Table Of Contents
TERATOGENICITY OF OCULAR THERAPEUTIC AGENTS
OPHTHALMIA NEONATORUM PROHYLAXIS
MYDRIATIC EYE DROPS
PHOTOTHERAPY FOR HYPERBILIRUBINEMIA
DEVELOPMENT OF VISUAL FUNCTION
|Certain ocular conditions, such as dacryocele, congenital cataract, and
retinoblastoma may be detected on prenatal ultrasound. The family with
a known genetic risk of ocular disease may have concerns about the future
of the child's health. Antenatal ophthalmology is the prenatal
diagnosis and counseling of patients with or at risk for ophthalmologic
abnormalities. Education of the family may occur prior to the stressful
time of delivery. The family with a remote history of ocular disease
may benefit from an update on current treatment options. Information
about the disease and treatment options may aid in a family's
decision concerning early delivery for a life-threatening condition, such
as retinoblastoma, found on prenatal ultrasound. The antenatal
consultation allows for prompt evaluation and treatment after birth.|
Some studies show an increased rate of chromosomal abnormalities in the population of infants born after in vitro fertilization. A rate of ocular abnormalities in infants born after in vitro fertilization was found to be 26% in one study. Abnormalities included refractive errors, anisometropia, and strabismus. Ocular structural abnormalities included Coats' disease, congenital cataract, coloboma, hypoplastic optic nerve, optic atrophy, congenital glaucoma, and retinoblastoma. Early detection and treatment of some of these conditions is essential for a good outcome. Careful attention to the ocular structures during prenatal ultrasound and in the early postnatal period is indicated in high-risk groups.1
|The hormonal changes that occur during normal pregnancy produce ocular
effects.2 Changes in levels of adrenocorticotropic hormone, corticoids, gonadotropic
hormone, estrogens, progesterones, melanocyte-stimulating
hormone, relaxin, and others affect salt and water retention, membrane
properties, vascular integrity, pigmentation, and tissue laxity.|
Intraocular pressure decreases during the second half of pregnancy, returning to previous levels approximately 2 months postpartum.3 This effect may be mediated through sex hormones affecting episcleral venous pressure or relaxin increasing facility of outflow.4–6 Ocular rigidity does not change.3
Corneal physiology is altered, yielding some edema with a minimal increase in thickness and secondary decrease in sensitivity.7,8 Refractive changes may occur. Because of these alterations, contact lenses may pose a particular problem.
Hormonally induced pigmentation produces melasma, also known as the mask of pregnancy. Krukenberg's spindles may occur.9 Results of ocular tension outflow studies remain normal, and the spindles usually show resolution in late pregnancy. Whether or not these hormonal stimuli increase the incidence or alter the course of malignant melanoma of the choroid is unclear, and there is no evidence that termination of pregnancy is beneficial.10,11
Central serous retinopathy has occurred during successive pregnancies, with remission after delivery or abortion, suggesting a hormonal influence.12 Amniotic fluid embolization may produce retinal arteriolar occlusion.13
Ptosis may occur in association with normal pregnancy. The pathophysiology is unknown. In the unusual case that does not resolve, excellent surgical correction has been obtained with small levator resections.14
Spontaneous carotid-cavernous fistulas and pituitary hypertrophy with resultant visual field changes may occur during pregnancy and be etiologically related to it.2,15 The incidence of pseudotumor cerebri does not increase in pregnancy.16
Toxemia of pregnancy is a secondary type of diastolic hypertension with associated proteinuria and edema occurring during the third trimester. It is divided into a preeclamptic stage, without seizures, and an eclamptic stage, with seizures. Retinal changes may result in visual blurring and scotomata. Initial preeclamptic changes of segmental retinal arteriolar narrowing occur first in the nasal periphery and spread toward the optic disc, followed by generalized arteriolar attenuation.17 Retinal findings, however, fail to distinguish normal from mild preeclampsia.18 Retinal hemorrhages, cotton-wool spots, intraretinal edema, ischemic optic neuropathy, papilledema, choroidal and retinal detachment, and transient cortical blindness may occur, especially with eclampsia.18–20 The severity and progression of retinal arteriolar changes correlate with fetal mortality and have been used as a determinant for termination of pregnancy.21 Children of toxemic mothers may show retinal changes similar to their mothers' retinal findings.22
The serous choroidal and retinal detachments are frequently bilateral. They may rarely occur without retinal arteriolar changes present.23 Leakage into the subretinal space may be related to choroidal vascular abnormalities, retinal pigment epithelial defects, or both.17,23–25 Reattachment usually occurs between 1 and 3 weeks postpartum, and the prognosis for visual return is favorable.26 Premature termination of pregnancy should be considered when retinal detachments are not responsive to medical control of toxemia.23
Diabetic retinopathy may be exacerbated by pregnancy.2,27 Background retinopathy should be carefully observed during pregnancy because a proliferative phase may ensue. Early photocoagulation for proliferative changes appears to improve the prognosis, especially if treatment precedes conception. Because the long-term visual prognosis does not appear altered and early termination of pregnancy may not affect the visual outcome, termination of pregnancy for proliferative retinopathy is seldom indicated.2,28
Therapy of any ocular condition during pregnancy must consider possible adverse fetal effects.29 These include abortifacient and teratogenic effects and certain transient physiologic alterations. An example of the latter is the lowering of fetal pseudocholinesterase levels through the transplacental action of echothiophate iodide eye drops used for the treatment of glaucoma. Data concerning transient physiologic effects of most therapeutic agents are few. All agents should be used cautiously and only with clear indications.
|A teratogen is an agent that by acting during the embryonic or fetal period
produces morphologic or functional malformations that become apparent
postnatally. Most known teratogens are drugs, environmental chemicals, infectious
agents, radiation, or deficiency states.|
Approximately 3% to 5% of all neonates have a congenital anomaly requiring medical attention, and approximately one third of these conditions are life-threatening.30–32 Congenital anomalies are the single largest cause of infant mortality, the second largest cause of death between ages 1 and 4 years, and the third largest cause of death between ages 5 and 14 years.33 It is estimated that almost half of the children in hospitals were admitted because of prenatally acquired defects.30 The specific contribution of teratogenicity to this enormous morbidity and mortality is unknown.
The mechanism of action of teratogenic agents is varied.34 These agents may act directly on the mother by interfering with the supply of vital nutrients, disturbing enzyme systems, or altering placental function. More commonly, they cross the placenta and directly affect the embryo or fetus. Malformations may result from disturbances in cell interactions and differentiation, cell biochemistry, cell migration, and vascularization inhibition pathways. Malformation production is dependent not only on the teratogenic potential of a substance but also on the time of exposure, dose, maternal factors, and embryo or fetal susceptibility.
The most vulnerable period for malformation production is during organogenesis. Organogenesis of the human eye occurs between 24 and 40 days' gestation.35 The developmental processes occurring at the time of insult are likely to be affected, producing sequential malformations. Thus, a rubella viremia in the first trimester often results in cataracts, glaucoma, and retinopathy.36 The eyes are usually spared in the congenital rubella complex if viremia occurs after major organogenesis is complete.37
Dose and the maternal immune state, patterns of enzyme detoxification, and placental status determine embryo and fetal exposure to these agents.38 Certain teratogens exhibit their effects at low doses, whereas a defined level is necessary for others.39 Except for radiation and radiomimetic agents, few direct data are available for humans.
Because it controls morphologic and biochemical development, the genotype of the embryo/fetus is a major determinant of teratogenic susceptibility.34 For example, thalidomide produced no teratogenic effects in rats and mice and was then marketed.40 Certain inbred strains of experimental animals have a much higher susceptibility to specific teratogens than do others of the same species.30,34 Perhaps similar multifactorial mechanisms are operative in the human phenytoin, trimethadione, and fetal alcohol syndromes, in which certain malformations are statistically increased yet their production is still not common.
Much of our knowledge of teratogenic agents comes from work with experimental animals. Because of biochemical, placental, and developmental differences, teratogenicity in animals does not imply teratogenicity in humans, nor does safe use in animals imply safe use in humans.31
Conditions necessary for establishing teratogenicity are convincing evidence of contact at critical developmental periods, reproducible epidemiologic data, and consistent set of defects.41
The literature on teratogenicity is vast; a number of excellent reviews and catalogs are available.30,32,42–48 More than 600 agents are known to be teratogenic for experimental animals, yet fewer than 25 are known to produce malformations in humans.
A detailed history of possible teratogenic exposure is indicated in the investigation of all birth defects. Any defect with a possible teratogenic etiology should be reported to the National Institute of Environmental Health Sciences' Environmental Teratology Information Center. Their in-depth listings are available through the National Library of Medicine (Toxline, Toxlit, Toxnet).
Caution should be exercised in exposing any woman of childbearing age to potential teratogenic agents. Much of the vulnerable period of organogenesis has usually occurred before pregnancy is diagnosed.
|A number of researchers have extensively reviewed drugs that are commonly
administered to pregnant women and environmental ocular teratogenic
chemicals to which pregnant women might be exposed.49–51|
SUGGESTIVE OCULAR TERATOGENICITY IN HUMANS
Certain agents are suggestive ocular teratogens in humans but lack the criteria for the establishment of definite teratogenicity. The suggestion is based on known teratogenicity in experimental animals, with or without isolated reports in humans, and the known pharmacologic effects of these agents. Rare human exposure, nonuniformity of postexposure anomalies, or failure to document effects prospectively or statistically casts some doubt on the ocular teratogenicity of these agents in humans. Still, to risk teratogenic exposure, patients must have an absolutely vital need for the agent.
Suggestive ocular teratogens include phenothiazines, chloroquine, quinine, anticonvulsants, coumarin derivatives, cancer chemotherapeutic agents, and various “street drugs.” Maternal hyperthermia is also a suggestive teratogen. The Prospective Collaborative Perinatal Project revealed a greatly increased risk for cataracts after first-trimester boric acid, iodide, and phenylpropanolamine exposure; this association was previously unsuspected and not correlated experimentally. A greater than fivefold risk of coloboma formation after sulfisoxazole exposure was also noted.42
Phenothiazine, Chloroquine, and Quinine
In utero exposure to phenothiazine and chloroquine has resulted in retinotoxic effects in experimental animals,52,53 with case reports in humans.54,55 Chloroquine-induced anophthalmia and microphthalmia have been noted in rats. Quinine exposure in utero has been associated with congenital glaucoma and ganglion cell toxicity resulting in optic atrophy.56–58
Anticonvulsant medication is necessary in approximately 1 in 200 pregnancies.62 Certain major malformations such as cleft lip and palate and congenital heart disease may be more frequent in offspring of epileptic women taking anticonvulsants. A host of other anomalies including ophthalmic abnormality are found.
A constellation of abnormalities has been found in infants exposed to phenytoin inutero.63–65 A pattern of abnormality sufficient to be ascribed to the phenytoin is found in 5% to 10% of infants exposed. Another 30% demonstrate some of the abnormalities. The original features of the fetal hydantoin syndrome are listed in Table 1.
* The number of patients with each abnormality includes only those patients for whom a definite decision could be made. In nine instances, historical information on birth length was not available; eight children were evaluated in the neonatal period and postnatal growth could not be assessed.
† Includes only children 4 years of age or older. Among the remaining 22 younger children, 3 show developmental delay.
‡ Includes one child with cleft lip and palate and one with submucous cleft and bifid uvula. One other child had only a bifid uvula.
§ Excludes mild or equivocal degrees.
|| Includes one case of atrial septal defect, ventricular septal defect, and pulmonic stenosis.
(Used with permission from: Hanson JW, Myrianthopoulos NC, Sedgwick et al; Risks to offspring of women treated with hydantoin anticonvulsants, with emphasis on the fetal hydantoin syndrome. J Pediatr 89:662, 1976.)
Whether or not in utero exposure to phenytoin increases the likelihood of mental deficiency or learning disability remains unresolved.74,75 There may be an increased incidence of malignancies, especially of the neural crest, such as neuroblastoma.76
(Used with permission from: Zackai EH, Mellman WJ, Neiderer B,et al: The fetal trimethadione syndrome. J Pediatr 87:280, 1975)
The features of the fetal hydantoin and trimethadione syndromes have significant overlap. Similar anomalies have been reported with other antiepileptic drugs including primidone,79 carbamazepine,80 and valproic acid.81 This general increase in abnormalities may be contributed to by individual drugs, a common teratogenic mechanism of drug metabolites, a common genetic predisposition to epilepsy and the malformation either through close linkage or etiologic mechanism, or deficiency states. Evidence that genetically determined levels of the enzyme epoxide hydrolase determine risk of anomaly helps explain many findings. This enzyme detoxifies common oxidative metabolites of antiepileptic drugs. Its level helps to explain individual susceptibility, familial recurrences, heteropaternal fraternal twin discordances, and the similarity of abnormality produced by various drugs.82
The risks to the fetus must be carefully explained to prospective mothers with epilepsy. It is hoped that enzyme assays will prove useful in better determining individual susceptibility to teratogenic effects.82 Because combination therapy is particularly hazardous, the minimal dose of a single control drug is recommended.64
A number of the ophthalmologic disorders found in children with fetal anticonvulsant exposure are potentially amblyogenic. Early ophthalmologic screening is suggested in this group of children.
An association exists between the use of coumarin derivatives (Coumadin, dicumarol, sodium-warfarin, phenindione) in the first trimester pregnancy and a phenocopy of the autosomal dominant Conradi-Hünermann syndrome, which is a form of chondrodysplasia punctata (dysplastic stippled epiphyses).85–87 As with Conradi's syndrome, cataracts are reported.88
Midtrimester use leads to a high incidence of central nervous system abnormality including optic atrophy and hydrocephalus.88–91
Microphthalmos, posterior embryotoxon/mesodermal dysgenesis, and hypertelorism have also been reported.91–93 Exposure to warfarin between 8 and 12 weeks' gestation resulted in an infant with the Dandy-Walker malformation, anterior segment dysgenesis (Peter's anomaly), and agenesis of the corpus callosum.93
Cancer Chemotherapeutic Agents
Through their mechanism of action, cancer chemotherapeutic agents are potent teratogens.30 All classes of these agents, including antibiotics (actinomycin D), metaphase inhibitors (vincristine, vinblastine, colchicine), alkylating agents (nitrogen mustard, tretamine, busulfan, cyclophosphamide), the antimetabolites (6-amine-nicotinamide, 6-mercaptopurine, idoxuridine, azaserine, cytosine arabin-oside, methotrexate), and procarbazine have been shown in experimental animals to result in major ocular abnormalities after in utero exposure. The abnormalities include anophthalmia, microphthalmia, and malformations of the lids, optic cup, cornea, lens, and retina.49,94–97 Although the agents are highly suggestive, the low fertility rate of women usually on multiple agents has made specific teratogenic detection difficult. Cloudy corneas were noted after in utero human exposure to busulfan (Myleran).98
Abusers of street drugs (cocaine, narcotics, marijuana, benzodiazepines, barbiturates, lysergic acid diethylamide [LSD], amphetamines, and others) usually use multiple drugs of unknown potency and purity, have poor prenatal care and a high incidence of other health problems, and frequently are malnourished.99 The teratogenic potential of these drugs is therefore difficult to assess. For all these drugs, the issue of congenital malformation production has been raised but has not been substantiated.48,99
Cocaine use leads to a high incidence of abruptio placentae.100 Neonatal cerebral infarcts and dilated/tortuous iris vessels are reported.101,102 Microphthalmia with persistent hyperplastic primary vitreous in one eye and a retinopathy of prematurity (ROP)-like picture in the contralateral eye in a mother who smoked “crack” cocaine throughout pregnancy is reported.103 She additionally abused marijuana, alcohol, and tobacco.103
Benzodiazepine has been reported to produce characteristic facies, growth aberrations, and central nervous system abnormality resembling the fetal alcohol syndrome.104
LSD, an apparent potent mutagen, may have teratogenic potential resulting in ocular abnormalities.105 Abnormalities of lens development have been induced in mice.106 Anophthalmia, microphthalmia, optic atrophy, persistent hyperplastic primary vitreous (PHPV), retinal detachment, and retinal dysplasia with intraocular cartilage have been reported in humans.107–109
Maternal hyperthermia of 102.2°F (39°C) or greater lasting for 1 or more days during the first trimester may result in a pattern of central nervous system dysfunction and facial dysmorphogenesis.110,111 Mental deficiency with altered muscle tone and increased deep tendon reflexes is characteristic. Facial features include microphthalmia, micrognathia, midfacial hypoplasia, palatal and lip clefts, and ear anomalies. Microphthalmia was found in more than 50% of those exposed between 4 and 7 weeks' gestation. Möbius' syndrome has also been attributed to maternal hyperthermia.112
DEFINITE OCULAR TERATOGENICITY IN HUMANS
Definite human ocular teratogenicity has been demonstrated for retinoids, thalidomide, folate antagonists, organic mercurials, ethanol, radiation, and infectious agents.
Long recognized as teratogenic in experimental animals, retinoids have now been shown to produce malformations in humans.113,114 Isotretinoin (Accutane) (13-cis-retinoic acid) is an oral synthetic vitamin A derivative useful in the treatment of cystic acne.115 It has been marketed in the United States since 1982. Exposure during the first trimester leads to a high incidence of anomaly.113,116 Affected infants typically exhibit defects of the central nervous system, head and face (particularly microtia/anotia, micrognathia, cleft palate and a flat depressed nasal bridge), heart (especially cotruncal and aortic arch anomaly), thymus, and ocular structures.113,116 Central nervous system abnormality includes microcephaly, hydrocephalus hydranencephaly, posterior fossa cysts, hypoplastic cerebellum, decreased cortical tissue, and calcifications.113,116–119 Ocular effects include microphthalmia, hypertelorism, antimongoloid slant of the palpebral fissures similar to Treacher Collins syndrome, and cortical blindness.116,117,119,120 Facial palsy is not uncommon.113
Another vitamin A congener, etretinate, introduced in the United States in 1986, is effective against psoriasis. Its teratogenic effects are similar to isotretinoin. Unlike isotretinoin, however, etretinate is stored in adipose tissue and released into the circulation for a long time even after treatment has been stopped. Teratogenic effects have been induced even 1 year after discontinuing the medication.121 No safe interval from the time of drug cessation has been established.
The introduction of thalidomide led to a dramatic increase in a particular malformation complex; with withdrawal of this drug from the market, this complex has virtually disappeared. Few agents represent such clear-cut teratogens in humans. Thalidomide, introduced in 1956, was in widespread use in Europe but never released in the United States. In 1961, an increased incidence of severe limb deformities was recognized.122,123 The drug was withdrawn in the same year. Ocular involvement occurred in 25% of children exposed. Teratogenicity of thalidomide occurs between 20 and 36 days after fertilization. Ocular abnormalities include uveal colobomas, pigmentary retinopathy, microphthalmos, glaucoma, ptosis, facial nerve palsy, aberrant lacrimation, pupillary abnormalities, and strabismus. Rarer eye movement abnormalities such as Möbius' and Duane syndromes are also reported.124
Folic Acid Antagonists
Folic acid antagonists are used as anticancer chemotherapeutic and antimicrobial agents. Members of this class have been shown to be potent abortifacients.125 Aminopterin (4-aminopteroylglutamic acid) produces proptosis and hypertelorism owing to abnormalities of cranial ossification.126–129 Methotrexate has produced similar abnormalities.130,131
Organic mercurials enter the environment as industrial wastes and through their use as fungicides. After introduction into the environment, concentration in seafood and grain-eating animals presents potential toxic sources. Toxic doses produce a neurologic disorder (Minamata disease) characterized by visual field constriction, decreased visual acuity leading to blindness, tremors, deafness, dementia, and death.132–134In utero exposure produces a similar condition, often of greater severity and permanence than that found in the mother.135–138 Blindness has resulted from in utero exposure.139
The commonly used preservative thimerosal is a mercury-containing fungicide. Very high dose thimerosal, typically applied to pregnant rabbits, resulted in fetal tissue accumulation without morphologic teratogenic effect.140
Ethanol used excessively during pregnancy results in a fetal malformation complex known as fetal alcohol syndrome (Figs. 3, 4, and 5) First described in 1967 and reported in 127 infants in 1968, its major features are listed in Table 3.141–143 Important criteria for diagnosis include low birth weight, growth retardation, central nervous system dysfunction, microcephaly, and characteristic facies.
* 2 SDs or more below the normal for age: equivalent to below the 2.5 percentile.
† Judging from standards of Chouke KS. The epicanthus or Mongolian fold in Caucasian children. Am J Phys Anthropol 13:255, 1929.
(Used with permission from: Hanson JW, Jones KL, Smith DW: Fetal alcohol syndrome: Experience with 41 patients. JAMA 235:1458, 1976. Copyright © 1976, American Medical Association)
Problems in development range from behavior and learning difficulties with normal intelligence to significant mental retardation. The fetal alcohol syndrome accounts for a significant percentage (8% to 17%) of children with developmental delay.144,145
The incidence of the full syndrome varies in the range of 1:300 to 1:750 of all live births.145 In children born to “drinking” alcoholic mothers, the incidence of the full syndrome is in the range of 30%.145,146 These drinking alcoholic mothers were those who reported drinking 1 ounce or more of absolute alcohol per day during pregnancy or before pregnancy recognition or reported drinking 45 or more drinks per month.146 A lesser percentage of children were affected among mothers who drank less than this. No level of alcohol consumption is known to be safe.
That the full-blown syndrome occurs in a minority of significantly exposed infants suggests genetic influences in susceptibility or detoxification. Whether alcohol itself or an oxidative metabolite such as acetaldehyde is the direct teratogen is unclear.147
The spectrum of ocular findings in the fetal alcohol syndrome suggests a risk of harmful effects on the eyes at any time in gestation.145
Horizontally short palpebral fissures constitute a hallmark of this condition. Palpebral fissure size as related to gestational age is shown in Figure 6.148 Palpebral fissure size in Hispanics and blacks at 3 days of age was found to be slightly larger than in Caucasians but well within the guidelines given in Figure 6.149 The horizontal shortening of the palpebral fissures is primarily the result of a marked increase in the intercanthal distances between the medial canthi with normal interpupillary distance (primary telecanthus).150
Other frequent (between one quarter and one half affected) ocular features include blepharoptosis, epicanthal folds, strabismus, retinal vascular tortuosity (both arterial and venous), and optic disc hypoplasia.145,150–152
Less frequent ocular findings are myopia, long eyelashes, microphthalmia, anterior segment dysgenesis (including unilateral/bilateral Peter's and Axenfeld's anomalies), steep corneal curvature, cataract (may be unilateral), and persistent hyaloid.145,150–152
A mouse model suggests that the anterior segment anomalies result from acute insult to the optic primordia at a very specific time that corresponds in humans to the third week after fertilization.153
Radiation is the best-studied teratogen. In utero radiation exposure of experimental animals produces cataracts, microphthalmia, anophthalmia, and coloboma in a high percentage of cases when 10 to 100 rad are delivered during sensitive development periods. These data have been summarized by Brent.154 Retinal cellular deficiency results from in utero loss of radiosensitive neuroblasts in monkeys exposed to 200 to 300 rad.155
Knowledge of the human teratogenicity of radiation has been obtained after atomic bomb explosions and therapeutic or diagnostic x-ray exposure. No increased incidence of ocular abnormalities (including cataracts) occurred among in utero survivors of the atomic explosions in Hiroshima and Nagasaki.156
Therapeutic radiation of 500 rad or more in the first trimester (especially 3 to 11 weeks' gestation) is associated with frequent microphthalmia, pigment degeneration of the retina, and cataracts.157 Because of these effects, therapeutic abortion has been recommended for fetuses receiving as little as 10 rad of radiation between the 18th day and the end of the first trimester.155
Rubella, cytomegalovirus, toxoplasmosis, mumps, Venezuelan equine encephalitis virus, syphilis, parvovirus B19, varicella, and perhaps herpes simplex and the acquired immunodeficiency syndrome160 produce human ocular teratogenicity.
|TERATOGENICITY OF OCULAR THERAPEUTIC AGENTS|
|Ophthalmologists must be aware of the teratogenic potential of any therapeutic
agent prescribed for women of childbearing age. Fortunately, few
agents likely to be used in the treatment of ocular disorders have
known teratogenic potential in humans. Topical ocular instillation of
substances with teratogenic potential has resulted in abnormalities in
Tetracycline produces staining of deciduous teeth after the fourth month of pregnancy. With administration close to term, the crowns of the permanent teeth may be stained.163
Pyrimethamine (Daraprim), a potent antifolate useful in the treatment of toxoplasmosis, has teratogenicity in experimental animals, resulting in limb defects.164 Because other antifolates are potent human teratogens, human teratogenicity is suggestive.165
Several cytotoxic agents, including chlorambucil and Cytoxan (occasionally used for ocular immune disorders) and the antiviral antimetabolite idoxuridine, are highly suggestive human teratogens.94 Chlorambucil exposure has resulted in ureter and kidney anomalies, and Cytoxan exposure has resulted in limb deformity. Topical idoxuridine has produced exophthalmos and limb anomalies in the offspring of rabbits.161
Ocular therapeutic agents with definite or suggestive teratogenicity only in animals include steroids and acetazolamide. Topical steroids induce cleft palate, cataract, and cerebral and cardiac anomalies in susceptible animals.162,166,167 Acetazolamide produces postaxial forelimb deformities in susceptible strains.168
|Trauma to the globe and ocular adnexa may occur during labor and delivery
as a result of pressure against the bony outlet, forceps compression, or
vacuum extraction.169 Lacerations of periocular structures during delivery by sharp obstetric
instruments are reported (Fig. 7).170,171|
Puncture by amniocentesis needles or monitoring electrodes may also produce such trauma.172,173 Injury to virtually every anatomic component of the globe and ocular adnexa has been described.174 These range from clinically insignificant subconjunctival hemorrhage to total luxation of the globe.175 The following description is limited to clinically significant injuries that occur with some frequency.
Corneal opacification may be caused by direct epithelial and stromal injury or may be secondary to rupture of Descemet's membrane. Fortunately, both types are usually unilateral. Direct epithelial and stromal injury is usually associated with evidence of lid trauma and subconjunctival hemorrhage. It clears rapidly, usually by 1 week of age.
Descemet's membrane ruptures result from deformation of the globe, most frequently because of direct compression by delivery forceps.176,177 The ruptures appear as curvilinear, frequently vertical, often crescentic striae, and consist of scroll-like detachments. Overlying stromal opacification may or may not be present at birth. As endothelial regeneration and Descemet's membrane reduplication occur, clearing of the cornea ensues. High corneal astigmatism and myopia may result from Descemet's breaks and, if uncorrected, may be amblyogenic.178 Decompensation with gutatta may result in overlying opacification decades later.179
Intraocular hemorrhage is frequently observed in neonates, most commonly as retinal hemorrhage. Hyphema and intravitreal hemorrhage are rarely encountered, usually after significant direct forceps or vacuum extraction trauma. Congenital hyphema has occurred after normal spontaneous deliveries.180 Intravitreal hemorrhage has been reported in the coagulation dysfunction associated with protein C deficiency.181
Retinal hemorrhage occurs with a reported frequency ranging from 2.6% to 50%.182,183 Intraretinal hemorrhages (flame-shaped, dot-blot, and larger dot-blot with white centers) are most commonly seen in the posterior pole but can be seen anteriorly (Fig. 8). Subhyaloid and subretinal hemorrhages occur much less frequently.
A number of factors are likely responsible but birth trauma is the principal etiologic agent.183–185 Hemorrhages may result from compressive congestion of the vessels of the neck or from cavernous sinus congestion resulting from head compression. Therefore, they are more common in primiparas, with nuchal cords, or after delivery assisted by forceps or vacuum extraction. They are uncommon after cesarean section. Hypoxic vascular damage, neonatal vascular fragility, and various dysfunctions of coagulation (vitamin K, platelets, prothrombin) have also been implicated. These latter factors may be operative in premature neonates, who have a relatively high incidence of retinal hemorrhage.184 Vitamin E therapy for neonates may increase the incidence of these hemorrhages.186
Large round hemorrhages are more frequent after neck or head compression. The superficial flame-shaped type is more commonly associated with hypoxia but is often present without such a history. Subhyaloid hemorrhages may be associated with subarachnoid or subdural hemorrhage.187
Neonatal retinal hemorrhages often resolve within a few days to 3 weeks. One recent study documented that all neonatal retinal hemorrhages resolve by 4 weeks. Retinal hemorrhages in infants older than 4 weeks of age should suggest the possibility of other etiologies including nonaccidental trauma. A clinical work-up should be conducted to rule out serious central nervous system components of shaken baby syndrome and other evidence of abuse (rib and long bone fracture).188 Localized pigmentary changes may occur, but visual sequelae are exceedingly uncommon. The incidence of retinal hemorrhage has been correlated with central nervous system hemorrhage.186 No significant correlation between retinal hemorrhages and later cognitive development of the child has been noted, however.183
Neurologic injury is a common sequela of birth trauma.189 Of ophthalmologic importance are various intracranial and peripheral nerve lesions. Intracranial bleeds and contusion with or without skull fracture produce an array of visual defects, including optic atrophy, field deficits, and cortical blindness.190
Traumatic peripheral nerve palsies result from pressure, stretch, or avulsion. A history of pressure of the head or shoulders against the bony canal, direct forceps pressure, or shoulder stretching during breech delivery is often elicited.
Peripheral facial nerve injury may result in an inability to close the eye on the affected side. Appropriate ocular lubricants or protective contact lenses are indicated. Unless necessary, moisture chambers and tarsorrhaphy are best avoided, because they may be amblyogenic. Most infants recover within days to weeks.191 Electrodiagnostic nerve excitability tests, nerve conduction latencies, chronaxy and strength duration curves, and electromyograms are useful in determining the nerve's status.192 Physical therapy, electrical stimulation, or surgical decompression may be indicated. Peripheral facial nerve injury must be differentiated from other causes of facial nerve palsy.
Brachial plexus palsy may occur after shoulder dystocia, especially with breech delivery.192 In addition to motor root injury, sympathetic denervation may occur, resulting in Horner's syndrome with heterochromia. Neonatal Horner's syndrome may also be due to cervical and mediastinal neuroblastoma.193
Congenital sixth-nerve palsies may be produced by a rise in intracranial pressure during labor and delivery. They are usually transient, resolving within 6 weeks, but may be permanent.194 Surgical intervention to achieve binocularity should be considered after 6 months if no improvement occurs.
The relationship of closed head birth trauma to fourth-nerve palsies is speculative. Because they are related to posture, signs of fourth-nerve palsy are rarely observed during the neonatal period. The frequency of occurrence and rate of spontaneous resolution of fourth-nerve palsies are therefore unknown.
Ptosis may result from birth trauma. Crawford195 found that 15 of 62 cases of traumatic ptosis resulted from birth trauma. A difficult labor or forceps delivery had occurred in all 15 cases. The mechanism is uncertain. Direct levator injury is most likely, although nerve injury is possible. Unless the pupil is occluded, surgical intervention should be deferred for at least 3 years because this condition may improve spontaneously.
Congenital eversion of the eyelids may result from an anatomic predisposition coupled with increased orbital pressure and a neonate's grimacing during delivery. A lack of fusion between the orbital septum and levator palpebrae aponeurosis is suspected. Keeping the conjunctiva moist and taping the lids in a normal position usually lead to resolution. Surgery may be necessary.196
|Low birth weight (less than 2500 g) signals a host of potential
problems to a pediatrician. Low birth weight results from a shortened
gestation, intrauterine growth retardation, or a combination of the
Estimation of gestational age is obstetrically based on the menstrual history, evaluation of known physical milestones during pregnancy, ultrasonographic and x-ray parameters, and the analysis of various chemical constituents of amniotic fluid. Gestational age estimates of neonates are made from various physical and neurodevelopmental attributes that appear predictably at known gestational ages.197,198
Involution of the anterior portion of the tunica vasculosa lentis (pupillary membrane) occurs predictably with gestational age.199 Direct ophthalmoscopic examination of the pupillary membrane within the first 24 to 48 hours of life, aided by dilating the pupil, allows an arbitrary grading that is highly correlated with gestational age (Fig. 9). This assessment is also valid for most infants who are small for gestational age (SGA).200 Its value in multiple pregnancy has been questioned.201 Abnormal persistence of the pupillary membrane and asymmetry between the eyes occur with congenital toxoplasmosis, rubella, cytomegalovirus, and herpes simplex infection.202
Premature infants have a higher incidence of central nervous system dysfunction resulting from metabolic imbalance, hypoxemia, intraventricular hemorrhage, and other insults. Sequelae include optic pathway disturbances such as optic atrophy and cortical blindness. Cerebral palsy is more common and frequently associated with strabismus.203
Even without central nervous system dysfunction or ROP, the incidence of strabismus and refractive errors (especially myopia and astigmatism) is higher in premature neonates.204 Transient lens changes appearing as clusters of small vacuoles at the lens periphery occur at the apexes of the Y suture.205
Other major ophthalmic considerations for premature neonates, such as ROP, vitamin E, and phototherapy for hyperbilirubinemia, are discussed elsewhere in this text.
Neonates with weight below the tenth percentile for gestational age are considered SGA. Similar terms include small-for-dates, pseudopremature, and intrauterine growth retarded. In the United States, approximately one third of all infants whose birth weight is less than 2500 g are SGA and not premature.206
Factors that influence intrauterine growth adversely can be divided into three categories: maternal, placental, and fetal. Maternal causes include low prepregnancy weight, poor nutrition, hypertension, preeclampsia, diabetes, congenital heart disease, sickle cell disease, autoimmune disease, drug ingestion, and multiple gestation. Any type of placental insufficiency such as chronic abruption, anatomic abnormalities or TORCH infection (villitis) may cause decreased intrauterine growth. Fetal factors involve chromosomal abnormalities, syndromes (Cornelia de Lange), metabolic disorders (galactosemia), and congenital infection (TORCH).207
|OPHTHALMIA NEONATORUM PROHYLAXIS|
|Ophthalmia neonatorum is conjunctivitis occurring in the first month of
life. Prophylaxis is aimed at the etiologic agent. The causes include Chlamydiatrachomatis, Streptococcus viridans, Staphylococcus aureus, Haemophilus influenzae, group D Streptococcus, Moraxella catarrhalis, Escherichia coli, other gram-negative rods, and Neisseria gonorrhoeae. N. gonorrhoeae is currently responsible for less than 1% of neonatal conjunctivitis
in developed countries. The decreased incidence is the result of
better prenatal screening and ocular prophylaxis for newborns.208|
Crede209 introduced instillation of 1% solution of silver nitrate in the eyes of an infant at birth, which significantly reduced the incidence of ophthalmia neonatorum.
Concentration of silver nitrate solution caused by evaporation caused severe chemical injury in the past. Use of sealed ampules has helped avoid the harmful concentration but chemical conjunctivitis occurs with the 1% solution as well.210
Both 0.5% erythromycin and 1% tetracycline ointments have been shown to be as effective as silver nitrate in preventing gonococcal ophthalmia. These agents are less irritating and are not associated with chemical conjunctivitis. Silver nitrate is still recommended in areas where there is significant penicillinase-producing N. gonorrhoeae. Infants born to mothers with untreated gonococcal infection should have one dose of ceftriaxone (25 to 50 mg/kg) or cefotaxime (100 mg/kg) administered as well as topical prophylaxis.208
A 2.5% ophthalmic solution of povidone-iodine may be an effective agent for prophylaxis against ophthalmia neonatorum. More studies are needed prior to its use. Its decreased cost, low toxicity, and ease of availability make it an attractive alternative.211 No commercial preparation is yet available.
Chlamydial trachomatis is a common cause of neonatal conjunctivitis. It is a benign ocular condition but may be associated with pneumonia and long-term respiratory problems. Because prophylaxis may mask the infection and delay diagnosis, it is important to screen pregnant women and treat them for infection to prevent perinatal infection.212–214
Efficacy of topical antibiotics and silver nitrate against ophthalmia neonatorum caused by C. trachomatis is unclear. Some evidence exists the 2.5% povidone-iodine solution may be a more effective agent for prophylaxis against chlamydial infection.211
Nongonococcal nonchlamydial ophthalmia neonatorum is effectively prevented by silver nitrate, povidone-iodine, and, probably, erythromycin.
Current recommendations for ocular prophylaxis call for the use of 1% silver nitrate, 0.5% erythromycin, or 1% tetracycline ointment placed in the conjunctival sac. None of the agents should be flushed from the eyes. Infants born via cesarean section should also receive prophylaxis since infection by the ascending route can occur. Prophylaxis should be given as expediently after birth as possible, however, delaying for as long as 1 hour has not been shown to change efficacy. Longer delays have not been studied.208
|MYDRIATIC EYE DROPS|
|Mydriatic ophthalmic solutions are used in infants for diagnostic fundoscopic
examinations. Premature and SGA infants are most sensitive to the
pharmacologic effects and may exhibit adverse systemic manifestations. Factors
responsible for the increased sensitivity include the greater
dose-to-body weight ratio, poor autonomic regulatory
mechanisms, and immature detoxification systems.|
Phenylephrine is an α-adrenergic agent. Only the 2.5% ophthalmic solution should be used in low-birth-weight infants. Adverse effects may include a negative influence on respiratory parameters in infants with bronchopulmonary dysplasia, systemic hypertension, and tachycardia.214–217
Cyclopentolate is an anticholinergic agent that inhibits the sphincter pupillae muscle. Concern about possible systemic side effects in low-birth-weight infants limits the use of cyclopentolate to the 0.5% concentration. Side effects include fever, tachycardia, abnormal thermoregulation, delayed gastric emptying, and decreased gastrointestinal secretions. The gastrointestinal side effects may predispose the infant to paralytic ileus and necrotizing enterocolitis.218
Tropicamide is an anticholinergic agent that inhibits the sphincter pupillae muscle. Concern about systemic side effects in low-birth-weight infants limits the use of tropicamide to the 0.5% concentration. Systemic side effects are similar to those with cyclopentolate.219 A commercially available combination ophthalmic preparation containing phenylephrine 1% and cyclopentolate 0.2% produces adequate mydriasis without significant systemic effect.216
|Vitamin E is the oldest recognized biologic antioxidant. Along with a number
of other nutrients and enzyme systems, vitamin E checks the damage
produced by superoxide free radicals.220,221 The transition from the intrauterine to the extrauterine environment is
marked by relative hyperoxemia. The hyperoxemia produced in the treatment
of the respiratory distress syndrome especially encourages the formation
of superoxide radicals. Defective antioxidant mechanisms may
contribute to retinal and pulmonary toxicity.|
Although body stores and serum levels of vitamin E are low at birth, serum levels usually rise to normal adult levels within several days of feeding of human milk or commercially available formulas.221,222 Deficiency of vitamin E in preterm infants may lead to a hemolytic anemia with edema and thrombocytosis, which may be exacerbated by iron supplementation. Supplemental vitamin E, in amounts above that found in human milk or commercial (vitamin E-fortified) formulas, may not be necessary to prevent anemia.222,223
ROP has been postulated to be the result of oxidant injury. Proposed mechanisms include oxidant injury to forming immature retinal capillaries either directly or through flow changes secondary to vasoconstriction.224,225 Another proposed mechanism involves the oxygen-induced formation of spindle cell gap junctions, which remove those cells from vasoformation.226 Vitamin E has also been shown to affect coagulation parameters, decrease production of the potent vasoconstrictor and platelet aggregator thromboxane, favor the production of the vasodilator prostacyclin, and act as an anti-inflammatory agent.227 Any of these functions could be affected by vitamin E deficiency.
The role of vitamin E supplementation of premature infants in the prevention or treatment of ROP is currently undetermined. Some studies have suggested a protective role of vitamin E in lessening the incidence of ROP,228 the severity of ROP,226,229,230 or the progression of ROP.228 Despite the theoretical advantages and the studies to the contrary, there is no conclusive statistical evidence that vitamin E either reduces the incidence or severity of ROP.231 Nor is there evidence that vitamin E prevents other ophthalmic sequelae, such as myopia, hyperopia, anisometropia, or amblyopia,232 in premature neonates.
Direct lung parenchymal injury by oxygen is likely to be responsible for neonatal bronchopulmonary dysplasia (BPD). Administration of vitamin E during the acute phase of the idiopathic respiratory distress syndrome has been reported to minimize the development of BPD.233 The efficacy of vitamin E for the treatment of BPD, however, has not been confirmed.234
Vitamin E supplementation to pharmacologic levels (5 mg/dL) has been reported to increase the incidence of necrotizing enterocolitis and sepsis in prematures,228 but most studies have failed to confirm this result.231 An intravenous vitamin E preparation, E-Ferol, consisting of the acetate ester of dl-α-tocopherol in a polysorbate vehicle, resulted in a clinical syndrome consisting of ascites, liver and renal failure, thrombocytopenia, and death among low-birth-weight infants in 1983 to 1984.235 Whether the tocopherol or the polysorbate vehicle of the E-Ferol was responsible is unclear. Oral preparations of vitamin E designed to achieve adult physiologic levels (1 to 3 mg/dL) may be irregularly absorbed in very-low-birth-weight neonates, resulting in higher pharmacologic (>3.5 mg/dL) levels.236
The early achievement and maintenance of physiologic levels of vitamin E appear to be free of side effects and may have beneficial effects regarding intraventricular hemorrhage, ROP, and BPD.237 This level is best achieved through normal nutritional sources or oral vitamin supplements. Vitamin E is a component of intravenous multivitamin supplements that may be used.237
|PHOTOTHERAPY FOR HYPERBILIRUBINEMIA|
|Neonatal jaundice is commonly treated by the photoreaction of bilirubin
to products that are more readily excreted and do not result in brain
damage.238–240 Intermittent or continuous illumination for 1 to 10 days is used as necessary. Phototherapy
units use either white “daylight” or
blue 440- to 470-nm fluorescent light tubes.239–243 The blue spectrum is most effective because it closely matches the absorption
spectrum of bilirubin.242,243 Maximum decline in serum bilirubin levels occurs when infants are exposed
to an irradiance of 1851 μW/cm2 (approximately 165 foot-candles) in the blue range (spectral
irradiance 23 μW/cm2 nm).243 This is the order of magnitude of irradiance produced by most commercial
units.241,242 Increasing irradiance over this saturation point does not significantly
improve the efficacy of phototherapy.|
Phototherapy units and other light sources of similar intensity and wavelength produce photoreceptor damage in experimental animals when used for periods similar to those used to treat human infants.244–247 Bilateral ocular occlusion is, therefore, recommended during phototherapy. Neither short-term nor long-term effects on fundus appearance or photoreceptor function, as measured by electroretinography and visual acuity, have been demonstrated in humans when phototherapy using bilateral ocular occlusion was used.248–250 Continuous 6-day exposure to a lesser fluorescent source (90 foot-candles) without ocular occlusion produced no photoreceptor dysfunction detectable by visual acuity or electroretinography.251
Bilateral ocular occlusion and dark rearing of experimental animals near birth result in changes in the visual cortex and abnormalities of ocular alignment.252–256 One study reported a higher incidence of strabismus for a small group of children bilaterally occluded for phototherapy.257 A larger study demonstrated no increase in the incidence of strabismus or loss of stereoacuity on long-term follow-up of children bilaterally occluded for phototherapy as infants.258
Accidental incomplete occlusion of one eye may not only lead to retinotoxic effects but may also be amblyogenic for the totally occluded eye. Kittens monocularly occluded during the fourth and fifth weeks for only a few days develop permanent amblyopia.259 The existence or timing of a similar critical period in humans is suspected but not known with certainty.260 Mask or eye-pad bilateral total ocular occlusion should be ensured.
|DEVELOPMENT OF VISUAL FUNCTION|
|Knowledge of visual function and its development in the very young has
wide-ranging clinical implications. It is necessary for the understanding
of many psychologic and social developmental events. It is
important for timely detection of, intervention in, and follow-up
of pathologic conditions that interrupt and may permanently disrupt
Underlying the cognitive recognition of the visual realm is a complex set of incompletely understood requisite, interrelated components. The function of these requisite components depends on the development of anatomic and neurophysiologic mechanisms. Oculomotor coordination, image formation, transmission, reception, integration, and cognition all are necessary for detail, color, form, movement, and spatial relationship appreciation.
Knowledge of the function and development of these requisites in neonates and infants must be determined by nonverbal means. Attention and response parameters that also require interpretation are thus imposed.
Technical advances and improved methodologies have aided in the understanding of the development of these requisite components. The component and level of the component that a particular method assesses require careful scrutiny. Extrapolation to cognitive perception is often unwarranted. Knowledge of these components does, however, provide clinically useful clues toward understanding neonatal and infant visual perception and its development.
|The length of the eye increases from approximately 17 mm at birth to 24 mm
in adulthood. More than half of this sagittal growth occurs during
the first year of life.261,262 Expansion of the posterior segment accounts for a disproportionate amount
of the eye's growth after birth.263|
The corneal diameter at birth is in the range of 9 to 10.5 mm, with a mean of 9.8 mm.264,265 In preterm neonates, the range is usually 7.5 to 9.2 mm, with a mean of 8.2.265 The corneal curvature is very steep at birth, with a mean of 47 to 51 D at term and even steeper preterm.262,266,267 The corneal curvature lessens significantly in the first few months.262,266 The lens also loses significant power (mean decrease 8 D) during the first year.262
The retina is generally well developed at term, with adult-like electroretinographic rod and cone responses.268 The foveal region, however, is immature at birth, reaching almost adult morphology by 4 months of age.268–270 Full anatomic foveal maturity may not be reached until 15 to 45 months of age.271
Neural morphology and myelination are immature at term. Cells in the lateral geniculate nucleus increase rapidly in size during the first 6 to 12 months, reaching adult size at age 2 years.272 Myelination of the optic nerve is not complete until 7 months, and there is continued thickening of the sheaths through age 2 years.273 The cortical net is immature and poorly myelinated at term.274
Optical clarity is present at term.275
|The steep corneal diameter and high lens power of a neonate are not enough
to overcome the short axial length in full-term newborns, so
the mean refractive error is usually a slight hyperopia.262 The spherical equivalent refractive error of full-term neonates
has generally been found to be normally distributed at approximately
a mean of +2 D, with a standard deviation of 2 D.276 For technical reasons, this degree of hyperopia may be more apparent than
real.277 Maximum visually evoked cortical potentials (VECP) amplitudes
to patterned stimuli were elicited with neonates viewing through +1 or +2 D
lenses. Preferential looking (PL) was also
improved with +1 or +2 D lenses.278|
Longitudinal studies show a rapid trend during the first 1 to 2 months toward hyperopia of approximately 2 D greater than that present at birth.276,279 Little change occurs for the next 6 months; subsequently, hyperopia gradually diminishes during infancy and childhood.276 There is a tendency for deviant errors in neonates to move toward the mean by 6 months, although hyperopic and myopic neonates tend to remain with their respective error.280
Astigmatic errors are more common in neonates and young infants than in older children and adults.276,281,282 Cycloplegic refraction reveals a peak incidence of 25% greater than 1 D of astigmatism, primarily against the rule, at 6 to 7 months; this gradually decreases to 15% by 1 year.275,281 Dynamic retinoscopy and photorefraction techniques uncover an even larger astigmatic incidence.283,284 Photorefraction may prove to be a sensitive and reliable screen in infants.285 Longitudinal studies of infants with greater than 2 D of astigmatism between ages 3 and 6 months revealed only one quarter remaining highly astigmatic at 1 year.283 The reason for this astigmatism remains speculative.276,281
Infant visual preference for gratings oriented to be in better focus for a particular astigmatic error has been demonstrated. Correction of the astigmatic error brings the acuity back to the norm for the previously blurred gratings.283,284
Astigmatism may lead to meridional amblyopia if persistent in later infancy.286 Premature infants tend to be less hyperopic or mildly myopic and more astigmatic at birth than do full-term infants.287–289 A pattern of increasing hyperopia and decreasing astigmatism during the first weeks of life, gradually plateauing at 6 to 8 months and then slowing, shifting toward emetropia, has been noted.262,276,279,280,287,290 Premature infants also have a high incidence of anisometropia.287 The myopia of prematurity may or may not become apparent in later childhood.280,287,288 SGA infants have the refractive status of their normal-weight gestational counterparts, demonstrating that prematurity and not low birth-weight is responsible for the refractive differences.291
|Accommodative ability is present in the first weeks in life and reaches
adult accuracy by 9 weeks of age.276,292,293 The motor ability to accommodate large amounts is present in neonates.294|
Accommodative responses in neonates are dependent on the ability to detect blur resulting from a focusing error. Because of small pupillary size and poor visual acuity, neonates have a great depth of focus. Image clarity therefore remains constant over a relatively large object distance range, and optical blur decreases vision much less than would occur in later life.295 As acuity improves and depth of focus decreases, measurable accommodative accuracy increases.292,296,297
Accommodative-convergence is demonstrable at 2 months of age.298
The accommodation mechanism does not appear to be a limiting factor in visual development.
Clinical assessment of central vision in neonates requires both experience and patience. Preliminary assessment should include evaluation of pupillary responses, observing alignment, noting the presence or absence of nystagmus, and demonstrating motor ability.299
Pupillary constriction to light should be present after 32 weeks postconception age.300 Neonates of less than 32 weeks' gestation may have fixed and dilated pupils.301 Pupillary constriction to darkness may be found with Leber's amaurosis, cone dystrophy, congenital stationary night blindness, congenital achromatopsia, albinism, Best's disease, optic nerve hypoplasia, dominant optic atrophy, anomalies of optic nerve development, congenital nystagmus, strabismus, and amblyopia.302
Strabismus often occurs with monocular visual loss on any basis. Nystagmus occurs between 1 and 3 months of age, when binocular visual loss prevents the establishment of the macula fixation reflex. Opacities of the ocular media and retinal and optic nerve dysfunctions may be etiologic. Once well developed, this nystagmus is permanent and sharp foveal fixation cannot be re-established, relegating vision to 20/200 (6/60) at best. It is not usually found with cortical visual impairment.
A strong light induces blinking even in the most immature infant.303 Turning toward a diffuse light falling on one side of the face usually can only be demonstrated between 32 and 36 weeks'postconception age.303
Fixation-and-following movements should be demonstrable by 3 to 4 months of age.304 Fixation and following may be elicited in most newborns if care is taken that they are alert and presented with proper stimuli. Neonates particularly fix and follow the human face or its likeness.305 The technique of testing for fixation and following should include binocular and then monocular assessment.306 In neonates, the following may be a jerky saccadic pursuit movement, which represents a series of hypometric saccades to localize the target.307
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 inducing vestibular nystagmus by rotating the child.308
The assessment of neonatal visual acuity is important for proper diagnostic and early intervention considerations. Because vision development is delayed in some infants who subsequently develop normal visual capability,309,310 prognostication must be done cautiously. Visual inattention may be a sign of significant neurologic sequelae such as cerebral palsy, mental retardation, and seizures, especially in preterm infants.311 Underestimating or overestimating a child's visual potential may have serious consequences.
Techniques are now available to help assess the visual resolution capability of the very young. These techniques include VECP, optokinetic nystagmus (OKN), and PL responses. Each of these demonstrates a dramatic improvement in “acuity” during the first year of life (Fig. 10).312–317
That each of these techniques yields somewhat different results is not surprising. The different stimuli used and response parameters measured determine the particular visual function and level being assessed. Each of these techniques is clinically useful for evaluating visual resolution in the very young.
Inconsistency in visual acuities determined by preferential looking technique and VECP has been demonstrated. Children with developmental delay may have poorer performance on preferential looking techniques. Severity of developmental delay correlates with greater disparity.318 Repeat testing using the same technique is necessary to document information used in a child's management.
Visually Evoked Cortical Potentials
By presenting a resoluble stimulus to a very young infant while monitoring and computer analyzing the resultant occipital cortical responses, an acuity function is obtained.313,316,319 Various stimuli, including flashed checkerboards, alternating checkerboards, and gratings, have been used.
Acuity function estimates are made by an analysis of the computer-averaged waveforms and amplitudes. This is variously accomplished by comparing various waves with data from optically blurred adults, determining the smallest stimulus pattern producing a measurable VECP, or extrapolating to zero-response amplitude a series of waves produced by various stimuli. General agreement exists among the different techniques used in VECP acuity estimates.313,319
VECP acuities are in the range of 20/400 (6/120)* during the first days of life, improving to close to normal adult 20/20 (6/6) equivalent responses by 5 to 6 months (Fig. 10).278,320–323 When a more rapid spatial frequency sweep VECP technique is used, even better neonatal acuity has been found.319
*Metric equivalent given in parentheses after Snellen notation.
Considerations in assessing the significance of VECP acuities include the following: Primary reception areas and not higher cognitive areas are monitored. The small signals detected by computer averaging of many responses may not be of threshold level for higher neural processing.
OKN is an involuntary response elicited by moving a series of objects across the visual field. OKN may be elicited in an awake neonate placed under a field of moving stripes. By varying the stripe width while observing for OKN, an acuity function is measured. Observation may be direct, by cinephotography, or may use electroretinography.324
Snellen acuity equivalents in the range of 20/300 to 20/400 (6/90 to 6/120) have generally been found for full-term newborns during the first week of life.325,326 Acuity as high as 20/150 (6/45) has been recorded in neonates but may have been the result of spurious techniques.313 Premature infants show lower acuities.327
Considerations in assessing the significance of OKN acuity are that the resolution of moving targets may not be comparable to stationary ones, OKN may be based more on peripheral than central vision, and subcortical pathways may play a large part in its production.312
Neonates and infants preferentially view a perceived patterned stimulus over a homogeneous one simultaneously presented.329,330 By varying the pattern of the stimulus and observing the response, an acuity function is measured (Fig. 11). Stimuli used include various stationary stripes, photographic patterns, or oscilloscope-generated gratings designed to match a homogeneous field of equal space-average luminance. An acuity estimate for a particular age of infant is determined by the smallest stimulus pattern preferentially viewed.
PL acuity may be determined with acuity cards by observing that stimulus choice is preferred as assessed by an observer who, only after presenting the stimulus and noting the response, looks at which side the stripes are on.317 The definity and correctness of the infants choice as subjectively assessed then determines the next grating presented (finer or coarser) or determines an end-point of resolution ability. This method has the advantages of being rapid (3 to 5 minutes) and improving testability. More than 80% of neonates (age 7 days or younger) were testable binocularly. At 1 month of age, 86% were testable monocularly.317 Commercial acuity cards and screens are available. Alternatively, PL acuity may be assessed by an observer who remains blind to the stimuli, attempting to choose which side the gradient is on by observing the infant's behavior through an entire series of gratings. This latter method, the forced-choice PL technique, is scored positively when the observer's choices are 75% correct. The forced-choice technique is slow, typically requiring 15 to 45 minutes, and, thus, limits testability.
Acuity estimates by PL techniques generally reveal acuities in the range of 20/400 at term; these increase to 20/150 at 6 months and 20/40 (6/12) by 1 year and approach 20/20 at age 2 (Fig. 10).317,328,331,332 Premature infants show poorer acuity than do full-term newborns. If conceptual age is considered, however, the acuities are similar for both groups.333
PL techniques may underestimate or overestimate neonatal and infant visual acuity. For neonates, behavioral and attention parameters may limit responses, and stimuli may not be optimum to elicit responses. PL measures a resolution task, not a recognition task. In older infants and children, acuity measured by PL exceeds recognition acuity (pictures or letters).334 This is especially true in the presence of amblyopia.334,335
|Neonates are able to discriminate curved shapes from straight ones as well
as horizontal stripes from vertical ones.336–337 Facelike stimuli are preferentially viewed by newborns, raising the question
of innate perceptual organization.315 Different domains in the brain for facial recognition are theorized: amygdala, parietal
lobe, and cerebral cortex. Face processing may require
interaction between multiple domains.338–340 By 1 month of age, a circle can be discriminated from a triangle.341 Dramatic changes occur at approximately 2 months of age. Discrimination
of shapes within identical frames is possible. Oculomotor development
is sufficient for smooth and thorough scanning of the visual realm.342|
Recognition of the solidity and permanence of visualized objects is present within the first few weeks of life,343 again raising the possibility of an innate perceptual organization. Within the first few months, recognition of an object by its features rather than movement or place occurs.343 The timing of this cognition has been debated.344–346
|Binocular fixation may be present at birth. By 3 months of age, infants
demonstrate consistent binocular ocular alignment to a point at or near
the fovea for a range of stimulus distances.347|
Fusion in infants has been demonstrated by observing ocular realignment after prism-induced monocular image shift. It develops between 4½ and 6 months of age.348 Fusion may be present even earlier, because the development of the observed motor response may be a limiting factor of the technique.
|The author and editors wish to acknowledge the contributions of Frederick M. Wang, MD, New York, NY, author of the previous chapter. Some of the material, including illustrations, have been included in this revision.|
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