Retinopathy of Prematurity
What is Retinopathy of Prematurity?
Retinopathy of prematurity (ROP) is an eye disease which results from abnormal development of the retina (the light sensitive lining of the eye) in premature babies.
Not all premature infants develop retinopathy of prematurity. And for many, it resolves without treatment in early stages. But for those babies in whom ROP progresses, treatment is necessary. It generally occurs in both eyes, but may be worse in one eye compared to the other. t s very rare that t occurs n one eye only. The two critical factors for predicting which children are most likely to develop ROP are:
- Birth weight of less than 1,500 grams (3 lbs 5 oz)
- Gestational age at birth (i.e. length of pregnancy) of less than 32 weeks
Although much has been written about the association of the high oxygen requirements of these children and the development of retinopathy of prematurity, oxygen is not the cause of retinopathy of prematurity - prematurity is. Even so, oxygen levels are still carefully monitored to ensure that these infants are given only the amount of oxygen absolutely necessary.
Infants weighing less than 1,000 grams (2 lbs 3 oz) at birth and who are born at 23 to 28 weeks gestational age have a particularly high chance of developing retinopathy of prematurity.
Infants are not born with retinopathy of prematurity. They are born with immaturity of the retina (i.e. incomplete development of the retinal blood supply).
The information 'contained in this article' is intended to help you understand the eye, the disease, and the treatment of ROP.
Structure and Function of the Eye
The adult eye is a sphere about 1 inch in diameter. The wall of the eye has three layers:
- Outer fibrous layer - the sclera
- Middle vascular layer, containing blood vessels - the choroid
- Inner nerve-containing layer - the retina
The cornea forms the front most part of the eye. It's transparent and curved to focus incoming light rays. The sclera, commonly called the "white of the eye," forms an opaque and fibrous coat that protects the eye. The conjunctiva is an extension of the inner layer on the eyelid that forms a thin transparent membrane over the front of the eye.
Many blood vessels and pigment (color) are contained in the choroid. An extension from the front section of the choroid forms the iris, or the colored part of the eye. The center of the doughnut-shaped iris is called the pupil. Just behind the iris is another extension from the choroid that contains muscles and ligaments that hold the lens in place and change its shape, from squashed for near vision to stretched for far vision.
The eye has two segments: The anterior segment is from the lens forward, includes the iris and is bound by the cornea at the front. Aqueous humor, a watery fluid, constantly flows into and out of the anterior segment. The posterior segment lies behind the lens and contains a gelatinous substance called vitreous humor. Vitreous humor is formed during the eye's development and, unless removed surgically, remains permanently in the eye. Together, aqueous and vitreous humor give the eye sufficient pressure, known as intraocular pressure, to keep it firm and spherical.
The retina forms the inner coat of the posterior segment and is comprised of two layers - a nerve-containing layer resting on top of a pigmented layer which is attached to the underlying choroid. The nerve containing retina is physically attached to the pigmented retina only at the front of the eye, just behind the lens and at the back of the eye, at the optic nerve. When one suffers a detached retina it is the nerve containing layer detaching from the pigmented retina, not the entire retina. The nerve layer contains cells - photoreceptors - that detect light rays and pass the impulse via the optic nerve, to the brain, which translates them into images. The central part of the retina - the macula - is responsible for central vision and is directly behind the lens. At the macula's center is the fovea, which is the area of sharpest vision. The retina outside the macula is known as the peripheral retina which allows peripheral vision.
There are two kinds of photoreceptors in the retina - rods and cones. Rods are much more sensitive to light and so allow night vision, which is colorless vision and provides only general outlines and objects. Rods predominate in the periphery of the retina, but are completely absent from the fovea. Cones, on the other hand, detect color and allow sharp vision. The cones are most concentrated in the fovea, but decrease in concentration in areas away from the macula.
The eyeball is held in place in the orbit of the skull by six muscles. Each muscle moves the eye in one primary direction. A given eye movement may involve more than one of the muscles.
Development of the Eye
The eye begins to form in the embryo's fourth week of development. The last 12 weeks of a full-term delivery, from 28-40 weeks gestation, are particularly active for the growth of the eye of the fetus. At term a baby's eye is almost half of the adult size and continues to develop over the next two years.
The anterior segment, or front of the eye is almost full size at term so most of the continued growth takes place in the posterior segment, just behind the lens in the periphery of the retina. Retinal surface area doubles between 6 months (26 weeks) of gestation and full term with a further 50% increase over the next two years.
The retina (the light-sensitive inner layer of the eye), the iris and the optic nerve (which transmits impulses received by the eye to the brain) all develop from the primitive forebrain. The lens and cornea are derived from the original surface "skin" of the head. (Both help to focus the incoming light rays on the light-sensitive retina). The embryonic layer between the brain and head gives rise to the vascular (blood vessel-containing) layer, the choroid and the outer fibrous layer, the sclera.
From about the sixth week of gestation a temporary network of blood vessels supplies the front of the eye via the hyaloid artery, which originates in the back of the eye, passes through the middle of the vitreous humor (the gelatin that fills the back segment of the eye) and wraps vessels around both surfaces of the lens and iris. The hyaloid artery later incorporates into the optic nerve behind the eye and disappears from inside the eye by seven months of gestation. The vessels around the lens usually disappear by 34 weeks gestation.
There are no blood vessels in the retina before the 16th week of gestation. From then on primitive cells extend out from the optic disc (where the optic nerve enters the eye) and stimulate the growth of normal blood vessels. Production of the new blood vessels is usually coomplete on the nasal side (towards the nose) of the eye by 8 months (35 weeks) gestation. The blood vessel networks on the temporal side of the eye (towards the side of the head or temples) are not mature until 2-3 months after normal term birth
Development of ROP
As discussed earlier, growth of the blood supply to the retina begins at 16 weeks of gestation and proceeds until a little after a full term birth. If the retinal blood supply in the premature infant continues its development just as if the baby were still in the uterus, then retinopathy of prematurity does not develop.
ROP occurs when abnormal blood vessels and scar tissue form at the edge of the normal retinal blood supply. The disease is caused by the abnormal retina's demand for oxygen. As it has no blood supply, the abnormal retina is starved for the oxygen needed for normal function. If the disease progresses to the stage requiring treatment, the initial treatment is to kill the abnormal retina and so eliminate its damaging demand for oxygen.
If retinopathy of prematurity develops, it usually appears between 35 and 45 weeks of conceptive age. That is if the infant is born at 30 weeks gestation, and if retinopathy of prematurity were to occur, it would appear when the infant is between 5 and 15 weeks old. In the majority of infants who develop ROP, the disease resolves spontaneously and the retinal blood supply develops normally. If retinopathy of prematurity regresses, the disease has usually lasted about 15 weeks.
However, ROP can progress to a serious, and potentially blinding, eye problem which is estimated to result in the blindness of approximately 500 infants in the United States per year.
Classification of ROP
In the 1980's an international standard classification of retinopathy of prematurity (known as ICROP) was developed by a team of 23 experts from around the world. It defines the disease by location relative to the optic nerve and macula, by extent of disease around the circumference of the eye, and by stages of progressive disease.
Blood vessel development in the retina occurs from the optic nerve out towards the periphery, that is, from the back of the eye towards the front. The location of the disease is referred to by the ICROP classification and is a measure of how far this normal progression of blood vessel development has progressed before the disease takes over. Generally Zone II disease is more severe than Zone III disease and Zone I disease is the most dangerous of all since progression to extensive scar tissue formation and total retinal detachment is most likely in this location.
From the "flattened" retina in the figure above you can see that:
- Zone I is a small area around the optic nerve and macula at the very back of the eye.
- Zone II extends from the edge of Zone I to the front of the retina on the nasal side of the eye (i.e. nose side) and part way to the front of the retina on the temporal side of the eye (i.e. temple side, or side of the head).
- Zone III is the remaining crescent of retina in front of Zone II on the temporal side of the eye.
Extent of Disease
Think of the eye as in time sections of a twelve hour clock. The extent of ROP is defined by how many clock hours of the eye's circumference is diseased. The numbers around the "flattened" retina in the figure show the hours of the clock for each eye. For example, 3 o'clock is to the right, which is on the nasal side for the right eye and temporal side for the left eye. Often the disease is not present around all twelve clock hours, so a description may often refer to "x" number of clock hours of disease (e.g. nine clock hours would mean that three quarters of the circumference of the retina is involved).
Stages of the Disease
Retinopathy of prematurity is a progressive disease. It starts slowly, usually anywhere from the fourth to the tenth week of life, and may progress very fast or very slowly through successive stages, from Stage 1 through Stage 5. Or it may stop at Stage 1, Stage 2 or mild Stage 3 and disappear completely.
Stage 1 ROP is characterized by a demarcation line separating the clearly normal retina from the undeveloped retina. This line is typically white and there is sharp contrast between the normal retina and the abnormal retina.
Stage 2 ROP displays a rolled ridge of scar tissue in place of the white demarcation line in Stage 1. It may be limited to a small area of the retina or it may encircle the entire inside of the eye like a belt around the middle of the eye.
Stage 3 ROP is characterized by the development of abnormal "new blood vessels" and fibrous tissue (like scar tissue) on the edge of the ridge seen in Stage 2 and extending into the vitreous (the back cavity of the eye).
Stage 3 is further divided into:
- "Mild" - with only a limited amount of abnormal tissue,
- "Moderate" - with significant amounts of abnormal tissue infiltrating into the vitreous, or
- "Severe" - massive amounts of abnormal tissue infiltrate into the vitreous.
Statistically, eyes which reach stage 3 moderate or severe have a 50% chance of proceeding to Stage 4 or Stage 5 and possible blindness. Therefore, it is at Stage 3 that treatment is instituted.
Stage 4 ROP is caused by the scar tissue formed in Stages 1 through 3 pulling on the retina and causing it to separate from the wall of the eyeball. The detachment in Stage 4 is partial, occurring in one section of the eye and, depending on its location, may or may not affect the infant's vision.
Stage 4 is further categorized depending on the location of the partial detachment:
Stage 4A is a partial detachment outside the macula - the area of central vision - in the preiphery of the retina. Therefore, the chance for usable vision, if the retina reattaches, is relatively good.
Stage 4B is partial detachment involving the macula, usually with a fold extending out through Zones I, II, and III. The involvement of the macula severely limits the prospect for usable vision in this eye.
Stage 5 ROP involves a complete retinal detachment, with the retina assuming a closed or partially closed funnel, from the optic nerve to the front of the posterior cavity fo the eye, just behind the lens. Infants with Stage 5 ROP have essentially no useful vision inthat eye. Treatment at this stage involves surgery to relieve the traction, causing the detachment, in an attempt to reattach the retina.
Some vision may be recovered by this surgery but the infant will most likely be legally blind in the involved eye.
Additional complications to those described in Stages 1 through 5 may involve abnormal blood vessels in the iris and engorgement and tortuosity of the normal blood vessels in the retina. If these additional symptoms are particularly bad, the plus ("+") designation is added to the Stage number, e.g. Stage 2+.
If ROP is located in Zone I and there is plus disease present, then progression of the disease may be particularly rapid. This form is sometimes called Rush Disease.
Diagnosis of ROP
Screening for ROP usually begins when the infant is about 4 to 6 weeks of age. An eye doctor (ophthalmologist), who specializes in either retinal disorders (retinal specialist) or children's eye diseases (pediatric ophthalmologist), uses a special instrument (an indirect ophthalmoscope) which allows a view through its optic lens into the back of the eye to examine the retina and determine whether development of the blood vessels is occurring normally or not.
The infant is usually given some eye drops to make the pupil dilate so that the viewing field is as wide as possible. A light anesthetic, in the form of numbing eye drops, may also be administered.
The examinations are usually performed in the neonatal intensive care nursery where the neonatal staff can continue to monitor the baby.
The infant will continue to be examined every 1 to 2 weeks until one of the following occurs:
Development of the normal blood supply to the retina is complete.
Two successive 2-week exams show Stage 2 in Zone III. Infants will then be examined every 4 to 6 weeks until the blood supply to the retina is fully developed.
ROP is at "prethreshold", just prior to requiring treatment. Follow-up exams will then occur every week until either Threshold ROP occurs, which requires treatment, or the retinopathy of prematurity disappears.
The ROP is disappearing.
After two successive 2-week exams have shown regression, examinations should be continued every 4 to 6 weeks.
Once the normal blood supply to the retina is completely developed, the infant will continue to be examined every 6 to 12 months by a pediatric ophthalmologist or retinal specialist to ensure that no further complications of ROP occur.
Treatment of ROP
The current standard for treatment involves a freezing process, called cryotherapy. In the late 1980's a nationally organized clinical trial established that this therapy improved the outcome of the disease for infants who had reached Threshold Stage 3+ in 50% of cases. That is, half of the treated eyes that would otherwise (i.e. without treatment) have progressed to retinal detachment and possible blindness did not do so.
The technique of cryotherapy involves freezing the retina by touching a cold probe to the outside of the eye and waiting to allow the freeze to reach the abnormal retina (i.e. the retina without a blood supply) inside the eye. The treatment kills the abnormal retina thus eliminating its demand for oxygen. The abnormal blood vessels disappear and the progression of scar tissue stops.
There are risks in performing cryotherapy. Severe decreases in heart rate and breathing rate may occur. For this reason heart rate and blood oxygen are monitored constantly during the cryotherapy procedure. Sometimes infants need to be placed back on a ventilator after the procedure if they are having trouble breathing on their own.
Cryotherapy is performed under either local anesthesia or general anesthesia. If local anesthesia is used, this can be administered and the procedure performed at the infant's bedside in the neonatal intensive care nursery. Administration of general anesthesia may require that the infant is transferred to the operating room. Neonatal staff also accompanies the baby to ensure constant monitoring of his or her condition. Some phsicians prefer to give general anesthesia because they believe that cryotherapy is such a painful procedure that it is in the infant's best interest to be fully anesthetized.
After cryotherapy there is usually a large amount of swelling around the eyes, bloody tears and redness. These effects go away in approximately one week.
A newer therapy, laser treatment, may achieve the same effects as cryotherapy with fewer side-effects, but to date cryotherapy is the only treatment proven in a large nationally-conducted clinical trial. Additional trials are underway to clinically compare results of laser therapy with results of cryotherapy.
Lasers have been used to successfully treat eye disorders in adults for over 20 years. Diabetic retinopathy is a retinal disease afflicting diabetics which is like retinopathy of prematurity in that it involves growth of abnormal blood vessels in the retina. Treatment of diabetic retinopathy was revolutionized by the advent of laser therapy. Prior to laser therapy there was no way to prevent blindness in these people.
Due to a technical advance in the last few years, laser therapy can now be administered to newborn infants. The same instrument that the doctor uses to examine the infant's retina - the indirect ophthalmoscope - can also deliver the laser treatment beam into the eye. So if the doctor sees abnormal retina with the indirect ophthalmoscope, it can also be treated.
Laser treatment acts in the same way as cryotherapy by killing the abnormal retinal tissue and so eliminates the growth of abnormal blood vessels and ends the progression of scar tissue formation.
The potential benefits of laser treatment are:
- Less need for anesthesia
- Less pain
- Less swelling after the procedure
- Less likelihood of damage to the eye
- Less chance of decreases in heart and breathing rates during the treatment
The drawback of laser therapy is that it has only been proven effective in a few small clinical trials and not in a large nationwide trial. Early trials indicate that laser therapy is at least as effective as cryotherapy and potentially better at preventing many infants progressing to retinal detachment. Currently a large nationwide trial is being organized.
Traditional laser systems were large, immobile units that required moving the infant to the laser rather than bringing the laser to the baby. Newer lasers - using semiconductors - are fully portable and can be taken to the nursery and attached to an indirect ophthalmoscope for treating ROP babies without disturbing their routine.
If cryotherapy, or laser treatment at Stage 3 is unsuccessful in preventing progression to retinal detachment stages - Stage 4 and Stage 5 - there are some surgical treatment options.
If the detachment is shallow (i.e. there is not a lot of space between the retina and the eye wall) a technique called scleral buckling may be effective. This involves placing a belt around the outside of the eye and tightening in until the retina is close enough to the wall to reattach itself.
Some studies have shown this technique to be effective in some cases of Stage 4a, Stage 4b and mild Stage 5. Vision after successful scleral buckling tends to be better than after the more invasive surgical procedures discussed below.
If scleral buckling is not possible or is unsuccessful a more direct technique for reattaching the retina, called a vitrectomy, can be performed.
In this procedure the eye is opened up, the lens is removed and some or all of the vitreous humor is removed so the surgeon can access the detached retina. The source of traction causing the detachment (i.e., the scar tissue or membrane that is tugging at the retina) is cut away from the retina and the retina is then laid back against the eye wall by injecting a gelatin-like material to replace the vitreous that was removed.
A vitrectomy is not always successful in reattaching the retina and even if the retina is reattached, only a fraction of the eyes achieve ambulatory vision, the ability to recognize faces.
Late Complications of Retinopathy of Prematurity
Most infants with mild retinopathy of prematurity (Stages 1 to mild 3) that spontaneously resolves itself will have no remaining scar tissue. However, some infants who undergo regression may still suffer further complications later in life. These later complications include:
Strabismus and Amblyopia
Strabismus (crossed eyes) and amblyopia (lazy vision in one eye) occur more frequently in infants with even the mildest stages of regressed ROP compared with premature infants who do not develop ROP. Eye muscle surgery (for strabismus) and patching (for amblyopia) are often necessary.
Myopia (near-sightedness) can occur with the mildest forms of regressed ROP. The nearsightedness is usually more severe when a greater amount of scar tissue remains from regressed ROP. Myopia is correctable with glasses.
Different forms of glaucoma (increased pressure in the eye) may develop in eyes that have regressed or treated ROP. Glaucoma may cause pain and does damage vision. Laser, or other types of surgery, are sometimes necessary to help the eye drain off the build-up of the watery fluid (aqueous humor) that bathes the front of the eye and causes the increased pressure.
Late-onset Retinal Detachment
Late Retinal Detachment may rarely occur in the mid-teens or early adulthood as a result of traction from scar tissue as the eye grows or as the vitreous gel shrinks, pulling holes in the retina. Surgery is usually necessary for repair.
Any person who experienced retinopathy of prematurity should therefore see a retina specialist and/or a pediatric ophthalmologist at least once a year during childhood and early adult years.