Intravitreal Aflibercept vs Laser Therapy for Retinopathy of Prematurity: Two-Year Efficacy and Safety Outcomes in the Nonrandomized Controlled Trial FIREFLEYE next.

Importance: Prospective long-term data after retinopathy of prematurity (ROP) treatment with anti-vascular endothelial growth factor injections vs laser therapy are scarce. The FIREFLEYE (Aflibercept for ROP IVT Injection vs Laser Therapy) next trial is prospectively evaluating the long-term efficacy and safety outcomes following ROP treatment with intravitreal aflibercept vs laser therapy. Objective: To evaluate 2-year ophthalmic and safety outcomes after 0.4-mg aflibercept injection or laser therapy in the 24-week randomized (2:1) FIREFLEYE trial (FIREFLEYE outcomes previously reported). Design, Setting, and Participants: This prospective nonrandomized controlled trial performed in 24 countries in Asia, Europe, and South America (2020-2025) follows up participants treated in the FIREFLEYE randomized clinical trial (2019-2021) through 5 years of age. Participants included children born very or extremely preterm (gestational age ≤32 weeks) or with very or extremely low birth weight (≤1500 g) who were previously treated with a 0.4-mg injection of aflibercept compared with laser therapy for severe acute-phase ROP. Data for the present interim analysis were acquired from March 18, 2020, to July 25, 2022. Interventions: Complications of ROP treated at investigator discretion (no study treatment). Main Outcomes and Measures: Efficacy end points included ROP status, unfavorable structural outcomes, ROP recurrence, treatment for ROP complications, completion of vascularization, and visual function. Safety end points included adverse events and growth and neurodevelopmental outcomes. Results: Overall, 100 children were enrolled (median gestational age, 26 [range, 23-31] weeks; 53 boys and 47 girls). Of these, 21 were Asian, 2 were Black, 75 were White, and 2 were of more than 1 race. At 2 years of age, 61 of 63 children (96.8%) in the aflibercept group vs 30 of 32 (93.8%) in the laser group had no ROP. Through 2 years of age, 62 of 66 (93.9%) in the aflibercept group and 32 of 34 (94.1%) in the laser group had no unfavorable structural outcomes. No new retinal detachment occurred during the study. Four children in the aflibercept group (6.1%) were treated for ROP complications before 1 year of age (2 had preexisting end-stage disease and total retinal detachment; 1 had reactivated plus disease; and 1 had recurrent retinal neovascularization not further specified). Most children were able to fix and follow a 5-cm toy (aflibercept group, 118 of 122 eyes [96.7%] among 63 children; laser group, 62 of 63 eyes [98.4%] among 33 children). High myopia was present in 9 of 115 eyes (7.8%) among 5 children in the aflibercept group and 13 of 60 eyes (21.7%) among 9 children in the laser group. No relevant differences in growth and neurodevelopmental outcomes by Bayley Scales of Infant and Toddler Development, Third Edition and Vineland Adaptive Behavior Scales, Second Edition were identified. Conclusions and Relevance: In this nonrandomized follow-up of a randomized clinical trial comparing treatment of severe acute-phase ROP with 0.4-mg injection of aflibercept and laser, disease control was stable and visual function was appropriate in children through 2 years of age. No adverse effects on safety, including growth and neurodevelopment, were identified. These findings provide clinically relevant long-term information on intravitreal aflibercept injection therapy for ROP. Trial Registration: ClinicalTrials.gov Identifier: NCT04015180.

Systemic exposure to aflibercept after intravitreal injection in premature neonates with retinopathy of prematurity: results from the FIREFLEYE randomized phase 3 study.

BACKGROUND: There are no data on pharmacokinetics, pharmacodynamics, and immunogenicity of intravitreal aflibercept in preterm infants with retinopathy of prematurity (ROP). FIREFLEYE compared aflibercept 0.4 mg/eye and laser photocoagulation in infants with acute-phase ROP requiring treatment. METHODS: Infants (gestational age ≤32 weeks or birthweight ≤1500 g) with treatment-requiring ROP in ≥1 eye were randomized 2:1 to receive aflibercept 0.4 mg or laser photocoagulation at baseline in this 24-week, randomized, open-label, noninferiority, phase 3 study. Endpoints include concentrations of free and adjusted bound aflibercept in plasma, pharmacokinetic/pharmacodynamic exploration of systemic anti-vascular endothelial growth factor effects, and immunogenicity. RESULTS: Of 113 treated infants, 75 received aflibercept 0.4 mg per eye at baseline (mean chronological age: 10.4 weeks), mostly bilaterally (71 infants), and with 1 injection/eye (120/146 eyes). Concentrations of free aflibercept were highly variable, with maximum concentration at day 1, declining thereafter. Plasma concentrations of adjusted bound (pharmacologically inactive) aflibercept increased from day 1 to week 4, decreasing up to week 24. Six infants experienced treatment-emergent serious adverse events within 30 days of treatment; aflibercept concentrations were within the range observed in other infants. There was no pattern between free and adjusted bound aflibercept concentrations and blood pressure changes up to week 4. A low-titer (1:30), non-neutralizing, treatment-emergent anti-drug antibody response was reported in 1 infant, though was not clinically relevant. CONCLUSIONS: 24-week data suggest intravitreal aflibercept for treatment of acute-phase ROP is not associated with clinically relevant effects on blood pressure, further systemic adverse events, or immunogenicity. GOV IDENTIFIER: NCT04004208.

The Structural Abnormalities Are Deeply Involved in the Cause of RPGRIP1-Related Retinal Dystrophy in Japanese Patients.

Leber congenital amaurosis (LCA) is the most severe form of inherited retinal dystrophy. RPGRIP1-related LCA accounts for 5-6% of LCA. We performed whole-exome sequencing and whole-genome sequencing (WGS) on 29 patients with clinically suspected LCA and examined ophthalmic findings in patients with biallelic pathogenic variants of RPGRIP1. In addition to five previously reported cases, we identified five cases from four families with compound heterozygous RPGRIP1 variants using WGS. Five patients had null variants comprising frameshift variants, an Alu insertion, and microdeletions. A previously reported 1339 bp deletion involving exon 18 was found in four cases, and the deletion was relatively prevalent in the Japanese population (allele frequency: 0.002). Microdeletions involving exon 1 were detected in four cases. In patients with RPGRIP1 variants, visual acuity remained low, ranging from light perception to 0.2, and showed no correlation with age. In optical coherence tomography images, the ellipsoid zone (EZ) length decreased with age in all but one case of unimpaired EZ. The retinal structure was relatively preserved in all cases; however, there were cases with great differences in visual function compared to their siblings and a 56-year-old patient who still had a faint EZ line. Structural abnormalities may be important genetic causes of RPGRIP1-related retinal dystrophy in Japanese patients, and WGS was useful for detecting them.

Effect of Intravitreal Aflibercept vs Laser Photocoagulation on Treatment Success of Retinopathy of Prematurity: The FIREFLEYE Randomized Clinical Trial.

Importance: Laser photocoagulation, which is the standard treatment for retinopathy of prematurity (ROP), can have adverse events. Studies of anti-vascular endothelial growth factor injections have suggested efficacy in the treatment of ROP, but few studies have directly compared them with laser treatments. Objective: To compare intravitreal aflibercept vs laser photocoagulation in infants with ROP requiring treatment. Design, Setting, and Participants: This noninferiority, phase 3, 24-week, randomized clinical trial was conducted in 27 countries (64 hospital sites) throughout Asia, Europe, and South America. Overall, 118 infants (gestational age ≤32 weeks at birth or birth weight ≤1500 g) with ROP severity (zone I stage 1+ [stage 1 plus increased disease activity], zone I stage 2+, zone I stage 3, zone I stage 3+, zone II stage 2+, or zone II stage 3+) requiring treatment or with aggressive posterior ROP in at least 1 eye were enrolled between September 25, 2019, and August 28, 2020 (the last visit occurred on February 12, 2021). Interventions: Infants were randomized 2:1 to receive a 0.4-mg dose of intravitreal aflibercept (n = 75) or laser photocoagulation (n = 43) at baseline. Additional treatment was allowed as prespecified. Main Outcomes and Measures: The primary outcome was the proportion of infants without active ROP and unfavorable structural outcomes 24 weeks after starting treatment (assessed by investigators). The requirement for rescue treatment was considered treatment failure. Intravitreal aflibercept was deemed noninferior if the lower limit of the 1-sided 95% bayesian credible interval for the treatment difference was greater than -5%. Results: Among 118 infants randomized, 113 were treated (mean gestational age, 26.3 [SD, 1.9] weeks; 53 [46.9%] were female; 16.8% had aggressive posterior ROP, 19.5% had zone I ROP, and 63.7% had zone II ROP) and 104 completed the study. Treatment (intravitreal aflibercept: n = 75; laser photocoagulation: n = 38) was mostly bilateral (92.9%), and 82.2% of eyes in the intravitreal aflibercept group received 1 injection per eye. Treatment success was 85.5% with intravitreal aflibercept vs 82.1% with laser photocoagulation (between-group difference, 3.4% [1-sided 95% credible interval, -8.0% to ∞]). Rescue treatment was required in 4.8% (95% CI, 1.9% to 9.6%) of eyes in the intravitreal aflibercept group vs 11.1% (95% CI, 4.9% to 20.7%) of eyes in the laser photocoagulation group. The serious adverse event rates were 13.3% (ocular) and 24.0% (systemic) in the intravitreal aflibercept group compared with 7.9% and 36.8%, respectively, in the laser photocoagulation group. Three deaths, which occurred 4 to 9 weeks after intravitreal aflibercept treatment, were considered unrelated to aflibercept by the investigators. Conclusions and Relevance: Among infants with ROP, intravitreal aflibercept compared with laser photocoagulation did not meet criteria for noninferiority with respect to the primary outcome of the proportion of infants achieving treatment success at week 24. Further data would be required for more definitive conclusions regarding the comparative effects of intravitreal aflibercept and laser photocoagulation in this population. Trial Registration: ClinicalTrials.gov Identifier: NCT04004208.

Optical coherence tomography and video recording of a case of bilateral contractile peripapillary staphyloma.

PURPOSE: To report a case of bilateral contractile peripapillary staphyloma (CPS) examined by optical coherence tomography (OCT) and video recording. OBSERVATION: We report the clinical history of a male infant with bilateral CPS. Two ophthalmic examinations under general anesthesia were performed during follow-up examinations. During the first fundus examination when the infant was 4 months old, we observed staphylomatous excavation around the optic disc, an almost normal disc appearance at the bottom of the excavation, and irregular contraction bilaterally. OCT images showed deep excavation around the optic disc bilaterally and hyperreflective tissue beneath the sclera in the right eye. During the second examination when the child was 4 years and 1 month, in addition to the previous fundus findings, the fundus examination showed white fibrous tissue on the optic disc and pigmentation around the optic disc in the right eye and a retinal cyst in the left eye. Bilateral simultaneous video recordings showed that the contractions were not synchronized between the eyes. CONCLUSIONS: In a patient with bilateral CPS, we observed unsynchronized contraction between the eyes and the presence of sequential hyperreflective tissue under the sclera using bilateral ophthalmic approaches.

Molecular Diagnosis of 34 Japanese Families with Leber Congenital Amaurosis Using Targeted Next Generation Sequencing.

Leber congenital amaurosis (LCA) is a genetically and clinically heterogeneous disease, and represents the most severe form of inherited retinal dystrophy (IRD). The present study reports the mutation spectra and frequency of known LCA and IRD-associated genes in 34 Japanese families with LCA (including three families that were previously reported). A total of 74 LCA- and IRD-associated genes were analysed via targeted-next generation sequencing (TS), while recently discovered LCA-associated genes, as well as known variants not able to be screened using this approach, were evaluated via additional Sanger sequencing, long-range polymerase chain reaction, and/or copy number variation analyses. The results of these analyses revealed 30 potential pathogenic variants in 12 (nine LCA-associated and three other IRD-associated) genes among 19 of the 34 analysed families. The most frequently mutated genes were CRB1, NMNAT1, and RPGRIP1. The results also showed the mutation spectra and frequencies identified in the analysed Japanese population to be distinctly different from those previously identified for other ethnic backgrounds. Finally, the present study, which is the first to conduct a NGS-based molecular diagnosis of a large Japanese LCA cohort, achieved a detection rate of approximately 56%, indicating that TS is a valuable method for molecular diagnosis of LCA cases in the Japanese population.

ATYPICAL FORM OF RETINOPATHY OF PREMATURITY WITH SEVERE FIBROVASCULAR PROLIFERATION IN THE OPTIC DISK REGION.

PURPOSE: To describe severe fibrovascular proliferation that developed in the optic disk region in an atypical form of retinopathy of prematurity (ROP). METHODS: Retrospective observational case reports. RESULTS: Four patients (8 eyes) with ROP were included. Three patients were born very prematurely (24-25 weeks of gestational age; weight, 500-1,000 grams); 1 patient was born at 33 weeks of gestational age. Among all eight eyes of four patients who received prompt ROP screening and underwent laser photocoagulation, six eyes had atypical and severe fibrovascular proliferation mainly in the optic disk region; the other two eyes, including one eye with classic ROP and one eye with aggressive posterior ROP, did not have the atypical form. All eight eyes had a total to partial retinal detachment. Among the six eyes with the atypical form, early vitreous surgery with lensectomy was possible in three eyes; only late vitreous surgery with lensectomy was possible in two eyes; one eye was inoperable. Three eyes had a partial or complete reattachment, whereas three eyes had a total retinal detachment. Among the six eyes with atypical fibrovascular proliferation, only two eyes obtained light perception vision. CONCLUSION: An atypical and severe form of ROP, in which fibrovascular proliferation grew mainly from the optic disk region, needs further investigation for treatment in addition to laser photocoagulation and vitreous surgery.

Characteristics of Retinal Breaks and Surgical Outcomes in Rhegmatogenous Retinal Detachment in Familial Exudative Vitreoretinopathy.

PURPOSE: To determine the characteristics of retinal breaks and surgical outcomes in eyes with a rhegmatogenous retinal detachment (RRD) with familial exudative vitreoretinopathy (FEVR). DESIGN: Retrospective, noncomparative case series. PARTICIPANTS: Thirty-seven patients (46 eyes) with a RRD in FEVR. METHODS: The medical records were reviewed and the types, directions, and positions of the retinal breaks and surgical outcomes were analyzed. MAIN OUTCOME MEASURES: Fundus examinations, including ophthalmoscopy, fluorescein angiography, and RetCam imaging (Natus Medical Incorporated, Pleasanton, CA). RESULTS: The retinal breaks were identified as tears in 12 eyes, atrophic holes in 24 eyes, tears and atrophic holes in 2 eyes, dialysis-related in 1 eye, a retinal break in the ora serrata in 1 eye, and unidentified in 6 eyes. Most retinal breaks (86.1%) were identified only in the temporal retina. Most tears (85.7%) were observed on the demarcation line, whereas atrophic holes were identified both on the demarcation line (53.8%) and the avascular retina (42.3%). The representative tears were almond-shaped, which differs from the typical horseshoe-shaped tears. Scleral buckling was performed as the initial surgery in 37 eyes and resulted in reattachment in 35 eyes (94.6%). Vitrectomy with or without scleral buckle was performed for eyes with more complex RRD in FEVR and resulted in reattachment in 5 of 9 eyes (55.6%). In total, reattachment was achieved in 40 of 46 eyes (87.0%). There was a history of stage 1A or 2A FEVR in 45 eyes and a history of stage 2B FEVR in 1 eye. CONCLUSIONS: Our data clarified the types, directions, and positions of the retinal breaks and the effectiveness of scleral buckling as the first surgical choice for treating RRDs in FEVR.

Atypical intravitreal growth of retinoblastoma with a multi-branching configuration.

PURPOSE: To report the clinical and histopathological findings of atypical intravitreal growth of a retinoblastoma with a multi-branching configuration. OBSERVATIONS: A 7-month-old boy was referred to our hospital due to leukocoria in the right eye. Ophthalmic examinations identified multi-branching vessels surrounded by diaphanous tissue behind the lens in the right eye. Imaging modalities showed microphthalmos, band-shaped calcification, and cystic lesions in that eye. Because it was difficult to rule out congenital anomalies such as persistent fetal vasculature due to the atypical clinical features of retinoblastoma, we performed a biopsy using a limbal approach. An intraoperative rapid pathological examination led to the definitive diagnosis of retinoblastoma. The right eye was enucleated and postoperative adjuvant chemotherapy was administered. Immunohistochemical staining of the enucleated eyeball showed that the tumoral cells and diaphanous tumoral tissue around the vessels were positive for neuron-specific enolase and Ki-67 and partially positive for glial fibrillary acidic protein (GFAP). The vessels of the diaphanous tissues near the tumoral mass were stained by GFAP and those behind the lens were stained faintly. CONCLUSIONS AND IMPORTANCE: We described an atypical retinoblastoma of pseudo-persistent fetal vasculature with a multi-branching configuration, which expanded the clinical spectrum of retinoblastoma. Such a specific growth pattern of the embryonic tumor might occur with a combination of retinal development, retinal vasculature, and hyaloid vascular system.

Long-term surgical outcome of conventional trabeculotomy for childhood glaucoma.

PURPOSE: To investigate the long-term surgical outcomes of conventional trabeculotomy in eyes with childhood glaucoma in a Japanese population. METHODS: In this retrospective observational study, we enrolled Japanese patients with childhood glaucoma who underwent a conventional trabeculotomy at least once before age 3 years from 1986 to 2014 in our hospital. RESULTS: One hundred seven eyes of 64 patients (24 girls, 40 boys; mean age, 2.8 ± 5.1 months) were included. Sixty-eight (64%) eyes had primary childhood glaucoma (PCG) and 39 (36%) eyes had secondary childhood glaucoma (SCG). The average numbers of surgical operations performed to treat the two glaucoma types that resulted in significantly (p < 0.001) different surgical success rates were 1.4 ± 0.7 and 2.1 ± 0.8. Statistical analysis showed that eyes with PCG, compared with those with SCG, were successfully treated by one trabeculotomy and up to three trabeculotomies (hazard ratios 6.66 and 4.02, respectively). Age, gender, systemic complications, corneal diameter, corneal edema, and preoperative intraocular pressure did not significantly affect the surgical outcomes. CONCLUSIONS: Most eyes with PCG are treatable with a maximum of three trabeculotomies. However, SCG usually is refractory to trabeculotomy, and a more promising surgery must be designed.

Anteroposterior Patterning of Gene Expression in the Human Infant Sclera: Chondrogenic Potential and Wnt Signaling.

Purpose/Aim: We sought to identify the anteroposterior spatial gene expression hierarchy in the human sclera to develop a hypothesis for axial elongation and deformity of the eyeball. MATERIALS AND METHODS: We analyzed the global gene expression of human scleral cells derived from distinct parts of the human infant sclera obtained from surgically enucleated eyes with retinoblastoma, using Affymetrix GeneChip oligonucleotide arrays, and compared, in particular, gene expression levels between the anterior and posterior parts of the sclera. The ages of three donors were 10M, 4M, and 1Y9M. RESULTS: K-means clustering analysis of gene expression revealed that expression levels of cartilage-associated genes such as COLXIA and ACAN increased from the anterior to the posterior part of the sclera. Microarray analyses and RT-PCR data showed that the expression levels of MGP, COLXIA, BMP4, and RARB were significantly higher in the posterior than in the anterior sclera of two independent infant eyes. Conversely, expression levels of WNT2, DKK2, GREM1, and HOXB2 were significantly higher in the anterior sclera. Among several Wnt-family genes examined, WNT2B was found to be expressed at a significantly higher level in the posterior sclera, and the reverse order was observed for WNT2. The results of luciferase reporter assays suggested that a GSK-3ß inhibitor stimulated Wnt/ß-catenin signaling particularly strongly in the posterior sclera. The expression pattern of RARB, a myopia-related gene, was similar in three independent eyes. CONCLUSIONS: Chondrogenic potential was higher and Wnt/ß-catenin signaling was more potently activated by a GSK-3ß inhibitor in the posterior than in the anterior part of the human infant sclera. Although the differences in the gene expression profiles between the anterior and posterior sclera might be involved only in normal growth processes, this anteroposterior hierarchy in the sclera might contribute to disorders involving abnormal elongation and deformity of the eyeball, including myopia.

Surgical outcomes of congenital and developmental cataracts in Japan.

PURPOSE: To retrospectively analyze the surgical outcomes of congenital/developmental cataracts in Japan. METHODS: A mail questionnaire was sent to facilities engaged in surgical treatment of congenital cataracts. RESULTS: Twenty-nine facilities reported on 809 eyes of 508 patients with congenital/developmental cataracts. Three hundred fifty-nine eyes underwent intraocular lens implantation (pseudophakia group), while 450 eyes were left aphakic (aphakia group). The average age at surgery was significantly higher in the pseudophakia group (70 ± 53 months) than in the aphakia group (14 ± 24 months) (P < 0.0001). A significantly larger proportion of patients with unilateral cataract (52.0 %) received IOL implantation than did those with bilateral cataracts (42.6 %) (P = 0.0224). The prevalence of associated ocular disorders, such as nystagmus, microcornea, nanophthalmos, and persistent fetal vasculature, was significantly higher in the aphakia group than in the pseudophakia group. Postoperatively, glaucoma developed more frequently in the aphakia group (5.8 %) than in the pseudophakia group (0.7 %) (P = 0.0003). Posterior capsule opacification developed more frequently in the pseudophakic eyes even when both posterior capsulotomy and anterior vitrectomy were performed, especially in patients aged 1 year or younger. Postoperative visual acuity was significantly better in the pseudophakia group than in the aphakia group, both in the unilateral and in the bilateral cases. CONCLUSIONS: Surgeons tended to select IOL implantation, rather than to leave the eye aphakic, in patients who were older at the time of surgery, had fewer coexisting ocular disorders, and suffered from unilateral cataract. Under such circumstances, pseudophakic eyes obtained significantly better postoperative visual acuity than did aphakic eyes.

Abnormal traction of the vitreous detected by swept-source optical coherence tomography is related to the maculopathy associated with optic disc pits.

BACKGROUND: Maculopathy associated with optic disc pits (ODP), which sometimes causes severe visual loss, usually appears in late childhood or early adulthood. However, it has long been unclear how the disease begins to develop at these ages. We evaluated the relationship between vitreous structure and maculopathy associated with ODP. METHODS: Six patients (seven eyes) with ODP were diagnosed between July 1990 and May 2013. Fundus photographs and swept-source optical coherence tomography (SS-OCT) images were evaluated retrospectively, and the vitreous at the vitreoretinal interface was visualized by reconstructing three-dimensional SS-OCT images. Vitrectomy was performed in the eyes with maculopathy. RESULTS: Among the six patients, five had ODP in one eye each and one patient had bilateral ODP. The pits were mainly located in the temporal quadrant, and maculopathy, including retinoschisis and retinal detachment, was detected in five eyes associated only with the temporal pits. A flat retinal detachment was observed in four eyes and identified within the vascular arcade except in one eye. A posterior precortical vitreous pocket (PPVP) was observed in all eyes except in one eye without maculopathy. Reconstructing images from SS-OCT showed the vitreoretinal interface abnormalities around the optic disc and the macular area in all eyes, which was completely different from the vitreoretinal interface in the normal pediatric eye. Vitrectomy was performed in four eyes with retinal detachment to resect the abnormal vitreous traction. Posterior vitreous detachment was created in two eyes. Retinal reattachment was achieved in three eyes, and subretinal fluid receded in one eye. The visual acuity improved in all four eyes. CONCLUSIONS: Abnormal traction of the vitreous due to an abnormality of the vitreoretinal interface, which may be strengthened by the development of a PPVP, generates the maculopathy associated with ODP.

A survey of the surgical treatment of congenital and developmental cataracts in Japan.

PURPOSE: To understand the current practice pattern for the surgical treatment of congenital/developmental cataracts in Japan. METHODS: A mail questionnaire was sent to facilities engaged in the surgical treatment of congenital cataracts in Japan. RESULTS: Thirty-four facilities reported their preferred methods for the surgical treatment of congenital cataracts, including data from 809 eyes of 508 patients who had undergone surgery. More than 85% of the respondents answered that they would consider surgery even if the visual prognosis was not promising because of possible form-deprivation amblyopia. The most commonly performed surgical maneuvers were scleral tunnel incision (88.4%), 3.0-mm or smaller incision (78.8%), manual anterior continuous curvilinear capsulorhexis (90.2% success rate), posterior capsulotomy (92.5% for patients aged ≤6 years), anterior vitrectomy by the limbal approach (85.9% for patients aged ≤6 years), and wound closure with sutures (93.2%). Posterior capsulotomy and vitrectomy were not usually performed in patients aged >6 years. Implantation of an intraocular lens (IOL) was mostly indicated in patients aged 2 years or older. Implantation of an acrylic foldable IOL (76.6%) into the capsular bag (89.7%) was the most common practice among the surgeons. CONCLUSIONS: Small incision surgery with implantation of an acrylic foldable IOL into the capsular bag combined with posterior capsulotomy was the preferred surgical treatment of choice for congenital/developmental cataracts.

Clinical characteristics of congenital and developmental cataract undergoing surgical treatment.

PURPOSE: To analyze the clinical characteristics of congenital/developmental cataract undergoing surgery. METHODS: A mail questionnaire was sent to 49 facilities engaged in surgical treatment of congenital cataracts, and data on preoperative clinical features were collected. RESULTS: Twenty nine facilities reported on 864 eyes of 521 patients with congenital/infantile cataract, ranging in age at initial visit from 0 to 18.8 years (2.6 ± 3.3 years, mean ± standard deviation). Among the patients, 65.8 % had bilateral cataracts and 34.2 % were unilaterally affected. Family history was found for 22.4 % of cases, of which 98.1 % were bilateral. Family history was positive for 33.1 % of bilateral and 1.3 % of unilateral cases. The most common main complaint was white pupil for 35.7 % of bilateral cases and 32.7 % for unilateral cases. Concomitant systemic abnormalities were more frequently associated with bilateral cases (31.6 %) than with unilateral cases (16.7 %). Associated ocular diseases, such as strabismus, persistent fetal vasculature, and posterior lenticonus, were more frequently seen among unilateral cases whereas nystagmus was more common among bilateral cases. CONCLUSIONS: Among congenital/developmental cataracts, the ratio of bilateral and unilateral cases was approximately 2:1. Almost all patients with a family history of congenital cataract were bilateral. Initial visits to a physician were rather late, 2.6 years from birth; this should be improved.

Three cases of rhegmatogenous retinal detachment associated with regressed retinoblastoma after conservative tumor therapy.

PURPOSE: To report three cases of rhegmatogenous retinal detachment associated with regressed retinoblastoma after conservative therapy. METHODS: Three eyes of three patients with rhegmatogenous retinal detachment, in which retinal breaks were present at the edge of the tumor scar, were treated with vitrectomy and scleral buckling. RESULTS: In two eyes, in which cryopexy and silicone oil injection were performed, a preretinal membrane was formed that was comprised primarily of glial cells. Additional vitrectomy and membrane peeling reattached the retina. In one eye, in which photocoagulation and gas injection were performed, an initial vitrectomy and scleral buckling reattached the retina without postoperative membrane formation. CONCLUSION: Vitrectomy and scleral buckling contributed to closure of the irregularly shaped retinal tear at the edge of the tumor scar. Photocoagulation and gas injection instead of cryopexy and silicone oil injection may avoid postoperative glial proliferation from the tumor scar.

Surgical outcomes of progressive tractional retinal detachment associated with familial exudative vitreoretinopathy.

PURPOSE: To evaluate various surgeries for treating retinal detachment (RD) associated with familial exudative vitreoretinopathy (FEVR). DESIGN: Retrospective, interventional case series. METHODS: The charts of 22 patients who underwent surgery were reviewed. A complete ophthalmic examination was performed including wide-field fundus images with fluorescein angiography. The primary and secondary outcomes were fundus features (vascular activity of the fibrovascular proliferation and extent of tractional RD) and visual acuity (VA), respectively. RESULTS: Thirty-one eyes were included (12 eyes underwent scleral buckling, 1 scleral buckling and vitrectomy, 7 vitrectomy alone, and 11 lensectomy and vitrectomy). Twenty-six eyes were reattached during 1 surgery. Scleral buckling resulted in cessation of fibrovascular proliferation and retinal reattachment; only 1 of these eyes required vitrectomy. Lens-sparing vitrectomy resulted in stabilized fibrovascular proliferation and retinal reattachment. Vitrectomy with lensectomy did not achieve retinal reattachment in 4 eyes. Fibrovascular proliferation has a rich vascular component in patients younger than 3 years, and collagen fibers were present mainly with more advanced age. The postoperative VA improved in 5 of 8 eyes examined, was unchanged in 1 eye, and decreased in 2 eyes with macular involvement. CONCLUSIONS: FEVR-induced RDs are highly variable and require careful preoperative evaluation to determine the best surgical procedure. Vitrectomy with release of posterior traction is essential in younger patients with vascularly active fibrovascular proliferation, whereas scleral buckling may be important for cases with peripheral traction anterior to the equator. In all cases, peripheral thermal treatment applied to all ischemic areas contributed to reduced peripheral neovascularization.

Mutation spectrum and phenotypic variation in nine patients with SOX2 abnormalities.

Multiple mutations in SOX2 have been identified in patients with ocular anomalies and/or pituitary dysfunction. Here, we identified SOX2 abnormalities in nine patients. The molecular defects included one missense, one nonsense and four frameshift mutations, and three submicroscopic deletions involving SOX2. Three of the six mutations and all deletions were hitherto unreported. The breakpoints determined in one deletion were located within Alu repeats and accompanied by an overlap of 11 bp. Three of the six mutations encoded SOX2 proteins that lacked in vitro transactivation activity for the HESX1 promoter, whereas the remaining three generated proteins with ∼15-∼20% of transactivation activity. All cases manifested ocular anomalies of various severities, together with several complications including arachnoid cyst and hamartoma. There was no apparent correlation between the residual activity and clinical severity. The results indicate that molecular defects in SOX2 are highly variable and include Alu repeat-mediated genomic rearrangements. Our data provide further evidence for wide phenotypic variation of SOX2 abnormalities and the lack of genotype-phenotype correlation in patients carrying SOX2 lesions.

Identification of a novel missense mutation of MAF in a Japanese family with congenital cataract by whole exome sequencing: a clinical report and review of literature.

Congenital cataracts are the most important cause of severe visual impairment in infants. Genetic factors contribute to the disease development and 29 genes are known to cause congenital cataracts. Identifying the genetic cause of congenital cataracts can be difficult because of genetic heterogeneity. V-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF) encodes a basic region/leucine zipper transcription factor that plays a key role as a regulator of embryonic lens fiber cell development. MAF mutations have been reported to cause juvenile-onset pulverulent cataract, microcornea, iris coloboma, and other anterior segment dysgenesis. We report on six patients in a family who have congenital cataracts were identified MAF mutation by whole exome sequencing (WES). The heterozygous MAF mutation Q303L detected in the present family occurs in a well conserved glutamine residue at the basic region of the DNA-binding domain. All affected members showed congenital cataracts. Three of the six members showed microcornea and one showed iris coloboma. Congenital cataracts with MAF mutation exhibited phenotypically variable cataracts within the family. Review of the patients with MAF mutations supports the notion that congenital cataracts caused by MAF mutations could be accompanied by microcornea and/or iris coloboma. WES is a useful tool for detecting disease-causing mutations in patients with genetically heterogeneous conditions.

Visual outcomes after early vitreous surgery for aggressive posterior retinopathy of prematurity.

IMPORTANCE: Aggressive posterior retinopathy of prematurity (AP-ROP) rapidly progresses to retinal detachment despite application of photocoagulation. Early vitreous surgery might achieve prompt regression of neovascular activity and a high incidence of retinal reattachment. OBJECTIVE: To evaluate visual outcomes in eyes with AP-ROP after early vitreous surgery. DESIGN: Retrospective nonrandomized study of patients who underwent early vitreous surgery with lensectomy when retinal detachment developed despite photocoagulation. Aphakic correction with spectacles or contact lenses and the use of orthoptics were continued postoperatively. The best-corrected visual acuity (VA) was measured in eyes with a total retinal reattachment using the preferential looking technique in patients ranging in age from 8 months to no more than 3 years and a VA chart with Landolt rings or pictures for older children. The VA findings were converted to Snellen lines. SETTING: Institutional ophthalmology practice. PARTICIPANTS: Of the 103 eyes (57 patients) that underwent early vitreous surgery for AP-ROP, the VA was measured in 58 (32 patients) at a corrected age ranging from 8 months to 4 years. INTERVENTIONS: Early vitreous surgery and VA measurement using the preferential looking technique and a VA chart. MAIN OUTCOMES AND MEASURES: Postoperative VA, ROP stage, extent of fibrovascular tissue (FT) growth, and laterality of the eyes that underwent surgery. RESULTS: The VAs ranged from 20/2000 to 20/40. The VA may not be related to the preoperative ROP stage 4A or 4B but may depend on the preoperative extent of FT growth. In 39 of 58 eyes (67.2%), the FT had not reached the vitreous base preoperatively, and foveal formation occurred postoperatively with nearly age-appropriate VA (range, 20/250 to 20/40). In 17 of 58 eyes (29.3%), the FT had reached the vitreous base, and no fovea formed (VA range, 20/2000 to 20/250). Two of 58 eyes (3.4%) had deprivation amblyopia with a VA worse than 20/1600. The difference in VA between both eyes of patients who underwent bilateral vitreous surgery depended on ROP progression; patients who underwent a unilateral procedure in which the fellow eyes with ROP stabilized after photocoagulation tended to have poor vision because of deprivation amblyopia. CONCLUSIONS AND RELEVANCE: Early vitreous surgery may be beneficial for AP-ROP and should be performed before the FT reaches the vitreous base to facilitate foveal formation and good VA outcomes. The roles of photocoagulation, vitreous surgery, and anti-vascular endothelial growth factor therapy in the treatment of AP-ROP should be investigated in randomized trials regarding efficacy, safety, convenience, and cost.