Chapter Contents
When does a neonatologist need an ophthalmologist? 838
Development of the eye 838
Development of vision 838
Amblyopia 838
Eye conditions that require screening examinations 838
Retinopathy of prematurity 838
History and epidemiology 838
Retinal blood vessel development 838
International classification of ROP 839
Pathogenesis 839
Risk factors for the development of ROP 840
Screening 840
Treatment 840
Congenital cataract 841
How to examine the red reflex 841
Causes of congenital cataracts 842
Ophthalmic management of congenital cataracts 842
Prenatal infections and the eyes 842
Teratogens and the eyes 842
Endogenous endophthalmitis in infants 842
Diagnostic clues seen in the eyes of dysmorphic or ill infants 842
Congenital abnormalities of the eyes: unusual appearances seen by the neonatologist 843
The infant with poor vision 843
Causes of reduced vision in infants and that are evident on ophthalmic examination 843
Causes of reduced vision in infants with normal ocular appearances 843
Disorders of the eyes and related tissues 843
Eyelid abnormalities 843
The whole eye: microphthalmia, anophthalmia and coloboma 844
Watering eyes: lacrimal problems 844
Congenital glaucoma 844
Congenital abnormalities of the iris and choroid 844
Congenital abnormalities of the vitreous and retina 845
Chorioretinal coloboma 845
Persistent hyperplastic primary vitreous 845
Vitreous haemorrhage 845
Retinal detachment 845
Leber’s congenital amaurosis 845
Norrie’s disease 845
Optic nerve hypoplasia 845
Delayed visual maturation 845
Cerebral visual impairment 845
The infant with unusual eye movements 846
Abnormal alignment of the eyes in neonates 846
Nystagmus 846
Ocular motor apraxia 846
Other patterns of eye movement disorder 846
When does a neonatologist need an ophthalmologist?
Neonatologists work closely with ophthalmologists in a number of areas. All neonatal units must have a retinopathy of prematurity (ROP) screening programme in place. All neonates must be screened for congenital cataract by examination of the red reflex. Congenital abnormalities of the eyes may be apparent at birth. The eyes may contain diagnostic clues to a number of dysmorphic syndromes and neonatal illnesses. At a slightly later age, neonatologists may encounter infants with reduced vision or abnormal eye movements.
Some common ophthalmic problems of neonates do not necessarily need the involvement of an ophthalmologist. Transient birth-induced eyelid bruising and subconjunctival haemorrhages may simply be observed. Retinal haemorrhages are seen in about 33% of infants following birth, and normally disappear within 1–2 weeks ( ). Neonatal conjunctivitis is common, and management is dependent on local microbiological investigation and treatment protocols. Chlamydia infection is prevalent in many countries ( ; ), and should be treated with systemic antibiotics, because of the associated risk of pneumonia. Epiphora due to congenital delay of canalisation of the nasolacrimal duct is common in infants ( ). As the natural history is spontaneous resolution in the vast majority of cases ( ), no action is needed for typical cases with minor clinical signs.
Development of the eye
Premature infants show embryonic development features of the eyes. The eyelids are fused in infants born below about 26 weeks’ gestation, and open spontaneously after about 5 days ( ). The embryonic blood vessels that surround the lens of the eye – the tunica vasculosa lentis – involute at about 32 weeks’ gestation. They inhibit visualisation of the posterior segment of the eye with an ophthalmoscope. They absorb laser energy during treatment of ROP, which may lead to the development of adhesions between the iris and the lens, or even to cataract ( ). The hyaloid artery may persist within the vitreous up to about 30 weeks’ gestation, but involutes at about the same time as the tunica vasculosa lentis.
The fovea is immature at birth, and develops throughout infancy ( ). Adult maturity is not achieved until age 5–6 years. Optic nerve myelination develops throughout infancy, and continues to mature during early childhood ( ).
Development of vision
Visual functions develop rapidly during the first 8–12 weeks of life. Vernier visual acuity ( ; ), visual acuity measured by ‘sweep’ visually evoked potentials (VEPs) ( ; ), stereoscopic vision ( ) and colour vision ( ) may all be measured by 3 months of age. Visual acuity measured by VEP shows near-adult responses by age 8 months ( ). All visual functions continue to mature throughout childhood ( ). Premature infants develop vision correct for their gestational age rather than postnatal age ( ).
Amblyopia
Development of vision is highly dependent on visual experience. High levels of cortical plasticity are limited to the first weeks of life. If a patterned visual image is not experienced by 10–12 weeks, permanent ‘visual deprivation’ amblyopia will occur ( ). Following surgery for congenital cataract, visual functions improve rapidly ( ). Eyelid abnormalities, such as severe congenital ptosis, corneal opacity or opacity of the vitreous, cause effects that are similar to congenital cataracts. Surgery for these conditions must therefore be performed urgently. Less severe forms of amblyopia develop at a later age. Strabismic amblyopia develops when input from a squinting eye is suppressed. Anisometropic amblyopia develops when the refractive focusing is significantly less normal in one eye. The treatment of amblyopia consists of treating the cause, and then temporarily reducing vision in the normal eye in order to allow competitive development of cortical connections using input from the amblyopic eye. Occlusion with an eye patch or blurring by cycloplegic eye drops may be used. Amblyopia treatment follows a dose–response curve, with a more rapid response in younger patients.
Eye conditions that require screening examinations
Retinopathy of prematurity
Premature birth may result in abnormal retinal blood vessel development, ROP, which may progress to blindness. Every neonatal unit requires an ROP screening service. Acute ROP develops approximately 6–12 weeks postnatally (gestational age approximately 32–38 weeks). The ‘window’ for treatment is narrow, 1–2 weeks in some cases, and failure to diagnose and treat ROP at the right time can lead to permanent, bilateral, complete blindness. ROP remains a leading cause of childhood blindness worldwide.
History and epidemiology
ROP was first described in 1942 ( ). An epidemic of blindness due to ROP occurred during the 1940s and early 1950s. In retrospect this was caused by the use of unrestricted oxygen. The results of a randomised controlled trial of restricted oxygen treatment published in 1956 ( ) led to a rapid reduction in the incidence of blindness due to ROP. Unfortunately, neurological morbidity ( ) and mortality increased. A second ‘epidemic’ of ROP emerged during the 1970s because of improved survival of very-low-birthweight infants ( ). Currently, ROP is especially prevalent in ‘middle-income’ countries ( ). In these countries, neonatal care is sufficiently developed to allow the survival of premature infants, but the quality of perinatal and neonatal care is suboptimal. This results in a mixture of the effects of the first and second epidemics. It is estimated that at present at least 50 000 children are blind from ROP globally ( ). Blindness due to ROP also continues to occur in developed countries ( ).
Retinal blood vessel development
The retinal blood vessels initially develop from cords of mesenchymal spindle-shaped cells that grow out from the optic disc, commencing at 15 weeks’ gestation ( ). Further development of retinal blood vessels peripherally, and more deeply into the outer retina, is dependent on the process of angiogenesis. Physiological hypoxia in tissues anterior to the developing blood vessels leads to hypoxia-inducible factor (HIF)-controlled production of vascular endothelial growth factor (VEGF) by glial cells ( ). The nasal ora serrata (the anterior edge of the retina) is vascularised by about 34–36 weeks’ gestation and the temporal ora serrata by 36–40 weeks’ gestation.
International classification of ROP
Clinical ROP is described using an internationally agreed classification system ( ).
Retinal zones
ROP disease is primarily evident at the junction of vascularised and avascular retina. The position of the anterior edge of retinal vascularisation is defined in zones. Zone 1 retina is defined as a circle, centred on the centre of the optic disc, with a radius of twice the distance from the optic disc to the centre of the macula ( Fig. 33.1 ). When parts of this zone remain avascular, the retinal vasculature is relatively immature. ROP in this zone progresses in an especially aggressive manner. Zone 2 retina is defined as the circle of retina, centred on the centre of the optic disc that lies anterior to zone 1, as far anteriorly as the nasal ora serrata. As the nasal ora serrata is closer to the optic disc than the temporal ora serrata, a peripheral crescent of retina lies anterior to zone 2 on the temporal side of the retina, and this is termed zone 3 retina. ROP confined to zone 3 carries a good prognosis.
Stages of ROP
The appearance of acute ROP disease at the junction of vascularised and avascular retina is described in stages. In stage 1 ROP a flat line delineates the junction of vascularised and avascular retina. Stage 2 ROP refers to the development of an elevated ridge of tissue ( Fig. 33.2A ). In stage 3 ROP, extraretinal angiogenesis is present – abnormal blood vessels grow out of the ROP ridge and the area immediately posterior to the ROP ridge into the vitreous. Stage 3 ROP represents a more severe form of ROP, with a potentially poor prognosis if not treated. The abnormal extraretinal blood vessels may proliferate further, and associated glial tissue may later contract. Contraction of the circular ring of glial tissue within the cavity of the eye causes the retina to be pulled out of position – traction retinal detachment. The presence of any area of traction retinal detachment is termed stage 4 ROP. The retina may become completely detached – stage 5 ROP. In general, stage 5 ROP causes complete, untreatable blindness.
Plus disease
More severe forms of ROP are associated with abnormalities of the posterior retinal blood vessels, and the iris blood vessels. This is termed plus disease ( Fig. 33.2B ). The posterior retinal blood vessels become dilated and tortuous, at least in part due to high levels of VEGF in the vitreous. The presence of plus disease is significant in the classification of ROP, as its presence is the main determinant of the need for interventional therapy ( ).
Pathogenesis
Premature birth interrupts normal retinal blood vessel development. The physiological environment of the retina of a premature infant is very different from that found in utero. Oxygen therapy reduces the physiological hypoxia drive of normal retinal angiogenesis. Reduced HIF-controlled production of VEGF leads to reduced endothelial cell proliferation and migration ( ). In addition, reduced postnatal insulin-like growth factor 1 (IGF-1) appears to result in reduced retinal endothelial cell growth ( ). Reduced early retinal blood vessel development leads to inadequately vascularised retina at 6–10 weeks postnatally. The peripheral avascular retina continues to mature, but is avascular and becomes ischaemic. High levels of tissue VEGF are produced, and an abnormal angiogenesis response occurs (stage 3 ROP).
Risk factors for the development of ROP
Early gestation and low birthweight remain the strongest risk factors for the development of severe ROP ( ). While infants of birth weight >1250 g born in developed countries are relatively unlikely to develop severe ROP ( ), the birthweight-specific incidence of ROP varies between countries ( ).
Oxygen
The optimal level of oxygen therapy for premature infants remains unknown. While it is known that unrestricted oxygen greatly increases the risk of ROP ( ), optimal treatment levels have not been defined. In general, lower ( ) and more stable ( ) oxygen levels are thought to protect from ROP. However, the effects of lower levels of oxygen therapy on other tissues and organs may be detrimental ( ). A number of collaborative international trials of oxygen therapy are currently in progress. Results from the SUPPORT trial indicate that, while lower oxygen levels are protective for ROP, they are associated with an increased risk of mortality ( ).
Nutrition and growth
Impaired early postnatal retinal blood vessel growth is important in the aetiology of ROP. Small-for-gestational-age infants are at higher risk of developing ROP ( ). Reduced postnatal growth velocity is an independent risk factor for the development of ROP ( ). Low levels of serum IGF-1 in the early postnatal period may predict the subsequent development of ROP ( ). Nutritional therapies that result in satisfactory early weight gain may prove to be important in the prevention of ROP ( ; ).
Blood transfusions and erythropoietin
Blood transfusions ( ) and raised levels of erythropoietin ( ) have been identified as risk factors for ROP. This may occur because of increased tissue delivery of oxygen. Alternatively, as with many risk factors identified for the development of ROP, ill infants may simply be at higher risk of developing ROP. Associations with necrotising enterocolitis, bronchopulmonary dysplasia and sepsis probably come within this category.
Screening
Screening guidelines have been developed in a number of countries. Guidelines developed in first-world countries are not applicable in less developed countries. The current UK guidelines are summarised in Table 33.1 ( ).
| Which infants should be screened? |
| All infants born <32 weeks’ gestation or <1500 g birthweight |
| When should the first screening examination be performed? |
| GESTATIONAL AGE AT BIRTH (WEEKS) | POSTNATAL AGE AT FIRST ROP EXAMINATION (WEEKS) |
|---|---|
| 23 | 7 |
| 24 | 6 |
| 25 | 5 |
| 26 | 4 |
| 27 | 4 |
| 28 | 4 |
| 29 | 4 |
| 30 | 4 |
| 31 | 4 |
Eye drops are instilled 30 minutes prior to retinal examination. A combination of cyclopentolate 0.5% (an anticholinergic drug that relaxes the pupil sphincter) and phenylephrine 2.5% (an adrenergic agonist that stimulates the pupil dilator) is used in the UK, because of commercial availability. Reduced drug concentrations, available in some countries, are equally effective. Immediately before examination, local anaesthetic drops are instilled. An eyelid speculum is used to hold the eyelids open. Retinal examination is performed using a binocular indirect ophthalmoscope, or a digital camera system that comes into contact with the cornea (RetCam) ( ). This form of examination is painful ( ) and some form of pain relief, such as sucrose ( ), is appropriate. Careful administration of ROP screening programmes is needed if infants are not to be lost to follow-up. This is especially the case when infants are transferred to other units, or discharged home prior to the completion of ROP screening.
Treatment
The severity of disease that requires intervention has been defined by the Early Treatment of ROP study ( ). ROP in zone 1 retina that has reached stage 3, or is accompanied by plus disease, should be treated. ROP in zone 2 that has reached stage 2 or 3, and is accompanied by plus disease, should be treated. Thus, the presence or absence of plus disease is critical to treatment decisions. Once a treatment decision has been made, treatment should be performed within 48–72 hours. Treatment currently consists of laser ablation of peripheral avascular, ischaemic retina ( Fig. 33.2C ). A general anaesthetic, topical anaesthetic with sedation or a combination of opiate analgesia, muscle relaxant and ventilation may be used. Laser is delivered to the retina anterior to the ROP ridge. This retina is ischaemic, and ablation leads to reduced VEGF production, with resolution of ROP. The treatment should be performed carefully in order to ablate all ischaemic retina and reduce the likelihood of the need for retreatment later. Potential complications include intraocular bleeding, iritis and cataract development. Steroid eye drops and pupil-dilating eye drops should be given for 1 week after laser treatment to prevent iritis and the subsequent development of adhesions between the lens and iris. Treatment is usually successful, leading to arrest and reversal of acute ROP changes. However, in a small proportion of cases, especially those with aggressive posterior disease, laser treatment may fail. Vitreoretinal surgery may then become necessary in order to preserve vision.
An alternative approach to treatment is the use of anti-VEGF monoclonal antibodies, injected into the vitreous. Trials are underway, and the initial results indicate that this form of therapy is a satisfactory alternative to laser ablation ( ).
Outcome of treatment
Treatment for acute ROP generally results in normal or near-normal anatomy of the macula and posterior retina. However, treatment fails in a small proportion of cases. Retinal detachment ensues, and prompt vitreoretinal surgery may then be needed to preserve vision. Severe visual impairment continues to occur in some infants.
Less severe forms of visual abnormality occur in many ex-premature children, irrespective of whether acute ROP occurred in the neonatal period ( ). Ocular causes of reduced vision include forms of retinal scarring ( Fig. 33.3 ), refractive errors, strabismus and amblyopia. Neurological causes of visual impairment are common, and are frequently underrecognised. Mild forms of cerebral visual impairment (CVI) are relatively common, especially when periventricular leukomalacia is present.
Congenital cataract
The incidence of congenital cataract in the UK is approximately 2.5 per 10 000 live births per year ( ). Surgery is required for most cases, and must be done within 6–8 weeks of birth in order to avoid irreversible visual loss due to amblyopia. Neonatal screening of all infants is necessary ( ). The ‘red reflex’ is examined, using a direct ophthalmoscope. When a clear red reflex appearance is not obtained, prompt referral to an ophthalmologist is required ( Fig. 33.4 ).
How to examine the red reflex
The examination should ideally be done in a dark or dimly lit room. The infant should be awake. The examiner should be about 30 cm from the infant’s face. Each of the infant’s eyes is observed through a direct ophthalmoscope. When light is directed into the pupil, a red reflection (from the choroidal circulation) is visible. If the reflex is dark, a cataract may be present. Darkly pigmented eyes can produce less clear red reflex appearances than lightly pigmented eyes. An abnormally white reflex can indicate the presence of cataract, but can also indicate the presence of retinoblastoma, or other pathology ( Fig. 33.5 and Box 33.1 ).
Retinoblastoma
Congenital cataract
Persistent hyperplastic primary vitreous
Coats’ disease
Chorioretinal colobomas
Causes of congenital cataracts
Two-thirds of cases are bilateral ( ). Unilateral cases are more frequently associated with additional ocular abnormalities, and are less likely to be associated with hereditary or systemic diseases ( ). Common associations of bilateral congenital cataracts are shown in Table 33.2 . Prenatal infections, due to rubella or toxoplasmosis, are now rare causes of congenital cataracts. All infants diagnosed as having congenital cataracts should be assessed for related systemic disease.
