activity, has been found to be elevated in aqueous humor and subretinal fluid of patients with stage 5 ROP who underwent open-sky vitrectomy. It is believed that 16K-PRL is involved in the regression of pathologic neovascularization, and offers a potential target for the treatment of this disease.

DIAGNOSIS AND ANCILLARY TESTING/DIFFERENTIAL DIAGNOSIS

Diagnosis of this disease is clinical. Patients at risk should be examined with their pupils dilated using an indirect ophthalmoscope, a condensing lens, a lid speculum, and a scleral indentator, following a screening protocol.16 No ancillary tests are usually required, but fundus photographs may be useful for follow-up.

Differential diagnosis of ROP stages 1–3 includes familial exudative vitreoretinopathy, and atypical cases of Coats’ disease or Eales’ disease. Differential diagnosis of ROP stages 4–5 must be made with causes of leukocoria, including retinoblastoma, persistent fetal vasculature, and Norrie’s disease.

SIGNS AND SYMPTOMS

CLASSIFICATION OF RETINOPATHY OF PREMATURITY

The classification of ROP was established by an international com­ mittee,17–19 and includes five stages, three zones, and the presence or absence of “plus” disease (Figure 25.1). Stage 1 consists of a demarcation line that separates avascular from vascularized retina. Stage 2 consists of an elevated ridge that separates avascular from vascularized retina. Stage 3 consists of a ridge with extraretinal fibrovascular proliferation. Stage 4 consists of a retinal detachment; when the macula is not involved, it is called stage 4A, and when the macula is detached, it is called stage 4B. Stage 5 implies a total retinal detachment that may be open or narrow in configuration.

The retinal zones center in the optic disc. Zone I corresponds to a circle with a radius that extends from the disc to twice the disc–fovea distance. Zone II corresponds to a circle that extends from the limits of zone I to the nasal ora serrata. Zone III corresponds to the remaining crescent-shaped area temporally between zone II and the ora serrata. The extent of the disease is expressed in clock hours. “Plus” disease is characterized by posterior venous and arterial tortuosity and dilation. “Threshold” ROP is defined as 5 or more contiguous or 8 cumulative

12

Zone I

Zone III

Zone II

6

Figure 25.1  Diagram of zones of the retina and clock hours used to describe the location and extent of retinopathy of prematurity.

clock hours of stage 3 ROP in the presence of “plus” disease. It is called “threshold” because it is predicted that, at this point, approximately 50% of patients will have an unfavorable outcome.

Aggressive posterior (AP) ROP consists of posterior location (usually zone I), “plus” disease without prominent ridge proliferation or classic stage 3, low-lying, tangled web of vessel (called flat neovascularization), that typically extends circumferentially. This is an uncommon form of ROP, which is severe and progresses rapidly to stages 4 and 5 if left untreated.

TREATMENT OPTIONS FOR RETINOPATHY OF PREMATURITY

Treatment options for ROP include the following:

●Cryotherapy to ischemic retina for patients with prethreshold and threshold disease with clear media

●Laser therapy to ischemic retina for patients with prethreshold and threshold disease with clear media

●Intravitreal antiangiogenic agents for patients with prethreshold and threshold disease, and some patients with opaque media and/or limited retinal detachment

●Lens-sparing vitrectomy for patients with ROP stage 4A or B

●Vitrectomy without sparing the lens for patients with ROP stage 5.

TREATMENT OUTCOMES AND

PROGNOSIS

CRYOTHERAPY AND LASER THERAPY

The Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) study was the first multicenter clinical trial for the treatment of ROP. In patients who developed bilateral threshold ROP, one eye was randomized to receive treatment with cryoablation of the peripheral avascular retina, and the other eye received no treatment. In patients with unilateral threshold ROP, the affected eye was randomized to either cryotherapy or no treatment. At 1-year follow-up, 44.7% of untreated eyes and 25.1% of treated eyes had an unfavorable structural outcome (defined as a retinal fold in the macula or the presence of retrolental tissue).20 At 15 years of follow-up, an unfavorable structural outcome was seen in 51.9% of untreated eyes and 30% of treated eyes.21

Several years later, the Early Treatment for Retinopathy of Prematurity (ET-ROP) study was designed in order to compare laser treatment for threshold disease (conventional treatment) with laser treatment for eyes with high-risk “prethreshold” disease (defined as zone I, any stage ROP, less than threshold; zone II, stage 2, with plus disease or stage 3 without plus disease; zone II, stage 3 with plus disease, but less than the threshold; the “high-risk” was calculated according to the retinal status and other risk factors about the infant, based on a theoretical model created with CRYO-ROP study data). The study showed that, at 9 months of postmenstrual age of follow-up, early treatment reduced unfavorable visual outcomes from 19.5% to 14.5% and reduced unfavorable structural outcome from 15.6% to 9.1%.22

INTRAVITREAL ANTI-VEGF THERAPY FOR ROP

Rationale for Treatment

The fact that VEGF levels are markedly increased in intraocular fluids of patients with ROP raises the question whether treatment directed to block VEGF and its effects would be helpful for the treatment of ROP or to avoid its complications. To date, only intravitreal bevacizumab

Pharmacotherapy to Amenable Diseases Retinal • 3 section