Neonatal Ophthalmology

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Chapter 15

Neonatal Ophthalmology

Normal Visual Development

Term newborns can often fixate on a target. The ability to track an object, however, does not generally develop until approximately 2 months after birth. Visual acuity, measured with visual evoked potentials, has been estimated around 20/400 at birth. Color vision and contrast sensitivity have only rudimentary function in the newborn. Best-corrected visual acuity gradually improves during early childhood as the brain and retina mature.

The central retina is still actively developing throughout the 20th and 30th weeks of gestation. Myelination of the optic nerves and radiations continues during this time as well. Infants have fused eyelids until 25 weeks’ gestational age (GA), and the lids can remain fused in some cases until 30 weeks’ GA. The effects of these changes on the development of visual function are still being studied. It is unknown whether earlier exposure to visual stimuli has a positive or negative effect on eventual visual development. However, premature infants may demonstrate delayed visual milestones in early infancy.

The pupillary light reflex should be observable after 31 weeks’ gestational age. A blink reflex to light can often be observed a few days after birth. 123

Basic Ocular Examination

The lids should be examined for any abnormalities, including malformation, swelling, or discharge. Pupils should be examined for signs of irregular shape. The cornea, lens, and retina should be assessed with the red reflex test.

The red reflex test was well described in a policy statement by the American Academy of Pediatrics in 2008, part of which is included here. The test uses the transmission of light from an ophthalmoscope through all the normally transparent parts of a subject’s eye, including the cornea, aqueous humor, lens, and vitreous. The light reflects off the retina and optic nerve, is transmitted back through the optical media and through the aperture of the ophthalmoscope, and is imaged in the eye of the examiner. Any factor that impedes or blocks this optical pathway will result in an abnormality of the red reflex.

The test is performed by holding an ophthalmoscope close to the examiner’s eye with power set at “0” and projecting the light simultaneously onto both eyes of the infant from a distance of approximately 18 inches away in a darkened room. Abnormalities include a diminished reflex, white reflex, or asymmetric reflexes.

Before discharge from the neonatal nursery, all children should have an examination of the red reflex of the eyes performed by a pediatrician or neonatologist. The test is important for the early detection of vision disorders and systemic diseases with eye manifestations. All infants with an abnormal or absent reflex should be referred immediately to an ophthalmologist.

In general, no. An adequate examination can usually be performed through the undilated pupil. There has been some question as to whether pupil-dilated red reflex examinations improve identification of conditions such as retinoblastoma and congenital cataract, but this has not been definitively established.

Leukocoria means “white pupil.” Differential diagnosis includes retinoblastoma, retinal detachment, cataract, retinopathy of prematurity (ROP), coloboma, primary persistent hyperplastic vitreous, congenital infection, and vitreous hemorrhage. Prompt ophthalmologic consultation is important in cases of suspected leukocoria.

Sclerocornea, Peters anomaly, forceps trauma, congenital glaucoma, congenital hereditary endothelial dystrophy, mucopolysaccaridoses, and corneal dermoids can result in a white or clouded appearance to the cornea and cause an abnormal red reflex. Prompt ophthalmologic consultation is important in cases of corneal clouding.

In a term baby tears are produced with crying beginning between month 1 and month 3 of life. Excessive tearing in the early stages of life most often represents congenital nasolacrimal duct obstruction, which is common and spontaneously resolves in approximately 90% of cases within the first year. However, excessive tearing associated with other abnormalities, such as blepharospasm and photophobia (in congenital glaucoma), or periocular erythema and edema (in dacryocystitis), warrants urgent evaluation.

Strabismus refers to misalignment of the eyes. Intermittent strabismus is often observed in the newborn and tends to resolve. Strabismus that persists beyond the first few months of life should be referred to an ophthalmologist for further evaluation. 45

ROP

ROP stands for retinopathy of prematurity. ROP is a vascular disease affecting the developing retina that is a leading cause of childhood blindness in the United States and throughout the world.

Retinal vascular development begins during the second trimester of pregnancy, and full maturation typically occurs during or after the third trimester of pregnancy. In premature babies much of this development is taking place ex utero. The abnormal retinal development seen in ROP is in response to the artificial environment experienced by the neonate after birth.

In the first phase of pathogenesis, hyperoxia leads to cessation of the normal vascular development of the peripheral retina. In the second phase increased metabolic demand causes relative hypoxia to the peripheral retina, which leads to increased production of pro-angiogenic growth factors such as vascular endothelial growth factor (VEGF) in the eye. This in turn stimulates abnormal proliferative vascular development. The proliferation can cause traction on the retina and bleeding inside the eye, which leads to vision loss ( Fig.15-1).

image

Figure 15-1 Schematic representation of IGF-1/VEGF control of blood vessel development in ROP. A, In utero, VEGF is found at the growing front of vessels. IGF-1 is sufficient to allow vessel growth. B, With premature birth, IGF-1 is not maintained at in utero levels, and vascular growth ceases despite the presence of VEGF at the growing front of vessels. Both endothelial cell survival (AKT) and proliferation (MAPK) pathways are compromised. With low IGF-1 and cessation of vessel growth, a demarcation line forms at the vascular front. High oxygen exposure (as occurs in animal models and in some premature infants) may also suppress VEGF, further contributing to inhibition of vessel growth. C, As the premature infant matures, the developing but nonvascularized retina becomes hypoxic. VEGF increases in retina and vitreous. With maturation, the IGF-1 level slowly increases. D, When the IGF-1 level reaches a threshold at 34 weeks’ gestation, with high VEGF levels in the vitreous, endothelial cell survival and proliferation driven by VEGF may proceed. Neovascularization ensues at the demarcation line, growing into the vitreous. If VEGF vitreal levels fall, normal retinal vessel growth can proceed. With normal vascular growth and blood flow, oxygen suppresses VEGF expression, so it will no longer be overproduced. If hypoxia (and elevated levels of VEGF) persists, further neovascularization and fibrosis leading to retinal detachment can occur. (Smith LEH. Pathogenesis of retinopathy of prematurity. Semin Neonatol 2003;8:469–73.)

The “first epidemic” of ROP occurred in the 1950s and involved premature babies exposed to high levels of oxygen after birth. In most developed countries the danger of high levels of oxygen to the neonatal eye is a well-known risk factor. Survival rates of extremely-low-birth-weight (ELBW) infants have increased as neonatal and oxygen management has improved in developed countries, and these ELBW infants are at high risk for ROP (“second epidemic”). In developing countries, where neonatal intensive care is still developing and infants are often exposed to high levels of supplemental oxygen, larger and more mature babies are once again getting ROP. This has been termed a potential “third epidemic” of ROP.

Risk factors for ROP include degree of prematurity; low birth weight; slow weight gain after birth; and general health factors, such as anemia; intraventricular hemorrhage; and acidosis. There may be a genetic predisposition to ROP, and advanced maternal age may also be an independent risk factor.

The frequency of ROP in the United States has been found to be approximately 65% in infants with birth weight below 1251 g. In most cases the disease is mild and spontaneously regresses. A small percentage of these infants will progress to disease requiring treatment, usually between 36 and 40 weeks postmenstrual age.

Infants with a birth weight of ≤1500 g or gestational age of 30 weeks or less (as defined by the attending neonatologist), and selected infants with a birth weight between 1500 and 2000 g or gestational age of >30 weeks with an unstable clinical course, should have retinal screening examinations. This examination is to take place either at 31 weeks’ GA or 4 weeks after birth, whichever is later.

The examination involves dilating the child’s pupils with eyedrops (e.g. Cyclomydril, which is a combination of 1% phenylephrine, a sympathomimetic, and 0.2% cyclopentolate, an anticholinergic). These drops are usually administered in each eye by the nursing staff. During the eye examination the ophthalmologist will typically look at the anterior segment (cornea, iris, and lens) of the eye with a penlight, and then examine the retina using indirect ophthalmoscopy (a headlamp with a handheld lens). The examination may include using a lid speculum to keep the eyelids open during the examination and pressing gently on the sclera using a small rod to view the peripheral retina. If retinopathy is noted, the severity (stage), extent (clock hours), location relative to the central retina (zone), and degree of vascular tortuosity (plus) are recorded. Examinations continue every 1 to 2 weeks until the peripheral retina is fully vascularized or more frequently if warranted by clinical findings ( Table 15-1).

TABLE 15-1

AGE AND TIMING OF FIRST ROP SCREENING EXAMINATION FOR INFANTS

AGE AT BIRTH TIMING OF FIRST ROP EXAMINATION
24 weeks GA 31 weeks GA
25 weeks GA 31 weeks GA
26 weeks GA 31 weeks GA
27 weeks GA 31 weeks GA
28 weeks GA 32 weeks GA
29 weeks GA 33 weeks GA
30 weeks GA 34 weeks GA
>30 weeks GA 4 weeks after birth

GA, Gestational age; ROP, retinopathy of prematurity.

Large, multicenter studies have shown that zone I disease with stage 3 severity, zone I disease in any stage with plus disease, or zone II disease with stage 2 or 3 severity and plus disease warrant prompt treatment. These entities were collectively defined by the Early Treatment for ROP (ETROP) study as “type 1 ROP.” Without prompt treatment a significant percentage of these children will progress to severe vision loss. On average, type 1 ROP occurs at 37 weeks’ postmenstrual age.

Laser treatment to the peripheral retina is currently the standard of care for the treatment of type 1 ROP. The treatment attempts to halt the production of VEGF by ablating the metabolically active, yet hypoxic peripheral retina. Ophthalmologists are divided regarding whether the infant should be intubated and anesthetized for the laser procedure or whether it may be performed at the NICU bedside with topical anesthesia and intravenous sedation. This varies depending on surgeon preference, extent of treatment, and other systemic comorbidities.

New data suggest that an injection of anti-VEGF medications such as bevacizumab (Avastin) directly into the vitreous of the eye may be beneficial for treatment of ROP, and the standard of care is still evolving in this area.

If the ROP progresses to the retinal detachment stage, further surgery is often required. This may consist of a vitrectomy (incisional surgery to remove fibrous tissue and flatten retinal detachment) or a scleral buckle (insertion of an encircling band around the eye to flatten retinal detachment).

Studies have shown that transient, small elevations in both heart rate and blood pressure may occur. These may result from both the administration of the dilating eyedrops and the eye examination itself. There are typically no lasting effects after the examination, but infants should be monitored carefully during ROP examinations.

In some centers bedside photographs of the retina with a specialized handheld camera (RetCam; Clarity Medical Systems, Pleasanton, Calif.) are obtained by trained staff in the NICU and sent electronically to an ophthalmologist for ROP screening and interpretation. This has been used in some areas, particularly where in-person ophthalmologic examination is difficult. The standard of care is still evolving in this area.

Many babies are discharged or transferred from the NICU at just about the time when most type 1 (treatment requiring) ROP will develop: at 37 weeks’ GA. It is imperative that the neonatologist, ophthalmologist, and discharge planner communicate and coordinate appropriately regarding discharge and follow-up in children who are high risk. ROP can progress rapidly, and even a short delay in a necessary follow-up ophthalmic examination can be the difference between a lifetime of functional vision and a lifetime of blindness for a premature child. Loss to timely outpatient ophthalmologic follow-up at the time of NICU discharge or transfer has been a common source of both poor visual outcome and malpractice claims against care providers.

Usually yes. Although severe complications are less frequent, follow-up with a pediatric ophthalmologist is recommended for infants with ROP who do not require treatment. This is because of the increased prevalence of myopia, strabismus, and astigmatic refractive errors in this population. 678910111213

Torch Complex

See Table 15-2.

TABLE 15-2

COMMON EYE MANIFESTATIONS OF TORCH INFECTIONS

NAME SYSTEMIC MANIFESTATIONS COMMON EYE MANIFESTATIONS
Toxoplasma gondii Hydrocephalus, intracranial calcifications Chorioretinitis
Rubella Deafness, heart disease Cataract, retinopathy, glaucoma
Cytomegalovirus Most asymptomatic Chorioretinitis
Herpes simplex virus Sepsis (natal/postnatal) Conjunctivitis, chorioretinitis
Syphilis Hepatosplenomegaly, rash Interstitial keratitis, cataract, chorioretinitis

Chorioretinal scar or active chorioretinitis is most characteristic. This has been reported in congenital toxoplasmosis, syphilis, cytomegalovirus, herpes simplex, lymphocytic choriomeningitis virus, varicella zoster virus, and West Nile virus. Chorioretinitis can be seen at birth but is often not evident until approximately the 10th day of life. 14

Cataract

A cataract is an opacity of the crystalline intraocular lens. Congenital cataracts can be associated with intrauterine infections, associated syndromes, metabolic disorders, genetic factors, or other ocular abnormalities. The prevalence is estimated to be between 1 and 13 cases per 10,000 births ( Table 15-3).

TABLE 15-3

CONGENITAL CATARACT ASSOCIATIONS

Intrauterine infections Toxoplasmosis, rubella, CMV, herpes, syphilis
Syndromes Trisomy 21: bilateral cataract eventually in 13% to 21% of patients, but only 1.4% presenting in neonatal period
Lowe syndrome
Genetics Autosomal dominant in approximately 25% of bilateral congenital cataract, but generally sporadic in unilateral congenital cataract
Other ocular disorders Aniridia, microphthalmos, anterior segment dysgenesis, persistent fetal vasculature
Metabolic Galactosemia, hypoparathyroidism, mannosidosis, hypoglycemia

CMV, Cytomegalovirus

Cataracts can cause blurring of the images reaching the retina or, in severe cases, block almost all light from reaching the retina. Visual stimuli to the developing retina are important for the early development of visual function in the brain. Lack of stimulation to the visual cortex during this critical developmental period results in decreased vision. Therefore if the retinal image is distorted from a cataract, the child may develop dense amblyopia and never develop normal vision, even if the cataract is removed later in life.

Bilateral cataracts with no family history should be further evaluated because they are often associated with an underlying etiology. Unilateral cataracts are rarely associated with other disease and generally do not require evaluation beyond clinical examination performed by an ophthalmologist.

Surgery is indicated if a congenital cataract is greater than 3 mm in diameter, prevents a good view of the retina, or is associated with either nystagmus or strabismus. Unilateral cataracts are often removed within the first 6 weeks after birth to prevent form-deprivation amblyopia. Bilateral cataracts are often removed within 10 weeks after birth. Postoperative visual rehabilitation often includes aphakic contact lenses, specialized glasses, and patching for an extended period of time. 15

Glaucoma

Glaucoma is a disease of the optic nerve that is associated in most cases with slow, progressive vision loss and elevated intraocular pressure. Congenital glaucoma is a particular subtype of glaucoma that is often caused by structural or developmental abnormalities of the newborn eye. In congenital glaucoma elevated pressure inside the eye can cause rapid loss of vision if left untreated.

Epiphora (excess tearing), blepharospasm (spastic lid closure), and photophobia (light sensitivity) are the classic triad of congenital glaucoma. Other signs and symptoms include buphthalmos (enlarged eye), corneal clouding (due to elevated intraocular pressure causing corneal edema), and pain.

In most cases surgery is required. Eyedrops and oral medications such as acetazolamide are often used as adjunctive therapy.

Cortical Visual Impairment

Cortical visual impairment describes abnormal vision resulting from brain dysfunction instead of eye dysfunction. Perinatal hypoxic ischemic injury is the most common cause of cortical visual impairment in children. Intracranial hemorrhage and periventricular leukomalacia can also cause cortical visual impairment. Cortical visual impairment is frequently accompanied by neurologic deficits. The eye examination reveals normal anatomy with normal pupil responses.

In severe cases there can be an inability to perceive light (i.e., complete blindness) in both eyes. It may be difficult to assess visual function in affected children in the perinatal period, and follow-up examinations after hospital discharge are needed to fully assess visual potential. 16

Nystagmus

Nystagmus is an involuntary, rhythmic pendular or jerking movement of the eyes.

Infantile nystagmus syndrome is an ocular motor disorder of unclear etiology, characterized by involuntary oscillations of the eye. These movements are usually horizontal with a small torsional component. Infantile nystagmus syndrome can occur in association with sensory visual defects, or it can be an isolated problem. Nystagmus that is secondary to severe visual loss is typically not observed at birth but instead develops approximately 2 to 3 months after birth.

Although nystagmus can be a sign of neurologic disease, nystagmus in the first 6 months of life is more likely caused by an ocular than by a neurologic disorder. Intermittent strabismus, or misalignment of the eyes, is common in the newborn period and should not be confused with nystagmus.

Children with suspected nystagmus should be referred to an ophthalmologist for further characterization. 1718

Periocular Problems

Most cases of NLDO in children result from blockage at the valve of Hasner, at the junction of the distal nasolacrimal duct and the inferior meatus of the nose. Excessive tearing and mucoid eye discharge can result. Most cases resolve spontaneously and are managed conservatively with massage and topical antibiotic eyedrops. However, some cases require probing and intubation of the nasolacrimal system. If infection of the lacrimal sac (dacryocystitis) develops, administration of intravenous antibiotics, surgical intervention, or both may be required.

The nasolacrimal duct can sometimes be obstructed both proximally and distally at birth. Mucus secreted by lacrimal sac tissue is then trapped inside the sac. This causes a bluish discoloration and distention to develop just below the medial canthus, adjacent to the nose. The discoloration and distention caused by dacryocystocele should be differentiated from discoloration and distention above the medial canthus, which is more likely to be caused by a deep hemangioma, meningioencephalocele, or dermoid.

Capillary hemangiomas and port-wine stains can occur on the face and eyelids. Large facial hemangiomas are sometimes associated with the PHACE syndrome (Posterior fossa malformation, Hemangioma, Arterial abnormalities, Cardiac abnormalities, Eye abnormalities) and can also cause ptosis or astigmatism. Port-wine stains on the face can be associated with Sturge–Weber syndrome and warrant a workup for associated ipsilateral glaucoma. Orbital cellulitis can also cause erythema and edema of the eyelid in the newborn, most often in association with a recent upper respiratory infection.

Congenital ptosis is an inability to raise one or both eyelids. Ptosis can cause significant astigmatism and can also cause form-deprivation amblyopia if the pupil is constantly occluded by the eyelid. A surgical procedure to raise the upper eyelids is often performed if amblyopia is present. 19

Genetics

See Table 15-4.

TABLE 15-4

GENETIC CONDITIONS FOR WHICH EYE EXAMINATION IS COMMONLY REQUESTED IN NICU

CONDITION EYE FINDINGS
Alagille syndrome Posterior embryotoxon
PHACE complex Lid hemangioma, microphthalmia, optic nerve hypoplasia, retinal vascular abnormalities
Down syndrome Prominent epicanthal folds, upward slanting palpebral fissures, cataract
Aicardi syndrome Chorioretinal depigmented lesions
CHARGE Coloboma
Moyamoya disease Morning Glory syndrome, Coloboma
Septo-optic dysplasia (de Morsier) Optic nerve hypoplasia

image KEY POINTS

1Mills MD. The eye in childhood. Am Fam Physician 1999;60(3):907–16.

3Repka MX. Ophthalmological problems of the premature infant. Mental Retardation and Developmental Disabilities Research Reviews 2002;8:249–57.

4Ramasubramanian A, Johnston S. Neonatal eye disorders requiring ophthalmology consultation. NeoReviews 2011;12(4):c216–c222.

5Buckley EJ, Ellis GS, Glaser S, for the American Academy of Pediatrics section on ophthalmology. Red reflex examination in neonates infants, and children. Pediatrics 2008;122:1401–1404.

2Hoyt CS, Good W, Petersen R. Disorders of the eye. In: Taeusch HW, Ballard RA, Avery ME, editors. Schafer and Avery’s diseases of the newborn. 6th ed. Philadelphia: Saunders; 1991.

6Chen J, Stahl A, Hellstrom A, et al. Current update on retinopathy of prematurity: screening and treatment. Curr Opin Pediatr 2011;23(2):173–8.

7Mills MD. Evaluating the cryotherapy for retinopathy of prematurity study (CRYO-ROP). Arch Ophthalmol 2007;125(9):1276–81.

8Good WV. Final results of the early treatment for retinopathy of prematurity (ETROP) randomized trial. Trans Am Ophthalmol Soc 2004;102:233–50.

9Mintz-Hittner HA, Kennedy KA, Chuang AZ for the BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med 2011;364:603–15.

10Darlow BA, Ells AL, Gilvert CE, et al. Are we there yet? Bevacizumab therapy for retinopathy of prematurity. Arch Dis Child Fetal Neonatal Ed 2013;98(2):F170–4

11Chiang MF, Melia M, Buffenn AN, et al. Detection of clinically significant retinopathy of prematurity using wide-angle digital retinal photography: a report by the American Academy of Ophthalmology.Ophthalmology 2012;119(6):1272–80.

12Richter GM, Williams SL, Starren J, et al. Telemedicine for retinopathy of prematurity diagnosis: evaluation and challenges. Surv Ophthalmol 2009;54:671–85.

13Laws DE, Morton C, Weindling M, et al. Systemic effects of screening for retinopathy of prematurity. Br J Ophthalmol 1996;80:425–8.

14Mets MB, Chhabra MS. Eye manifestations of intrauterine infections and their impact on childhood blindness. Surv Ophthalmol 2008;53(2):95–111.

15Krishnamurthy R, Vanderveen DK. Infantile cataracts. Int Ophthalmol Clin 2008;48(2):175–92.

16Flanagan C, Kline L, Curè J. Cerebral blindness. Int Ophthalmol Clin 2009;49(3):15–25.

17Hertle RW. Nystagmus in infancy and childhood. Semin Ophthalmol 2008;23:307–317.

18Kline LB, Chair. Section 5: Neuro-ophthalmology. In: Basic and clinical science course 2009–2010. American Academy of Ophthalmology; 2009.

19Holds JB, Chair. Section 7: Orbit, eyelids, and lacrimal system. In: Basic and clinical science course 2009–2010. American Academy of Ophthalmology; 2009.

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