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Combination of ROP treatments may help eliminate ‘destructive’ laser therapy
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Retinopathy of prematurity is a disease in premature infants who today, secondary to advanced neonatal intensive care units, are surviving at ever lower birth weights and weeks of gestation. These infants almost universally require oxygen supplementation, and both excess oxygen and hypoxia can contribute to the disease.
At about 16 weeks, the retina begins to develop vascularization, and this process is mediated by many cytokines and growth factors, including VEGF. The vessels grow outward from the optic nerve toward the retinal periphery, and this process is not fully completed in the temporal periphery until after full-term birth. The normal growth of blood vessels is directed toward relatively low oxygen areas of the retina. If excess oxygen is given, these normal blood vessels can fail to develop or regress. When the excess oxygen is removed, the blood vessels grow rapidly and are associated with fibrous tissue proliferation, which can also extend outside the retinal plane into the vitreous. Vitreous hemorrhage, retinal detachment, cataract, myopia, secondary glaucoma, strabismus and amblyopia are frequently associated with ROP.
All infants with a gestational age of less than 31 weeks or a birth weight of less than 1,250 g (2.76 lb) require screening for ROP. The examination requires indirect ophthalmoscopy with scleral depression, and significant skill is required to detect subtle changes. In some centers, retinal photography with a RetCam (Clarity Medical Systems) is utilized and reviewed by an ophthalmologist expert in diagnosis and staging.
The International Classification of Retinopathy of Prematurity (ICROP) uses a number of parameters to stage the disease. The retina is divided into zones. Zone 1 extends from the optic disc in a radius two times the distance to the macula. Zone 2 is the distance to the nasal ora serrata extended in a circle temporally. Zone 3 is the residual temporal crescent. These zones are utilized to localize the disease, and then it is staged. Stage 1 is a faint demarcation line, stage 2 has an elevated ridge, stage 3 includes extraretinal fibrovascular tissue, stage 4 has a sub-total retinal detachment, and stage 5 has a total retinal detachment. Plus disease describes complicating factors such as significant vessel dilation or tortuosity, vitreous or anterior chamber haze, iris vascular engorgement, or a persistent tunica vasculosa.
I still remember my 3 months on the pediatric ophthalmology service during my residency, making daily visits to the neonatal intensive care unit and doing my best to examine, diagnose and stage this disease. For me, it was an extremely difficult and emotional task, requiring the patience and assistance of the unit staff. The prognosis worsens as the disease extends into zone 2 or zone 1, with a higher numerical stage and with plus disease. Examinations are required weekly during the active stage of ROP.
Peripheral retinal laser ablation is the classic treatment. It is delivered in most cases through an indirect ophthalmoscope and can require general anesthesia and more than an hour to deliver an adequate number of burns. This again requires significant skill and experience. Cryotherapy is more easily delivered, but less ideal due to secondary damage and more inflammation. Vitrectomy and a scleral buckle can be required for retinal detachment, again a very demanding procedure for both the anesthetist and the surgeon.
It is no surprise based on both pathophysiology and ease of treatment that intravitreal anti-VEGF therapy is attracting advocates. Early outcomes suggest good efficacy, somewhat dependent on the stage of the disease, but safety needs further study. Just like too much or too little oxygen can result in a poor outcome for a premature infant, it is likely the proper dose of anti-VEGF will be critical to achieve an ideal outcome in the eye with minimal systemic side effects.
While pilot studies by the pioneers are required, in the end we will need a well-performed prospective randomized clinical trial to guide therapy. This is currently being planned in the so-called RAINBOW trial evaluating the safety and efficacy of Lucentis (ranibizumab, Genentech). It is likely that other studies looking at Eylea (aflibercept, Regeneron) will follow. Oral propranolol, quite effective in accelerating hemangioma regression, is also being evaluated.
These children require lifelong therapy and are usually best managed in a collaborative manner at major institutions. However, many of these patients live in rural areas, so the comprehensive ophthalmologist will often be engaged in their management as well. Great progress has been made in this field since I was in training, and it would be wonderful if these patients could be managed with some combination of intravitreal and oral medication, eliminating the need for destructive laser therapy.