Retinopathy of Prematurity Clinical Presentation

In 1984, a committee consisting of 23 ophthalmologists from 11 countries formed the International Classification of Retinopathy of Prematurity (ICROP). This new classification system demarcated the location of the disease into zones of the retina (1, 2, and 3), the extent of the disease based on the clock hours (1-12), and the severity of the disease into stages (0-5).

In obtaining a history for a premature infant, note the following:

• Gestational age at birth, especially if younger than 32 weeks' gestation
• Birth weight of less than 1500 g, especially less than 1250 grams
• Other possible risk factors (eg, supplemental oxygen, hypoxemia, hypercarbia, concurrent illness)

See the image below.

ROP is categorized in zones, with stages depicting the severity of the disease. The smaller and younger the infant at birth, the more likely the disease will involve the central zones with advanced stages.

ROP is categorized by the lowest zone and the highest stage observed in each eye.

Zone 1

Zone 1 is the most labile.

The center of zone 1 is the optic nerve. It extends twice the distance from the optic nerve to the macula in a circle. Using a 28-diopter lens, if any portion of the optic nerve is in the same view as the ridge of ROP, that is considered zone 1

Any disease in zone 1 (even stage 0, immature) is critical and must be monitored closely. Zone 1 does not follow the ICROP rules. The area is very small and changes can occur very quickly, sometimes within days. The hallmark of the disease worsening is not the presence of neovascularization (as in other zones, as specified by the ICROP) but is by the increasing dilation and tortuosity of the vessels. The vascularized retina seems to rise (like a soufflé) probably because of the increased arteriovenous shunting. Many ROP experts feel that any disease in zone 1, and certainly any plus disease, requires treatment.

Zone 2

Zone 2 is a circle surrounding the zone 1 circle with the nasal ora serrata as its nasal border.

The disease may progress quickly but usually there are warning signs that predate the threshold by 1-2 weeks, as follows: (1) The ridge shows signs of vascular arcading (increased branching); this is usually a sign that the disease is starting to become aggressive. (2) Increasing vascular dilation and tortuosity is present. (3) A "hot dog" on the ridge is seen; this is a thickened vascular ridge that may not show the typical fronds of neovascularization. Rather the demarcation of vascularized and nonvascular retina is a thickened red 3-dimensional roll. This usually is seen in posterior zone 2 (borders zone 1) and is a poor prognostic indicator. (4) The Cryotherapy for Retinopathy of Prematurity Cooperative Group (CRYO-ROP) study described threshold disease as 5 contiguous or 8 noncontiguous hours of neovascularization (stage 3) with plus disease in zone 1 or 2. Of threshold eyes left untreated, 50% would develop adverse structural outcomes (eg, retinal detachment) 12 months after randomization.

Zone 3

Zone 3 is the crescent that the circle of zone 2 did not encompass temporally.

Aggressive disease rarely is seen in this zone. Typically, this is slowly vascularizing and requires evaluations every few weeks.

Many infants show inactive disease in zone 3 with a demarcation line and nonvascularized retina. This has been noted in toddlers and can be considered cicatricial peripheral disease. No ill sequelae are known to occur from this ridge.

Stage 0

This is the mildest form of ROP. It is immature retinal vasculature. No clear demarcation of vascularized and nonvascularized retina is present. Only a suggestion of the border is noted on examination.

• In zone 1, this may appear as a vitreous haze, with the optic nerve as the only landmark. Weekly examinations should be performed.
• In zone 2, bimonthly examinations should be performed.
• In zone 3, examination every 3-4 weeks should be sufficient.

Stage 1

A fine, thin demarcation line between the vascular and avascular region is present. This line has no height and no thickness.

• In zone 1, this should appear as a flat, thin line (usually nasally first). No elevation from the avascular retina should be present. The retinal vessels should be smooth, thin, and supple. Weekly examinations should be performed.
• In zone 2, bimonthly examinations should be performed.
• In zone 3, examination every 2-3 weeks should be sufficient.

Stage 2

A broad, thick ridge clearly separates the vascular from the avascular retina.

• In zone 1, if there is any hint of pink or red in the ridge, this is an ominous sign. If there is any vessel engorgement, the disease should be considered threshold and treatment commenced within 72 hours.
• In zone 2, if there are no vascular changes and the ridge has no engorgement, the eye should be examined within 2 weeks. Prethreshold is defined as stage 2 with plus disease.
• In zone 3, examination every 2-3 weeks should be sufficient, unless of course there is any vascular tortuosity or straightening of the vascular arcades.

Stage 3

The extraretinal fibrovascular proliferation (neovascularization) may be present on the ridge, on the posterior surface of the ridge or anteriorly toward the vitreous cavity. The neovascularization gives the ridge a velvety appearance, a ragged border.

• In zone 1, if there is any neovascularization, it is serious and requires treatment.
• In zone 2, prethreshold is defined as stage 3 without plus disease, or stage 3 with less than 5 contiguous or 8 noncontiguous hours. Threshold is stage 3 with at least 5 contiguous or 8 noncontiguous hours and plus disease.
• In zone 3, examination every 2-3 weeks should be sufficient, unless there is any vascular tortuosity or straightening of the vascular arcades.

Stage 4

This stage is a subtotal retinal detachment beginning at the ridge. The retina is pulled anteriorly into the vitreous by the fibrovascular ridge.

• Stage 4A does not involve the fovea.
• Stage 4B involves the fovea.

Stage 5

This stage is a total retinal detachment in the shape of a funnel.

• Stage 5A is an open funnel.
• Stage 5B is a closed funnel.

Plus disease is defined as arteriolar tortuosity and venous engorgement of the posterior pole, iris vascular engorgement, pupillary rigidity, and vitreous haze, which are part of the subclassification given to the above stages. The presence of plus disease is an ominous sign.

Pre-plus disease is defined as vascular abnormalities of the posterior pole that are insufficient for the diagnosis of plus disease but that demonstrate more arteriolar tortuosity and more venular dilatation than normal. Signs of pre-plus disease early in the course of ROP were shown to be strongly associated with development of severe ROP that required laser treatment. The diagnosis of pre-plus disease adds prognostic value beyond that already known with birth weight, gestational age, ROP zone, and ROP stage.^[9]

Other terms mentioned with ROP include the following:

• Popcorn: Regressed neovascularization seen anterior to the internal limiting membrane. This is a cicatricial change and usually regresses completely over several weeks.
• Hot dog: A "red hot" active ridge, probably the site of increasing vascular channels. This is a critical hot area of activity. If noted on zone 1 or 2, this is an ominous sign. This area may regress with cicatrix floating in the vitreous cavity and nonpatent ghost vessels still visibly attached to the retina (a second ridge would clearly be identified anterior to this cicatrix). In less fortunate eyes, this area may be the site of a true retinal detachment (no advancing ridge would be visible and the vessels would not be ghostly but engorged).
• Rush disease: A very rapidly progressive subtype of ROP is called rush disease. If plus disease is accompanied by vascularization ending in zone 1 or in very posterior zone 2, the risk of rush disease is significant.

ROP is a disease of premature infants. All babies less than 1500 g birth weight or younger than 32 weeks' gestational age at birth are at risk of developing ROP.

Tolsma et al found that late neonatal bacteremia appears to be an independent risk factor for prethreshold/threshold ROP and plus disease. The study also found that presumed late bacteremia was associated with prethreshold/threshold ROP.^[10]