Retinopathy of Prematurity (ROP)

4.1  Introduction

Retinopathy of prematurity (ROP) formerly known as retrolental fibroplasia (RLF) is an enigmatic disease of the developing retinal vasculature of the prematurely born infant. It is a disease of modern times. Many diseases have been discovered or recognized in the past decades, yet they have existed for centuries. Quite the contrary, the first ever cases of ROP occurred around 1940. ROP was a creation of modern medical technology. It was an unexpected consequence of applying technology to save the lives of premature infants, just as industrial workers fell ill from unanticipated side effects of modern progress. In that sense it is an iatrogenic disease. ROP could not exist without technologic intervention. It is very much an expected side effect of such treatment. And despite our now much more sophisticated understanding of the disease, its incidence continues unabated. Having said this, ROP is manifestly not an exclusively environmental disease. It is an environmental disease that is superimposed on a receptive physiology not only in the now classic sense of genetic susceptibility, but in a more subtle, universally applicable way. The truth of that will be seen as the story of ROP unfolds.

As modern medical interventions produce this disease, modern medicine has been utilized to solve it, and we have come a long way in alleviating the dreaded outcome of blindness. But unfortunately this disease remains significant for a variety of reasons. While the incidence of ROP has been steady for at least two decades, medical advances have reduced the level of blindness in those

affected [1, 2]. However, despite our best efforts, poor visual outcomes have not been eliminated. It seems self evident, but the health related quality of life is poorer in children with poorer vision [3] and a lifetime of blindness magnifies the socioeconomic impact of each affected individual. In calculating the number of “blind years,” one child blind from ROP could equal ten or more of the elderly disabled by macular degeneration [4]. Assessing the magnitude of the problem from another angle, ROP represented one of the three leading causes of pediatric blindness in the U.S. between 1989 and 1999 [5] and this is after an effective treatment was discovered. Yet more evidence of the continuing significance of ROP comes from the Blind Babies Foundation which confirms ROP as the leading cause of preventable blindness in the US [6]. So in relative numbers or in societal cost, ROP remains a hugely relevant disease.

There is another major ongoing societal concern with ROP. There continues to be no effective prevention. Our current methods of intervention hinge on high cost, technology based treatment of the advanced states of the disease requiring special skill sets and mass screenings. This type of intervention carries worldwide implications regarding resource commitment. So this complex ongoing disease requiring massive resources to screen and treat, with major societal implications, is far from solved. In order to understand where ROP is headed it is critical to understand from where it came. Thus our story starts in 1942.

J.D. Reynolds 

University at Buffalo Department of Ophthalmology, Ross Eye Institute, 1176 Main Street, Buffalo, NY 14209-2102, USA e-mail: jreynold@buffalo.edu

Terry was not the first to observe this disease, but he was the first to report it as a short case in the American Journal of Ophthalmology in 1942 [7].

He followed this up with a presentation at the American Ophthalmological Society in 1942 which was published in 1943 [8]. He reported on both his own observations and those of others and interestingly noted credit to Dr. Harry Messenger for coining the term RLF, the name by which it would be known for 40 more years. It is evident that no one knew what they were observing. They knew it was dramatic, bilateral, blinding, and associated with prematurity. But the feeling that it was connected to past cases and that it was related to “persistence of the hyaloid artery and tunica vasculosa lentis and growth of embryonic connective tissue behind the lens” was wrong [8].

This misinterpretation was understandable when faced with clinical and pathologic specimens of RLF which represented the cicatricial end stage of this disease as well as any superimposed complications. Such eyes have little in common with acute ROP changes. The search for the truth on this great unknown has been intriguingly cataloged by Jacobson and Feinstein [9]. They demonstrate a “decade of errors” in a series of dead ends. The investigations relied on small sample sizes based on misleading assumptions and biases, utilizing poor methodology and empirical observations with classic lack of randomized controls. As fascinating as it is to read about these blind alleys, it is even more so to appreciate the story of how researchers arrived at correct determinations.

Owens and Owens reported the first series of babies with RLF in which observations were made on what we now recognize as the acute phase of the disease rather than the cicatricial endpoint with which Terry was familiar [10]. This made it clear that the pathogenesis did not relate to congenital hyaloid abnormalities. By this time the disease had reached epidemic proportions in surviving premature infants and RLF was clearly a progressive, acquired disease associated with prematurity.

Patz has recently recounted the exciting tale of how he and others began to suspect and investigate a link between RLF and supplemental inspired oxygen [11]. In telling his story, he also highlights the early contributions of Campbell as well as his own [12–16]. These early workers, among others, were crucial in building the case for a cooperative study. The correlation to oxygen was proven by a multicenter randomized clinical trial, the National Cooperative Study [17, 18]. This multicenter trial would be the first of many successful NIH trials in ROP. However, none

would be more significant. The Cooperative Study resulted in immediate changes in the current nursery practices, dramatically curtailing supplemental oxygen and reducing RLF blindness.

However, this was not the end of the oxygen story. It was in fact, the beginning. A strong case can be made that it over simplified the disease and a medical community grateful for an answer to 10,000 blind babies in the decade long epidemic overreacted to the evidence [9]. The work of these early investigators cannot be praised enough, but there was and is much more to oxygen than its retinal toxicity. While oxygen can be undeniably toxic to the lung, brain, retina, and other tissues, it is also obviously a very real essential element of life. In the mad dash to restrict the liberal oxygenation policies of nurseries, mortality and systemic morbidity rose dramatically [19]. As the realization of this took hold supplemental oxygen use was liberalized [20]. A happy medium was sought where enough oxygen was provided to promote systemic well being while continuing to provide some limits so as to minimize ROP. The trouble was that this was done empirically with all the potential inherent methodologic errors creeping in. Not too much, not too little is not achievable based on observational studies alone [21]. Silverman has dramatically summarized the state of the oxygen Goldilocks, “there has never been a shred of convincing evidence to guide the limits for the rational use of supplemental oxygen in the care of extremely premature infants” [22]. It seems that the lessons of Jacobson and Feinstein remain unlearned [9]. Ironically, those two authors did not learn their own lessons. In chronicling that preoxygen phase of RLF research, they ridicule investigators who “even believed that RLF could be cured by a high concentration of oxygen” [9]. We now know that quite to the contrary, reputable investigators have suggested and found some evidence just to that effect [23–28]. So the oxygen saga continues. At this point in our knowledge we do not understand the complexities of how oxygen is involved in ROP.

All this is presented for more than historical interest. It is strong evidence that ROP is highly complex. Controversy, empiricism, and bias continue to plague our understanding of this disease and any disease so puzzling requires investigative techniques that rely on randomized, controlled, and robust research. We can now summarize the current state of our knowledge of ROP.

4.3  Classification

A serious impediment to scientific progress is posed by an inability to communicate. Investigators must share a common language with shared definitions. Such a critical foundation was lacking in ROP for many years. However, the International Classification of Retinopathy of Pre­ maturity (ICROP) changed all that [29]. This system of consistently describing the salient clinical characteristics of acute ROP was rapidly adopted worldwide. It was the necessary foundation that served as a catalyst to the subsequent multicenter trials. Perhaps equally important to providing a common language, it brought major investigators together in a collaborative frame of mind.

This original classification has stood the test of time well. The same group added a classification of retinal detachment/cicatricial disease 3 years later [30]. And nearly 20 years later in 2005, revised the original, keeping most but adding important new elements that had developed from years of collaborative effort [31]. Additional terminology has also become generally accepted, usually arising from the large, NIH funded multicenter trials, STOP-ROP (supplemental therapeutic oxygen for prethreshold ROP); CRYO-ROP (cryotherapy for ROP); LIGHT-ROP (light reduction in ROP); and ET-ROP (early treatment for ROP) [24, 32–35].

The following discussion with tables and illustrative photos and figures summarizes the current classification in wide use today. If some element is not universal, in the early stages of acceptance, that is so noted. The severity of acute disease is classified in stages (Table 4.1). The location of disease is also critical to the potential severity. The retina was divided into concentric zones (Table 4.2).

Table 4.2  Retinal location of acute ROP

Zone I Concentric circle, centered on the optic nerve, with a radius of 2 times the distance from the center of the nerve to the center of the fovea

Zone II Diagrammatically a concentric annular area arising from the outer border of zone I and ending at the ora nasally and just beyond the equator temporally

Zone III A large temporal crescent arising from the outer border of zone II and terminating at the temporal ora serrata. (Fig. 4.17)

Table 4.1  Severity of acute ROP

Fig. 4.1  Stage 1 ROP. Demarcation line with schematic. (Reprinted from [29]. Copyright American Medical Association, 1984. All rights reserved)

The system of applying the stages and zones is to classify ROP according to the highest stage present in any part of the retina and the most posterior zone touched by disease in any part of the retina. It is convenient to divide the retina into quadrants i.e., superior temporal, superior nasal, inferior temporal, and inferior nasal, which corresponds to the normal vascular arcade and clinical practice. The retina is also divided

Fig. 4.2  Stage 1 ROP. Demarcation line

Fig. 4.3  Stage 2 ROP. Ridge with schematic. (Reprinted from [29]. Copyright American Medical Association, 1984. All rights reserved)

into twelve clock hours which is used to classify the extent of each stage of disease. Although not official, it is not uncommon to refer to the disease as encompassing 360° when fully circumferential rather than be limited to clock hours alone. There are some potential concerns with the location assessment which will be subsequently noted. Additional classification definitions are as follows:

Fig. 4.4  Stage 2 ROP. Ridge with some intraretinal neovas­ cularization

Fig. 4.5  Stage 3 ROP. Extraretinal neo. with schematic. (Reprinted from [29]. Copyright American Medical Association, 1984. All rights reserved)

Plus disease: posterior venous dilation and arteriolar tortuosity of at least a photographically defined minimum (Figs. 4.18–4.20).

Preplus disease: vascular abnormalities of the posterior pole that are insufficient for the diagnosis of plus disease but that demonstrate more arteriolar tortuosity and more venous dilation than normal [31].

Fig. 4.19 Plus disease

Threshold ROP: at least five contiguous or eight cumulative clock hours of stage 3 zone I or II with plus. Threshold ROP has less meaning now in the wake of the Early Treatment for Retinopathy of Prematurity Trial (ET-ROP) establishing new criteria for intervention [32, 35] (Fig. 4.21).

Regression: This denotes disease involution or disappearance. It is gradual, can be very prolonged, and difficult to recognize early in its course [36].

Popcorn: Isolated tufts of neovascular tissue. When occurring early in the course of disease they can be a harbinger of more confluent stage 3 disease. When later they can actually represent a regression [37] (Figs. 4.22–4.23).

The cicatricial consequences for the foveal anatomy can also be more useful than simply dividing the macula into 4a or 4b. The following macular scoring system wasdevelopedaspartoftheCryotherapyforRetinopathy of Prematurity Trial (CRYO-ROP) [38] (Table 4.3).

There are several points about classification that require clarification. Staging of ROP ideally requires a

Fig. 4.22  Popcorn ROP. Photo courtesy of D. Wallace

Fig. 4.23  Popcorn ROP. Photo courtesy of D. Wallace

three dimensional view as one appreciates with the indirect ophthalmoscope aided by scleral depression. Elevation or extraretinal determinations are best made in this way. The stages are usually very recognizable except in zone I where the changes can be more subtle. There are also two dimensional cues that can be helpful.

A stage 1 line is not only flat, but is whitish, thin, circumlinear and occurs at the border between vascularized and avascular retina. A stage 2 ridge is not only elevated, it is thicker, more prominent, and can be less white, even somewhat reddened. Stage 3 neovascularization is a continuous sheet of solid pinkish tissue with various heights of elevation. A stage 4 retinal detachment can be exudative, especially if early, or tractional as part of the change over from acute to cicatricial disease. Rhegmatogenous detachments are very late events, sometimes years later if they occur.

Division of the retina into zones has very real clinical significance, but the actual definitions were arbitrarily chosen for their ease of recognition. The only anatomic elements that require identification are the optic nerve, macula, and ora serrata. The lack of temporal landmarks arose from the paucity of consistently recognizable anatomy there. So the transition from zone II to zone III is defined only in relation to the nasal ora. Perhaps not so obviously this has been responsible for rare but very dramatic problems. Zone

Fig. 4.25  Macular heterotopia

I disease is serious, zone II can be serious, and zone III disease is safe, with one very real and clinically significant caveat.

Vascularization proceeds centrifugally from the optic nerve to the ora. Since the fovea is the true anterior-­ posterior center of the eye, the optic nerve source of vascularization is shifted nasally. This accounts for nasal retina completing vascularization prior to temporal completion and hence the genesis of zone III. But disease can occur in fits and starts, in patches, and be clearly asymmetric and nonconcentric. In the potentially worst case scenario, disease could appear in the temporal retina only and subsequent full nasal vascularization occurs.

This temporal zone II disease remains zone II and progresses, and an unfavorable outcome develops. The well known safety point of zone III has been reached but the reality of temporal zone II disease has not changed. Examiners can be severely misled by this unrecognized flaw in the classification system. The recognition of this has been highlighted in several publications [36, 39–41]. We will rerefer to this when screening is discussed.

Plus and Preplus disease are critical to determine accurately. Plus disease has increased in importance while the extent (clock hours) of disease has diminished­

[35]. Plus disease can arise gradually or very rapidly. It is often associated with iris vessel engorgement, ­pupillary miosis and resistance to dilating medications, vitreous haze, and of course serious disease. The newly accepted preplus serves as a warning and allows for a little less anxiety in the examiner’s judgment call of the presence or absence of plus disease by the only mechanism possible – comparison to the single ­standard reference photograph.