BACKGROUND Retinopathy of prematurity is a leading cause of childhood blindness worldwide. Peripheral retinal ablation with conventional (confluent) laser therapy is destructive, causes complications, and does not prevent all vision loss, especially in cases of retinopathy of prematurity affecting zone I of the eye. Case series in which patients were treated with vascular endothelial growth factor inhibitors suggest that these agents may be useful in treating retinopathy of prematurity. METHODS We conducted a prospective, controlled, randomized, stratified, multicenter trial to assess intravitreal bevacizumab monotherapy for zone I or zone II posterior stage 3+ (i.e., stage 3 with plus disease) retinopathy of prematurity. Infants were randomly assigned to receive intravitreal bevacizumab (0.625 mg in 0.025 ml of solution) or conventional laser therapy, bilaterally. The primary ocular outcome was recurrence of retinopathy of prematurity in one or both eyes requiring retreatment before 54 weeks’ postmenstrual age. RESULTS We enrolled 150 infants (total sample of 300 eyes); 143 infants survived to 54 weeks’ postmenstrual age, and the 7 infants who died were not included in the primary-outcome analyses. Retinopathy of prematurity recurred in 4 infants in the bevacizumab group (6 of 140 eyes [4%]) and 19 infants in the laser-therapy group (32 of 146 eyes [22%], P = 0.002). A significant treatment effect was found for zone I retinopathy of prematurity (P = 0.003) but not for zone II disease (P = 0.27). CONCLUSIONS Intravitreal bevacizumab monotherapy, as compared with conventional laser therapy, in infants with stage 3+ retinopathy of prematurity showed a significant benefit for zone I but not zone II disease. Development of peripheral retinal vessels continued after treatment with intravitreal bevacizumab, but conventional laser therapy led to permanent destruction of the peripheral retina. This trial was too small to assess safety.

for the BEAT-ROP Cooperative Group IMPORTANCE Children born prematurely who develop retinopathy of prematurity (ROP) often develop myopia, and those who require laser treatment may develop very high myopia, which has considerable clinical consequences.OBJECTIVE To report refractive outcomes in preterm infants who developed ROP in zone I or zone II posterior as stage 3+ ROP or aggressive posterior ROP (APROP). DESIGN, SETTING, AND PARTICIPANTSAll infants received intravitreal bevacizumab or laser therapy in a prospective, stratified, randomized, controlled, masked, multicenter clinical trial, Bevacizumab Eliminates the Angiogenic Threat for ROP (BEAT-ROP). Children who received intravitreal bevacizumab or laser in the BEAT-ROP clinical trial, with treatment randomized by infant, underwent cycloplegic retinoscopic refraction at a mean age of 2½ years. Fifteen centers with both pediatric and vitreoretinal ophthalmologists participating in level 3 neonatal intensive care units in academic centers with institutional review board approval were included in the trial. Of the originally enrolled 150 infants (300 eyes) in the BEAT-ROP clinical trial, 13 infants (26 eyes) died (6 received intravitreal bevacizumab; 7 received laser) and 19 eyes had intraocular surgery (6 infants bilaterally). Thus, 45 eyes (19 infants bilaterally) were excluded, leaving 131 infants (255 eyes, including 21 eyes that received a successful second treatment for recurrence).INTERVENTIONS Follow-up of the BEAT-ROP cohort. MAIN OUTCOMES AND MEASURES Spherical equivalent refractive outcomes and their distribution by ROP zone and treatment.RESULTS Refractions were available for 109 of 131 eligible infants (83.2%) and 211 of 255 eyes (82.7%). Mean (SD) spherical equivalent refractions were as follows: zone I, −1.51 (3.42) diopters (D) in 52 eyes that received intravitreal bevacizumab and −8.44 (7.57) D in 35 eyes that received laser treatment (P < .001); and zone II posterior, −0.58 (2.53) D in 58 eyes that received intravitreal bevacizumab and −5.83 (5.87) D in 66 eyes that received laser treatment (P < .001). Very high myopia (Ն−8.00 D) occurred in zone I in 2 of 52 (3.8%) eyes that received intravitreal bevacizumab and in 18 of 35 (51.4%) eyes that received laser treatment (P < .001). Very high myopia occurred in zone II posterior in 1 of 58 (1.7%) eyes that received intravitreal bevacizumab and in 24 of 66 (36.4%) eyes that received laser treatment (P < .001).CONCLUSIONS AND RELEVANCE More very high myopia was found in eyes that received laser treatment than in eyes that received intravitreal bevacizumab. This difference is possibly related to anterior segment development that is present with intravitreal bevacizumab but minimal or absent following laser treatment. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00622726

Electrical coupling of neurons is widespread throughout the CNS and is observed among retinal photoreceptors from essentially all vertebrates. Coupling dampens voltage noise in photoreceptors and rod-cone coupling provides a means for rod signals to enter the cone pathway, extending the dynamic range of rod-mediated vision. This coupling is dynamically regulated by a circadian rhythm and light adaptation. We examined the molecular mechanism that controls photoreceptor coupling in zebrafish retina. Connexin 35 (homologous to Cx36 of mammals) was found at both cone-cone and rod-cone gap junctions. Photoreceptors showed strong Neurobiotin tracer coupling at night, extensively labeling the network of cones. Tracer coupling was significantly reduced in the daytime, showing a 20-fold lower diffusion coefficient for Neurobiotin transfer. The phosphorylation state of Cx35 at two regulatory phosphorylation sites, Ser110 and Ser276, was directly related to tracer coupling. Phosphorylation was high at night and low during the day. Protein kinase A (PKA) activity directly controlled both phosphorylation state and tracer coupling. Both were significantly increased in the day by pharmacological activation of PKA and significantly reduced at night by inhibition of PKA. The data are consistent with direct phosphorylation of Cx35 by PKA. We conclude that the magnitude of photoreceptor coupling is controlled by the dynamic phosphorylation and dephosphorylation of Cx35. Furthermore, the nighttime state is characterized by extensive coupling that results in a well connected cone network.

PURPOSE To determine (1) incidence, (2) risk factors, (3) risk period, and (4) characteristics of recurrent retinopathy of prematurity (ROP) treated by intravitreal bevacizumab (IVB) monotherapy. DESIGN Retrospective case series. PARTICIPANTS Premature infants developing Type 1 ROP [subdivided into ROP stage 3+ and aggressive posterior ROP (APROP)] in zone I or zone II posterior, receiving IVB monotherapy, and followed for at least 65 weeks adjusted age (AA). METHODS Retrospective review of infants who developed recurrence of Type 1 ROP following IVB monotherapy was performed including examination of RetCam fundus photographs and fluorescein angiograms. MAIN OUTCOMES MEASURES Incidence, risk factors, risk period, and characteristics of recurrent ROP. RESULTS IVB monotherapy in 241 infants (471 eyes) was reviewed. (1) Recurrence incidence was 8.3% (20/241) for infants and 7.2% (34/471) for eyes. (2) Recurrence risk factors of greatest significance were appearance of neovascularization as APROP (P=0.006), extended duration of hospitalization (P=0.01), and lower birth weight (P=0.024). (3) Recurrence risk period was between ≈45 and ≈55 weeks AA [90.0% (18/20) for infants and 94.1% (32/34) for eyes] with mean recurrence of 51.2 weeks AA (±4.6; range 45.7 to 64.9), and mean interval of 16.2 weeks (±4.4) between treatments. (4) Recurrence characteristics included plus disease, (20/20 infants; 100%) and neovascularization appeared at the following sites: (i) ROP stage 3+ with confluent neovascularization recurred both at the advancing edge and at the initial ridge and extra-retinal fibrovascular proliferative complex (12/14 infants; 85.7%). However, (ii) APROP (6/6 infants; 100%) [and ROP stage 3+ with non-confluent neovascularization (2/14 infants; 14.3%)] recurred only at the advancing edge. Also, the anterior extent of retinal vascularization was decreased (mean 1.76 versus 4.48 disc diameters [DD]), and the rate of retinal vascularization was delayed (mean 0.11 versus 0.23 DD/week) in those with versus without recurrence, respectively. Following retreatment with IVB, plus disease persisted, neovascularization regressed, and retinal vascularization proceeded minimally and slowly. CONCLUSIONS Premature children developing severe ROP are being treated successfully with IVB monotherapy. However, recurrence is not uncommon, so vigilant follow-up is necessary to ensure timely re-treatment when needed. Knowledge of recurrence incidence, risk factors, risk period, and characteristics allows tailored clinical management.