References

1.What is retinopathy of prematurity?

Retinopathy of prematurity (ROP) is a vasoproliferative retinal disease that affects infants born prematurely. It has two phases. In the acute phase, normal vascular development goes awry with the development of abnormal vessels that proliferate, occasionally with associated fibrous proliferation. In the chronic or late proliferation phase, retinal detachment, macular ectopia, and severe visual loss may occur. More than 90% of cases of acute ROP go on to spontaneous regression.

2.Who is at risk for retinopathy of prematurity?

Infants weighing less than 1500 grams at birth and those born at a gestational age of 32 weeks or less are at risk for developing ROP. The disease is more likely to affect the smallest and most premature of infants. The incidence of acute ROP in infants weighing less than 1 kg at birth is three times greater than that of infants weighing between 1 and 1.5 kg. Infants born at 23 to 27 weeks of gestation have a particularly high chance of developing ROP.

3.Who should be screened for retinopathy of prematurity?

Guidelines published by the American Academy of Pediatrics, Section on Ophthalmology; the American Association of Pediatric Ophthalmology and Strabismus; and the American Academy of Ophthalmology recommend that all infants weighing less than 1500 grams at birth or those with a gestational age of 28 weeks or less should be examined. Selected infants with a birth weight between 1500 and 2000 grams with an unstable clinical course should also be examined.

4.Which infants are at highest risk for retinopathy of prematurity?

Infants at particularly high risk are those who weigh less than 1000 grams at birth and those born at less than 27 weeks’ gestation. The first exam should take place 4 to 6 weeks after birth or between 31 and 33 weeks of postconceptional or postmenstrual age.

5.When should follow-up exams be done when screening for retinopathy of prematurity?

The frequency of follow-up examinations is based on the retinal status at the time of the first exam. Exams should be done every 1 to 2 weeks, either until there is complete retinal vascularization or until two successive 2-week examinations show stage 2 ROP in zone III (more on staging is discussed later in this chapter). Infants should then be examined every 4 to 6 weeks until the retina is fully vascularized. If there is prethreshold disease (see further discussion), examinations should be done every week until threshold disease occurs (at which point treatment should be offered) or until the disease regresses.

KEY POINTS: INDICATIONS FOR SCREENING INFANTS FOR ROP

1. All infants weighing less than 1500 grams at birth 2. All infants with a gestational age of 28 weeks

3. Infants with a birth weight between 1500 and 2000 grams with an unstable clinical course 4. Any infant that the neonatologist considers at risk because of an unstable clinical course

6.How is retinopathy of prematurity classified?

The International Classification of Retinopathy of Prematurity (ICROP) is the system used for describing the findings in ROP. ICROP defines the location of disease in the retina and the extent of involvement of the developing vasculature. It also specifies the stage of involvement with levels of severity ranging from 1 (least affected) to 5 (severe disease).

350

http://ophthalmologyebooks.com

CHAPTER 44  RETINOPATHY OF PREMATURITY  351

12

6

Figure 44-1.  The zones of retinopathy of prematurity are shown schematically.

7.What are the zones of retinopathy of prematurity?

For the purpose of defining location, the retina is divided into three zones, with the optic nerve as the center because vascularization starts from the optic nerve and progresses peripherally (Fig. 44-1). Zone I consists of a circle, the radius of which subtends an angle of 30 degrees and extends from the disc to twice the distance from the disc to the center of the macula (twice the disc-to-fovea distance in all directions from the optic disc). Zone II extends from the edge of zone I peripherally to a point tangential to the nasal ora serrata and around to an area near the temporal anatomic equator. Zone III is the residual temporal crescent of retina anterior to zone II.

8.Describe the stages of retinopathy of prematurity.

Staging pertains to the degree of abnormal vascular response observed. Staging of the eye as a whole receives the stage of the most severe manifestation present.

Stage 1 is a demarcation line. It is a thin but definite structure that separates avascular retina anteriorly from the vascularized retina posteriorly. Abnormal branching of vessels can be seen leading up to the line. It is flat and white and is in the plane of the retina.

Stage 2 is a ridge. The line of stage 1 has height and width and occupies a volume extending out of the plane of the retina. The ridge may be pink or white. Vessels may leave the plane of the retina to enter it. Small tufts of new vessels may be seen on the surface of the retina posterior to the ridge. These vessels do not constitute fibrovascular growth.

Stage 3 is the ridge of stage 2 with extraretinal fibrovascular proliferation (Fig. 44-2). Stage 4 ROP is a subtotal retinal detachment. Retinal detachments in ROP are concave, tractional retinal

detachments. Stage 4A ROP is a subtotal retinal detachment that does not involve the central macula. Typically, it is present in the temporal region of zones II and III. Stage 4B ROP is a subtotal retinal detachment that involves the central macula.

Last, stage 5 ROP is a total retinal detachment. These retinal detachments are funnel-shaped but may have an open or closed configuration in their anterior and posterior areas.

9.What is plus disease?

Plus disease is indicative of progressive vascular incompetence and is a strong risk factor for the development of more severe ROP. Anteriorly, plus disease is iris vascular engorgement and pupillary rigidity. Posteriorly, plus disease appears as retinal venous dilation and arterial tortuosity in the posterior pole. It is graded as mild, moderate, or severe (Fig. 44-3). When plus disease is present in the posterior pole, a plus sign (i.e., +) is added to the number stage of the disease, i.e., stage 3+.

352  OPHTHALMOLOGY SECRETS IN COLOR

Figure 44-2.  Stage 3 retinopathy of prematurity.

Figure 44-3.  Moderately severe plus disease.

Before the appearance of plus disease, increasing dilation and tortuosity of the posterior vessels signify increased activity of ROP. Pre-plus disease is present when there are vascular abnormalities of the posterior pole that are insufficient for the diagnosis of plus disease, but that demonstrate more venous dilation and arterial tortuosity than normal.

10.What is the worst form of acute retinopathy of prematurity?

There is a more virulent retinopathy usually observed in the lowest-birth-weight infants that is called aggressive posterior ROP (AP-ROP). This form of ROP is posteriorly located and has prominent plus disease with ill-defined retinopathy. The plus disease is out of proportion to the peripheral retinopathy and usually progresses rapidly to stage 5 disease. AP-ROP typically extends circumferentially and is associated with a circumferential vessel.

11.What is the rationale for treating acute retinopathy of prematurity?

Because ROP can lead to blindness from retinal detachment, treatment to prevent progression to retinal detachment is indicated. However, 90% of infants who develop acute ROP undergo spontaneous regression. Treatment should therefore be performed only for those infants who have a high risk of developing retinal detachment.

12.What did the Cryotherapy for Retinopathy of Prematurity study teach us?

The Cryotherapy for Retinopathy of Prematurity (Cryo-ROP) study set out to determine whether treatment for ROP would prevent poor outcomes. For the purposes of that study, a level of disease (called threshold disease) was chosen at which 50% of infants were predicted to go blind without treatment. This prediction was appropriate for the Cryo-ROP study and remains the level of clinical disease at which treatment is recommended.

Threshold disease is defined as the presence of at least five contiguous or eight cumulative 30-degree sectors (clock hours) of stage 3 ROP in zone I or II, in the presence of plus disease (Fig. 44-4). Thus, prethreshold ROP is defined as zone I, any stage; zone II, stage 2 with plus disease; or zone II with extraretinal fibrovascular proliferation less than threshold. When ROP reaches prethreshold, examinations should be performed weekly.

CHAPTER 44  RETINOPATHY OF PREMATURITY  353

Figure 44-4.  The Cryo-ROP definition of threshold disease is shown schematically.

13.Do all treated infants do well?

Analysis of natural history data from the Cryo-ROP study indicated that certain infants are at high risk for an unfavorable outcome. Infants with zone I ROP are included as infants at high risk for an unfavorable outcome. The Early Treatment for Retinopathy of Prematurity (ETROP) study used a risk model (RM-ROP2) based on the natural history data from the Cryo-ROP study to identify infants at high risk for an unfavorable outcome. The model used demographic characteristics of the infants and clinical features of ROP to classify eyes with prethreshold ROP at high or low risk. High-risk prethreshold eyes that received conventional management had a much higher likelihood of unfavorable structural outcome (10% versus 1% at 6 months).

14.What did the ETROP study teach us?

The ETROP study described a clinical algorithm for which eyes should be treated. High-risk eyes (termed type 1 ROP) were those with the following findings: zone I, any stage ROP with plus disease; zone I, stage 3 ROP with or without plus disease; and zone II, stage 2 or 3 ROP with plus disease. Plus disease requires that there be at least two quadrants of dilation and tortuosity of the posterior pole vessels. With these criteria to apply laser treatment to the anterior avascular zone of affected high-risk prethreshold eyes, there was a reduction from 19.5% to 14.5% in an unfavorable grating visual acuity measurement and from 15.6% to 9.1% in an unfavorable structural outcome at 9 months compared to the control group, which was not treated until threshold was reached. Less severely advanced, low-risk prethreshold eyes (termed type 2 ROP) included the following: zone I, stage 1 or

2 ROP without plus disease, and zone II, stage 3 ROP without plus disease. It was recommended that infants with type 2 ROP should be monitored closely and treated if they progress to type 1 ROP or to threshold disease. The recommendation to treat type 1 eyes and adopt a “wait-and-watch” approach for type 2 eyes (treat if the eyes progress to type 1 or threshold) was supported by the final results of the ETROP study.

15.How do you treat acute retinopathy of prematurity?

Cryotherapy was the standard of care for treating acute ROP. More recently, multiple studies have reported on the efficacy of treating ROP with laser photocoagulation delivered by the indirect ophthalmoscope. Indirect laser has become the most common form of treatment for acute ROP.

Indirect laser can be delivered in the intensive care nursery without having to take the infant to an operating room. Intravenous sedation is administered at the discretion of a neonatologist, who should be immediately available to manage any possible systemic complications. Laser is applied to the entire peripheral avascular zone, with the use of a laser indirect ophthalmoscope. The laser spot desired is a dull white or gray spot, and the spots are placed approximately 1 to 1.25 lesion-widths apart (Fig. 44-5). Critical focus on the retina is essential.

354  OPHTHALMOLOGY SECRETS IN COLOR

Figure 44-5.  Appearance of the peripheral fundus immediately after laser treatment.

16.How is cryotherapy applied?

Cryotherapy is still preferred by some ophthalmologists for managing acute ROP. As with laser treatment, intravenous sedation can be administered at the discretion of the neonatologist. Some ophthalmologists prefer general anesthesia because of the greater stress on the infant and the greater risk of cardiopulmonary complications with cryotherapy than with laser photocoagulation. Cryotherapy is applied to the entire peripheral avascular zone using a handheld cryo-pencil. The peripheral retina is brought into view using the cryo-pencil as a scleral depressor. A white freeze spot seen for 1 to 2 seconds is the desired endpoint. The lesions are placed contiguously.

17.Does posterior retinopathy of prematurity respond to treatment?

Zone I and posterior zone II disease have a worse prognosis than more anterior ROP. Cryotherapy is often ineffective in posterior ROP. Investigations have shown that laser photocoagulation for posterior disease can limit the likelihood of an unfavorable anatomic outcome to approximately 20%. Applying the criteria of the ETROP noted previously will result in a better prognosis for zone I disease.

18.What is the expected result after laser treatment for retinopathy of prematurity?

Various reports have quoted a regression rate of approximately 90% after laser photocoagulation for threshold ROP. If regression is to occur, plus disease is usually less on the first week’s follow-up visit. There may not be much change in the extraretinal fibrovascular proliferation (ERFP). By 2 weeks, one should start to see a reduction in the ERFP.

19.When should you consider retreatment for retinopathy of prematurity?

Laser photocoagulation for threshold ROP is successful at inducing regression of the acute disease in approximately 90% of cases. Occasionally supplemental treatment after the initial session is necessary to induce regression. Retreatment should be considered if there is worse disease (worse plus disease and increased extraretinal fibrovascular proliferation) at the 1-week visit or persistently active disease (ERFP with plus disease) and the presence of “skip lesions” (areas of apparently missed treatment) or widely spaced laser lesions at the 2-week follow-up visit. Additional treatment should be applied to previously untreated areas rather than treating over old laser spots. In a similar fashion, supplemental cryotherapy can be applied to “skip areas” if there has not been an adequate response to initial cryotherapy treatment.

KEY POINTS: INDICATIONS FOR LASER TREATMENT OF ROP

1. Eyes with type 1 ROP

2. Zone I, any stage ROP with plus disease 3. Zone II, stage 2 or 3 ROP with plus disease

4. Eyes with threshold ROP: At least five contiguous or eight cumulative 30-degree sectors (clock hours) of stage 3 ROP in zone I or II, in the presence of plus disease

20.Are there any options other than laser for acute retinopathy of prematurity?

Many ophthalmologists are now using an intravitreal anti-vascular endothelial growth factor injection (usually bevacizumab) to induce regression of plus disease and ERFP. There is evidence that this