Eye and Vision Disorders

The Newborn Eye Examination: Approach and Equipment

Screening eye examinations are important in all infants, regardless of gestational age. All neonates should have an examination of the red reflex before discharge from the newborn nursery.

A more thorough eye examination, although necessary, can be stressful and sometimes painful for a newborn or a young infant. ROP examinations in particular, which often necessitate the use of an eyelid speculum to retract the eyelids and scleral indentation to visualize the peripheral retina, have been associated with an increase in pain. The procedure has also been associated with other adverse effects, including episodes of desaturations, bradycardia, hypertension, and prolonged crying times. Swaddling, nesting, nonnutritive sucking, and oral administration of sucrose before, during, and after an examination can be very helpful in this regard, particularly for premature babies undergoing serial ROP examinations. The most distressing aspects of the eye examination are generally the bright light of the ophthalmoscope and the insertion of the speculum. The use of a topical anesthetic, such as proparacaine hydrochloride 0.5% or tetracaine 0.5% drops, reduces the discomfort but is not always sufficient and should be supplemented with other measures, such as sucrose, pacifiers, and nesting. In addition, NICU and office staff should be aware that the repetitive use of topical anesthetics can result in corneal ulceration and melting, so bottles should be properly disposed of and not confused with other medications, such as topical lubricants or antibiotics. The use of an indirect ophthalmoscope without a speculum may produce less pain response than that noted during examination with a speculum or with a contact fundus camera, such as the RetCam (Clarity Medical Systems, Pleasanton, California, United States). Nevertheless, a speculum is often necessary to adequately visualize ocular structures and should always be used if adequate visualization of the fundus is otherwise not possible. Assistance with comforting the baby and monitoring vital signs is important. In addition, the head and body of the infant may need to be securely held to allow both a detailed and a safe examination. Finally, a particular note should be made of the oculocardiac reflex, a dysrhythmia, typically bradycardia, resulting from direct manipulation of the eye during and immediately after the examination; monitoring by an assistant during and after the examination is therefore important. Nevertheless, it is extremely rare for a properly supported infant to be unable to tolerate a quick fundus examination, the discomfort of any observers notwithstanding. Eye examinations should not be postponed unilaterally without first discussing with the ophthalmologist the risk of ROP in each specific infant.

Pharmacologic dilation with mydriatic eye drops is commonly performed by consulting ophthalmologists, typically on all new patient evaluations and at all ROP examinations. Occasionally, a pediatrician may find it helpful to dilate the pupils to better visualize the red reflex or optic nerve head. Use of drops is better deferred if an ophthalmology consultation will be requested, because dilating the pupils may make it difficult or impossible to accurately assess the pupils, ocular alignment, intraocular pressure, and iris. Dilating eye drops include sympathomimetic drugs (e.g., phenylephrine) and anticholinergic drugs (e.g., tropicamide, cyclopentolate, and atropine). Potential side effects of these drugs include elevated blood pressure, increased heart rate, cardiac arrhythmias, feeding intolerance, slowed gastric emptying, urticaria, contact dermatitis, and seizures. Bradycardic and apneic episodes following administration of these eye drops are pain response reactions and not a direct effect of the drugs. Cohen et al. analyzed masked videotapes from before, during, and after eye drop administration and found that one-third of infants have a significant pain response to mydriatic eye drops. Supportive measures, therefore, can also be used at the time of administration of dilating eye drops. Adverse effects are potentially of greater concern in preterm infants, who are of lower weight and typically require multiple doses to achieve adequate dilation, as do many children with dark irides. Therefore it may be prudent to use reduced concentrations of mydriatics in premature infants, particularly cyclopentolate. A randomized masked trial concluded that cyclopentolate 0.2% with phenylephrine 2.5% is the mydriatic of choice in preterm infants with dark irides because higher concentrations of cyclopentolate (0.5%, 1.0%) were more likely to result in increased mean blood pressure or feeding intolerance. In all children, systemic absorption of eye drops can be minimized by compression of the lacrimal sac for 1 to 2 minutes after instillation. It is also recommended to wipe all the overflow drops from the skin as local vasoconstriction and pallor of the periorbital skin are frequently observed in premature neonates in whom the epidermal permeability barrier is still incompetent. These authors typically use three drops of Cyclomydril (cyclopentolate hydrochloride 0.2% and phenylephrine hydrochloride 1%) or tropicamide 1% and phenylephrine 2.5% separated by 5 minutes in each eye, 30 to 60 minutes before the examination. Multiple doses are necessary because, in premature and newborn babies, adequate pupil dilation is often difficult to obtain because of the immaturity of the dilator muscle of the pupil; the pupils of babies with dark irides, in particular, may be more difficult to dilate because of pigment binding of the mydriatic drugs, and higher concentration or more frequent administration may be required. We recommend avoiding the use of cyclopentolate 1% in children younger than 6 months.

Red reflex testing with a direct ophthalmoscope (described in detail later) is a mandatory element of all newborn and well-baby physical examinations. Numerous vision-threatening and even life-threatening ocular diseases are primarily identified by the checking of red reflexes. The direct ophthalmoscope may, of course, be used to directly visualize the optic nerve head and retina, but particular considerations and limitations must be kept in mind. Pupil size must be maximal; typically this means pharmacologic dilation (see above). If mydriatics are not used, dimming ambient light will maximize pupil dilation. The examiner must be very close to the infant (a few centimeters at most). Approaching from a slightly lateral angle and following the “arrows” of branching vessels back to the nerve head will help to identify the optic disc. Most important, the field of view or “spot size” of the direct ophthalmoscope is approximately the size of the optic nerve head, which represents but a tiny fraction of the ocular fundus. Therefore it is not possible to adequately evaluate the retina for ROP or other peripheral retinal diseases with a direct ophthalmoscope; instead, an indirect ophthalmoscope is needed. This instrument requires both greater skill and a handheld lens to use but provides binocular viewing with depth perception and a much wider field of view. Pharmacologically dilated funduscopic examination with an indirect ophthalmoscope is required for ROP and other retinal diagnostic examinations, such as for retinoblastoma or retinal hemorrhage (RH) in suspected abusive head trauma (AHT).

In addition to red reflex testing, the eyes should be closely examined with proper lighting and magnification as part of a newborn general exam. The periocular and ocular structures should be approached in a systematic manner. One option is to begin with the external structures and work inward and posteriorly, looking at each eye carefully and comparing the two eyes with each other. As a guideline, any abnormality or asymmetry noted on examination should be referred to a pediatric ophthalmologist for further management. The urgency with which to seek consultation depends on the specific finding, and guidelines appear throughout this chapter. However, one should err on the side of urgency, because the neonatal period is a critical period in visual development. To adequately inspect the eyes, familiarity with normal anatomy is required. A general overview of these structures follows ( Fig. 96.1 ).

The eyelids protect the eyes. The eyelids contain numerous glands, which produce tears to keep the ocular surface well lubricated. Blinking spreads the tears and actively pumps the tears into the lacrimal drainage system. An inability to adequately close the eyes presents a major problem and can result rapidly in surface drying, corneal epithelial breakdown, and vision- or eye-threatening complications, such as ulceration, infection, or scarring. Use of an overhead heater should be avoided for infants who have poor eyelid closure (e.g., congenital eyelid abnormalities, neurologic problems), as the ocular surface can rapidly decompensate in such cases; alternative sources of maintaining body temperature should be used, and an ophthalmology consultation should be requested to manage the ocular surface.

The nasolacrimal duct provides a means of egress for tears, which pass through the puncta, canaliculi, and lacrimal sac to the duct. The duct is blocked at birth in 5% to 20% of newborns, resulting in epiphora and discharge in an otherwise white and quiet eye; more than 90% of such blockages clear by 1 year of age. Of note, congenital glaucoma can manifest itself with epiphora as well (see Corneal Clouding).

The conjunctiva is a translucent membrane that overlies the surface of the eye and the inside of the eyelids. The sclera is the white, fibrous wall of the eye. It is relatively flexible at birth and gradually toughens over the first few years of life. The cornea is continuous with the sclera, which it meets at the limbus, and is a clear dome-shaped structure in the center of the globe (eye). The iris is a donut-shaped structure posterior to the cornea. The anterior chamber of the eye lies between the cornea and the iris and is best visualized with slit lamp examination but this is often not possible in neonates and infants. The iris is an immature structure at birth. The color tends to be gray, blue, or light brown and may become darker as the pigmented layer of the iris stroma becomes more fully developed, which typically occurs by about 6 months of age. Heterochromia refers to differences in the color of the iris between or within eyes and can be seen in congenital Horner syndrome (with mild ptosis and a miotic pupil), as well as syndromic conditions such as Waardenburg syndrome or Hirschsprung disease. Behind the iris lies the crystalline lens. An opacity in the lens is referred to as a cataract (see Leukocoria and Abnormal Red Reflex). The uvea is composed of the iris, the ciliary body, and the choroid. The retina is a multilayered, complex, highly metabolically active structure that lines the inside surface of the globe and contains photoreceptors that receive light and generate neuronal signals that are ultimately perceived as visual images. The macula is the central, posterior retina, between the superior and inferior temporal retinal vascular arcades, and the fovea is the very central retina containing the highest concentration of photoreceptors and producing central, high-resolution vision. Visual signals are transmitted through the optic nerve, whose cell bodies lie in the most anterior retina and which is composed of approximately 1 million individual nerve fibers. The proximal end of the optic nerve is visible as a normally golden disc approximately 15 degrees nasal and just superior to the fovea. The optic nerves lead to the optic chiasm and continuing visual and pupillary pathways in the brain.

Knowledge of normal eye structures and certain growth parameters in the newborn is important because a deviation from the averages can be associated with significant disease. For example, in congenital glaucoma, the corneal diameter is increased, and the axial length (sagittal length) of the eye is a parameter that is carefully followed by the ophthalmologist, with the aid of an ultrasound examination, to determine if the intraocular pressure is adequately controlled. At birth, the eyeball is 70% of the adult size (the average axial length in a newborn is 17 mm) and reaches 95% of the adult size by age 3 years. The corneal horizontal diameter is usually 9.5 mm at birth, which is 80% of the adult diameter. Corneal diameter can be assessed by simple bedside examination.

The visual system is immature at birth. The fovea is not completely differentiated until 15 to 45 months, and myelination of the optic nerve is not completed until about 1 year of age. The eye continues to develop synapses in the visual cortex during the first 10 years after birth, and although visual acuity reaches normal adult ranges by 2 years of age, this period continues to be important because any abnormality can lead to amblyopia (see the definition later). Color vision improves greatly during the first 3 months after birth, and most normal 3-month-olds have at least some color vision; color visual processing mechanisms continue to mature throughout the first year of life.

Because of the immaturity of the system at birth, qualitatively estimating the vision of a newborn is seldom attempted, and other clues to the status of visual function are more commonly used. However, clinical and laboratory techniques can be used to estimate vision in special situations. These include eliciting a nystagmus response with optokinetic targets (striped patterns), Teller cards for preferential forced looking (a test that depends on an infant’s preference to look at patterns—grating of black and white stripes—rather than homogeneous fields), visual evoked potentials, and electroretinogram. Each of these techniques uses different stimuli and yields somewhat different results, but they all demonstrate a dramatic improvement in “acuity” during the first year of life. Most commonly, visual function in a newborn is assessed by the detection of light aversion, which implies light perception. A bright light is shone into each eye or even through the thin eyelids to elicit the closing or squeezing of the lids. Although visual fixation may be intermittently present soon after birth, it is not well developed until after the second month; in contrast, a blink response to light is already present at 26 weeks’ postmenstrual age (PMA), and head turning to a diffuse light starts around 32 weeks’ PMA. A blink in response to an approaching object (visual threat response) does not develop until approximately 16 weeks’ postnatal age. An infant should fix on and follow a face or object by 2 to 3 months of age. A clever technique that is based on the observation that neonates and infants will attend to the reflection of their own faces in a mirror has been described. Measurement of the “mirror distance” is a simple and reliable technique to estimate visual acuity in infants that can be used as a screening test similar to the traditional “fix and follow” (see later) and is a useful additional tool for detecting impaired visual function at this early age. Generally, the absence of visual responsiveness by a developmental or corrected age of 2 months should be taken seriously and prompt an urgent ophthalmologic evaluation.

Poor vision or blindness should be suspected in any infant with absent or poor pupillary responses, paradoxical pupillary response (initial brisk constriction of the pupil when the lights are turned off), and nystagmus or roving eye movements, although these are not usually present until 2 to 3 months of age. Constant poking or rubbing of the eyes can also be a sign of poor vision.

Causes of congenital blindness or poor vision include Leber congenital amaurosis (an early and severe form of retinitis pigmentosa), other retinal dystrophies (achromatopsia and congenital stationary night blindness), congenital cataract, glaucoma, aniridia, albinism, optic nerve abnormalities (hypoplasia and coloboma), chorioretinal colobomas, high refractive errors, and congenital infections. In most babies, the cause of poor vision is obvious after a complete ophthalmologic examination. Occasionally, further investigation is necessary and may include electrophysiologic testing and neuroimaging. Babies with cerebral (central or cortical) visual impairment (CVI) have normal eye examination findings, including normal pupillary responses and no nystagmus. CVI is used to describe children with visual impairment as a result of neurologic disease, which may be congenital or acquired. Perinatal causes include intrauterine infection, cerebral dysgenesis, asphyxia, hypoglycemia, intracranial hemorrhage, periventricular leukomalacia, hydrocephalus, trauma, meningitis, and encephalitis. In developed countries, CVI is the single greatest cause of visual impairment in children, and most of these children have an associated neurologic deficit (usually epilepsy or cerebral palsy), which places a major burden on children’s special services in these countries.

The prevention of all causes of blindness in infants and children is considered a high priority within the World Health Organization. This is because many causes of blindness in childhood are preventable or treatable and many of the conditions associated with blindness in children are also causes of child mortality (e.g., premature birth, congenital rubella syndrome, Vitamin A deficiency). Prevention of blindness in children is therefore closely linked to child survival, in addition to decreasing the economic, emotional, and social burden of a lifetime of blindness. This, however, imposes particular challenges as children are born with an immature visual system and, for normal visual development to occur, they need clear, focused images to be transmitted to the higher visual centers in the brain. Failure of normal visual maturation (amblyopia) cannot be corrected in adult life, so there is a level of urgency in treating childhood eye diseases.

Amblyopia is defined as a reduction in best-corrected vision that cannot be attributed directly to any structural abnormality of the eye or proximal visual pathway. Amblyopia is the maldevelopment of the visual centers of the brain as a result of abnormal visual experiences early in life. It includes three etiologic categories, which often overlap. Deprivational amblyopia results from obstruction at any point in the visual axis that causes the retina to perceive poor-quality, distorted, or no images. The causes of deprivational amblyopia include congenital or acquired cataracts, corneal opacity, ptosis, and vitreous hemorrhage. Strabismic amblyopia results from a child’s preferring one eye over the other when the visual axes are misaligned. Refractive amblyopia is a consequence of either a significant inequality of the refractive error in each eye or very high refractive errors in both eyes. Any of these forms of amblyopia can be encountered in the first few months of postnatal life. Because amblyopia is responsible for more cases of unilaterally reduced vision in childhood than all other causes combined, and because it is highly preventable with early detection and treatment, all newborns and infants suspected of having any of these conditions should be referred promptly to an ophthalmologist.

The onset of the pupillary light reflex (constriction in response to light) occurs around 30 to 34 weeks’ gestation and is not fully developed until the first month after birth. The pupils should be examined for size, shape, symmetry, reactivity to light, and afferent defects.

As the light passes through the pupils and is reflected through the normal clear media of the anterior and posterior segments of the eye, a characteristic red reflex is produced. The reflex is generated not from the retina, which is transparent, but from the choroidal pigmentation and vasculature. The red reflex test is vital for the early detection of vision and potentially life-threatening conditions such as cataracts, glaucoma, retinoblastoma, retinal abnormalities, systemic diseases with ocular manifestations, and high refractive errors. Red reflex assessment is an essential component of every neonatal and infant physical examination. The American Academy of Pediatrics currently recommends that all neonates have an examination of the red reflex before discharge from the neonatal nursery. In addition, the test should be performed during all subsequent routine health supervision visits.

The red reflex test should be performed in a darkened room, projecting the largest white-light circle light of the ophthalmoscope onto both eyes of the infant—first simultaneously, from approximately 18 inches away, while looking through the aperture of the ophthalmoscope. Once the reflexes have been assessed together to allow comparison, specific abnormalities can be more closely inspected by examination of each eye separately at a nearer distance. Since neonates and infants are frequently asleep and it is difficult to open their eyes and keep them open, the red reflex test may be challenging. A useful technique to encourage a neonate to spontaneously open the eyes is the use of a primitive reflex seen in neurologically healthy children up to 6 months old: the child is supported by a hand on the thorax at approximately a 45-degree angle from the horizontal with use of the other hand to jiggle the child’s bottom.

It is not necessary to pharmacologically dilate the pupils, although the reflexes are easier to assess with larger pupils; indeed, the most common cause of an absent reflex is small pupils. Darkening the room or changing the light beam of the ophthalmoscope will usually overcome this problem. Although traditionally the normal reflex has been described as “red,” it can often be yellow, orange, or maroon, depending on the amount of skin/eye pigmentation (i.e., light orange-yellow in lightly pigmented blue eyes or dark red in darkly pigmented brown eyes). A common cause of misdiagnosis is the inability to appreciate variations of normal due to a reference comparison to the color reflected from a blonde fundus. Darkly pigmented individuals often have a duller red reflex due to the increased amount of melanin in their fundus. Therefore, the symmetry of the color, clarity, and intensity of the red reflex between the eyes is usually more useful than the qualitative assessment of each red reflex independently. A markedly diminished or dim reflex, the presence of a white reflex (leukocoria), dark spots in the reflex, or an asymmetric reflex between the eyes is an indication for immediate referral to an ophthalmologist experienced in the examination of children. An exception to this rule is a transient opacity in the tear film from mucus or a foreign body that is mobile and completely disappears with blinking or manual opening and closing of the eyelids, after which the red reflex should appear normal. Unequal or high-refractive errors (need for glasses) and strabismus may also produce abnormal or asymmetric red reflexes. An additional observation is the position of the light reflex on the corneal surface. Asymmetric positioning of this reflex can indicate misalignment of the eyes (strabismus; see later).

In addition, the shape and regularity of each pupillary aperture should be assessed to look for colobomas ( Fig. 96.2A ) and other congenital abnormalities (see Common Diagnostic Problems). Asymmetry of pupil size (anisocoria) can be a sign of Horner syndrome, trauma, or a congenital third nerve palsy. The tunica vasculosa lentis is a plexus of vessels that crosses the pupil, visible in preterm babies up to 34 weeks’ PMA. The extent of this anterior lens capsule vascularity can be used to estimate gestational age in babies between 27 and 34 weeks’ gestation. A failure of these vessels to regress can occasionally be seen as a persistent pupillary membrane, which appears as a regular arrangement of vessels looping into the pupillary axis in front of or behind the lens.

Although the extraocular muscles are formed by 12 weeks’ gestation and fetal eye movements can be detected as early as 16 weeks’ gestation, the supranuclear eye movement system is not fully developed until after birth in full-term neonates. The eyes of a neonate commonly appear misaligned. It is not unusual to see the eyes shift from straight (orthotropia) to crossed inward (esotropia) to outward (exotropia). Transient deviations (neonatal ocular misalignments) occur very commonly in the first month of life in visually normal infants. At this age, it is not possible to distinguish those infants who will progress to develop pathologic strabismus from those who will develop normal binocular vision. Exotropia is commonly observed in newborn nurseries and has been reported to occur in up to 33% of infants; however, most exodeviations will usually resolve with the development of the fixation reflex and are rarely observed beyond 6 months of age. In contrast, transient esodeviations in patients who do not go on to develop infantile esotropia do not usually persist beyond 10 weeks of age. Most full-term infants establish normal ocular alignment within the first 8 weeks of life. In some babies the epicanthal folds of the eyelids hide the medial aspect of the sclera, creating the appearance of strabismus; however, in these cases, the visual axes are not misaligned. This common condition is referred to as pseudostrabismus ( Fig. 96.3B ) and can be confirmed by the directing of a bright light to both eyes simultaneously and observing that the reflection of the light on the corneas appears symmetric between the eyes with respect to the center of the pupil; the reflexes will appear asymmetric between the eyes if a true misalignment exists ( Fig. 96.3A ).

Most cases of strabismus in infants are not paralytic in origin, but congenital third, fourth, and sixth nerve palsies can occur, as well as early acquired cranial neuropathies due to trauma, infection, and other central nervous system abnormalities. When there is doubt, any apparent misalignment after 3 to 4 months of age should be considered pathologic and referred for evaluation. This is especially important as, in some cases, strabismus can also be the first sign of serious ocular or systemic disorders. Premature and low birth weight infants are at increased risk of developing strabismus and other amblyogenic conditions throughout their childhood. Perinatal stroke is also associated with a high incidence of strabismus, early head turn, visual field cuts, and other vision abnormalities. Such high-risk infants as well as those with a strong family history of strabismus or amblyopia should be referred for evaluation.

It is recommended that all newborns have an ocular motility assessment. In addition, since vision in young nonverbal children is mostly assessed by evaluation of the child’s ability to fix on and follow an object, this test provides information on the status of the visual and extraocular muscle systems. A standard assessment strategy is to determine whether each eye can independently fixate on the object, maintain fixation on it for a short period, and then follow it as it is moved in various directions. Neonates and young infants particularly fix and follow the human face or its likeness. This assessment should be performed binocularly and then monocularly in an awake and alert child. In neonates, the following may be a jerky saccadic pursuit movement, which represents a series of hypometric saccades to localize the target. If following cannot be demonstrated, it should be verified that the motor system is intact. Range of motion and the ability to generate a saccade may be assessed by the inducement of vestibular nystagmus by rotation of the child. If poor fixation and following are noted after 3 months of age, a significant ocular or neurologic abnormality is suspected and should be referred for evaluation.

Leukocoria and Abnormal Red Reflex

The term leukocoria means “white pupil.” It is often used more broadly to encompass a spectrum of opacities and abnormalities. On inspection, the pediatrician may grossly visualize a white lesion in the pupillary space or identify an abnormal red reflex. A white or abnormal reflex may also be identified in recreational photographs taken by family members. The differential diagnosis for leukocoria includes vision- and life-threatening conditions, and leukocoria in an infant or older child requires urgent ophthalmologic evaluation. These conditions include cataract, retinoblastoma, chorioretinal or optic nerve head coloboma, retinal detachment, vitreous hemorrhage, advanced ROP, persistent fetal vasculature, Coats disease, familial exudative vitreoretinopathy, toxocariasis, and uveitis. The distribution differs widely with the population studied. In one series, 60% of 71 children who presented to a tertiary referral center with leukocoria had cataracts, 28% had retinoblastoma, and 12% had other retinal abnormalities.

Cataract

A cataract is any opacification of the normally clear crystalline lens of the eye. Although congenital cataract is much less common than age-related cataract, it is among the top 3 causes of preventable childhood blindness and is responsible for approximately 10% of childhood blindness worldwide. Congenital cataracts may be isolated, seen in association with another ocular developmental abnormality, or associated with systemic diseases. The incidence of congenital cataract is approximately 2 to 4 in 10,000 live births. Some subtypes of congenital cataracts are small and nonprogressive; dense central opacities larger than 3 mm are considered visually significant. Successful treatment of congenital cataracts may be extremely difficult, and intervention must occur very early in life; therefore early diagnosis is essential. Useful vision can be restored if the surgery is completed within the first 6 weeks after birth. Beyond this time, visual restoration becomes progressively more difficult because of irreversible deprivation amblyopia. The appearance of nystagmus before surgery is an ominous sign of poor visual outcome and adds further urgency for surgical intervention. Therefore it is essential that all newborns and young infants have screening eye examinations by a pediatrician because the visual prognosis is directly tied to timely ophthalmologic referral. Cataracts can develop or progress with time, so examination for an abnormal red reflex should be repeated at each well-child visit even if prior examination findings appeared normal.

Most patients with isolated nonsyndromic cataracts have no identifiable cause. Although teratogenic agents (e.g., rubella) may account for a proportion of cases, such insults normally give rise to other systemic malformations in addition to cataracts. Genetic mutation is likely to be the most common cause, particularly for bilateral cataracts; it is estimated that hereditary cataracts constitute 22% of global childhood cataracts. Genetic inheritance is most commonly autosomal dominant and rarely autosomal or X-linked recessive. Multiple genes are involved in lens development; mutation screening of inherited congenital cataracts have identified nearly 200 locus and more than 100 causative genes.

Marked variability can be present even within the same pedigree, and children with a family history of infantile or juvenile cataracts should be examined early by a pediatric ophthalmologist. The same is true of children with one of the numerous systemic conditions associated with cataracts: intrauterine infections (rubella, varicella); metabolic and endocrine disorders (galactosemia, neonatal hypoglycemia, diabetes mellitus, and hypoparathyroidism); fetal alcohol syndrome; chromosomal disorders (trisomy 21, Turner syndrome, trisomies 13 and 15); dermatologic diseases (congenital ichthyosis, ectodermal dysplasia); skeletal and connective tissue disorders (Smith-Lemli-Opitz, Marfan, Conradi, and Weill-Marchesani syndromes); renal disorders (Lowe, Alport, and Hallermann-Streiff-François syndromes); neurofibromatosis; and myotonic dystrophy. A selective diagnostic evaluation may be pursued in infants with cataracts, particularly bilateral cataracts, and may include TORCH titers (including syphilis); urine tests for reducing substance (galactosemia); plasma urea, electrolyte, and urinary amino acid levels (Lowe syndrome); complete blood count and ferritin, blood glucose, calcium, and phosphate levels; quantitative amino acid levels and red blood cell enzyme levels (galactokinase, galactose1-phosphate uridyltransferase); genetic consultation; chromosome analysis and next-generation sequencing and ocular examination of parents and siblings. Infants with isolated unilateral cataracts often do not have a family history and rarely have associated systemic disorders.

Retinoblastoma

Retinoblastoma is the most common ocular malignancy of childhood and accounts for 3% of all childhood cancers. The average age-adjusted incidence rate of retinoblastoma in the United States and Europe is 2 to 5 per million children or 1 in 14,000 to 18,000 live births but is higher in India and Africa (resulting in approximately 9000 new cases per year, of which fewer than 300 are in the United States). Seventy-five percent of patients have unilateral retinoblastoma, and 25% have bilateral retinoblastoma. The successful management of retinoblastoma depends on the ability to detect the disease while it is still intraocular; disease stage correlates with delay in diagnosis. Untreated retinoblastoma is almost uniformly fatal, and the long-term survival rate for disease diagnosed after it has spread outside the eye is less than 50%. In contrast, 5-year survival rates are greater than 90% when timely recognition and referral to centers specializing in retinoblastoma treatment occur ( http://www.1rbw.org ).

Two-thirds of patients receive a diagnosis before 2 years of age, and 95% receive a diagnosis before the age of 5 years. The earliest age at diagnosis reported is 21 weeks’ gestation by prenatal ultrasound examination. Abramson et al. reviewed 1831 consecutive cases of retinoblastoma. The most common presenting sign was leukocoria (54%), followed by strabismus (19%), poor vision (4%), family history with request for early examination (5%), and red eye (5%). The presenting sign was identified first by a family member or friend in 80% of cases, a pediatrician in 8% of cases, and an ophthalmologist in 10% of cases. Among patients presenting with leukocoria, the sign was first identified by a family member in 90% of cases. These findings stress the importance of routine red reflex testing for all children seen by pediatricians, beginning with newborns. Any child found to have leukocoria should be referred to an ophthalmologist for urgent evaluation.

The retinoblastoma gene, RB1 , located on chromosomal region 13q14, was the first tumor suppressor gene to be described. Five percent of patients with bilateral disease carry a large deletion involving the 13q14 locus. In those cases, retinoblastoma is part of a more complex syndrome characterized by facial dysmorphic features (thick anteverted earlobes, high and broad forehead, prominent philtrum, and short nose), skeletal abnormalities, mental retardation, and motor impairment. Children with germline mutations are at increased risk of developing nonocular tumors. Genetic counseling of affected parents is critical to estimate the risk of transmitting the disease to their children. Regardless of the clinical presentation, it is recommended that all patients undergo genetic testing.

Persistent Hyperplastic Primary Vitreous (Persistent Fetal Vasculature)

PFV is a congenital ocular dysgenesis in which the hyaloid embryonal vasculature does not regress completely. During embryogenesis and fetal development, the “primary vitreous” contains the hyaloid vasculature system, which fills the posterior segment of the eye and comes forward to surround the lens. This system normally disappears, and a spectrum of abnormalities can be seen when these structures fail to regress, ranging from persistent pupillary strands to a vascular stalk remnant to a retrolenticular membrane and retinal disorganization or detachment. Involved eyes are typically microphthalmic, and an abnormal red reflex or leukocoria may be identifiable. Depending on the extent, surgical intervention may help to avoid recurrent hemorrhage, glaucoma, and phthisis bulbi (atrophy and degeneration of a blind eye, which can become painful), and in some cases, useful vision can be achieved. Persistent hyperplastic primary vitreous (PHPV) is the most common retinoblastoma-simulating lesion, followed by Coats disease and presumed ocular toxocariasis.

Coloboma

An ocular coloboma is a congenital anatomic defect or cleft that results from the failure of the optic fissure to close during embryogenesis. The result is essentially an area of missing tissue in the eye, most commonly in the inferonasal quadrant. Depending on the population studied, its incidence ranges from 0.5 to 7.5 per 10,000 births and accounts for 3% to 11% of blind children worldwide. Involved structures can include the iris, ciliary body, retina, choroid, and optic nerve (see Fig. 96.2 ). An iris coloboma appears as an irregular “keyhole,” or “cat’s-eye” pupil (see Fig. 96.2A ). A chorioretinal or optic nerve head coloboma, depending on the size, will appear as an abnormal red reflex or leukocoria. The affected eye may be microphthalmic (see Fig. 96.2B ). The visual prognosis depends on whether the central macula is involved, and children may have good central vision despite upper visual field defects if the macula is spared. Long term, there is a variable risk of complicating retinal detachment or choroidal neovascularization associated with retinal and optic nerve colobomas. An ocular coloboma can be isolated or syndromic. There are numerous ocular abnormalities and systemic findings associated with coloboma, and more than 200 syndromes have been described. Examples include the CHARGE association, 22q11 deletion, and Treacher Collins, Walker-Warburg, and Aicardi syndromes. The systemic diagnostic testing in patients with apparently isolated bilateral or unilateral uveal coloboma should include a kidney ultrasound examination, audiometry, and spine radiographs. In addition, an echocardiogram and neuroimaging could be considered.