Retinopathy of Prematurity & Anti-VEGF Therapy

Retinopathy of prematurity (ROP) is a potentially blinding eye disorder that primarily affects premature infants weighing about 2¾ pounds (1250 grams) or less that are born before 31 weeks of gestation (a full-term pregnancy has a gestation of 38–42 weeks).

The smaller a baby is at birth, the more likely that baby is to develop ROP. This disorder — which usually develops in both eyes — is one of the most common causes of visual loss in childhood and can lead to lifelong vision impairment and blindness. Retinopathy of Prematurity was first diagnosed in 1942.

The retinas are the light-sensitive linings of the insides of the eyes. In infants born prematurely, the blood vessels that supply the retinas are not yet completely developed.

Although blood vessel growth continues after birth, these vessels may develop in an abnormal, disorganized pattern, known as ROP. In some affected infants, the changes associated with ROP spontaneously subside.

However, in others, ROP may lead to bleeding, scarring of the retina, retinal detachment and visual loss.

Even in cases in which ROP changes cease or regress spontaneously, affected children may have an increased risk of certain eye (ocular) abnormalities, including nearsightedness, misalignment of the eyes (strabismus), and/or future retinal detachment.

The two major risk factors for ROP are a low birth weight and premature delivery.

Signs & Symptoms

Retinopathy of prematurity (ROP) is characterized by abnormal and uncontrolled development of blood vessels in the back of the eye (i.e., the retina) in premature infants.

The retina is the innermost tissue layer in which images are focused at the back of the eye; it contains light-responding nerve cells (rods and cones) that convert light images into nerve impulses, which are conveyed via the optic nerve to the brain.

During fetal development–at about 16 weeks’ gestation–blood vessels that supply the retina begin to bud from the center of the retina (i.e., near the optic nerve), gradually reaching the front edges (periphery) of the retina at about the time of normal delivery.

Thus, when infants are born prematurely, this process is incomplete. (Gestation is the period of time from fertilization to birth. Full term is the normal period of human gestation from about 38 to 42 weeks.)

ROP occurs when the blood vessel development is abnormal, with disorganized branching of retinal vessels and anomalous interconnections.

ROP is descriptively localized within the eye according to three anatomic “zones”, based on the specific areas of the retina that are malformed (i.e., posterior (rear-most), middle, and anterior (most forward in the eye) zones).

It is also classified into five sequential stages, based on the severity of the disease. In infants with early-stage ROP, the normal growth of blood vessels ends abruptly (stage 1), marked by a flat, whitish, “demarcation” line separating retinal regions that are and are not supplied with blood vessels (vascularized and avascular retina); multiple, abnormal, wide-branching blood vessels often lead into the line.

In some cases, this line may then grow into a “ridge” that is higher and wider, extends inward above the plane of the retina, and may change in color from white to pink (if the central core fills with blood) (stage 2).

Stages 1 and 2 may improve without treatment (spontaneous involution). In stage 3, the ridge increases in dimension, and new, abnormal blood vessels extend internally toward the vitreous humor gel that fills the large rear cavity of the eye between the retina and the lens., or on and along the retinal surface (stage 3).

Stage 3 often requires treatment intervention. (For information on treatment, see the Standard Therapies section below.)

The overgrowth of these abnormal blood vessels in the wrong locations may lead to development of scar tissue. The scars may then contract and tug on the retina, causing its separation from underlying, supporting tissue (retinal detachment).

Stage 4 is characterized by partial detachment of the retina, potentially resulting in loss of vision. This stage is further categorized into two phases, based on whether the macula (the center vision area) is or is not involved.

Macular detachment results in a marked deterioration of vision. Stage 5 indicates complete and total retinal detachment, sometimes leading to a white mass behind the pupil, cataract, and blindness.

In some affected infants, unusual blood vessel appearance may suggest a rapidly progressive course of disease.

These cases have abnormal growth, widening (dilation), and twisting (tortuosity) of blood vessels near the optic nerve in the back of the eye and on the surface of the colored region surrounding the pupil of the eye (iris); rigidity of the pupil (meaning that it is difficult to dilate); and haziness of the vitreous humor.

This situation labels “Plus Disease”, and this is a marker of poor prognosis unless treatment performs.

According to medical literature, the disease process ceases and returns to its original condition (involutes) spontaneously in approximately 90 percent of affected infants. In the birth weight category under 2 lb. 2 oz. (1250 g), fewer than 10 percent of cases progress to severe ROP, characterized by proliferation of blood vessels outside the retina, retinal detachment, and visual loss.

In those affected by end-stage disease, the eyes may be unusually small and sunken (phthisis bulbi), when the retina appears as a whitish mass pressing against the lens (leukokoria). Some may also develop increased fluid pressure within the eye (glaucoma), loss of transparency of the lens of the eye (cataract), signs of inflammation, and/or other changes.

Even after the disease subsides, affected children may have an increased risk of certain eye (ocular) abnormalities.

In some instances, arrested or regressed ROP may leave demarcation lines or changes of the underlying pigment layer of the retina, retinal scarring and displacement of the macula, and may increase the risk of retinal detachment later in life.

Affected children also have an increased incidence of nearsightedness (myopia); decreased clearness of vision (visual acuity) due to lack of a clear image falling on the retina (amblyopia); misalignment of the eyes (strabismus); unequal focusing ability of the two eyes (anisometropia); and/or other abnormalities.

Advancements in antenatal care, along with the increased establishment of neonatal intensive care units, have resulted in improved survival of preterm and lowbirth-weight infants.

ROLE OF VEGF IN ROP AND TREATMENT EVOLUTION

Vascular endothelial growth factor (VEGF) is an important angiogenic factor during embryonic vascular development.

It leads to the growth of retinal blood vessels toward the avascular peripheral retina. Phase 1 ROP occurs during 22 to 30 weeks of gestation, whereby relative hyperoxia causes low VEGF levels and cessation of blood vessels growth (vasoattenuation).

Subsequently, phase 2 ROP occurs during 31 to 41 weeks of gestation. The increased metabolic demand in peripheral avascular retina induces a hypoxic milieu, stimulating VEGF release and abnormal vessel proliferation (vasoproliferation).

Over the past 50 years, ROP treatment has limited treatment modalities such as cryotherapy and laser photocoagulation. More recently, there has been growing evidence to support the use of anti-VEGF agents for the treatment of ROP.

Figure 1 shows both regression of retinopathy of prematurity (ROP) after treatment by laser photocoagulation or intravitreal injection of anti-VEGF.

Currently, the use of anti-VEGFs is off label. However, there are increasing numbers of studies examining their efficacy and safety in treating ROP.

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