Neurodevelopmental outcome of preterm infants enrolled in myo-inositol randomized controlled trial.

OBJECTIVE: This study evaluates the 24-month follow-up for the NICHD Neonatal Research Network (NRN) Inositol for Retinopathy Trial. STUDY DESIGN: Bayley Scales of Infants Development-III and a standardized neurosensory examination were performed in infants enrolled in the main trial. Moderate/severe NDI was defined as BSID-III Cognitive or Motor composite score <85, moderate or severe cerebral palsy, blindness, or hearing loss that prevents communication despite amplification were assessed. RESULTS: Primary outcome was determined for 605/638 (95%). The mean gestational age was 25.8 ± 1.3 weeks and mean birthweight was 805 ± 192 g. Treatment group did not affect the risk for the composite outcome of death or survival with moderate/severe NDI (60% vs 56%, p = 0.40). CONCLUSIONS: Treatment group did not affect the risk of death or survival with moderate/severe NDI. Despite early termination, this study represents the largest RCT of extremely preterm infants treated with myo-inositol with neurodevelopmental outcome data.

Effects of Myo-inositol on Type 1 Retinopathy of Prematurity Among Preterm Infants <28 Weeks' Gestational Age: A Randomized Clinical Trial.

Importance: Previous studies of myo-inositol in preterm infants with respiratory distress found reduced severity of retinopathy of prematurity (ROP) and less frequent ROP, death, and intraventricular hemorrhage. However, no large trials have tested its efficacy or safety. Objective: To test the adverse events and efficacy of myo-inositol to reduce type 1 ROP among infants younger than 28 weeks' gestational age. Design, Setting, and Participants: Randomized clinical trial included 638 infants younger than 28 weeks' gestational age enrolled from 18 neonatal intensive care centers throughout the United States from April 17, 2014, to September 4, 2015; final date of follow-up was February 12, 2016. The planned enrollment of 1760 participants would permit detection of an absolute reduction in death or type 1 ROP of 7% with 90% power. The trial was terminated early due to a statistically significantly higher mortality rate in the myo-inositol group. Interventions: A 40-mg/kg dose of myo-inositol was given every 12 hours (initially intravenously, then enterally when feeding; n = 317) or placebo (n = 321) for up to 10 weeks. Main Outcomes and Measures: Type 1 ROP or death before determination of ROP outcome was designated as unfavorable. The designated favorable outcome was survival without type 1 ROP. Results: Among 638 infants (mean, 26 weeks' gestational age; 50% male), 632 (99%) received the trial drug or placebo and 589 (92%) had a study outcome. Death or type 1 ROP occurred more often in the myo-inositol group vs the placebo group (29% vs 21%, respectively; adjusted risk difference, 7% [95% CI, 0%-13%]; adjusted relative risk, 1.41 [95% CI, 1.08-1.83], P = .01). All-cause death before 55 weeks' postmenstrual age occurred in 18% of the myo-inositol group and in 11% of the placebo group (adjusted risk difference, 6% [95% CI, 0%-11%]; adjusted relative risk, 1.66 [95% CI, 1.14-2.43], P = .007). The most common serious adverse events up to 7 days of receiving the ending dose were necrotizing enterocolitis (6% for myo-inositol vs 4% for placebo), poor perfusion or hypotension (7% vs 4%, respectively), intraventricular hemorrhage (10% vs 9%), systemic infection (16% vs 11%), and respiratory distress (15% vs 13%). Conclusions and Relevance: Among premature infants younger than 28 weeks' gestational age, treatment with myo-inositol for up to 10 weeks did not reduce the risk of type 1 ROP or death vs placebo. These findings do not support the use of myo-inositol among premature infants; however, the early termination of the trial limits definitive conclusions.

Medical and developmental outcomes of bevacizumab versus laser for retinopathy of prematurity.

BACKGROUND: Infants with stage 3+ retinopathy of prematurity (ROP) in zone I or zone II posterior were randomized to initial treatment with bevacizumab or laser in a multicenter trial (BEAT-ROP). The purpose of this study was to assess the effects of bevacizumab on nonophthalmologic outcomes. METHODS: At one study site, inborn infants of <27 weeks' gestational age underwent medical and standardized neurologic and developmental assessments at 18-22 months' corrected age (age after expected date of full-term delivery). RESULTS: Of the 18 infants enrolled at our site, 16 (7 bevacizumab, 9 laser) were evaluated for medical and neurodevelopmental outcomes at 18-28 months' corrected age. For each of the groups, the medians and ranges of growth percentiles were low compared with norms for healthy infants. The ranges for Bayley III developmental scores were also low relative to expected norms for healthy infants. There were no significant differences between the bevacizumab and laser therapy groups in weight (median percentile: bevacizumab, 18; laser, 7), length, head circumference, cerebral palsy, or Bayley scores (median Cognitive Composite Score: bevacizumab, 85; laser, 65). There was a significant difference in length of hospital stay (median days, 98 vs 140 days) favoring the bevacizumab group. CONCLUSIONS: In this patient cohort 2-year follow-up evaluation of infants treated with bevacizumab versus laser therapy for retinopathy of prematurity showed no adverse effects on medical or neurodevelopmental outcomes.

Clinical Management of Recurrent Retinopathy of Prematurity after Intravitreal Bevacizumab Monotherapy.

PURPOSE: To determine incidence, risk factors, risk period, and characteristics of recurrent retinopathy of prematurity (ROP) treated by intravitreal bevacizumab (IVB) monotherapy. DESIGN: Retrospective case series. PARTICIPANTS: Premature infants with type 1 ROP (subdivided into stage 3+ ROP and aggressive posterior ROP [APROP]) in zone I or zone II posterior who received IVB monotherapy and were followed up for at least 65 weeks adjusted age (AA). METHODS: Retrospective review of infants who demonstrated recurrence of type 1 ROP after IVB monotherapy, including examination of RetCam fundus photographs and fluorescein angiograms. MAIN OUTCOMES MEASURES: Incidence, risk factors, risk period, and characteristics of recurrent ROP. RESULTS: Intravitreal bevacizumab monotherapy in 241 infants (471 eyes) was reviewed. Recurrence incidence was 8.3% (20/241) for infants and 7.2% (34/471) for eyes. 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). Recurrence risk period was between approximately 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 weeks; range, 45.7-64.9 weeks) and mean interval of 16.2 weeks (±4.4 weeks) between treatments. Recurrence characteristics included plus disease (20/20 infants [100%]) and neovascularization, which appeared at the following sites: stage 3+ ROP with confluent neovascularization recurred both at the advancing edge and at the initial ridge and extraretinal fibrovascular proliferative complex (12/14 infants [85.7%]). However, APROP (6/6 infants [100%]) and stage 3+ ROP with nonconfluent neovascularization (2/14 infants [14.3%]) recurred only at the advancing edge. Also, the anterior extent of retinal vascularization was decreased (mean, 1.76 disc diameters [DD] vs. 4.48 DD), and the rate of retinal vascularization was delayed (mean, 0.11 DD/week vs. 0.23 DD/week) in those with versus without recurrence, respectively. After retreatment with IVB, retinal vascularization proceeded minimally and slowly. CONCLUSIONS: Premature children with 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. Knowledge of recurrence incidence, risk factors, risk period, and characteristics allows for tailored clinical management.

Review of effects of anti-VEGF treatment on refractive error.

To examine the effect of anti-vascular endothelial growth factor (anti-VEGF) agents on refractive error in the setting of retinopathy of prematurity (ROP) through a review of the literature, a PubMed search was performed of appropriate search terms, and the results of all relevant studies were extracted and compiled. Eleven relevant articles were identified in the literature, totaling 466 eyes, treated with varied anti-VEGF agents (bevacizumab, ranibizumab, and aflibercept) with mean spherical equivalent refractions ranging from +0.75 D to -3.57 D, with prevalence of high myopia ranging from 0 to 35%. Anti-VEGF monotherapy for ROP leads to low levels of myopia, and there may be a differential effect of specific anti-VEGF agents utilized on refractive outcomes.

Refractive outcomes following bevacizumab monotherapy compared with conventional laser treatment: a randomized clinical trial.

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 PARTICIPANTS: All 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 (≥-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.

Treatment of retinopathy of prematurity with vascular endothelial growth factor inhibitors.

ROP remains a major cause of childhood blindness worldwide. The smallest, sickest infants develop the most severe forms of zone 1 ROP. Such eyes may not be successfully treated by near confluent laser to the avascular retina (current standard of care). With an understanding of ROP pathogenesis, vascular endothelial growth factor inhibitors (anti-VEGF) are being given only when VEGF is elevated in retina and vitreous. Careful screening allows proper timing of administration. Ideal dose (perhaps different for mild and severe cases) and drug (interrupting only pathologic neovascularization and not normal angiogenesis) remain unproven. The author discusses controversial use of anti-VEGF with documented efficacy, observed local complications, and potential systemic toxicities (none observed in six years) to allow retention of vision for severe zone 1 ROP. The benefits have been demonstrated, however, local and systemic risks in these developing premature infants must be carefully studied (both short and long term).

Intravitreal pegaptanib as adjunctive treatment for stage 3+ ROP shown to be effective in a prospective, randomized, controlled multicenter clinical trial.

PURPOSE: Both intravitreal pegaptanib with laser therapy and intravitreal bevacizumab monotherapy have been found to be more efficacious than laser therapy alone in prospective, randomized, controlled clinical trials. RESULTS: The use of pegaptanib with laser therapy was efficacious in 91.2% compared with 69.0% in controls. The use of bevacizumab monotherapy was efficacious in 95.7% compared with 78.1% in controls. CONCLUSIONS: The use of anti-vascular endothelial growth factor therapy for retinopathy of prematurity has been shown to be efficacious, without toxicity reported to date; however, the best drug and dose which allows greatest efficacy with fewest recurrences and without toxicity must be determined.

Recessive mutations in TSPAN12 cause retinal dysplasia and severe familial exudative vitreoretinopathy (FEVR).

PURPOSE: Familial exudative vitreoretinopathy (FEVR) is an inherited disorder that disrupts the development of the retinal vasculature and can result in blindness. FEVR is genetically heterogeneous and mutations in four genes, NDP, FZD4, LRP5, and TSPAN12, encoding components of a novel ligand-receptor complex that activates the Norrin-ß-catenin signaling pathway, account for approximately 50% of cases. We recently identified mutations in TSPAN12 as a cause of dominant FEVR. The purpose of this study was to identify recessive TSPAN12 mutations in FEVR patients. METHODS: Mutation screening was performed by directly sequencing PCR products generated from genomic DNA with primers designed to amplify the coding sequence of TSPAN12. Splicing defects were verified by reverse transcriptase PCR of leukocyte cDNA. RESULTS: TSPAN12 screening in a large dominant FEVR family unexpectedly led to the identification of homozygous mutations in severely affected family members, whereas mildly affected family members were heterozygous. Further screening in a cohort of 10 retinal dysplasia/severe FEVR patients identified an additional three cases with recessive TSPAN12 mutations. In all examined cases, single mutation carriers were mildly affected compared to patients harboring two TSPAN12 mutations. CONCLUSIONS: We report for the first time recessive mutations in TSPAN12 and describe the first genetic cause for the clinical variation seen in FEVR families. Our data raise the possibility that patients with severe FEVR actually may harbor two mutant alleles, derived either from the same gene or potentially from other genes encoding components of the Norrin-ß-catenin signaling pathway.

Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity.

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. (Funded by Research to Prevent Blindness and others; ClinicalTrials.gov number, NCT00622726.).

Antivascular endothelial growth factor for retinopathy of prematurity.

PURPOSE OF REVIEW: This review will discuss a potentially more effective treatment for retinopathy of prematurity (ROP) with fewer acute and long-term complications. Avastin (bevacizumab) therapy is a promising anti-vascular endothelial growth factor (anti-VEGF) administered directly into the vitreous. RECENT FINDINGS: Recent reports detail the use of Avastin alone, and in combination with light amplification by stimulated emission of radiation (LASER) therapy and vitrectomy, for ROP stages 3, 4, and 5. Currently, one clinical trial is studying Avastin alone for acute vision-threatening ROP stage 3 in zone I and posterior zone II without LASER therapy. Another clinical trial is investigating Avastin following LASER therapy for recurrent ROP stages 4 and 5. SUMMARY: Treatment for ROP has evolved from later, more destructive (cryotherapy) to earlier, less destructive (LASER therapy) peripheral retinal ablation. If evidence-based data supports early findings, the use of Avastin may be recommended without the need for ablative LASER therapy and before retinal detachment develops. Avastin will be especially useful for ROP stage 3 cases with hemorrhage decreasing retinal visualization, rigid pupils, intravitreal neovascularization with early or developing (minimal) fibrous membranes, or aggressive posterior retinopathy of prematurity (AP-ROP). These cases all continue to have poor outcomes with LASER therapy.

Intravitreal injection of bevacizumab (avastin) for treatment of stage 3 retinopathy of prematurity in zone I or posterior zone II.

PURPOSE: To report a retrospective, consecutive, noncomparative case series of moderate and severe stage 3 retinopathy of prematurity (ROP) in zone I or posterior zone II treated by bilateral intravitreal injections of bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA). METHODS: Eleven infants weighing from 515 g to 1,015 g at birth (mean, 706.4 g) with gestational ages from 23 weeks to 28 weeks (mean, 24.3 weeks) received intravitreal injections of bevacizumab (0.625 mg [0.025 mL]) at 9.0 weeks to 15.0 weeks of age (mean, 11.0 weeks) and never had laser therapy. Length of follow-up was from 13.0 weeks to 85.0 weeks (mean, 48.5 weeks). RetCam photography (Clarity Medical Systems, Pleasanton, CA) was used to document preinjection retinal appearance and to follow postinjection retinal appearance. RESULTS: All 22 eyes were treated successfully (no retinal detachment, macular ectopia, high myopia, anisometropia, or other ocular abnormalities) with only 1 injection. No complications (local or systemic) were encountered. CONCLUSIONS: Intravitreal injection of bevacizumab was safe and effective in treating stage 3 ROP in zone I and posterior zone II in this small series of patients. A prospective, randomized, controlled, multicenter clinical trial has been initiated to investigate further this promising treatment.

Laser in situ keratomileusis for treated anisometropic amblyopia in awake, autofixating pediatric and adolescent patients.

PURPOSE: To establish the safety and efficacy of laser in situ keratomileusis (LASIK) in pediatric and adolescent patients with anisometropic amblyopia who completed amblyopia therapy and had a visual acuity of 20/30 or better bilaterally. SETTING: Department of Ophthalmology and Visual Science, University of Texas-Houston Medical School, Houston, Texas, USA. METHODS: From August 2000 to March 2002, LASIK was performed in 21 eyes of 19 consecutive patients meeting eligibility requirements. The procedure was performed with the Summit Autonomous LADARVision 4000 excimer laser (Alcon Laboratories, Inc.) in the amblyopic eye for the correction of anisometropia or in both eyes. All patients were awake and autofixating during the procedure. RESULTS: The mean patient age was 13.14 years (range 8 to 19 years). Seventeen patients were treated in the amblyopic eye only to correct anisometropia; treatment was performed in both eyes of 2 patients who were older than 18 years. Patients were followed for a mean of 18.0 months (range 8.6 to 26.5 months). Anisometropia was greater than 2.00 diopters (D) in all cases (mean 4.43 D, range 13.25 to 2.25 D). The percentage deviation from the attempted correction in the myopic group was 4.0% +/- 4.0% (SD) (range 2.0% to 10.0%) and 38.0% +/- 13.0% (range 5.0% to 58.0%) in the hyperopic group. Anisometropia decreased uniformly to less than 2.00 D in all patients (mean 1.52 D). The percentage of patients with stereo acuity increased from 63.0% preoperatively to 84.0% postoperatively. CONCLUSIONS: Laser in situ keratomileusis safely and effectively reduced anisometropia in these patients. If stereo acuity is not possible preoperatively, it may be obtained postoperatively.

Laser in situ keratomileusis for high hyperopia in awake, autofixating pediatric and adolescent patients with fully or partially accommodative esotropia.

PURPOSE: To establish the safety and efficacy of laser in situ keratomileusis (LASIK) in pediatric and adolescent patients with bilateral visual acuity of 20/30 or better and accommodative or partially accommodative esotropia. SETTING: Department of Ophthalmology and Visual Science, University of Texas-Houston Medical School, Houston, Texas, USA. METHODS: The study comprised 30 eyes of 15 consecutive patients with accommodative or partially accommodative esotropia who met eligibility requirements and had bilateral LASIK using the Alcon Summit Autonomous LADARVision excimer laser to correct a refractive error after January 2001. All patients were awake and autofixating during the procedure. RESULTS: The mean age of the patients was 13.9 years (range 9.1 to 18.8 years) and the mean refractive error, +5.35 diopters (D) (range +3.75 to +8.50 D) with anisometropia of 2.0 D or less. The mean follow-up was 15.7 months (range 9.5 to 22.5 months). No intraoperative complications were encountered. The percentage of undercorrection [100% -[(treatment achieved/treatment attempted) x 100%]] [mean 34% +/- 17% (SD), coefficient of variation (SD/mean) 0.50, range 5% to 58%] was higher than expected. Seven patients (47%) required enhancement due to undercorrection of hyperopia with diplopia (6 patients) or astigmatism with decreased visual acuity (1 patient). In this small series, no patient lost best corrected visual acuity or stereo acuity. CONCLUSION: Laser in situ keratomileusis can safely and effectively reduce refractive error in this group of patients; however, patient selection is extremely critical and enhancement was required in almost half the patients.

VSX1 (RINX) mutation with craniofacial anomalies, empty sella, corneal endothelial changes, and abnormal retinal and auditory bipolar cells.

PURPOSE: To present a previously unreported African American family with 1 variation and 1 mutation of the homeobox transcription factor gene, VSX1 (RINX), and to describe the clinical features of family members. DESIGN: Family genotype and clinical studies. PARTICIPANTS: A 3-generation family with 7 available family members. METHODS: Blood was drawn from all available family members, and the VSX1 (RINX) gene was sequenced. Craniofacial abnormalities, central nervous system defects, anterior segment features, and retinal and auditory function were assessed. MAIN OUTCOME MEASURES: Main outcome measures included identification and molecular characterization of 1 variation and 1 mutation in VSX1 (RINX) of 4 affected family members (3 adults and 1 child). Craniofacial features were documented. Central neuroimaging was performed. Ophthalmologic findings were described. Retinal and auditory functions were quantified. RESULTS: Two changes in VSX1 (RINX) were identified: a variation (R131S) not in a critical region and in few controls, and a mutation (A256S) in the critical CVC-domain and not in any controls. Both were present on 1 chromosome at 20p11.2 and were segregated with the 4 affected patients. Clinical features demonstrated extremely variable expressivity. Craniofacial features, including wide interpupillary distance and unusual pinnae, occurred in the 4 affected patients. Neuroimaging demonstrated that the propositus had an empty sella turcica, a posterior fossa cyst, an anterior encephalocele, hypertelorism, and severe hydrocephalus; her mother had a partially empty sella turcica, a small pituitary gland without any subarachnoid extension of fluid, and hypertelorism; and her older sister had hypertelorism but otherwise normal neuroimaging results. Anterior segment anomalies of the corneal endothelium were a constant finding in all affected family members. Electrophysiologic examination provided evidence for abnormal cone bipolar cells (visual evoked response and electroretinogram) in the adult affected patients and for abnormal auditory bipolar cells (audiogram and audio-evoked brainstem response) in the propositus. CONCLUSIONS: The new mutation in the VSX1 (RINX) gene described in this report results in abnormal craniofacial features, absence of the roof of the sella turcica, and anomalous development of the corneal endothelium. This mutation also impacts on the maintenance of cone bipolar cells of the visual system and of bipolar cells of the auditory system.