The continuing worldwide epidemic of retinopathy of prematurity (ROP), a leading cause of childhood visual impairment, strongly motivates further research into mechanisms of the disease. Although the hallmark of ROP is abnormal retinal vasculature, a growing body of evidence supports a critical role for the neural retina in the ROP disease process. The age of onset of ROP coincides with the rapid developmental increase in rod photoreceptor outer segment length and rhodopsin content of the retina with escalation of energy demands. Using a combination of non-invasive electroretinographic (ERG), psychophysical, and image analysis procedures, the neural retina and its vasculature have been studied in prematurely born human subjects, both with and without ROP, and in rats that model the key vascular and neural parameters found in human ROP subjects. These data are compared to comprehensive numeric summaries of the neural and vascular features in normally developing human and rat retina. In rats, biochemical, anatomical, and molecular biological investigations are paired with the non-invasive assessments. ROP, even if mild, primarily and persistently alters the structure and function of photoreceptors. Post-receptor neurons and retinal vasculature, which are intimately related, are also affected by ROP; conspicuous neurovascular abnormalities disappear, but subtle structural anomalies and functional deficits may persist years after clinical ROP resolves. The data from human subjects and rat models identify photoreceptor and post-receptor targets for interventions that promise improved outcomes for children at risk for ROP.
Purpose-To determine whether recovery of scotopic sensitivity occurs in human ROP, as it does in rat models of ROP.Methods-Following a cross-sectional design, scotopic electroretinographic (ERG) responses to full-field stimuli were recorded from 85 subjects with a history of preterm birth. In 39 of these subjects, dark adapted visual threshold was also measured. Subjects were tested post term as infants (median age 2.5 months) or at older ages (median age 10.5 years) and stratified by severity of ROP: severe, mild, or none. Rod photoreceptor sensitivity, S ROD , was derived from the a-wave and post-receptor sensitivity, log σ, was calculated from the b-wave stimulus-response function. Dark adapted visual threshold was measured using a forced-choice preferential procedure.Results-For S ROD , the deficit from normal for age varied significantly with ROP severity but not with age group. For log σ, in mild ROP, the deficit was smaller in older subjects than in infants, while in severe ROP, the deficit was quite large in both age groups. In subjects who never had ROP, S ROD and log σ in both age groups were similar to those in term born controls. Deficits in dark adapted threshold and log σ were correlated in mild but not in severe ROP.Conclusions-The data are evidence that sensitivity of the post-receptor retina improves in those with a history of mild ROP. We speculate that beneficial reorganization of the post-receptor neural circuitry occurs in mild but not in severe ROP.
Keywordsretinopathy of prematurity; neural retina; electroretinogram; rod photoreceptor; dark adapted visual threshold Retinopathy of prematurity (ROP), even if mild, causes long term deficits in rod and roddriven post-receptor retinal function that persist long after acute phase ROP has resolved. Compared to term born controls, in the majority of ROP subjects, both rod photoreceptor and post-receptor response parameters are below average from early infancy into adulthood; former preterms who never had ROP do not differ from age-similar controls [1]. Rod and post-receptor retinal dysfunction are also noted in rat models of ROP [2][3][4][5][6][7][8][9]. In rats followed longitudinally, postreceptor sensitivity recovers whereas photoreceptor sensitivity remains abnormal [2].To determine if there is evidence of recovery of sensitivity in human ROP, we reviewed rod photoreceptor and post-receptor ERG parameters in infants and older subjects with a history of preterm birth. Dark adapted visual thresholds were also evaluated for significant relationship to ERG indices of sensitivity. The effects of age and ROP severity on these cross-sectional ERG and threshold data from infant and older subjects were analyzed.
METHODS
SubjectsRod and rod-driven ERG parameters from 85 subjects with a history of preterm birth were analyzed (Table 1A). Peripheral dark adapted visual thresholds obtained from 39 of these subjects were also analyzed (Table 1B). ERG parameters from 68 of the subjects [1] and threshold data from 11 [10] have been reported previously....
Retinopathy of prematurity (ROP) is a neurovascular disease that affects prematurely born infants and is known to have significant long term effects on vision. We conducted the studies described herein not only to learn more about vision but also about the pathogenesis of ROP. The coincidence of ROP onset and rapid developmental elongation of the rod photoreceptor outer segments motivated us to consider the role of the rods in this disease. We used noninvasive electroretinographic (ERG), psychophysical, and retinal imaging procedures to study the function and structure of the neurosensory retina. Rod photoreceptor and post-receptor responses are significantly altered years after the preterm days during which ROP is an active disease. The alterations include persistent rod dysfunction, and evidence of compensatory remodeling of the post-receptor retina is found in ERG responses to full-field stimuli and in psychophysical thresholds that probe small retinal regions. In the central retina, both Mild and Severe ROP delay maturation of parafoveal scotopic thresholds and are associated with attenuation of cone mediated multifocal ERG responses, significant thickening of post-receptor retinal laminae, and dysmorphic cone photoreceptors. These results have implications for vision and control of eye growth and refractive development and suggest future research directions. These results also lead to a proposal for noninvasive management using light that may add to the currently invasive therapeutic armamentarium against ROP.
ROP has less effect on the cone than on the rod photoresponses, suggesting that cones are more resistant to the ROP disease process. The similar shape of the b-wave stimulus-response function in preterms and control subjects is evidence that ROP does not alter the balance of ON and OFF signals in the cone pathway.
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