Retinopathy of prematurity
Retinopathy of prematurity (ROP) was previously known as retrolental fibroplasia (RLF). It is a potentially blinding disease caused by abnormal development of the retinal blood vessels in preterm infants. It belongs to the group of vitreoretinal dystrophies.
The disease was described for the first time in 1941 in Boston by T. L. Terry. Over a hundred further cases have been seen in the USA in 1942-1943. A relationship between the first reports of ROP and the developing neonatal care has initially been suggested.
Epidemiology
ROP occurs primarily in premature infants.
It is estimated that ROP occurs in over 15-20 % of all premature births and the incidence correlates with the birth weight, reaching approximately 50-70 % in infants whose weight is less than 1250 g at birth.
In addition to prematurity, other risk factors include: infants born under 32 weeks gestation, weight less than 1500 g, apnea, mechanical ventilation, high levels of supplemental oxygen, high carbon dioxide levels, seizures, anemia, bradycardia.
ROP is prevalent worldwide and seems to affect equally male and female infants. Some reports, however, indicate a slight male predilection. Increased severity of the disease has also been reported in male infants. Reduced risk of severe ROP in black infants compared to Caucasian and Asian infants have been reported.
ROP was the leading cause of blindness in children in the 1940s and 1950s. Today, there is an increase in ROP due to the neonatal care advances and the rising number of surviving premature babies.
Classification
According to the International Classification of Retinopathy of Prematurity (1984, revised in 2005), ROP is classified in stages that are applicable to diagnosis, treatment and ocular prognosis:
Stage I: Mildly abnormal blood vessel growth; white demarcation line between vascularized and non-vascularized retina; usually gets better without any treatment and has no long-term effects.
Stage II: Moderately abnormal growth of retinal blood vessels; characterized by an elevated ridge rather than a flat demarcation line; neovascularization may be present posterior to the ridge; usually gets better without any treatment and has no long-term effects.
Stage III: Severely abnormal retinal vessel growth; protrusion of the extraretinal vessels from the ridge into the vitreous; may require treatment and has a higher risk of long-term vision problems. Infants with "plus" disease, a sign that ROP is advancing quickly, usually require treatment at this stage
Stage IV: Severely abnormal blood vessel growth and partial retinal detachment; usually requires treatment and may lead to long-term vision problems or blindness. At this stage, the retina may sometimes reattach spontaneously.
Stage V: Total retinal detachment which is funnel-shaped and may be either open or closed at the anterior and posterior ends; requires treatment and may lead to long-term vision problems or blindness.
The location of ROP is described in zones centered on the optic nerve (I-III).
The circumferential extent of the disease is based on the clock hours (1-12):
Zone I is the posterior zone of the retina, defined as the circle with a radius extending from the optic nerve to double the distance to the macula; any disease in zone I is critical and must be monitored closely.
Zone II is an annulus with the inner border defined by zone I and the outer border defined by the radius defined as the distance from the optic nerve to the nasal ora serrata; the disease may progress quickly but usually there are warning signs.
Zone III is the residual temporal crescent of the retina; the disease in this zone is usually inactive, with no ill sequelae.
"Plus" disease refers to severe tortuosity of the vessels, iris vascular engorgement, pupillary rigidity, and vitreous haze. "Pre-plus" disease is characterized by more arterial tortuosity and venous dilatation than normal but not severe enough to be classified as "plus disease". Rapidly progressing "plus" disease is sometimes referred to as Rush disease.
Clinical features, etiology and pathogenesis
Clinical features
ROP usually develops in both eyes. Ocular findings include retinal neovascularization, fibrous proliferation and end-stage retrolental fibroplasia, progressing towards partial and complete retinal detachment and blindness. Severe damage may lead to retinal folds involving the macula and macula ectopia and phthisis bulbi
Clinical features that are mostly present in severe and untreated ROP are myopia, amblyopia, strabismus, nystagmus, glaucoma, cataracts. Retinal detachment is the main cause of total blindness in ROP.
Etiology and pathogenesis
ROP refers to damage to the blood vessels of the developing eye. Normally, the blood vessels of the retina begin to develop 3 months after conception and achieve a complete development at the time of normal birth. In preterm infants, however, the vessel growing is disrupted. This gives rise to development of abnormal vessels and fibrovascular proliferation that can lead to vitreoretinal traction and retinal detachment.
The etiology of ROP appears to be multifactorial. The role of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) that are critical to normal vascular development is under extensive investigation.
There are clear evidences that genetic susceptibility plays an important pathogenetical role but the exact mechanisms involved remain to be elucidated. ROP involves retinal changes similar to those found in familial exudative vitreoretinopathy (FEVR), Norrie disease and Coats disease. Mutations in the NDP gene on chromosome Xp11.4 were identified not only in Norrie disease and X-linked FEVR but also in premature infants with advanced ROP. The NDP gene encodes for the 133 amino acids protein Norrin, which acts as a ligand in a Wnt receptor-β-catenin signal transduction pathway. The latter plays a regulatory role in retina development and is necessary for regression of hyaloid vessels in the eye. No phenotype-associated NDP mutations have been identified so far. Despite some controversies on the importance of the NDP gene in the pathogenesis of ROP, NDP mutations may account for at least a proportion of advance cases of ROP.
Diagnosis
As affected newborns have no symptoms, diagnosis in high-risk preterm infants depends on a careful ophthalmologic examination carried by a retinal specialist or pediatric ophthalmologist in a neonatal care unit.
In general, guidelines for screening include:
- Infants born at 23-24 weeks should be examined within three to four weeks;
- Infants born at or beyond 25 to 28 weeks should be examined by the fourth to fifth week;
- Infants born after 29 weeks should be examined prior to discharge from the hospital.
Eye examinations every six months are recommended for all infants born under 32 weeks or that weigh less than 1500 g. Screening can stop if the blood vessels in both retinas have completed normal development. Newborns who developed severe retinopathy must have life-long eye examinations at least once a year.
Differential diagnosis
The main differential diagnoses of ROP are familial exudative vitreoretinopathy (FEVR) and Persistent fetal vascular syndrome also known as Persistent hyperplastic primary vitreous.
Management
In majority of cases, the milder stages of the disease (I and II) resolve by themselves without treatment. However, if the disease progresses and the vision is at risk, treatment is needed. A partial retinal detachment (stage IV) may get better on its own, or may require surgery. A completely detached retina (stage V) almost always requires surgery.
As the disease can advance very quickly, timing is one of the important factors for successful treatment. Recent research indicates that early treatment of severe forms of ROP is effective in decreasing the permanent eye damage, while delayed treatment may reduce the chances of success.
Treatment for ROP depends on the stage and severity of the condition. In general, treatment is undertaken if any of the following indications are reached:
- Zone I, any ROP with "plus" disease;
- Zone I, Stage III without "plus" disease;
- Zone II, Stage III with "plus" disease.
The main goal of treatment is to reduce the risk of retinal detachment. This is achieved by cryotherapy, laser therapy, and retinal surgeries.
Laser therapy usually has better results than cryotherapy and with fewer side effects. Other advantages are that the laser spots are visible during treatment, minimizing the risk of missing. In ROP fails to regress after the initial treatment, re-treatment can be performed in 10-14 days.
Both cryotherapy and laser therapy works by destroying the retina that is deprived of retinal vessels. This helps to shrink the new vessels and prevents the formation of dense scars that may cause traction on the retina. Possible side effects after cryotherapy and laser treatment are intraocular haemorrhage and cataracts. Other treatment complications may include vitreous detachment at 5 weeks, iris atrophy, hypotony, corneal haze, rupture of Bruch's membrane, conjunctival lacerations and nystagmus.
In case of retinal detachment, scleral buckling may be required.
In the more severe cases of ROP, vitrectomy is used to remove scar tissue. During the vitrectomy, the eye lens is usually removed as well.
Education of patients and parents is an important step in the management of ROP. Visual stimulation techniques, proper toys selection, creating proper contrast, alternate learning methods, parental narration and control of light and glare must be planned. Appropriate educational environment should be developed for each child.
ROP patients frequently develop high myopia that requires correction with spectacles. Children should wear adequate protective eyewear fulltime (polycarbonate lenses are preferred because of their high impact resistance) and have non-traumatic activities to reduce the risks for retinal detachment.
Prognosis and prevention
Prognosis
The prognosis may be predicted by the stage of ROP. In general, most infants who did not progress beyond stages I or II have a good prognosis and can be expected to recover completely. However, some infants who undergo regression may have late complications of ROP, including late onset retinal detachment.
About 10 % of the infants with early changes develop more severe retinal disease that may lead to significant vision impairment and blindness. The most important factor in the outcome is early detection and treatment. ROP with "plus" disease and stages 3 - 5 is referred to as severe, with a significant risk of poor visual outcome.
Prevention
The most effective prevention of ROP is prevention of premature birth.
Preventing other complications of prematurity (such as neonatal respiratory distress syndrome) may also help the prevention of ROP. Careful monitoring of oxygen therapy and the other risk factors (mentioned above) are crucial to preventing ROP.
Despite advances in neonatology, ROP remains one of the most common causes of visual loss in childhood. At present, the treatment is not always successful and it is still difficult to distinguish infants in whom the disease will spontaneously regress from those in whom it is likely to progress despite of adequate treatment. Lifelong follow-up evaluation of the patients is essential.
References
Sims, Katherine B. NDP-Related Retinopathies. July 23, 2009. NCBI Bookshelf GeneReviews. [http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene∂=Norrie].
Holmström G, van Wijngaarden P, Coster DJ, Williams KA. Genetic susceptibility to retinopathy of prematurity: the evidence from clinical and experimental animal studies. Br J Ophthalmol. 2007 Dec;91(12):1704-8.
Dickinson JL, Sale MM, Passmore A, FitzGerald LM, Wheatley CM, Burdon KP, Craig JE, Tengtrisorn S, Carden SM, Maclean H, Mackey DA. Mutations in the NDP gene: contribution to Norrie disease, familial exudative vitreoretinopathy and retinopathy of prematurity. Clin Experiment Ophthalmol. 2006, 34 (7): 682-8.
Committee for the Classification of Retinopathy of Prematurity. "The International Classification of Retinopathy of Prematurity revisited". Arch Ophthalmol. 2005 Jul 123 (7): 991-9.
Hutcheson KA, Paluru PC, Bernstein SL, Koh J, Rappaport EF, Leach RA, Young TL. Norrie disease gene sequence variants in an ethnically diverse population with retinopathy of prematurity. Mol Vis. 2005 Jul 14;11:501-8.
Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter Trial of Cryotherapy for Retinopathy of Prematurity: ophthalmological outcomes at 10 years. Arch Ophthalmol. Aug 2001;119(8):1110-8.
Contributors
Katia Marazova, MD, PhD (January 2010), Prof. José Alain Sahel, MD, PhD and Dr Caroline Laurent-Coriat, MD, PhD
Disclaimer: This document contains information based on published scientific articles and is for educational purposes only. It is in no way intended as a substitute for qualified medical professional help, advice, diagnosis or treatment.
