ocular outcomes at 12 months' corrected age for eyes that received a dose of 0.625 mg, 0.25 mg, 0.125 mg, 0.063 mg, or 0.031 mg of bevacizumab for type 1 retinopathy of prematurity. Design, Setting, and Participants: This prospective cohort study used a masked, multicenter, phase 1 dose de-escalation study design and was conducted from April 2016 to October 2017. Study eyes were treated with a dose of 0.25, 0.125, 0.063, or 0.031 mg of bevacizumab; fellow eyes were treated with a dosage 1 level higher than the study eye. Additional treatment after 4 weeks was at investigator discretion. Data analysis occurred from November 2018 to March 2019. Interventions: Intravitreous bevacizumab injections of 0.625 mg to 0.031 mg. Main Outcomes and Measures: Visual fixation, amblyopia, alignment, nystagmus, cycloplegic refraction, and ocular examinations were assessed at 12 months' corrected age as preplanned secondary outcomes. The primary outcome 4 weeks after treatment and secondary outcomes after 6 months' corrected age have been previously reported. Results: Forty-six of 61 infants (75%) had a 12-month follow-up examination (46 study eyes and 43 fellow eyes; median [interquartile range] birth weight, 650 [590-760] g). Of 87 eyes with a cycloplegic refraction, 12 (14% [95% CI, 7%-27%]) had myopia of more than -5.00 D spherical equivalent; 2 (2%; [95% CI, 0%-8%]) had hyperopia greater than 5.00 D spherical equivalent; and 5 infants (11% [95% CI, 4%-24%]) had anisometropia greater than 1.50 D spherical equivalent. Abnormalities of the cornea, lens, or anterior segment were reported in 1 eye (1% [95% CI, 0%-6%]), 3 eyes (3% [95% CI, 1%-10%]), and 3 eyes (3% [95% CI, 1%-10%]), respectively. Optic nerve atrophy was identified in 11 eyes (13% [95% CI, 6%-26%]), and 1 eye (1% [95% CI, 0%-6%]) had total retinal detachment. Strabismus was reported in 13 infants (30% [95% CI, 17%-45%]), manifest nystagmus in 7 infants (15% [95% CI, 6%-29%]), and amblyopia in 3 infants (7% [95% CI, 1%-18%]). Overall, 98% of infants had central fixation in each eye (44 of 45 eyes). Conclusions and Relevance: In this study of low-dose bevacizumab, the secondary outcomes of high myopia, strabismus, retinal detachment, nystagmus, and other ocular abnormalities at 1 year were consistent with rates reported in other studies with higher dosages. Trial Registration: ClinicalTrials.gov identifier: NCT02390531.

Cortical Visual Impairment in Congenital Cytomegalovirus Infection.

PURPOSE: To describe the presentation, evolution, and long-term outcome of cortical visual impairment (CVI) in patients with symptomatic congenital cytomegalovirus (CMV) infection, and to identify risk factors for the development of CVI in patients with symptomatic congenital CMV. METHODS: Retrospective subanalysis of a long-term prospective cohort study with data gathered from 1982 to 2013. RESULTS: Eleven of 77 (14.3%) patients with symptomatic CMV, 0 of 109 with asymptomatic CMV, and 51 control patients had CVI. Overall, patients with symptomatic CMV had worse vision than patients with asymptomatic CMV, who in turn had worse vision than control patients. Microcephaly, intracranial calcification, dilatation of ventricles, encephalomalacia, seizure at birth, optic atrophy, chorioretinitis/retinal scars, strabismus, and neonatal onset of sensorineural hearing loss were risk factors associated with CVI. CONCLUSIONS: CVI may result from symptomatic congenital CMV infection. The relationship of CVI and its risk factors in patients with CMV suggests the potential to predict the development of CVI through predictive modeling in future research. Early screening of CVI in children born with symptomatic congenital CMV can facilitate educational, social, and developmental interventions. [J Pediatr Ophthalmol Strabismus. 2019;56(3):194-202.].

Long-term Visual and Ocular Sequelae in Patients With Congenital Cytomegalovirus Infection.

BACKGROUND: Cytomegalovirus (CMV) is the most common congenital viral infection in the United States. Visual and ocular sequelae in adolescents and adults who are congenitally infected with CMV have not been well studied. Better understanding of the long-term visual and ocular sequelae can help with early detection, intervention and appropriate educational accommodations. METHODS: This study evaluated 237 patients (77 symptomatic, 109 asymptomatic and 51 control) who underwent a series of age-appropriate ophthalmologic, audiologic and neurodevelopmental examinations from 1982 to 2013. The frequency and etiology of visual impairment and other nonophthalmologic findings were recorded for each patient. Ophthalmologic findings were tabulated, and risk factors for abnormalities were analyzed. RESULTS: Fourteen of the 77 (18.2%) symptomatic and none of the asymptomatic and control subjects had severe visual impairments (P ≤ 0.006). Moderate visual impairment did not differ between symptomatic and asymptomatic subjects. Three asymptomatic subjects had retinal scars. The most common visual or ocular sequelae in the symptomatic group were strabismus (23.4%), chorioretinal scars (19.5%), cortical visual impairment (14.3%), nystagmus (14.3%) and optic nerve atrophy (11.7%). Three symptomatic patients had delayed visual deterioration because of later occurring retinal disorders: peripheral retinal scar, rhegmatogenous retinal detachment and Coats' disease. CONCLUSION: Symptomatic CMV patients experienced more ophthalmologic sequelae and significantly worse visual outcomes than asymptomatic CMV and control patients. Later occurring retinal disorders were found in symptomatic patients, and there is no clear evidence that CMV can reactivate in the retinas of children who were congenitally infected. Major risk factors for severe visual impairment included symptomatic status, optic nerve atrophy, chorioretinitis, cortical visual impairment and sensorineural hearing loss.

Multimodality Image-Guided Sclerotherapy of Low-Flow Orbital Vascular Malformations: Report of Single-Center Experience.

PURPOSE: To evaluate the role of multimodality imaging tools for intraprocedural guidance and outcome evaluation during sclerotherapy of low-flow orbital vascular malformations. MATERIALS AND METHODS: A retrospective review was performed of 17 consecutive patients with low-flow orbital malformations (14 lymphatic, two venous, and one venolymphatic) who underwent multimodality image-guided sclerotherapy between November 2012 and May 2015. Sclerotherapy technique, image guidance tools, and complications were recorded. Sclerotherapy outcome was evaluated using clinical response, magnetic resonance (MR) image-based lesion volumetry, and proptosis quantification. RESULTS: There were 22 sclerotherapy sessions performed. Intraprocedural ultrasound (US), fluoroscopy, cone-beam computed tomography (CT) and MR image fusion were used for image guidance with 100% technical success. Resolution of presenting symptoms was observed in all patients at 1-month follow-up. Four major sclerotherapy complications were successfully managed. Statistically significant reduction in lesion volume (P = .001) and proptosis (P = .0117) by MR image analysis was achieved in all patients in whom 3-month follow-up MR imaging was available (n = 13/17). There was no lesion recurrence at a median follow-up of 18 months (range, 8-38 mo). CONCLUSIONS: Multimodality imaging tools, including US, fluoroscopy, cone-beam CT, and MR fusion, during sclerotherapy of low-flow orbital malformations provide intraprocedural guidance and quantitative image-based evaluation of treatment outcome.

Pharmacokinetics of bevacizumab and its effects on serum VEGF and IGF-1 in infants with retinopathy of prematurity.

PURPOSE: To measure serum levels of bevacizumab and to compare serum levels of free vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) in infants who were treated with either intravitreal injection of bevacizumab (IVB) or laser for type 1 retinopathy of prematurity (ROP). METHODS: Twenty-four infants with type 1 ROP were randomized into three treatment groups: IVB at 0.625 mg per eye per dose, IVB at 0.25 mg per eye per dose, and laser. Blood samples were collected prior to treatment and on posttreatment days 2, 14, 42, and 60. Weekly body weights were documented from birth until 60 days post treatment. Serum levels of bevacizumab, free VEGF, and IGF-1 were measured with enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum bevacizumab was detected 2 days after the injection, peaked at 14 days, and persisted for up to 60 days with half-life of 21 days. Area under the curve (AUC) analysis showed that systemic exposure to bevacizumab was variable among the subjects and was dose dependent. Serum free VEGF levels decreased in all three subgroups 2 days post treatment, with more significant reductions found in both IVB-treated groups, P = 0.0001. Serum IGF-1 levels were lower in both IVB-treated groups. CONCLUSIONS: Clearance of bevacizumab from the bloodstream in premature infants takes at least 2 months. Although serum free VEGF levels decreased following either laser or bevacizumab treatment, the reductions were more significant in the IVB-treated groups. Potential long-term effects of systemic exposure to bevacizumab in infants need to be studied further.

Evaluating the association of autonomic drug use to the development and severity of retinopathy of prematurity.

PURPOSE: To explore the association of autonomic agents with the development and severity of retinopathy of prematurity (ROP). METHODS: The medical records of all preterm infants screened for ROP were retrospective reviewed. The association between development and severity of ROP and the use and dose(s) of autonomic agents was analyzed, after adjustment for the covariates gestational age, weight, development of septicemia, intraventricular hemorrhage, and respiratory distress syndrome. RESULTS: A total of 350 infants were screened. Caffeine was used in 338 infants; dopamine in 98 infants. There was a significant association between the use of dopamine and development of ROP (P < 0.001; relative risk [RR] = 1.6 [95% CI, 1.23-2.06]) and the need for ROP treatment (P = 0.001; RR = 4.63 [95% CI, 1.82-11.79]). The number of dopamine doses was significantly associated with the development of any ROP (P < 0.001; RR = 1.07 [95% CI, 1.03-1.1]), the severity of ROP (P < 0.001; RR = 1.09 [95% CI, 1.05-1.14]), and the need for treatment (P < 0.001; RR = 1.09 [95% CI, 1.05-1.14]). The total dose of caffeine was significantly associated with the development of any ROP (P = 0.003; RR = 1.03 [95% CI, 1.01-1.05]) and the need for treatment (P = 0.006, RR = 1.073 [95% CI; 1.021-1.13]). CONCLUSIONS: Although a causal relationship was not identified, the use of the autonomic agents caffeine and dopamine was associated with the development and severity of retinopathy of prematurity in this cohort.

An update on progress and the changing epidemiology of causes of childhood blindness worldwide.

PURPOSE: To summarize the available data on pediatric blinding disease worldwide and to present current information on childhood blindness in the United States. METHODS: A systematic search of world literature published since 1999 was conducted. Data also were solicited from each state school for the blind in the United States. RESULTS: In developing countries, 7% to 31% of childhood blindness and visual impairment is avoidable, 10% to 58% is treatable, and 3% to 28% is preventable. Corneal opacification is the leading cause of blindness in Africa, but the rate has decreased significantly from 56% in 1999 to 28% in 2012. There is no national registry of the blind in the United States, and most schools for the blind do not maintain data regarding the cause of blindness in their students. From those schools that do have such information, the top three causes are cortical visual impairment, optic nerve hypoplasia, and retinopathy of prematurity, which have not changed in past 10 years. CONCLUSIONS: There are marked regional differences in the causes of blindness in children, apparently based on socioeconomic factors that limit prevention and treatment schemes. In the United States, the 3 leading causes of childhood blindness appear to be cortical visual impairment, optic nerve hypoplasia, and retinopathy of prematurity; a national registry of the blind would allow accumulation of more complete and reliable data for accurate determination of the prevalence of each.