International Classification of Retinopathy of Prematurity, Third Edition.

PURPOSE: The International Classification of Retinopathy of Prematurity is a consensus statement that creates a standard nomenclature for classification of retinopathy of prematurity (ROP). It was initially published in 1984, expanded in 1987, and revisited in 2005. This article presents a third revision, the International Classification of Retinopathy of Prematurity, Third Edition (ICROP3), which is now required because of challenges such as: (1) concerns about subjectivity in critical elements of disease classification; (2) innovations in ophthalmic imaging; (3) novel pharmacologic therapies (e.g., anti-vascular endothelial growth factor agents) with unique regression and reactivation features after treatment compared with ablative therapies; and (4) recognition that patterns of ROP in some regions of the world do not fit neatly into the current classification system. DESIGN: Review of evidence-based literature, along with expert consensus opinion. PARTICIPANTS: International ROP expert committee assembled in March 2019 representing 17 countries and comprising 14 pediatric ophthalmologists and 20 retinal specialists, as well as 12 women and 22 men. METHODS: The committee was initially divided into 3 subcommittees-acute phase, regression or reactivation, and imaging-each of which used iterative videoconferences and an online message board to identify key challenges and approaches. Subsequently, the entire committee used iterative videoconferences, 2 in-person multiday meetings, and an online message board to develop consensus on classification. MAIN OUTCOME MEASURES: Consensus statement. RESULTS: The ICROP3 retains current definitions such as zone (location of disease), stage (appearance of disease at the avascular-vascular junction), and circumferential extent of disease. Major updates in the ICROP3 include refined classification metrics (e.g., posterior zone II, notch, subcategorization of stage 5, and recognition that a continuous spectrum of vascular abnormality exists from normal to plus disease). Updates also include the definition of aggressive ROP to replace aggressive-posterior ROP because of increasing recognition that aggressive disease may occur in larger preterm infants and beyond the posterior retina, particularly in regions of the world with limited resources. ROP regression and reactivation are described in detail, with additional description of long-term sequelae. CONCLUSIONS: These principles may improve the quality and standardization of ROP care worldwide and may provide a foundation to improve research and clinical care.

Speed and accuracy of saccades in patients with glaucoma evaluated using an eye tracking perimeter.

BACKGROUND: To examine the speed and accuracy of saccadic eye movements during a novel eye tracking threshold visual field assessment and determine whether eye movement parameters may improve ability to detect glaucoma. METHODS: A prospective study including both eyes of 31 patients with glaucoma and 23 controls. Standard automated perimetry (SAP) and eye tracking perimetry (saccadic vector optokinetic perimetry, SVOP) was performed. SVOP provided data on threshold sensitivity, saccade latency, and two measures of accuracy of saccades (direction bias and amplitude bias). The relationship between eye movement parameters and severity of glaucoma was examined and Receiver Operating Characteristic curves were used to assess ability to detect glaucoma. RESULTS: Patients with glaucoma had significantly slower saccades (602.9 ± 50.0 ms versus 578.3 ± 44.6 ms for controls, P = 0.009) and reduced saccade accuracy (direction bias = 7.4 ± 1.8 versus 6.5 ± 1.5 degrees, P = 0.006). There was a significant slowing of saccades and saccades became less accurate with worsening SAP sensitivity. Slower saccades were associated with increased odds of glaucoma; however, the AUC for saccade latency was only 0.635 compared to 0.914 for SVOP sensitivity. CONCLUSION: Patients with glaucoma had significant differences in eye movements compared to healthy subjects, with a relationship between slower and less accurate eye movements and worse glaucoma severity. However, in a multivariable model, eye movement parameters were not of additional benefit in differentiating eyes with glaucoma from healthy controls.

Outcomes of Two Trials of Oxygen-Saturation Targets in Preterm Infants.

BACKGROUND: The safest ranges of oxygen saturation in preterm infants have been the subject of debate. METHODS: In two trials, conducted in Australia and the United Kingdom, infants born before 28 weeks' gestation were randomly assigned to either a lower (85 to 89%) or a higher (91 to 95%) oxygen-saturation range. During enrollment, the oximeters were revised to correct a calibration-algorithm artifact. The primary outcome was death or disability at a corrected gestational age of 2 years; this outcome was evaluated among infants whose oxygen saturation was measured with any study oximeter in the Australian trial and those whose oxygen saturation was measured with a revised oximeter in the U.K. trial. RESULTS: After 1135 infants in Australia and 973 infants in the United Kingdom had been enrolled in the trial, an interim analysis showed increased mortality at a corrected gestational age of 36 weeks, and enrollment was stopped. Death or disability in the Australian trial (with all oximeters included) occurred in 247 of 549 infants (45.0%) in the lower-target group versus 217 of 545 infants (39.8%) in the higher-target group (adjusted relative risk, 1.12; 95% confidence interval [CI], 0.98 to 1.27; P=0.10); death or disability in the U.K. trial (with only revised oximeters included) occurred in 185 of 366 infants (50.5%) in the lower-target group versus 164 of 357 infants (45.9%) in the higher-target group (adjusted relative risk, 1.10; 95% CI, 0.97 to 1.24; P=0.15). In post hoc combined, unadjusted analyses that included all oximeters, death or disability occurred in 492 of 1022 infants (48.1%) in the lower-target group versus 437 of 1013 infants (43.1%) in the higher-target group (relative risk, 1.11; 95% CI, 1.01 to 1.23; P=0.02), and death occurred in 222 of 1045 infants (21.2%) in the lower-target group versus 185 of 1045 infants (17.7%) in the higher-target group (relative risk, 1.20; 95% CI, 1.01 to 1.43; P=0.04). In the group in which revised oximeters were used, death or disability occurred in 287 of 580 infants (49.5%) in the lower-target group versus 248 of 563 infants (44.0%) in the higher-target group (relative risk, 1.12; 95% CI, 0.99 to 1.27; P=0.07), and death occurred in 144 of 587 infants (24.5%) versus 99 of 586 infants (16.9%) (relative risk, 1.45; 95% CI, 1.16 to 1.82; P=0.001). CONCLUSIONS: Use of an oxygen-saturation target range of 85 to 89% versus 91 to 95% resulted in nonsignificantly higher rates of death or disability at 2 years in each trial but in significantly increased risks of this combined outcome and of death alone in post hoc combined analyses. (Funded by the Australian National Health and Medical Research Council and others; BOOST-II Current Controlled Trials number, ISRCTN00842661, and Australian New Zealand Clinical Trials Registry number, ACTRN12605000055606.).

Raised intracranial pressure and retinal haemorrhages in childhood encephalopathies.

AIM: To explore the relationship between raised intracranial pressure (RICP) and retinal haemorrhages in traumatic and non-traumatic childhood encephalopathies. METHOD: A prospective study of 112 children (35 females and 77 males, age range 0.01mo-17y 8.3mo; mean 5y 8.6mo, median 4y 5.6mo) included 57 accidental traumatic brain injuries (ATBIs), 21 inflicted traumatic brain injuries (ITBIs), and 34 non-traumatic encephalopathy cases. Measurements included intracranial pressure (ICP), cerebral perfusion pressure, pressure-time index of ICP, and number, zone, and layer of retinal haemorrhages on retinal imaging. RESULTS: Group I had measured elevated ICP (n=42), Group II had clinical and/or radiological signs of RICP (n=21), and Group III had normal ICP (n=49). In the combined Groups I and II, 38% had retinal haemorrhages. Multiple logistic regression confirmed that the presence of retinal haemorrhages was significantly related to the presence of RICP independent of age and aetiology; however, the occurrence and overall numbers were not significantly related to the specific ICP level. The numbers of intraretinal (nerve-fibre layer and dot blot) retinal haemorrhages were significantly greater in those with RICP. The ITBI population was significantly different from the other combined aetiological categories. INTERPRETATION: The study results indicate a complex RICP/retinal haemorrhage relationship. There was no evidence of existing retinal haemorrhages being exacerbated or new retinal haemorrhages developing during periods of confirmed RICP.

Oxygen saturation and outcomes in preterm infants.

BACKGROUND: The clinically appropriate range for oxygen saturation in preterm infants is unknown. Previous studies have shown that infants had reduced rates of retinopathy of prematurity when lower targets of oxygen saturation were used. METHODS: In three international randomized, controlled trials, we evaluated the effects of targeting an oxygen saturation of 85 to 89%, as compared with a range of 91 to 95%, on disability-free survival at 2 years in infants born before 28 weeks' gestation. Halfway through the trials, the oximeter-calibration algorithm was revised. Recruitment was stopped early when an interim analysis showed an increased rate of death at 36 weeks in the group with a lower oxygen saturation. We analyzed pooled data from patients and now report hospital-discharge outcomes. RESULTS: A total of 2448 infants were recruited. Among the 1187 infants whose treatment used the revised oximeter-calibration algorithm, the rate of death was significantly higher in the lower-target group than in the higher-target group (23.1% vs. 15.9%; relative risk in the lower-target group, 1.45; 95% confidence interval [CI], 1.15 to 1.84; P=0.002). There was heterogeneity for mortality between the original algorithm and the revised algorithm (P=0.006) but not for other outcomes. In all 2448 infants, those in the lower-target group for oxygen saturation had a reduced rate of retinopathy of prematurity (10.6% vs. 13.5%; relative risk, 0.79; 95% CI, 0.63 to 1.00; P=0.045) and an increased rate of necrotizing enterocolitis (10.4% vs. 8.0%; relative risk, 1.31; 95% CI, 1.02 to 1.68; P=0.04). There were no significant between-group differences in rates of other outcomes or adverse events. CONCLUSIONS: Targeting an oxygen saturation below 90% with the use of current oximeters in extremely preterm infants was associated with an increased risk of death. (Funded by the Australian National Health and Medical Research Council and others; BOOST II Current Controlled Trials number, ISRCTN00842661, and Australian New Zealand Clinical Trials Registry numbers, ACTRN12605000055606 and ACTRN12605000253606.).

Genome-wide association study identifies genetic risk underlying primary rhegmatogenous retinal detachment.

Rhegmatogenous retinal detachment (RRD) is an important cause of vision loss and can potentially lead to blindness. The underlying pathogenesis is complex and incompletely understood. We applied a two-stage genetic association discovery phase followed by a replication phase in a combined total of 2833 RRD cases and 7871 controls. The discovery phase involved a genome-wide association scan of 867 affected individuals and 1953 controls from Scotland, followed by genotyping and testing 4347 highest ranking or candidate single nucleotide polymorphisms (SNPs) in independent sets of cases (1000) and controls (2912) of Dutch and British origin. None of the SNPs selected reached a Bonferroni-corrected threshold for significance (P < 1.27 × 10(-7)). The strongest association, for rs12960119 (P = 1.58 × 10(-7)) located within an intron of the SS18 gene. Further testing was carried out in independent case-control series from London (846 cases) and Croatia (120 cases). The combined meta-analysis identified one association reaching genome-wide significance for rs267738 (OR = 1.29, P = 2.11 × 10(-8)), a missense coding SNP and eQTL for CERS2 encoding the protein ceramide synthase 2. Several of the top signals showing suggestive significance in the combined meta-analysis encompassed genes with a documented role in cell adhesion or migration, including SS18, TIAM1, TSTA3 and LDB2, which warrant further investigation. This first genetic association study of RRD supports a polygenic component underlying RRD risk since 27.4% of the underlying RRD liability could be explained by the collective additive effects of the genotyped SNP from the discovery genome-wide scan.

Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): five-year outcomes of a randomised trial.

Background: Concerns remain over the long-term safety of vascular endothelial growth factor (VEGF) inhibitors to treat retinopathy of prematurity (ROP). RAINBOW is an open label randomised trial comparing intravitreal ranibizumab (in 0.2 mg and 0.1 mg doses) with laser therapy in very low birthweight infants (<1500 g) with ROP. Methods: Of 201 infants completing RAINBOW, 180 were enrolled in the RAINBOW Extension Study. At 5 years, children underwent ophthalmic, development and health assessments. The primary outcome was visual acuity in the better-seeing eye. The study is registered with ClinicalTrial.gov, NCT02640664. Findings: Between 16-6-2016 and 21-4-2022, 156 children (87%) were evaluated at 5 years. Of 32 children with no acuity test result, 25 had a preferential looking test, for 4 children investigators reported low vision for each eye, and in 3 further children no vision measurement was obtained. 124 children completed the acuity assessment, the least square mean (95% CI) letter score in the better seeing eye was similar in the three trial arms-66.8 (62.9-70.7) following ranibizumab 0.2 mg, 64.6 (60.6-68.5) following ranibizumab 0.1 mg and 62.1 (57.8-66.4) following laser therapy; differences in means: ranibizumab 0.2 mg v laser: 4.7 (95% CI: -1.1, 10.5); 0.1 mg v laser: 2.5 (-3.4, 8.3); 0.2 mg v 0.1 mg: 2.2 (-3.3, 7.8). High myopia (worse than -5 dioptres) in at least one eye occurred in 4/52 (8%) children following ranibizumab 0.2 mg, 8/55 (15%) following ranibizumab 0.1 mg and 11/45 (24%) following laser therapy (0.2 mg versus laser: odds ratio: 3.99 (1.16-13.72)). Ocular and systemic secondary outcomes and adverse events were distributed similarly in each trial arm. Interpretation: 5-year outcomes confirm the findings of the original RAINBOW trial and a planned interim analysis at 2 years, including a reduced frequency of high myopia following ranibizumab treatment. No effects of treatment on non-ocular outcomes were detected. Funding: Novartis Pharma AG.

Large scale international replication and meta-analysis study confirms association of the 15q14 locus with myopia. The CREAM consortium.

Myopia is a complex genetic disorder and a common cause of visual impairment among working age adults. Genome-wide association studies have identified susceptibility loci on chromosomes 15q14 and 15q25 in Caucasian populations of European ancestry. Here, we present a confirmation and meta-analysis study in which we assessed whether these two loci are also associated with myopia in other populations. The study population comprised 31 cohorts from the Consortium of Refractive Error and Myopia (CREAM) representing 4 different continents with 55,177 individuals; 42,845 Caucasians and 12,332 Asians. We performed a meta-analysis of 14 single nucleotide polymorphisms (SNPs) on 15q14 and 5 SNPs on 15q25 using linear regression analysis with spherical equivalent as a quantitative outcome, adjusted for age and sex. We calculated the odds ratio (OR) of myopia versus hyperopia for carriers of the top-SNP alleles using a fixed effects meta-analysis. At locus 15q14, all SNPs were significantly replicated, with the lowest P value 3.87 × 10(-12) for SNP rs634990 in Caucasians, and 9.65 × 10(-4) for rs8032019 in Asians. The overall meta-analysis provided P value 9.20 × 10(-23) for the top SNP rs634990. The risk of myopia versus hyperopia was OR 1.88 (95 % CI 1.64, 2.16, P < 0.001) for homozygous carriers of the risk allele at the top SNP rs634990, and OR 1.33 (95 % CI 1.19, 1.49, P < 0.001) for heterozygous carriers. SNPs at locus 15q25 did not replicate significantly (P value 5.81 × 10(-2) for top SNP rs939661). We conclude that common variants at chromosome 15q14 influence susceptibility for myopia in Caucasian and Asian populations world-wide.

Time Course of Retinopathy of Prematurity Regression and Reactivation After Treatment with Ranibizumab or Laser in the RAINBOW Trial.

PURPOSE: To study the time course of retinopathy of prematurity (ROP) regression and reactivation after treatment with intravitreal ranibizumab or laser in the ranibizumab compared with laser therapy for the treatment of infants born prematurely with ROP trial. DESIGN: Post hoc analysis of a randomized, clinical trial. SUBJECTS: A total of 225 infants (448 eyes) were randomized to ranibizumab 0.2 mg (n = 74, 148 eyes), ranibizumab 0.1 mg (n = 77, 152 eyes), and laser (n = 74, 148 eyes). METHODS: Features of disease regression were measured using time-to-event analysis per eye, corrected for within-subject association. Analyses of disease reactivation and additional treatments were descriptive. MAIN OUTCOME MEASURES: Median time to regression of plus disease, stage 3 ROP, aggressive posterior (AP)-ROP to 24-week follow-up and disease reactivation and first additional treatment to 2-year follow-up. RESULTS: The median times to regression after ranibizumab 0.2 mg vs. laser were as follows: plus disease, 4 vs. 16 days (P < 0.001); stage 3 ROP, 8 vs. 16 days (P = 0.004); and AP-ROP, 7.3 vs. 22 days (P = 0.03). Results for ranibizumab 0.1 mg were similar to those for 0.2 mg, with a median of 4, 9, and 8 days, respectively. Additional treatments were given in 34 (25%) of 138 eyes after laser and 40 (27%) of 146 and 42 (28%) of 152 eyes after 0.2 mg and 0.1 mg ranibizumab, respectively. Incomplete disease regression requiring additional treatment occurred in 30 (22%) of 138 eyes after laser after a median interval of 15 days compared with 11 (8%) of 146 and 9 (6%) of 152 after 0.2 mg and 0.1 mg ranibizumab after a median interval of 21 and 13 days, respectively. Retinopathy of prematurity reactivation requiring additional treatment occurred in 3 (2%) of 138 eyes after laser after a median interval of 43 days compared with 22 (15%) of 146 and 26 (17%) of 152 after 0.2 and 0.1 mg ranibizumab after a median interval of 53.5 (maximum, 105) and 54.5 days (maximum, 128), respectively. CONCLUSIONS: Intravitreal 0.2 or 0.1 mg ranibizumab induced a faster regression of plus disease, stage 3 ROP, and AP-ROP than laser did. Ranibizumab was associated with fewer additional treatments for incomplete disease regression but more for disease reactivation.

The predisposing pathology and clinical characteristics in the Scottish retinal detachment study.

PURPOSE: To describe the predisposing pathology and clinical features of all incident cases of rhegmatogenous retinal detachment (RRD) recruited in Scotland during a 2-year period. DESIGN: Prospective surveillance study of incident cases of RRD. PARTICIPANTS: All incident cases of RRD recruited as part of the Scottish Retinal Detachment Study. METHODS: During a 2-year period, we coordinated a comprehensive system in which every case of primary RRD presenting to 1 of 6 vitreoretinal surgical sites in Scotland was examined and approached for study inclusion. MAIN OUTCOME MEASURES: Rhegmatogenous retinal detachment incidence, predisposing features, and clinical characteristics. RESULTS: A total of 1202 cases were recruited. Detailed clinical information was available on 1130 (94%) of cases. By causative break, the proportions of RRD were horseshoe tear (HST) associated with posterior vitreous detachment (PVD) in 86.2%, giant retinal tear (GRT) and PVD in 1.3%, non-PVD round hole (RH) in 4.9%, retinal dialysis in 5.9%, and retinoschisis RRD in 1.6%. One in 10 cases reported significant ocular trauma. One in 5 cases were pseudophakic. Round hole RRD more frequently presented with multiple retinal breaks compared with HST RRD (67.8% vs. 48.7%; P = 0.003). In PVD-associated RRD, 56.1% (95% confidence interval [CI], 53.8-58.3) of breaks were identified in the superotemporal retina. In non-PVD RRD, 54.6% (95% CI, 47.9-61.1) of breaks were inferotemporal, followed by superotemporal in 34.9% (95% CI, 28.7-41.5). Lattice degeneration was present in 18.7% of affected eyes and more common in RH RRD (35.7%) than in HST RRD (19.3%) (P = 0.003). Seven percent reported an affected first-degree relative, and these cases were significantly more myopic than nonfamilial cases. CONCLUSIONS: More than 85% of RRD cases are associated with PVD and related tractional tears. Non-PVD RH RRD occurred in younger and more myopic individuals. The majority of cases are caused by more than 1 retinal break, and the macula is affected in more than 50% at presentation. Ocular trauma, previous cataract surgery, family history, and lattice degeneration are important predisposing features.

The Assessment of Visual Fields in Infants Using Saccadic Vector Optokinetic Perimetry (SVOP): A Feasibility Study.

Purpose: To examine the feasibility of saccadic vector optokinetic perimetry (SVOP), an automated eye tracking perimeter, as a tool for visual field (VF) assessment in infants. Methods: Thirteen healthy infants aged between 3.5 and 12.0 months were tested binocularly using an adapted SVOP protocol. SVOP uses eye tracking technology to measure gaze responses to stimuli presented on a computer screen. Modifications of SVOP for testing infants included adjusting the fixation target to display a short animation, increasing the stimulus size to equivalent to Goldmann V, and introducing a tiered test pattern strategy. Binocular, single-quadrant confrontation VF testing and Keeler preferential looking cards visual acuity testing was also performed. Results: Using multiple test attempts when required, all but the youngest infant (12 of 13 [92.3%]) successfully completed a 4-point screening test. Seven infants (53.8%) successfully completed the 12-point test, four (30.8%) successfully completed the 20-point test, and three (23.1%) successfully completed the 40-point test. The effect of multiple test attempts and the complexity of the test pattern (number of test points) on performance was investigated, including test completion rate, percentage of correctly seen stimuli, and average time per tested stimulus. Conclusions: The modified SVOP test strategy allowed successful assessment of binocular VFs in healthy infants. Future data collection from larger cohorts of infants is needed to derive normative limits of detection and assess accuracy in detecting and monitoring infant VF abnormalities. Translational Relevance: Eye tracking perimetry may provide a useful method of automated VF assessment in infants.

A case control study examining the feasibility of using eye tracking perimetry to differentiate patients with glaucoma from healthy controls.

To explore the feasibility of using Saccadic Vector Optokinetic Perimetry (SVOP) to differentiate glaucomatous and healthy eyes. A prospective case-control study was performed using a convenience sample recruited from a single university glaucoma clinic and a group of healthy controls. SVOP and standard automated perimetry (SAP) was performed with testing order randomised. The reference standard was a diagnosis of glaucoma based a comprehensive ophthalmic examination and abnormality on standard automated perimetry (SAP). The index test was SVOP. 31 patients with glaucoma and 24 healthy subjects were included. Mean SAP mean deviation (MD) in those with glaucoma was - 8.7 ± 7.4 dB, with mean SAP and SVOP sensitivities of 23.3 ± 0.9 dB and 22.1 ± 4.3 dB respectively. Participants with glaucoma were significantly older. On average, SAP sensitivity was 1.2 ± 1.4 dB higher than SVOP (95% limits of agreement = - 1.6 to 4.0 dB). SVOP sensitivity had good ability to differentiate healthy and glaucomatous eyes with a 95% CI for area under the curve (AUC) of 0.84 to 0.96, similar to the performance of SAP sensitivity (95% CI 0.86 to 0.97, P = 0.60). For 80% specificity, SVOP had a 95% CI sensitivity of 75.7% to 94.8% compared to 77.8% to 96.0% for SAP. SVOP took considerably longer to perform (514 ± 54 s compared to 267 ± 76 s for SAP). Eye tracking perimetry may be useful for detection of glaucoma but further studies are needed to evaluate SVOP within its intended sphere of use, using an appropriate design and independent reference standard.

Pathogenesis of rhegmatogenous retinal detachment: predisposing anatomy and cell biology.

BACKGROUND: The pathogenesis of rhegmatogenous retinal detachment is complex, and our knowledge of the exact mechanism of vitreoretinal attachment and detachment remains incomplete. METHODS: We performed a Medline, Ovid, and EMBASE search using search words rhegmatogenous, retinal detachment, vitreous, and retinal adhesion. All appropriate articles were reviewed, and the evidence was compiled. RESULTS: Cortical vitreous contains fibrillar collagens type II, V/XI, and IX. The inner limiting membrane of the retina contains collagens type I, IV, VI, and XVIII as well as numerous other glycoproteins and potential adhesion molecules. The distribution and age-related changes in the structure of these molecules play an important role in the formation of a retinal break, which may compromise and disrupt the normal mechanisms of neurosensory retinal adhesion. CONCLUSION: Rhegmatogenous retinal detachment development is intimately related to changes in the fibrillar structure of the aging vitreous culminating in posterior vitreous detachment with regions of persistent and tangential vitreoretinal traction predisposing to retinal tear formation. A complex interplay of factors such as weakening of vitreoretinal adhesion, posterior migration of the vitreous base, and molecular changes at the vitreoretinal interface are important in predisposing to focal areas of vitreoretinal traction precipitating rhegmatogenous retinal detachment. Once formed, the passage of liquefied vitreous through a retinal break may overwhelm normal neurosensory-retinal pigment epithelium adhesion perpetuating and extending detachment and causing visual loss. To understand the molecular events underlying rhegmatogenous retinal detachment so that new therapies can be developed, it is important to appreciate the structural organization of the vitreous, the biology underlying vitreous liquefaction and posterior vitreous detachment, and the mechanisms of vitreoretinal attachment and detachment.

Tubulointerstitial nephritis and uveitis (TINU) syndrome and recent Streptococcus infection in a 9-year-old girl.

A 9-year-old girl presented to hospital with a 6-week history of non-specific constitutional symptoms and weight loss. She initially underwent extensive medical investigation without diagnosis being achieved. Although raised inflammatory markers and impaired renal function were noted during her initial admission to hospital, it was her subsequent presentation 2 weeks later with sudden-onset bilateral anterior uveitis that prompted a renal biopsy that indicated acute tubulointerstitial nephritis. A diagnosis of tubulointerstitial nephritis and uveitis (TINU) syndrome was made and systemic glucocorticoid treatment initiated to prevent visual loss and preserve renal function. She has subsequently been reviewed in multidisciplinary outpatient clinics and treated with a tapering regimen of immunosuppressive therapy. Her treatment has been complicated by the side effects of glucocorticoids and by persistent relapses in ocular disease and abnormalities on urinalysis. Recent clinical investigations indicate that her uveitis is controlled and that renal function remains well preserved.

Ranibizumab Population Pharmacokinetics and Free VEGF Pharmacodynamics in Preterm Infants With Retinopathy of Prematurity in the RAINBOW Trial.

Purpose: To develop a population pharmacokinetic (PK) model for intravitreal ranibizumab in infants with retinopathy of prematurity (ROP) and assess plasma free vascular endothelial growth factor (VEGF) pharmacodynamics (PD). Methods: The RAnibizumab compared with laser therapy for the treatment of INfants BOrn prematurely With retinopathy of prematurity (RAINBOW) trial enrolled 225 infants to receive a bilateral intravitreal injection of ranibizumab 0.1 mg, ranibizumab 0.2 mg, or laser in a 1:1:1 ratio and included sparse sampling of blood for population PK and PD analysis. An adult PK model using infant body weight as a fixed allometric covariate was re-estimated using the ranibizumab concentrations in the preterm population. Different variability, assumptions, and covariate relationships were explored. Model-based individual predicted concentrations of ranibizumab were plotted against observed free VEGF concentrations. Results: Elimination of ranibizumab had a median half-life of 5.6 days from the eye and 0.3 days from serum, resulting in an apparent serum half-life of 5.6 days. Time to reach maximum concentration was rapid (median: 1.3 days). Maximum concentration (median 24.3 ng/mL with ranibizumab 0.2 mg) was higher than that reported in adults. No differences in plasma free VEGF concentrations were apparent between the groups or over time. Plotted individual predicted concentrations of ranibizumab against observed free VEGF concentrations showed no relationship. Conclusions: In preterm infants with ROP, elimination of ranibizumab from the eye was the rate-limiting step and was faster compared with adults. No reduction in plasma free VEGF was observed. The five-year clinical safety follow-up from RAINBOW is ongoing. Translational Relevance: Our population PK and VEGF PD findings suggest a favorable ocular efficacy: systemic safety profile for ranibizumab in preterm infants.

Development of an Age-corrected Normative Database for Saccadic Vector Optokinetic Perimetry (SVOP).

PRECIS: Normal age-corrected threshold sensitivity values were determined for a new eye tracking perimeter and compared with standard automated perimetry (SAP). PURPOSE: The purpose of this study was to determine threshold visual field sensitivities in normal subjects performing saccadic vector optokinetic perimetry (SVOP), a new eye tracking perimeter. PATIENTS AND METHODS: A total of 113 healthy participants performed SVOP and SAP in both eyes with the order of testing randomized. The relationship between SAP and SVOP sensitivity was examined using Bland-Altman plots and 95% limits of agreement. The relationship between sensitivity and age was examined by pointwise linear regression and age-corrected normal threshold sensitivities were calculated. RESULTS: After excluding unreliable tests, 97 participants with a mean age of 65.9±10.1 years were included. Average SAP mean deviation was -0.87±1.56 dB, SAP sensitivity was 29.20±1.68 dB and SVOP sensitivity was 32.18±1.96 dB. SVOP had a longer test duration (431±110 compared with 307±42 seconds for SAP, P<0.001). On average, the mean sensitivity obtained using SVOP was 2.98 dB higher than average SAP sensitivity, with 95% limits of agreement of -0.11 to 6.15 dB. For each decade older, SAP sensitivity decreased by 0.93 dB (95% confidence interval: 1.21 to 0.64) and SVOP sensitivity decreased by 1.15 dB (95% confidence interval: 1.47 to 0.84). CONCLUSIONS: The results provide age-corrected normative values for threshold sensitivities from SVOP. Overall, SVOP provided a similar shaped hill of vision as SAP however threshold sensitivities were higher, meaning results are not interchangeable.

Feasibility of saccadic vector optokinetic perimetry: a method of automated static perimetry for children using eye tracking.

PURPOSE: To determine the feasibility of a new technique for suprathreshold automated static perimetry in children. DESIGN: Evaluation of diagnostic test or technology. PARTICIPANTS: The study included 29 subjects comprising 4 groups: 12 adults with normal fields, 4 children aged less than 10 years with normal fields, 8 adults with visual field defect, and 5 children aged less than 10 years with suspected visual field defects. METHODS: The system comprises a personal computer, display, and eye tracker to monitor gaze position when stimuli are presented in the visual field. The natural saccadic eye movement to fixate on the stimuli, if seen, can be detected and measured to produce a visual field plot. Subjects performed 3 eye-tracking tests, unless unable to do so for any reason: a 40-point binocular test and two 41-point tests for each eye. The tests were based on the Humphrey Field Analyzer (HFA) Central-40 point screening test with a stimulus size of Goldmann III and intensity of 14 decibels (dB). Adults also performed the equivalent Humphrey screening test in each eye for comparison. MAIN OUTCOME MEASURES: Comparison of visual field plot results between the eye-tracking tests and HFA tests in adults. Correlation between the eye-tracking tests and the clinical assessment in the children with suspected visual field defects. RESULTS: In the eyes of all normal adult and child subjects performing the eye-tracking test, the percentage of points in agreement with a healthy visual field was 99.2% and 99.1%, respectively. The percentage of points agreeing with the HFA's screening test in the adult eyes with visual field defects was 89.8%. Visual field defects were also correctly identified by the eye-tracking system in the eyes of children with suspected visual field defects. CONCLUSIONS: The results demonstrate that suprathreshold automated static perimetry using eye tracking is a promising method of perimetry for use with children.

Rhegmatogenous retinal detachment in Scotland: research design and methodology.

BACKGROUND: Rhegmatogenous retinal detachment (RRD) is a potentially blinding condition and a common cause of ocular morbidity. Establishing an accurate estimate of disease incidence and distribution is an important first step in assessing the healthcare burden related to this condition and in subsequent planning and provision of treatment strategies. The aim of this study is to obtain a first estimate incidence of RRD in Scotland, to estimate the incidence of familial RRD and to describe the known associations of RRD within the study population. METHODS/DESIGN: We have established a national prospective observational study seeking to identify and recruit all incident cases of RRD in the Scottish population over a 2 year period. After fully informed consent, all participants will have a blood sample taken and a full medical history and clinical examination performed including visual acuity, refraction, slit-lamp examination, intra-ocular pressure measurement and detailed fundal examination. We describe the study design and protocol. CONCLUSION: This study will provide the first estimate of the annual incidence of RRD in Scotland. The findings of this study will be important in estimating the burden of disease and in the planning of future health care policy related to this condition. This study will also establish a genetic resource for a genome wide association study to investigate if certain genetic variants predispose to RRD.

Pathogenesis of retinopathy of prematurity and possible preventive strategies.

Retinopathy of Prematurity (ROP) occurs when premature birth interrupts normal retinal vascular development. Postnatal tissue oxygen levels are significantly higher than those present in utero. Oxygen therapy further increases oxygen levels in the developing retina. Hypoxia driven, VEGF mediated, retinal endothelial cell proliferation is reduced. Low IGF-1 levels may also contribute to delayed retinal vascular development. The neural structures of the peripheral avascular retina continue to develop, and become more metabolically active. Complex, as yet poorly understood abnormalities of structural and molecular interactions between immature endothelial cells and immature astrocytes at the anterior "leading edge" of retinal vascular development leads to the development of an ROP ridge. VEGF produced by the hypoxic peripheral retina, along with structural abnormalities of cell relationships within, and at the vitreoretinal interface of the ROP ridge, results in extraretinal angiogenesis - stage 3 ROP. Stage 3 ROP may resolve spontaneously, or may progress to traction retinal detachment and blindness.