Anne Moskowitz

The Neurovascular Retina in Retinopathy of Prematurity

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.

Retinal degenerative and hypoxic ischemic disease.

A broad spectrum of retinal diseases affects both the retinal vasculature and the neural retina, including photoreceptor and postreceptor layers. The accepted clinical hallmarks of acute retinopathy of prematurity (ROP) are dilation and tortuosity of the retinal vasculature. Additionally, significant early and persistent effects on photoreceptor and postreceptor neural structures and function are demonstrated in ROP. In this paper, we focus on the results of longitudinal studies of electroretinographic (ERG) and vascular features in rats with induced retinopathies that model the gamut of human ROP, mild to severe. Two potential targets for pharmaceutical interventions emerge from the observations. The first target is immature photoreceptors because the status of the photoreceptors at an early age predicts later vascular outcome; this approach is appealing as it holds promise to prevent ROP. The second target is the interplay of the neural and vascular retinal networks, which develop cooperatively. Beneficial pharmaceutical interventions may be measured in improved visual outcome as well as lessening of the vascular abnormalities.

Rod and rod-driven function in achromatopsia and blue cone monochromatism.

PURPOSE To evaluate rod photoreceptor and postreceptor retinal function in pediatric patients with achromatopsia (ACHR) and blue cone monochromatism (BCM) using contemporary electroretinographic (ERG) procedures. METHODS Fifteen patients (age range, 1-20 years) with ACHR and six patients (age range, 4-22 years) with BCM were studied. ERG responses to full-field stimuli were obtained in scotopic and photopic conditions. Rod photoreceptor (S(rod), R(rod)) and rod-driven postreceptor (log sigma, V(max)) response parameters were calculated from the a-wave and b-wave. ERG records were digitally filtered to demonstrate the oscillatory potentials (OPs); a sensitivity parameter, log SOPA(1/2), and an amplitude parameter, SOPA(max), were used to characterize the OP response. Response parameters were compared with those of 12 healthy control subjects. RESULTS As expected, photopic responses were nondetectable in patients with ACHR and BCM. In addition, mean scotopic photoreceptor (R(rod)) and postreceptor (V(max) and SOPA(max)) amplitude parameters were significantly reduced compared with those in healthy controls. The flash intensity required to evoke a half-maximum b-wave amplitude (log sigma) was significantly increased. CONCLUSIONS Results of this study provide evidence that deficits in rod and rod-mediated function occur in the primary cone dysfunction syndromes ACHR and BCM.

The cone electroretinogram in retinopathy of prematurity.

PURPOSE To test the hypothesis that retinopathy of prematurity (ROP) affects the cone photoreceptors less than the rod photoreceptors. METHODS Electroretinogram (ERG) responses to a 1.8-log-unit range of red flashes on a white, rod-saturating background were recorded in 42 subjects with a history of preterm birth and ROP (28 untreated; 6 treated) or no ROP (n = 8). The sensitivity (S(CONE)) and saturated amplitude (R(CONE)) of the cone photoresponse were calculated by fit of a model of the activation of cone phototransduction to the a-waves. The cone-driven b-wave amplitude was evaluated as a function of stimulus intensity. S(CONE) and R(CONE) were compared to the rod response parameters (S(ROD), R(ROD)) recorded from the same preterm subjects. Responses in the former preterm subjects were compared to those in control subjects. RESULTS The values of S(CONE) and R(CONE) in the preterm subjects overlapped broadly with those in the control subjects. The shapes of the b-wave stimulus-response functions did not differ between preterm and control subjects. The relative value of S(CONE) was significantly greater than that of S(ROD). CONCLUSIONS 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.

Early Ametropia and Rod Photoreceptor Function in Retinopathy of Prematurity

Purpose. Early ametropia, particularly myopia, is frequent in children with a history of preterm birth and retinopathy of prematurity (ROP). The retina is known to govern eye growth and refractive development. We tested the hypothesis that deficits in retinal function are significantly associated with early ametropia in ROP subjects. Methods. Scotopic electoretinogram (ERG) responses to full field stimuli were studied in 40 ROP subjects aged 8 weeks to 18 years. The ROP was categorized as treated, untreated, or none. Refractive development of each ROP subject was monitored and compared with normal for age. The rod photoresponse parameters were calculated and the postreceptoral responses derived. The ERG parameters in the ROP subjects were compared with normal values for age. Results. Twelve ROP subjects developed early ametropia, 10 myopia, and two hyperopia. In the majority of ROP subjects, receptoral and postreceptoral response parameters were below the normal mean for age. In the 12 children with early ametropia, rod photoreceptor sensitivity was significantly lower than in emmetropic ROP subjects; and in five tested in infancy, deficits in rod photoreceptor sensitivity antedated development of ametropia. The myopic control subjects had no deficits in response parameters. Conclusions. Retinal dysfunction is significantly associated with early ametropia in these ROP subjects. Thus, mechanisms for the development of ametropia in ROP subjects may involve rod and rod-mediated postreceptoral activity.

Pursuit Eye Movements in Late-Onset Esotropia

Horizontal, smooth pursuit eye movements were recorded from adults and children with infantile and late-onset esotropia using a remote, video-based, eye-movement recording system. Each subject monocularly tracked a 0.5-degree target moving back and forth on a video monitor at a constant velocity of 10 degrees, over a range of 12 degrees. Each subjects nasal and temporal gain (eye velocity/target velocity) was measured. Confirming the results of previous studies, we found that infantile esotropes had asymmetrical pursuit eye movements (nasal gain greater than temporal gain) while late-onset esotropes had symmetrical gains. However, unlike previous investigators, we found that half of the late-onset esotropes had impaired pursuit gain. The magnitude of the pursuit abnormality and the amount of refractive error were correlated--patients with the highest refractive error had the lowest pursuit gain.

The neural retina in retinopathy of prematurity

ABSTRACT 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. HIGHLIGHTSRetinopathy of prematurity (ROP) involves the neurosensory retina.The status of the immature rods may be a driver of ROP pathogenesis.Evidence of photoreceptor injury persists years after ROP is an active disease.Post‐receptor retina reorganizes to compensate for deficient photoreceptor inputs.The late maturing central retinal is especially vulnerable to the effects of ROP.

Development of rod function in term born and former preterm subjects.

Purpose. To provide an overview of some of our electroretinographic (ERG) and psychophysical studies of normal development of rod function and their application to retinopathy of prematurity (ROP). Methods. ERG responses to full-field stimuli were recorded from dark adapted subjects. Rod photoreceptor sensitivity (SROD) was calculated by fit of a biochemical model of the activation of phototransduction to the ERG a-wave. Dark adapted psychophysical thresholds for detecting 2° spots in parafoveal (10° eccentric) and peripheral (30° eccentric) retina were measured and the difference between the thresholds, &Dgr;10-30, was examined as a function of age. SROD and &Dgr;10-30 in term born and former preterm subjects were compared. Results. In term born infants, (1) the normal developmental increase in SROD changes proportionately with the amount of rod visual pigment, rhodopsin, and (2) rod-mediated function in central retina is immature compared with that in peripheral retina. In subjects born prematurely, deficits in SROD persist long after active ROP has resolved. Maturation of rod-mediated thresholds in the central retina is prolonged by mild ROP. Conclusions. Characterization of the development of normal rod and rod-mediated function provides a foundation for understanding ROP.

Retinal, visual, and refractive development in retinopathy of prematurity

The pivotal role of the neurosensory retina in retinopathy of prematurity (ROP) disease processes has been amply demonstrated in rat models. We have hypothesized that analogous cellular processes are operative in human ROP and have evaluated these presumptions in a series on non-invasive investigations of the photoreceptor and post-receptor peripheral and central retina in infants and children. Key results are slowed kinetics of phototransduction and deficits in photoreceptor sensitivity that persist years after ROP has completely resolved based on clinical criteria. On the other hand, deficits in post-receptor sensitivity are present in infancy regardless of the severity of the ROP but are not present in older children if the ROP was so mild that it never required treatment and resolved without a clinical trace. Accompanying the persistent deficits in photoreceptor sensitivity, there is increased receptive field size and thickening of the post-receptor retinal laminae in the peripheral retina of ROP subjects. In the late maturing central retina, which mediates visual acuity, attenuation of multifocal electroretinogram activity in the post-receptor retina led us to the discovery of a shallow foveal pit and significant thickening of the post-receptor retinal laminae in the macular region; this is most likely due to failure of the normal centrifugal movement of the post-receptor cells during foveal development. As for refractive development, myopia, at times high, is more common in ROP subjects than in control subjects, in accord with refractive findings in other populations of former preterms. This information about the neurosensory retina enhances understanding of vision in patients with a history of ROP, and taken as a whole, raises the possibility that the neurosensory retina is a target for therapeutic intervention.

Temporal summation in children with a history of retinopathy of prematurity.

PURPOSE To assess temporal summation in children with a history of retinopathy of prematurity (ROP) by determining the critical duration (tCRIT) for complete temporal summation under rod-mediated conditions. From prior ERG studies, it is known that the kinetics of activation of phototransduction are prolonged in the ROP rod photoreceptor. METHODS Dark-adapted thresholds for detecting 10° diameter stimuli with durations from 10 to 640 ms were measured. A two-alternative, spatial, forced-choice psychophysical procedure was used. The tCRIT for complete summation was estimated in former preterm subjects with a history of severe ROP (n = 7), mild ROP (n = 23), and no ROP (n = 15). The subjects ranged in age from 10.4 to 17.6 (median 15.6) years. Age-similar term-born control subjects (n = 5) were also tested. RESULTS Critical duration was significantly longer in subjects with a history of ROP than in subjects who never had ROP or who were born at term. Mean tCRIT in the mild ROP group [127.5 (SD = 19.9) ms] and severe group [147.6 (SD = 18.9) ms] did not differ significantly, but both were significantly longer than in former preterms who never had ROP [101.1 (SD = 16.5) ms] and in term-born controls [101.0 (SD = 19.5) ms]. CONCLUSIONS In ROP subjects, tCRIT is significantly prolonged. This is likely due to abnormal kinetics in the rod outer segment.