Key Features
Avascular Retina
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Stage 1: demarcation line between normal and avascular retina.
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Stage 2: elevated ridge between normal and avascular retina.
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Stage 3: extraretinal fibrovascular proliferation on the ridge.
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Stages 4 and 5: tractional retinal detachment due to contraction of extraretinal fibrovascular proliferation.
Avascular Retina
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Stage 1: demarcation line between normal and avascular retina.
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Stage 2: elevated ridge between normal and avascular retina.
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Stage 3: extraretinal fibrovascular proliferation on the ridge.
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Stages 4 and 5: tractional retinal detachment due to contraction of extraretinal fibrovascular proliferation.
Introduction
First described in 1942, retinopathy of prematurity (ROP) is a proliferative retinopathy affecting premature infants of low birth weight (BW) and young gestational age (GA). Despite—and partly due to—major advances in neonatology, ROP remains a leading cause of lifelong visual impairment among children in developed countries. About 1100–1500 infants annually in the United States develop ROP that is severe enough to require medical treatment, and of them 400–600 infants each year in the United States become legally blind from ROP.
Pathogenesis
The pathogenesis of ROP is multifactorial where developmental, genetic, and environmental factors come into play. During normal retinal development, vasculogenesis transforms precursor mesenchymal cells into capillary networks beginning at about 16 weeks of gestation. Mature vessels differentiate from these networks and reach the nasal and temporal ora serrata at about 36 and 39–41 weeks, respectively. Therefore, full retinal vascular development is mostly accomplished in utero, where the fetus is in a relatively hypoxic environment (average PaO 2 is 25–35) and exposed to the placental and maternal cytokines and growth factors. In addition, several pivotal cell-signaling pathways and growth factors involved in retinal vasculogenesis and neural development—including the VEGF-signaling pathway, insulin-like growth factor 1 (IGF-1), and the Wnt-signaling pathway —are disrupted by premature birth and the ex utero hyperoxic environment. Taken together, premature birth disrupts this well-orchestrated process, as the fetus is exposed to a new environment, and the ophthalmoscopic findings of ROP stem from this arrested development and aberrant retinal tissue response to it.
High oxygen administration at birth was among the first factors to be found critical to the pathogenesis of ROP. Excessively high levels of oxygen in incubators, used to save the lives of premature infants, led to an ROP epidemic and the realization that reducing the level of oxygen given to premature babies reduces the incidence of ROP. The detrimental effects of high and/or fluctuating oxygen concentrations were validated in the oxygen-induced retinopathy models, where alternating oxygen concentrations induce retinal neovascularization. Although these models lack significant features of human ROP [absence of ridge tissue, involution of retinal neovascularization (RNV), and absence of neovascular complications such as hemorrhage and tractional retinal detachment], they have been instrumental in the dissection of the molecular mechanisms involved in ROP and retinal neovascular diseases in general.
The association between high oxygen levels and ROP led to the development of the two-phase hypothesis for ROP almost 30 years before the classification of human ROP in zones and stages. According to this, in the first phase there is a delay or halting in physiological retinal vascular development due to prematurity as well as hyperoxia-induced endothelial cell damage and subsequent vasoattenuation. As the peripheral avascular retina continues to develop in the absence of a developing vascular bed, it becomes relatively hypoxic and secretes proangiogenic factors, which promote retinal neovascularization and abnormal vasoproliferation in the vitreous (second phase).
Given its pivotal role in other retinal neovascular diseases, increasing attention has been focused on vascular endothelial growth factor (VEGF). In ROP, VEGF has been shown to be elevated in both the vitreous and serum of infants with ROP, and the importance of VEGF upregulation in the proliferative phase of this disease has been shown in humans, since blockade of VEGF with anti-VEGF antibodies (bevacizumab) has considerable efficacy. However, this dual role of VEGF in development and disease raises concerns about the timing and safety of VEGF inhibition in ROP (discussed later).
Genetic factors may play a role in the development of severe ROP as well. Some clinical features of ROP noted in near-term and full-term infants may resemble those seen in familial exudative vitreoretinopathy (FEVR), the X-linked form of which is associated with mutations in the Norrie’s disease (NDP) gene. Shastry et al. investigated a cohort of 16 premature infants with ROP and found missense mutations in four infants with advanced disease. None of the parents or 50 healthy controls had mutations. The NDP gene product, norrin, is a ligand that activates a signal transduction pathway necessary for early retinal development and vasculogenesis. Subsequent studies have suggested up to 2% of infants with ROP have NDP mutations. It is likely that other genes involved in this signal transduction pathway may harbor mutations or polymorphisms that predispose premature babies to increased rates of ROP.
Clinical Features and Classification
The International Classification of Retinopathy of Prematurity (ICROP) was instrumental in establishing the standards and nomenclature for the clinical assessment of ROP based on the anatomical location (zone) and severity (stage) of disease. Zone I is defined as a circle, the center of which is the disc and the radius of which is twice the distance of the disc to the fovea. Zone II is a doughnut-shaped region that extends from the anterior border of zone 1 to within one disc-diameter of the ora serrata nasally and to the anatomical equator temporally. Zone III encompasses the residual temporal retina ( Fig. 6.21.1 ).
The first sign of ROP (stage 1) is the appearance of a thin, flat, white structure (termed a demarcation line) at the junction of vascularized retina posteriorly and avascular retina anteriorly ( Fig. 6.21.2A ). Stage 2 ROP occurs as the demarcation line develops into a pink or white elevation (ridge) of thickened tissue ( Fig. 6.21.2B ); small tufts of vessels may be seen posterior to the ridge. Vessel growth into and above the ridge (extraretinal fibrovascular proliferation) characterizes stage 3 ROP ( Fig. 6.21.2C ). This fibrovascular proliferation may extend into the overlying vitreous and cause preretinal or vitreous hemorrhage ( Fig. 6.21.2C ). Contraction of fibrovascular proliferation exerts traction on the retina, leading to partial retinal detachment (stage 4 ROP), either without foveal involvement (stage 4A) ( Fig. 6.21.2D ) or with foveal involvement (stage 4B) ( Fig. 6.21.2E ). Stage 5 ROP denotes a total retinal detachment ( Fig. 6.21.2F ). Stage 5 detachments are funnel shaped and described as open or closed anteriorly and open or closed posteriorly. The term retrolental fibroplasia , originally coined by Terry in 1942, refers to what we know today as stage 5 ROP.
In its acute (neovascular) phase, ROP is a progressive vascular disease with increasing dilatation and tortuosity of peripheral retinal vessels, engorgement of iris vessels, and pupillary rigidity. “Plus disease” refers to the presence of marked venous dilatation and arterial tortuosity in the posterior pole ( Fig. 6.21.3A ) secondary to arteriovenous shunting at the level of the ridge and constitutes the hallmark of progressive, treatment-warranting ROP. In the CRYO-ROP Study, plus disease was defined as significant dilation and tortuosity in all four vascular arcade quadrants, yet in subsequent studies (STOP-ROP, ET-ROP) and current practice, the diagnosis of plus disease is made if sufficient vascular dilation and tortuosity are present in at least two quadrants of the eye. The term pre-plus disease was introduced later to highlight the fact that plus disease does not appear as an all-at-once phenomenon but as a continuum of progressively increasing neovascular activity at the ridge manifested with arborization and tortuosity of the blood vessels ( Fig. 6.21.3B ). To this aim, pre-plus disease is defined as increased dilation and/or tortuosity of retinal arteries and/or veins in at least two quadrants, of insufficient severity for the diagnosis of plus disease. The presence of pre-plus disease can be predictive of progression to severe ROP requiring laser treatment.
Aggressive posterior ROP (AP-ROP) is an uncommon severe form of ROP encountered in extremely premature infants (23–26 GA on average in some series ) that is characterized by very posterior (zone I) disease, neovascular fronds that lie flat on the retinal surface (flat neovascularization), absence of ridge tissue, and dilated tortuous vessels in a syncytial pattern ( Fig. 6.21.3C ). AP-ROP can progress rapidly to stage 4 and 5 if left untreated, and eyes with AP-ROP have poorer prognosis than classic (zone II disease) ROP, with retinal detachment rates as high as 45%.
Finally, the definition of “threshold” ROP has varied in successive clinical trials. In the CRYO-ROP study it was defined as the severity of ROP for which there was an equal chance of spontaneous regression or progression to an unfavorable outcome. This was defined as stage 3+ ROP in zones I or II, occupying at least five contiguous clock-hours or eight noncontiguous clock-hours of retina. For eyes with zone II ROP, this estimation proved quite precise: 62% of untreated eyes with threshold ROP went on to an untoward visual outcome. However, untreated threshold zone I eyes had a 90% chance of unfavorable outcome. Roughly 44% of eyes with zone II ROP in the CRYO-ROP had an unfavorable outcome despite appropriate intervention. To address this problem, the multicenter study of Early Treatment for Retinopathy of Prematurity (ETROP) compared early treatment of high-risk eyes (prethreshold type 1) versus treatment at threshold to show that early laser treatment improves both structural and visual outcomes. Two categories of prethreshold disease were created and management dictated by high-risk (type 1) or low-risk (type 2) prethreshold disease. ETROP findings suggest that type 1 prethreshold ROP receive laser ablation of the peripheral avascular retina. Type 2 prethreshold ROP is observed weekly or twice weekly based on the extent of ROP noted. When compared to the results of the CRYO-ROP study, the ETROP study suggests that early treatment of high-risk prethreshold ROP significantly decreases unfavorable visual acuity outcomes (19.5%–14.5%; p = 0.01) and structural outcomes (15.6%–9.1%; p < 0.001).
Diagnosis and Screening
Initial examination of the anterior segment is performed with specific attention to the iris vessels, lens, and tunica vasculosa lentis. Poor pupillary dilation and iris vascular engorgement can be a sign of plus disease. After pupillary dilation, fundus examination is performed with an indirect ophthalmoscope and a 28.00 diopter (D) or 30.00 D lens. The posterior pole is examined without depression for plus disease. Clinically, the entire zone I can be seen through a 28.00 D lens when the view is centered on the optic nerve. Scleral depression is then used to examine the temporal retina, followed by the nasal retina, to establish the proximity of retinal vessels to the ora serrata.
Given the progressive nature of ROP, as well as the proven benefits of early diagnosis and timely intervention to minimize the risk of severe visual loss, a joint statement outlining the principles of a screening program for ROP has been set forth:
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Screening for ROP should be performed in all infants with a birth weight at or above 1500 g or gestational age of 30 weeks or less (as defined by the attending neonatologist) and selected infants with a birth weight between 1500 and 2000 g or gestational age of more than 30 weeks with an unstable clinical course.
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In most cases, at least two examinations should be performed. One examination may suffice if it shows unequivocally that retinal vascularization is complete bilaterally. The first examination should be performed between 4 and 6 weeks of chronological (postnatal) age or between 31 and 33 weeks of postmenstrual age (PMA) (calculated as GA plus chronological age), whichever is later.
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Infants with immature retinas (no ROP) vascularized into zone II or III may be examined at 2-week intervals.
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Infants with type 2 prethreshold disease require weekly or twice weekly exams.
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Infants with type 1 prethreshold disease should be considered for peripheral laser ablation.
Role of Telemedicine in ROP Screening
The historical gold standard method for ROP screening has been bedside examination with binocular indirect ophthalmoscopy (BIO). However, a significant limitation of bedside examination is the subjectivity of the examiner’s impression of the BIO findings with its subsequent documentation. Several studies have shown a wide range of disagreement of ROP diagnosis and severity among healthcare professionals screening for ROP. In the pivotal CRYO-ROP trial, there was disagreement between two unmasked, certified examiners as to whether threshold disease was present in 12% of eyes. Moreover, accurate documentation of retinal pathology in ROP is critical for longitudinal comparison and demonstration of sound clinical practice, especially in the complex medicolegal climate that surrounds ROP.
The feasibility of remote digital fundus imaging in screening for ROP was first demonstrated in 2000, and since then numerous studies, clinical trials, and live telemedicine programs have validated the accuracy and sensitivity of “store-and-forward” telemedicine in effectively detecting treatment and/or referral-warranted ROP using contact wide-field digital cameras. These results are fairly consistent among different camera operators, including trained ophthalmologists, trained neonatal personnel, and ophthalmic photographers. The latter is of great importance for communities with limited access to ROP providers and geographically restricted neonatal intensive care units and for connecting ROP screeners with experts for management of complex cases.
Differential Diagnosis
In a premature infant of low BW with characteristic findings of immature retinal development, the diagnosis of ROP is generally straightforward. FEVR is the main masquerader that may mimic ROP in infancy. With its characteristic skin findings and gender predilection, incontinentia pigmenti is another pediatric retinal vasculopathy that shares similar clinical features with ROP. On the other hand, if a premature infant has not been screened or treated appropriately, the presenting finding may be leukocoria due to retrolental fibrous proliferation. In such infants, the differential diagnosis is broader and includes:
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Retinoblastoma.
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Persistent fetal vasculature (formerly called persistence of primary hyperplastic vitreous; usually unilateral and associated with microphthalmia and prominent ciliary processes).
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Exudative retinal detachment (most commonly from Coats’ disease; usually unilateral and more common in boys).
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Infectious causes such as endogenous endophthalmitis, toxocariasis, or toxoplasmosis (all of which may be diagnosed by appropriate microbiological and immunological testing).
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Coloboma of the optic disc or choroid.
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Cataract.
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Genetic syndromes, such as trisomy 13, Norrie’s disease, and Warburg syndrome (all of which may be diagnosed by genetic testing and/or characteristic systemic physical findings).
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