Alistair R. Fielder

Characteristics of infants with severe retinopathy of prematurity in countries with low, moderate, and high levels of development: implications for screening programs.

Objective. Retinopathy of prematurity (ROP) is a potentially avoidable cause of blindness in children. The proportion of blindness as a result of ROP varies greatly among countries depending on their level of development, being influenced by the availability of neonatal care, neonatal outcomes, and whether effective screening and treatment programs are in place. The objective of this study was to compare characteristics of premature infants who developed severe ROP between 1996 and 2002 in highly developed countries with less developed countries. Methods. This was an observational study. A questionnaire was completed by ophthalmologists in countries with low, moderate, and high development rankings (3 highly developed countries and from 10 less well-developed countries) who screen for ROP in which they supplied birth weights and gestational ages (GAs) of infants who were treated for threshold ROP or identified with more advanced stages of the disease. Birth weights and GAs of infants with severe ROP were measured. Results. The mean birth weights of infants from highly developed countries ranged from 737 to 763 g compared with values ranging from 903 to 1527 g in less developed countries. Mean GAs of infants from highly developed countries ranged from 25.3 to 25.6 weeks compared with 26.3 to 33.5 weeks in less developed countries. A total of 13.0% of 1091 infants from poorly developed countries exceeded United Kingdom screening criteria; 3.6% exceeded a criteria of <34 weeks’ GA and/or <1750 g birth weight. Conclusions. These findings suggest that larger, more mature infants are developing severe ROP in countries with low/moderate levels of development compared with highly developed countries. ROP screening programs need to use criteria that are appropriate for their local population.

Heterozygous mutations of OTX2 cause severe ocular malformations

Major malformations of the human eye, including microphthalmia and anophthalmia, are examples of phenotypes that recur in families yet often show no clear Mendelian inheritance pattern. Defining loci by mapping is therefore rarely feasible. Using a candidate-gene approach, we have identified heterozygous coding-region changes in the homeobox gene OTX2 in eight families with ocular malformations. The expression pattern of OTX2 in human embryos is consistent with the eye phenotypes observed in the patients, which range from bilateral anophthalmia to retinal defects resembling Leber congenital amaurosis and pigmentary retinopathy. Magnetic resonance imaging scans revealed defects of the optic nerve, optic chiasm, and, in some cases, brain. In two families, the mutations appear to have occurred de novo in severely affected offspring, and, in two other families, the mutations have been inherited from a gonosomal mosaic parent. Data from these four families support a simple model in which OTX2 heterozygous loss-of-function mutations cause ocular malformations. Four additional families display complex inheritance patterns, suggesting that OTX2 mutations alone may not lead to consistent phenotypes. The high incidence of mosaicism and the reduced penetrance have implications for genetic counseling.

Preterm-associated visual impairment and estimates of retinopathy of prematurity at regional and global levels for 2010

Background:Retinopathy of prematurity (ROP) is a leading cause of potentially avoidable childhood blindness worldwide. We estimated ROP burden at the global and regional levels to inform screening and treatment programs, research, and data priorities.Methods:Systematic reviews and meta-analyses were undertaken to estimate the risk of ROP and subsequent visual impairment for surviving preterm babies by level of neonatal care, access to ROP screening, and treatment. A compartmental model was used to estimate ROP cases and numbers of visually impaired survivors.Results:In 2010, an estimated 184,700 (uncertainty range: 169,600–214,500) preterm babies developed any stage of ROP, 20,000 (15,500–27,200) of whom became blind or severely visually impaired from ROP, and a further 12,300 (8,300–18,400) developed mild/moderate visual impairment. Sixty-five percent of those visually impaired from ROP were born in middle-income regions; 6.2% (4.3–8.9%) of all ROP visually impaired infants were born at >32-wk gestation. Visual impairment from other conditions associated with preterm birth will affect larger numbers of survivors.Conclusion:Improved care, including oxygen delivery and monitoring, for preterm babies in all facility settings would reduce the number of babies affected with ROP. Improved data tracking and coverage of locally adapted screening/treatment programs are urgently required.

Refractive adaptation in amblyopia: quantification of effect and implications for practice

Aim: To describe the visual response to spectacle correction (“refractive adaptation”) for children with unilateral amblyopia as a function of age, type of amblyopia, and category of refractive error. Method: Measurement of corrected amblyopic and fellow eye logMAR visual acuity in newly diagnosed children. Measurements repeated at 6 weekly intervals for a total 18 weeks. Results: Data were collected from 65 children of mean (SD) age 5.1 (1.4) years with previously untreated amblyopia and significant refractive error. Amblyopia was associated with anisometropia in 18 (5.5 (1.4) years), strabismus in 16 (4.2 (0.98) years), and mixed in 31 (5.2 (1.5) years) of the study participants. Mean (SD) corrected visual acuity of amblyopic eyes improved significantly (p<0.001) from 0.67 (0.38) to 0.43 (0.37) logMAR: a mean improvement of 0.24 (0.18), range 0.0–0.6 log units. Change in logMAR visual acuity did not significantly differ as a function of amblyopia type (p = 0.29) (anisometropia 0.22 (0.13); mixed 0.18 (0.14); strabismic 0.30 (0.24)) or for age (p = 0.38) (“under 4 years” 0.23 (0.18); “4–6 years” 0.24 (0.20); “over 6 years” 0.16 (0.23)). Conclusion: Refractive adaptation is a distinct component of amblyopia treatment. To appropriately evaluate mainstream therapies such as occlusion and penalisation, the beneficial effects of refractive adaptation need to be fully differentiated. A consequence for clinical practice is that children may start occlusion with improved visual acuity, possibly enhancing compliance, and in some cases unnecessary patching will be avoided.

Natural history of retinopathy of prematurity: A prospective study

The natural history of retinopathy of prematurity (ROP) has been studied prospectively in 572 infants &leq;1,700 g birthweight using a protocol designed specifically to investigate the subtle features of this condition. Acute ROP developed in 50.9%. All ROP stages 1 and 2 underwent complete resolution and of the 27 (4.7%) infants with stage 3/4 disease, cicatricial sequelae developed in six. Incidence and severity increased with decreasing birthweight and gestational age. Onset was not confined to the temporal retina but exhibited a predilection to start first in the nasal retina of the most immature neonate. The vertical retinal regions were relatively spared. Retinal arteriolar tortuosity developed around three months postnatally and was related to ROP severity but not its presence. The age at onset and rate of progression of retinopathy were largely determined by the stage of development but were also modified by systemic and local factors. The relevance of these findings to ROP screening is discussed.

Objectively monitored patching regimens for treatment of amblyopia: randomised trial.

Objectives To compare visual outcome in response to two prescribed rates of occlusion (six hours a day and 12 hours a day). Design Unmasked randomised trial. Setting Research clinics in two London hospitals. Participants 97 children with a confirmed diagnosis of amblyopia associated with strabismus, anisometropia, or both. Interventions: 18 week period of wearing glasses (refractive adaptation) followed by occlusion prescribed (“patching”) for six or 12 hours a day. Main outcome measures Visual acuity measured by logMAR letter recognition; objectively monitored rate of occlusion (hours a day). Results The mean age of children at study entry was 5.6 (SD 1.5) years. Ninety were eligible for occlusion but 10 dropped out in this phase, leaving 80 children who were randomised to a prescribed dose rate of six (n=40) or 12 (n=40) hours a day. The mean change in visual acuity of the amblyopic eye was not significantly different (P=0.64) between the two groups (0.26 (95% confidence interval 0.21 to 0.31) log units in six hour group; 0.24 (0.19 to 0.29) log units in 12 hour group). The mean dose rates (hours a day) actually received, however, were also not significantly different (4.2 (3.7 to 4.7) in six hour group v 6.2 (5.1 to 7.3) in 12 hour group; P=0.06). The visual outcome was similar for those children who received three to six hours a day or more than six to 12 hours a day, but significantly better than that in children who received less than three hours a day. Children aged under 4 required significantly less occlusion than older children. Visual outcome was not influenced by type of amblyopia. Conclusions Substantial (six hours a day) and maximal (12 hours a day) prescribed occlusion results in similar visual outcome. On average, the occlusion dose received in the maximal group was only 50% more than in the substantial group and in both groups was much less than that prescribed. Younger children required the least occlusion. Trials registration Clinical Trials NCT00274664.

Compliance in amblyopia therapy: objective monitoring of occlusion.

AIM/BACKGROUND--This study aimed to determine the feasibility of objective compliance monitoring of amblyopia therapy in clinical research. Occlusion has been the mainstay of amblyopia therapy for over 250 years, yet it has never been subjected to rigorous evaluation. Treatment regimens range arbitrarily from a few minutes to most of the waking hours of the day. Compliance is problematic and as, hitherto, accurate objective monitoring has been impossible it is not known how much occlusion is required to effect an improvement in vision. METHODS--An occlusion dose monitor (ODM) has been developed. The ODM consists of a modified occlusion patch and a miniature battery driven datalogger which periodically monitors patch skin contact. The patch is a standard disposable item with two miniature electrocardiogram electrodes attached to its undersurface. The datalogger comprises a high speed static RAM and a clock driven address counter. Data are retrieved using an IBM PC/AT computer. Fifteen child amblyopes were randomly allocated unilateral occlusion of 1, 4, or 8 hours per day for 4 weeks. Owing to data loss, presumed because of accumulation and discharge of static electricity, an additional child was included in the 8 hour group. Outcome measures were objective (ODM) and subjective (diary) compliance with treatment, logMAR visual acuity, and contrast sensitivity. RESULTS--Objective monitoring of occlusion is technically feasible and clinically informative. CONCLUSION--Objective monitoring of occlusion has opened up new research opportunities which, it is hoped, will enable the dose-effect relation of occlusion therapy in the various types of amblyopia to be investigated objectively, and facilitate the design of effective therapeutic regimens.

Does stereopsis matter in humans

Stereopsis has been one of the most popular fields of vision research for well over a century and is routinely measured in clinical practice, yet its functional significance has been largely neglected. Stereopsis is disrupted by blur, amblyopia and strabismus and is of potential value as a means of indirect screening for visual disorders in childhood. However, evidence for the functional effects of stereoscopic deficits is sparse. Recent investigations indicate that binocularity is an advantage in certain tasks, especially in the comprehension of complex visual presentations and those requiring good hand—eye coordination. The assumption derived from the evolutionary theory that stereopsis represents an adaptation by primates to arboreal life needs to be questioned. While the functional aspects of stereopsis are still not fully understood the direction that future research should take to unravel this important issue is apparent.

Semiautomated computer analysis of vessel growth in preterm infants without and with ROP

Aims: To measure characteristics of the retinal blood vessels close to the optic disc in full term and preterm infants, with and without retinopathy of prematurity (ROP), using digital imaging. To determine whether these measures are indicative of the presence or severity of ROP in the retinal periphery. Methods: 52 digital fundus images from 42 babies were analysed with a semiautomated analysis program developed at Imperial College London. Analysis was limited to the principal temporal vessels close to the optic disc: recording venular diameter and arteriolar diameter and tortuosity. Results: Each result was categorised by the gestational age of the infant (“very premature” 24–27 weeks, “moderately premature” 28–31 weeks, and “near term” ⩾32 weeks) and by the highest stage of ROP present (“no ROP,” “mild ROP” stage 1 or 2, and “severe ROP” stage 3). Arteriolar tortuosity was found to vary significantly (Kruskal-Wallis p = 0.002) with ROP severity. Although venular and arteriolar diameters increased monotonically with ROP severity the differences were not significant. Venular diameter, arteriolar diameter, and arterial tortuosity did not vary significantly between gestational age groups. Conclusions: This study confirms it is possible to quantify the size and tortuosity of retinal blood vessels in term and preterm babies using digital image analysis software. This method detected significant increases in arteriolar tortuosity with increasing ROP severity.

Change of refractive state and eye size in children of birth weight less than 1701 g

Aims: To determine the refractive status and ocular dimensions of a cohort of children at age 10–12 years with birth weight below 1701 g, and also the relation between the neonatal ophthalmic findings and subsequent refractive state. Methods: 293 low birthweight children who had been examined in the neonatal period were assessed at 10–12 years of age. The examination consisted of autorefraction, keratometry, and A-scan. Results of right eyes were compared with published normative data. Results: 293 of the birth cohort of 572 children consented to participate. The average mean spherical equivalent (MSE) in the low birthweight cohort was +0.691 dioptre, significantly higher than the control data (+0.30D, p = 0.02). The average change in MSE over the 10–12 year period was −1.00 dioptre (n = 256), but only 62.1% of cases showed a shift in refractive error of the appropriate magnitude and direction. The presence of any retinopathy of prematurity (ROP) increases the risk of developing anisometropia sixfold. Conclusions: Low birth weight and ROP both significantly impact the refractive state in the long term. At age 10–12 years children born preterm have an increased prevalence of all refractive errors. In low birthweight children refractive state is relatively stable over the first decade of life with a shift towards myopia of 1 dioptre.