Retinopathy Of Prematurity

Introduction

Retinopathy of Prematurity (ROP) is a retinal vascular disease affecting premature newborns of low birth weight. The smaller and younger the neonate, the greater is the risk for this potentially blinding disease. Apart from prematurity and low birth weight, excessive oxygen use, and various neonatal illnesses are risk factors.

Twenty-two percent of the burden of childhood blindness can be attributed to retinal disease, of which ROP is an important cause¹. At least 50,000 children worldwide are estimated to be blind due to retinopathy of prematurity and the number is ever-increasing².

While progress in neonatology has seen an increase in survival rates of extremely low birth weight babies (ELBW)³, there has been a corresponding rise in the incidence of Retinopathy of prematurity⁴.

Indian studies have shown that in low birth weight babies, the incidence of ROP varies from 38-51.9%^5,6,7.

India is now considered at high risk for retinopathy of prematurity, as it is a country whose neonatal care services have improved with better survival rates, while at the same time the existing screening protocols and level of care for ROP are not adequate. Thus has emerged what is considered to be the ‘Third Epidemic of ROP’ of which India, along with several middle-income nations, is a part.⁸

The pediatrician and the neonatologist are the first line of defense against this epidemic. While the preterm newborn is at risk of the disease, it must be emphasized that the baby does not have the disease at birth. ROP develops typically by 3-4 weeks of life, yielding a golden window period for detection and treatment. Thus the timely referral of the ‘at risk’ babies to the ophthalmologist for screening is crucial in the final visual outcome.

Recognizing the urgency, the Ministry of Health and Welfare, India has included Retinopathy of prematurity in the screening guidelines of newborns in the ‘Rashtriya Bal Swasthya Karyakram’ (an initiative launched in 2013)⁹. ‘The India Newborn Action Plan’ launched in September 2014 by the Health Minister of India, once more emphasizes ROP screening in the ‘Care of the small and sick newborn’ section of the plan¹⁰.

Retinopathy of Prematurity - History

ROP is a fairly new disease and was first described by Terry in the 1940s¹¹.

1942: Terry identified the disease & coined the term ‘Retrolental Fibroplasia’.¹¹

1951: Campbell suggested that the toxic effects of oxygen in the neonates caused the disease¹².

1952: Heath coined the term Retinopathy of Prematurity, which became the more accepted nomenclature¹².

1953: Studies proved that high concentrations of oxygen were causative¹².

Retinopathy of Prematurity - Etiopathogenesis

Development of retinal vasculature¹³

The retina is avascular to 14 weeks of intrauterine life. At around the 4th month of gestation, the vascular complexes grow from the optic disc outwards towards the periphery, in the form of an expanding vascular apron. The vasculature reaches the nasal ora Serrata at 8 months of gestation; however, the temporal retina is not completely vascularised until 1 month after delivery

Theories of Pathogenesis

1. Classical Theory (Ashton Patz)¹⁴: Oxygen is implicated as the major causative factor. Hyperoxia occurs due to high concentrations of oxygen given to the baby. This causes a retinal arteriolar spasm which later on becomes permanent closure. When the neonate returns to room air, there is endothelial proliferation adjacent to the closed vessels leading to neovascularization and retinal traction.
2. Spindle cell or Gap Junction theory (Kretzer)¹⁵: The avascular retina of the premature neonate contains spindle cells. These cells are attacked by the toxic oxygen metabolites limiting their migration and canalization. Gap junctions are formed between adjacent spindle cells, through which abnormal vessels erupt.
3. Current Theory or Growth Factor theory¹⁶: Vascular Endothelial Growth Factor (VEGF) plays an important role in the vascularisation of the normal retina. In conditions of increased oxygen saturation, VEGF is inhibited, thus resulting in the avascular retina. This hypoxic retina shows a rebound increase in VEGF leading to uncontrolled neovascularization.

Risk Factors

The risk factors for ROP are listed below^17,18:

• Prematurity and low birth weight
• High oxygen levels
• Septicemia
• Acidosis
• Hyperglycemia
• Multiple gestation
• Anemia
• Respiratory distress syndrome
• Apnoeic spells
• Intraventricular hemorrhage

Retinopathy of Prematurity - Symptoms

Ideally, the disease is picked up at an asymptomatic stage by a screening of at-risk neonates.

However it is common that the parents directly present at a later stage with the complaints of: -

• Inability of the child to see
• Abnormal pendular or searching movements of the eyes
• White reflex in the pupillary area (when the child has the stage 5 disease which Terry had described as Retrolenticular Fibroplasia).

In modern times, with the various studies done and treatment options available, a neonate at risk developing advanced disease without having had an ophthalmic check-up or referral done, can have severe medicolegal repercussions for the primary treating pediatrician or neonatologist.

Retinopathy of Prematurity - Examination

The pupillary reaction is assessed with the help of torchlight or the indirect ophthalmoscope with the aid of the 20 Dioptre lens for magnification. A rigid pupil that does not even respond to dilating drops is a sign of ‘Plus Disease’ (described later) indicating a tendency to progression. The neonate at risk is examined by Indirect Ophthalmoscopy. The pupil is dilated with tropicamide 0.5-1% with phenylephrine 2.5%¹⁹. Cyclopentolate 0.5-1% can also be used¹⁹. A single drop is instilled in each eye 5-10 minutes apart and 2-3 installations are usually adequate¹⁹.

Atropine drops or ointment are not to be used for dilation as tachycardia, hyperthermia or severe dehydration can occur in premature babies. In India, Phenylephrine drops are available in 10% concentration and can be diluted (1:4) with distilled water or a lubricant to get a concentration of 2.5%¹⁹.

Diagnosis And Categorization

The diagnosis of ROP is made by an indirect ophthalmoscopic examination. The complete diagnosis also should have a description of the magnitude of the disease.

An International Classification of Retinopathy of Prematurity (ICROP) was presented in 1984 (and then revised in 2005), which describes the magnitude, in the form of ‘Zones’, ‘Extent’ and ‘Stages’ of the disease and whether ‘Plus disease’ is present or absent.²⁰. These descriptions help to define which neonates can be observed and which require treatment.

Zones

Extent

The extent is described in terms of the number of clock hours involved²⁰.

Stages²⁰

The more premature the baby, the less of the retina is vascularized. The avascular hypoxic retina is opaque, while the well-vascularised retina is transparent and the junction between the two has a demarcation line. Branching vessels within the plane of the retina are often seen running till the demarcation line (Stage 1).

If it progresses the line acquires height and volume and now appears like a pink or white ridge (Stage 2).

Continued VEGF production causes extraretinal fibrovascular proliferation, which is recognized by vessels growing from the ridge into the vitreous (Stage3). The Fibrous tissue then begins to contract, exerting a pull on the retina (Stage 4). In advanced disease, the entire retina is detached (Stage 5).

Plus Disease and Preplus Disease

Plus disease was described by the International Classification of Retinopathy of Prematurity (ICROP) in 1984, as ROP in which there was engorgement of retinal veins and tortuosity of arterioles²⁰. It occurs due to vascular shunting through the neovascularisation and indicates severe disease. Other features include vitreous haze, dilated iris vessels, nondilating pupil.

In the 2005 modification of the ICROP the definition of Pre plus disease was added, which described dilated tortuous veins, but to a lesser degree than that seen in plus disease²⁰.

Threshold disease & Prethreshold disease

The definitions of threshold and pre threshold disease are important for decision making regarding treatment.

The multicenter trial for cryotherapy for retinopathy of prematurity (CRYO ROP), defined threshold disease as ‘5 contiguous or 8 cumulative clock hours of stage 3 disease in Zone I or II, with Plus disease’²¹. Neonates with threshold disease should be treated, as they have a 50% chance of progression to retinal detachment if left untreated.

The Early Treatment of Retinopathy of Prematurity trial (ETROP) explored the need for treatment even before threshold disease and defined Prethreshold disease which is further classified into types 1 & 2²².

Aggressive Posterior ROP (APROP)

Along with pre plus disease, the 2005 modification of the ICROP also described APROP also called ‘Rush Disease’. The disease involves the posterior pole and progresses rapidly without necessarily going through the classic stages²⁰. This disease affects the lowest birth weight babies. The fundus shows ‘brush-like neovascularisation’ with shunting of blood from arterioles to venules such that both become tortuous and dilated and it becomes difficult to differentiate between the two. Since there is rapid progression to stage 5 disease, urgent treatment is warranted²⁰.

Retinopathy of Prematurity - Natural History

80% of the time, ROP regresses spontaneously, with the fibrovascular structures becoming fibrotic. The more florid the disease at the time of involution, the more severe are the cicatricial sequelae¹³. The stages of cicatrization are given as follows:-

Stage 1: Shows peripheral retinal disturbances

Stage 2: There is straightening out of the temporal retinal vascular arcades, with peripheral vitreoretinal fibrosis. There is ‘dragging’ of the macula temporally due to the fibrosis.

Stage 3: Excessive fibrosis results in a falciform retinal fold.

Stage 4: Partial retinal detachment.

Stage 5: Complete ring of retro lenticular fibrovascular tissue with total retinal detachment.