Visual Development and Amblyopia 4

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Visual Development and Amblyopia

Kenneth W. Wright

NORMAL VISUAL DEVELOPMENT

Monocular Visual Development

At birth, visual acuity is poor, in the range of hand motions to count ﬁngers. For the most part, this is due to immaturity of visual centers in the brain responsible for vision processing.

Visual acuity rapidly improves during the first few months of life as clear in-focus retinal images stimulate neurodevelopment of visual centers, including the lateral geniculate nucleus and striate cortex.⁵²Dropout and growth of neuronal connections give rise to the organizational refinement and establish high- resolution receptive fields corresponding to the central foveal area.^18,23Normal visual development requires appropriate visual stimulation, including clear retinal images, with equal image clarity in both eyes (Table 4-1).

Visual development is most active and vulnerable during the ﬁrst 3 months of life, which is termed the critical period of visual development.¹³Figure 4-1 shows a curve of visual acuity improvement versus age. Note the curve is steepest during the ﬁrst months of life, relative to the critical period of visual development. Visual acuity development continues up to 7 to 8 years of age, but development is slower and plasticity is progressively less in later childhood. Abnormal visual stimulation by a blurred retinal image or strabismus during early visual development (e.g., congenital cataract, strabismus) can result in permanent damage to visual centers in the brain (see section on amblyopia later in this chapter). Early treatment of pediatric eye disorders is important to promote normal visual development.

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Binocular Visual Development

Binocular visual development occurs in concert with improving monocular vision.⁷ Basic neuroanatomy tells us that the two eyes are linked, as nasal retinal axons cross to meet temporal retinal axons in the chiasm, then proceed to join neurons in the lateral geniculate nucleus. Neurons in the lateral geniculate nucleus project to the striate cortex to connect with binocular cortical neuronsthat respond to stimulation of either eye and monocular cortical neuronsthat respond to the stimulation of only one eye. In humans, and in most animals with binocular vision, approximately 70% of the neurons in the striate cortex are binocular neurons whereas the minority are monocular.

Binocular cortical neurons along with neurons in visual associ- ation areas of the brain produce binocular stereoscopic vision.

Animal studies demonstrate that binocular cortical neurons are present from birth.^37,57Maintenance and reﬁnement of these binocular neuroanatomic connections and the development of normal binocular visual function, however, are dependent on 104 handbook of pediatric strabismus and amblyopia

TABLE 4-1. Requirements for Normal Visual Development.

Clear retinal images Equal image clarity Proper eye alignment

FIGURE 4-1. Curve represents visual acuity development with age on the horizontal axis and Snellen acuity on the vertical axis. Note the expo- nential improvement in visual acuity during the critical period of visual development (birth to 3 months). m, months; y, years.

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appropriate binocular visual stimulation. Requirements for normal binocular visual development include clear and equal retinal stimulation and proper eye alignment (see Table 4-1).

Binocular vision and fusion have been found to be present between 1.5 and 2 months of age,^4,26while stereopsis develops later, between 3 and 6 months of age.^2,3,17This author cared for a patient with a transient congenital sixth nerve palsy who presented at 3 weeks of age with a compensatory face turn to obtain binocular fusion. This single case suggests that early motor fusion may be present as early as 3 weeks of age.

NEONATAL ALIGNMENT

Eye alignment is variable during the ﬁrst few weeks of life. In a study by Sondhi et al.³⁹of 2271 newborns, 67% showed an exodeviation, 30% had essentially straight eyes, 2% swung between eso- and exodeviations, and only 1% had an esodevia- tion. By 2 months of age, all the esodeviations resolved, and 97%

of exodeviations cleared by 6 months. Thus, almost all newborns have straight eyes or an exotropia, but esotropia is rare.

The presence of an exodeviation at birth allows our innate strong fusional convergence to align the eyes. An esotropia, on the other hand, is more difﬁcult to control because fusional diver- gence is weak.

EYE MOVEMENT DEVELOPMENT AND SMOOTH PURSUIT ASYMMETRY

Neonates typically have sporadic, jerky eye movements made up of saccadic eye movements without smooth pursuit. Initially, saccades are hypometric, but they continue to improve throughout infancy and childhood. Smooth pursuit eye movements develop after 4 to 6 weeks of age, with most infants having accurate smooth pursuit by 2 months of age. Horizontal smooth pursuit develops for targets moving in a temporal to nasal direction before pursuit movements in a nasal to temporal direction develop. This developmental lag in nasally directed smooth pursuit is called smooth pursuit asymmetry and is only seen under monocular conditions with one eye covered. During development, nasal to temporal pursuit movements are hypometric, requiring saccadic intrusion eye movements to keep up

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with the moving target.¹ Smooth pursuit asymmetry can be detected clinically by testing monocular optokinetic nystagmus (OKN). Neonates will show a diminished OKN response with the drum rotating nasal to temporal as compared to temporal to nasal. Normally, smooth pursuit asymmetry becomes symmetrical between 4 to 6 months of age.^31,32If binocular visual development is disrupted during the ﬁrst few months of life (e.g., congenital esotropia and a unilateral cataract), smooth pursuit asymmetry and OKN asymmetry will persist throughout life.12,41,42,54,55Smooth pursuit asymmetry does not interfere with normal visual function or the ability to read, as it is not present under binocular viewing. It is, however, an important phenomenon that shows a physiological link between ocular motor development and the development of binocular vision.

VISUAL DEVELOPMENTAL MILESTONES

Central fixation and accurate smooth pursuit are important clinical milestones of normal visual development (Table 4-2). Most children will show central fixation and accurate smooth pursuit eye movements by 2 to 3 months of age, but some infants may show delayed visual maturation. Poor fixation at 6 months of age is usually pathological, and should prompt a full evaluation 106 handbook of pediatric strabismus and amblyopia

TABLE 4-2. Important Visual Developmental Milestones.

Age Visual Milestones 0–2 months Pupillary response

Sporadic ﬁx and follow Jerky saccadic eye movements

Alignment: exodeviations common, but esodeviations rare 2–6 months Central ﬁx and follow (mother’s face)

Accurate binocular smooth pursuit

Monocular smooth pursuit asymmetry: temporally directed, slow; nasally directed, accurate optokinetic nystagmus (OKN) present

Alignment: orthotropia with few exodeviations and no esodeviations

Esotropia considered abnormal 6 months–2 years Central ﬁxation, reaches for toys and food

Accurate and smooth pursuit eye movements Alignment: orthotropia

3–5 years 20/40 and not more than 2 Snellen lines difference

5 years 20/30 and not more than 2 Snellen lines difference

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for oculomotor or afferent visual pathway disease, including electrophysiology and neuroimaging studies.

Abnormal Visual Development

A unilateral or bilateral blurred retinal image or strabismus will disrupt early visual development and can cause permanent visual loss. Following is a discussion of cortical suppression and amblyopia.

CORTICAL SUPPRESSION

Strabismus, or a monocular blurred retinal image, causes dis- similar retinal images to fall on corresponding retinal areas of each eye. If the dissimilarity between the retinal images is great and the images cannot be fused, the visually immature adapts by inhibiting cortical activity from the blurred or deviated eye.

This cortical inhibition usually involves the central portion of the visual field and is termed cortical suppression. Images that fall within the field of cortical suppression are not perceived, forming an area called a suppression scotoma. Suppression only occurs during binocular conditions with the dominant eye actively viewing or “fixating” and disappears when the dominant eye is occluded. Suppression has been shown to reduce the first positive peak (P-1) of the pattern visual evoked potential (P.VEP) (Fig. 4-2).⁵⁸ The P-1 reflects early visual processing at the level of striate cortex, so it is likely that suppression occurs at, or before, the primary visual cortex. In Figure 4-2B, both eyes are open and the dominant eye is fixing whereas the nondominant eye is stimulated with the pattern. There is no P-1 response from the nondominant eye because the visual activity from the fixing eye cortically suppresses visual activity from the nondominant eye. Note that (in Fig. 4-2C) if the dominant eye is occluded in a patient with esotropia, there is no suppression and a high-amplitude P-1 is recorded from the nondominant eye.

Cortical suppression interferes with the development of binocular cortical cells, resulting in abnormal binocular vision and poor, or no, stereoscopic vision. If suppression alternates between eyes, visual acuity will develop equally, albeit sepa- rately without normal binocular function. Constant suppression of one eye, on the other hand, not only results in poor binocularity but also causes poor vision (i.e., amblyopia).

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AMBLYOPIA

Amblyopia occurs in approximately 2% of the general popula- tion and is the most common cause of decreased vision in child- hood. The term amblyopia is derived from the Greek language and means dull vision: amblys dull, ops eye. Generally 108 handbook of pediatric strabismus and amblyopia

A

B

C

Amblyopic eye

ET F

Fixing eye Suppression amblyopic eye

No suppression amblyopic eye

No response

P-1

Good response Occipital

electrode TV

AMP P-VEP

Response Monitor

F

Check stimulus No stimulus

FIGURE 4-2A–C. (A) Diagram of effect of suppression on the pattern visual evoked potential (P.VEP). The patient being tested has an esotropia and ﬁxates with the dominant right eye. An alternating check stimulus is presented to the deviated left eye during binocular viewing (B) and again to the left eye, but with the dominant right eye occluded (C).

(B) The patient is fixating with the dominant right eye and is cortically suppressing the deviated left eye. A check stimulus is presented to the deviated left eye, but there is no P.VEP response recorded when the right eye is fixing because visual information from the left eye is cortically suppressed. (C) The dominant right eye is occluded and the left eye is stimulated, resulting in a high-amplitude P.VEP response. There is no suppression because the patient is monocularly fixing with the left eye.

The check stimulus now results in a robust cortical response from the left eye.

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speaking, amblyopia can refer to poor vision from any cause but, in this volume and in most ophthalmic literature, amblyopia refers to poor vision caused by abnormal visual development secondary to abnormal visual stimulation. Other terms for this type of amblyopia include functional amblyopia and amblyopia ex anopsia.Children are susceptible to amblyopia between birth and 7 years of age.²⁵The earlier the onset of abnormal stimulation, the greater is the visual deﬁcit. The critical period for visual development is somewhat controversial but probably ranges from 1 week to 3 months of age. For practical purposes, amblyopia is deﬁned as at least 2 Snellen lines difference in visual acuity between the eyes, but amblyopia is truly a spec- trum of visual loss, ranging from missing a few letters on the 20/20 line to hand motion vision.

Functional amblyopia, or “amblyopia,” should be distin- guished from organic amblyopia, which is poor vision caused by structural abnormalities of the eye or brain that are independ- ent of sensory input, such as optic atrophy, a macular scar, or anoxic occipital brain damage. Functional amblyopia is reversible when treated with appropriate visual stimulation during early childhood, whereas organic amblyopia does not improve by visual stimulation.

Pathophysiology and Classiﬁcation of Amblyopia

Amblyopia is caused by abnormal visual stimulation during visual development, resulting in abnormalities in the visual centers of the brain. There are two basic forms of abnormal stim- ulation: pattern distortion (i.e., blurred retinal image) and corti- cal suppression(i.e., constant suppression of one eye). Pattern distortion and cortical suppression can occur independently or together to cause amblyopia in the visually immature. Ambly- opia can be created by blurring one or both retinal images or by inducing strabismus in visually immature animals (Fig. 4-3).

Strabismus will cause amblyopia in infant animals if the animal ﬁxates with one eye and constantly suppresses the fellow eye.

Strabismic animals that alternate ﬁxation do not develop amblyopia; however, they do not develop binocular vision. Pathologi- cal changes associated with induced amblyopia in the animal model occur in the lateral geniculate nucleus (LGN) and the striate cortex.20,21,23,24,44,48,49 Figure 4-4 shows the pathological changes in the lateral geniculate nucleus of a monkey raised

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with a monocular blurred retinal image. Normally, there are six nuclear layers of the LGN: three layers corresponding to the right eye and three layers corresponding to the left eye. Because of the blurred retinal image, only three layers corresponding to the eye with the clear retinal image developed. Due to the increased visual stimulation of the good eye, these three layers are darker stained and larger than normal.⁵⁷Ocular dominance columns in the striate cortex are also damaged as a result of a unilateral blurred image during early development (Fig. 4-4B).²¹ Von Noorden^46,47bridged the gap between human and animal research when he identiﬁed similar neural anatomic changes in a pathological study of humans with anisometropic amblyopia and strabismic amblyopia. Thus, this evidence has shown that the poor vision found with amblyopia is caused by brain damage.

Clinically, amblyopia is associated with strabismus and strong ocular dominance (monocular suppression), a unilateral blurred retinal image secondary to refractive error or media opacity (pattern distortion and suppression), and bilateral blurred retinal images (bilateral pattern distortion). Table 4-3 lists a classiﬁcation of amblyopia based on etiology.

Strabismic Amblyopia

Amblyopia can occur in patients with a constant tropia who show strong ﬁxation preference for one eye and constantly suppress cortical activity from the deviated eye. Amblyopia can also occur despite the fact that both eyes have clearly focused retinal images. Patients with strabismus who alternate ﬁxation and alternate suppression do not have amblyopia, but they do have abnormal binocular function. The mechanism for strabismic amblyopia is constant cortical suppression that degrades neuronal connections to the deviated eye. Strabismic amblyopia occurs in approximately 50% of patients with congenital esotropia (a constant tropia), but is very uncommon in patients with intermittent strabismus (e.g., intermittent exotropia) or those with incomitant strabismus (e.g., Duane’s syndrome and Brown’s syndrome) as they maintain central fusion by adopting a compensatory face turn. Strabismic amblyopia can be moder- ate to severe, and in some cases even results in visual acuity of 20/200 or worse.

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FIGURE 4-3. Diagram of cortical sensory adaptation to various visual stimuli during early visual development in the cat. Bars indicate per- centage of occipital cortical cells that are either monocular cells, con- nected to the right eye (R) or left eye (L), or binocular cells, connected to both eyes (B). First column, normal visual development, no amblyopia or strabismus. Note that the majority of cortical cells are binocular, and the right and left eye monocular cell populations are equal. Second column, cortical adaptation to alternating esotropia. Note that the monocular cortical cells of left and right eye are now in the majority and there are relatively few binocular cells. There is no amblyopia, however, as the right and left eye monocular cell populations are equal. Third column, effect of a left esotropia with strong preference for the right eye so the left eye is amblyopic. The majority of cortical cells are right eye monocular cells, and there is a severe reduction of monocular left eye cells and binocular cells. Fourth column, effect of monocular pattern distortion by blurring the vision of the left eye with atropine. Left eye is amblyopic so it has the lowest representation, and the majority of cortical cells are connected to the right eye. Note that the binocular cells are diminished from normal but are relatively well preserved because of peripheral fusion; this is analogous to the monoﬁxation syndrome associated with anisometropic amblyopia. Fifth column, effect of equal pattern distortion to both eyes by blurring vision in both eyes with atropine. Both eyes become amblyopic, but the binocular cortical representation is essentially normal with the majority of cortical cells being binocular, and the left and right eye control similar numbers of monocular cells; this is analogous to ametropic amblyopia. (From Ref. 24, with permission.)

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A

B1

FIGURE 4-4A,B. (A) Pathology of amblyopia (LGN): Cross-section of lateral geniculate nucleus (LGN) from a normal monkey (left ﬁgure) vs.

amblyopic monkey caused by a unilateral blurred image (right ﬁgure).

Note that the normal LGN has 6 nuclear layers (darkly stained cell layer- left ﬁgure) and the amblyopic LGN has only 3 layers, and they are thicker than normal (right ﬁgure).^56,57

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Unilateral Pattern Distortion Amblyopia

Unilateral, or asymmetrical, retinal image blur can produce amblyopia and loss of binocularity depending on the severity of the condition. The ophthalmic literature often refers to amblyopia associated with monocular image blur as “pattern depriva- tion amblyopia.” This term is misleading, because unilateral image blur results in pattern distortion and cortical suppression, both of which contribute to the amblyopia.

Clinically, mild image blur (e.g., blur associated with mild anisometropia) causes mild anisometropic amblyopia and allows for the development of peripheral fusion and stereopsis (i.e., B2

FIGURE 4-4A,B. (B) Pathology of amblyopia in monkey striate cortex (visual cortex). Well-defined cortex dominance columns are seen in normal specimen (B1 figures), but cortex columns are underdeveloped in specimen for amblyopic monkey (B2 figures).²¹

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monofixation syndrome). A significant blurred image during infancy (e.g., unilateral congenital cataract or corneal opacity), however, can result in severe amblyopia. Vision can be as poor as count fingers with total loss of binocular function manifested by the development of sensory strabismus.

Anisometropic amblyopia, one of the most common types of amblyopia, is caused by a difference in refractive errors that results in a unilateral or asymmetrical image blur. Most patients with anisometropic amblyopia have straight eyes and appear

“normal,” so the only way to identify these patients is through vision screening. Stereoacuity testing has had limited value in screening for anisometropic amblyopia because most patients have relatively good stereopsis (between 70 and 3000 s arc).

Patients with anisometropic amblyopia usually have peripheral fusion, and most have the monoﬁxation syndrome.³⁵Myopic anisometropia is generally less amblyogenic than hypermetropic anisometropia. As little as 1.00 hypermetropic anisometropia and2.00 myopic anisometropia can be associated with amblyopia.⁵¹ Astigmatic anisometropic amblyopia does not occur unless there is a unilateral astigmatism greater than 1.50 D.⁵¹ 114 handbook of pediatric strabismus and amblyopia

TABLE 4-3. Classiﬁcation of Amblyopia.

A. Strabismic amblyopia (suppression) 1. Congenital esotropia 2. Congenital exotropia

3. Acquired constant tropia in childhood 4. Accommodative esotropia

5. Small-angle tropia (monoﬁxation syndrome)

6. Intermittent exotropia (rarely associated with amblyopia) B. Monocular pattern distortion (suppression and pattern distortion)

1. Anisometropia a. Hyperopia 1.50 b. Myopia 3.00 c. Meridional 1.50 2. Media opacities

a. Unilateral cataract

b. Unilateral corneal opacity (Peter’s anomaly) c. Unilateral vitreous hemorrhage or vitreous opacity C. Bilateral pattern distortion (pattern distortion)

1. Ametropia

a. Bilateral high hypermetropia 5.00 b. Bilateral meridional (astigmatic) 2.50 2. Media opacity

a. Bilateral congenital cataracts

b. Bilateral corneal opacities (Peter’s anomaly) c. Bilateral vitreous hemorrhages

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For practical purposes, however, we do not see signiﬁcant anisometropic amblyopia unless differences between the two eyes are greater than 1.50 in hyperopes and greater than 3.00 in myopes. Myopic anisometropic amblyopia is often amenable to treatment even in late childhood whereas hypermetropic amblyopia is often difﬁcult to treat past 4 or 5 years of age, probably because high myopia is usually acquired after the critical period of visual development, and the more myopic eye is in focus for near objects (a baby’s world is up close). In contrast, patients with hypermetropic anisometropia always use the less hypermetropic eye because it requires less accommodative effort and constantly suppress the more hypermetropic eye.

Bilateral Blurred Retinal Image

Pattern distortion in its pure form without suppression occurs when there is bilateral symmetrical image blur and no strabismus. Clinically, the effects of pure image blur are seen in cases of bilateral high hypermetropia or bilateral symmetrical astigmatism, or with bilateral ocular opacities such as bilateral congenital cataracts and bilateral Peter’s anomaly. Bilateral pattern distortion causes bilateral poor vision. Depending on the extent of the distortion, some binocular fusion can develop, usually associated with gross stereopsis. If severe image blur occurs during the neonatal period so that essentially no pattern stimulation is provided, extremely poor vision and sensory nystagmus develop. Bilateral amblyopia and nystagmus will occur in cases of dense bilateral congenital opacities unless the image is cleared by 2 months of age. This type of nystagmus is called sensory nystagmusand is associated with bilateral severe amblyopia, or other causes of congenital blindness such as macular or optic nerve pathology. Sensory nystagmus does not occur with cortical blindness because extrastriate visual pathways anterior to the occipital cortex supply the fixation reflex. Acquired opacities after 6 months of age usually do not cause sensory nystagmus because the motor component of fixation has already been established. The presence of sensory nystagmus indicates severe amblyopia, usually 20/200 visual acuity or worse.

Ametropic amblyopia (bilateral hypermetropic amblyopia) usually occurs with hypermetropia greater than 5.00D without signiﬁcant anisometropia.³⁶In these cases, visual acuity is decreased in each eye, the eyes are usually straight, and the patients usually have gross stereopsis. When patients are ﬁrst

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given their optical correction, visual acuity does not signiﬁ- cantly improve. The lack of improvement with spectacle correction often leads the examiner to seek an organic cause for the decreased vision. The treatment of bilateral high hypermetropic amblyopia is to prescribe full hypermetropic correction. In most cases, visual acuity will slowly improve if the glasses are worn full-time, with ﬁnal visual acuity usually in the range of 20/30 to 20/25 achieved over a period of 6 months to a year.

Bilateral meridional amblyopiais caused by bilateral astigmatism and, like bilateral hypermetropic amblyopia, is secondary to pattern distortion. Signiﬁcant meridional amblyopia occurs with astigmatism greater than 2.50D. To avoid meridional amblyopia, astigmatisms of 2.50 D or more should be treated in preschool children, and astigmatisms over 3.00 D to 4.00 D should be treated in infants.

Amblyopic Vision

The visual deficit associated with amblyopia has certain unique characteristics, including the crowding phenomenon, the neutral density filter effect, and eccentric fixation. The crowd- ing phenomenon relates to the fact that patients with amblyopia have better visual acuity reading single optotype than reading multiple optotypes in a row (linear optotypes). Often, patients with amblyopia will perform 1 or 2 Snellen lines better when presented with single optotypes versus linear optotypes. This crowding phenomenon may have something to do with the relatively large receptive field associated with amblyopia.

Crowding bars are often used around a single optotype to provide a more sensitive test for amblyopia.

A neutral density ﬁlter reduces overall luminance without inducing a color change. Decreased luminance of the visual target results in diminished central acuity in normal eyes.

Decreased illumination of visual targets has less of an effect on amblyopic eyes because they are not using central acuity. The intraocular differences in visual acuity between the amblyopic eye and the sound eye diminish when the patient looks through a neutral density ﬁlter that lowers the luminance of the visual target. For example, a patient with a left amblyopia has 20/20 vision in the right eye and 20/60 in the left eye under photopic conditions (4 lines difference). He may have visual acuities of 20/50 right eye and 20/60 left eye under scotopic conditions (1 line difference).

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All amblyopes have some degree of extrafoveal ﬁxation.

Mild amblyopes (20/40–20/100) fixate so close to the fovea that they appear to fixate centrally. Severe amblyopes, usually 20/200 to count fingers, use a large parafoveal area for viewing (Fig. 4- 5). This area of eccentric fixation is not a pinpoint location but a general area of viewing.

The presence of eccentric fixation is a clinical sign of severe amblyopia and has a poor visual prognosis. Remember that anomalous retinal correspondence is quite different from eccen- tric fixation. Anomalous retinal correspondence (ARC) is a binocular sensory adaptation to strabismus that allows accept- ance of images on noncorresponding retinal points. ARC is only active during binocular viewing and, when one eye is covered, fixation reverts back to the true fovea. Eccentric fixation, on the other hand, is dense amblyopia without foveal fixation and is present under monocular or binocular conditions.

B A

FIGURE 4-5A,B. Eccentric fixation. (A) Sound eye fixes with the fovea (left) and the amblyopic eye eccentrically fixates in an area of fixation (right). (B) Right eye is covered, and eccentric fixation persists with patient viewing in an eccentric area.

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DIAGNOSING AMBLYOPIA

Visual Acuity Testing

When evaluating for amblyopia, linear acuity is more desirable than single optotype presentation because single optotype presentation underestimates the degree of amblyopia. Surround bars have been used to create crowding in a single optotype and are useful in children who get confused with the multiple optotypes used in linear acuity testing. There are many ways to test visual acuity in preschool children, including Allen picture figures, LEA figures, HOTV, illiterate E game, and the recently developed Wright figures^©. The Wright figures are composed of black and white bars with a constant gap throughout the figure (Fig.

4-6). A recent study using the Wright figures on the Portal Stimuli System (Haag-Streit) found that the Wright figures tested two-point discrimination acuity, similar to Snellen acuity. Another advantage of the Wright figures is that their overall shape or footprint is similar for all figures, which prevents the child from determining the figure by the shape rather than internal two-point discrimination. (Dr. Wright collaborated with Gregg and Paul Podnar from Accommodata, Inc., Cleve- land, OH, developers of the Portal System, to refine the figures for use in this system and perform the study.) Visual acuity can often be measured in children as young as 2 to 3 years of age using preschool optotypes.

FIGURE 4-6. Wright figures consist of black and white bars with con- stant thickness and white gaps. The overall shape or footprint is similar for all figures, which prevents the child from determining the figure by the shape alone. The Wright figures correlate well with Snellen acuity.

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Fixation Testing for Amblyopia

Preverbal children can be tested for amblyopia by examining the quality of monocular ﬁxation or binocular ﬁxation preference.

MONOCULARFIXATIONTESTING

Normally developed children more than 2 to 3 months of age should show central fixation with accurate smooth pursuit and saccadic refixation eye movements. Test for central fixation by covering one of the patient’s eyes, then move a target slowly back and forth in front of the child to observe the accuracy of fixation. A child with central fixation looks directly at the target, visually locks on the target, and accurately follows the moving target. Infants often find the human face a much more compelling target than toys or pictures, so try moving your head side to side to evaluate the quality of fixation. Central fixation indicates foveal vision usually in the range of 20/100 or better.

ECCENTRICFIXATION

Eccentric ﬁxation means the fovea is not ﬁxating and the patient is viewing from an extrafoveal part of the retina (Fig. 4-5).

Patients with eccentric ﬁxation appear to be looking to the side, not directly at the ﬁxation target. They have poor smooth pur- suits, so they do not accurately follow a moving target.

VISUSCOPE

One way to identify the eccentric fixation point in older coop- erative children is to use a Visuscope, which is a type of direct ophthalmoscope that projects a focused image onto the retina so the examiner can see the image on the retina. First, the image is projected onto the parafoveal retina, then the patient is asked to look at the image. If the patient has central fixation, the patient refixates to place the image precisely on the fovea.

However, with eccentric fixation, the patient will view with the parafoveal retinal area and show a wandering, unsteady fixation (see Fig. 4-5). The more peripheral the eccentric fixation, the denser the amblyopia.

FIXATIONPREFERENCETESTING

Testing for ﬁxation preference is useful in preverbal strabismic children to identify amblyopia that might be missed by mono-

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cular fixation testing. It is based on the premise that strong fixation preference indicates amblyopia. If a patient with strabis- mus spontaneously alternates fixation, using one eye, then the other, this indicates equal fixation preference and no amblyopia (Fig. 4-7).

A

B

FIGURE 4-7A,B. Infant with congenital esotropia and alternating ﬁxa- tion. Alternating ﬁxation indicates equal visual preference; no amblyopia.

(A) Patient is ﬁxing with the left eye. (B) Patient has switched ﬁxation to the right eye.

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Patients with a ﬁxation preference may have amblyopia.

The strength of fixation preference indicates if amblyopia is present, with the weaker preference for one eye being the amblyopic eye. Fixation preference can be quantified by briefly covering the preferred eye to force fixation to the nonpreferred eye.

Remove the cover from the preferred eye, then observe how well and how long the patient will maintain fixation with the nonpreferred eye before refixating back to the preferred eye. If fixation immediately goes back to the preferred eye after the cover is removed, then this indicates strong fixation preference for the preferred eye and amblyopia of the deviated eye (Fig. 4-8).

However, if the patient maintains fixation with the nonpreferred eye through smooth pursuit, through a blink, or for at least 5 s, there is mild fixation preference and no significant amblyopia (vision within 2 Snellen lines difference) (Fig. 4-9). The ability to maintain fixation with the nonpreferred eye while following a moving target is a very reliable indicator of equal vision and detects no significant amblyopia.

The reliability of fixation preference testing for diagnosing amblyopia has been shown to be quite good in patients with large-angle strabismus, more than 10 to 15 PD.⁶²Patients with small-angle strabismus, however, will show strong fixation FIGURE 4-8. Measuring fixation preference. Patient has strong fixation preference for the left (left figure) and amblyopia in the right eye.

Temporarily covering the left eye (center figure) forces fixation to the right eye, but when the cover is removed, the patient refixates to the left eye (right figure). This indicates strong fixation preference, i.e., amblyopia.

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preference in 50% to 70% of cases, even if the vision is equal to within a 2 Snellen lines difference.^63,64This high overdiagnosis rate in children with small-angle strabismus occurs because they have monofixation syndrome. These patients have peripheral fusion but suppress one fovea, so they show strong fixation preference even if vision is equal. The overdiagnosis of amblyopia in patients with small-angle strabismus can be rectified by using the vertical prism test, which disrupts peripheral fusion and temporarily breaks down the monofixation syndrome.

VERTICALPRISMTEST(INDUCEDTROPIATEST, 10 DIOPTERFIXATIONTEST)

The vertical prism test is used in preverbal children with straight eyes or small-angle strabismus to accurately diagnose amblyopia.^62,63It is performed by placing a 10 to 15 PD prism base-up or base-down in front of one eye, thereby inducing a vertical tropia (Fig. 4-10). With the induced vertical strabismus, ﬁx- ation preference can be determined as shown in Figure 4-11. In Figure 4-11A, a base-down prism is placed over the right eye.

The right eye is fixing because both eyes move up as the right eye fixates through the prism. In Figure 4-11B, the prism is placed over the left eye, but the patient still fixates with the right eye, evidenced by the fact that both eyes are in primary 122 handbook of pediatric strabismus and amblyopia

FIGURE 4-9. Patient prefers to fix with the left eye (left figure). Occlud- ing left eye forces fixation to right eye (center figure), and when the occluder is removed (right figure), the patient maintains fixation with the nonpreferred eye, indicating no amblyopia.

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position, ignoring the prism in front of the left eye. If the patient can hold fixation with either eye through a blink or through smooth pursuit eye movements, no significant amblyopia is present. A strong fixation preference indicates amblyopia.

CROSS-FIXATION

Patients with a large-angle esotropia and tight medial rectus muscles will have difﬁculty bringing the eyes to primary position, so the eyes stay adducted. These patients “cross-ﬁxate.”

The right adducted eye fixes on objects in left gaze, and the left adducted eye fixates on objects in right gaze. Cross-fixation has been said to be a sign of equal vision, but cross-fixation does not guarantee that a patient sees equally with each eye. The ability to hold fixation past midline or to hold fixation through smooth pursuit with either eye is a better criterion for equal vision.

LATENTNYSTAGMUS

Patients with strabismus often have latent nystagmus, which is a horizontal jerk nystagmus that occurs or gets worse in both eyes if one eye is occluded. Thus, covering one eye in a patient with latent nystagmus will increase nystagmus and diminish visual acuity. To evaluate monocular visual function, blur one

FIGURE 4-10. Vertical prism test of a patient fixing with the left eye because of a right amblyopia. A vertical prism is placed in front of the left eye and, because the left eye is fixing, the left eye elevates to pick up the fixation. As per Hering’s law, both eyes will elevate if the left eye is fixing.

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A

B

FIGURE 4-11A,B. (A) Vertical prism is placed in front of one eye to iden- tify which eye is fixing, and therefore fixation preference can be deter- mined. (A) One can identify that the right eye is fixing because the right eye is in primary position and the patient is ignoring the vertical displaced image in the left eye. (B) Patient is still fixing with the right eye. Both eyes shift upward because the right eye is viewing through the prism.

This is a base-down prism, so the eyes move up.

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eye with a plus lens rather than occluding one eye. Blurring one eye induces less nystagmus than occlusion. Use the minimum amount of plus necessary to force ﬁxation to the fellow eye. The vertical prism test can identify which eye is ﬁxing. Usually, a

5.00D lens is sufficient to blur distance vision enough to force fixation to the fellow eye. Linear presentation of optotypes is dif- ficult for patients with nystagmus because the optotypes tend to run together, so try a single optotype presentation. Also, take a binocular visual acuity measurement in addition to a monocular acuity in patients with nystagmus because binocular vision is usually better than monocular vision. To assess the best functional visual acuity potential in a patient with nystagmus, test binocular vision while allowing the patient to adopt their preferred face turn or head tilt.

VISION SCREENING

Early detection and treatment of pediatric ocular disease is critical. Diseases such as congenital cataracts, retinoblastoma, and congenital glaucoma require early treatment during infancy.

Delay in diagnosis may result in irreversible vision loss and, in the case of retinoblastoma, even death. Patients with congenital cataracts treated during the ﬁrst weeks of life have a relatively good prognosis, whereas surgery performed after 2 to 3 months of age is considered late and is associated with a poor visual outcome. It is, therefore, imperative to perform effective vision screening for all children from newborn infants to older children.

Vision screening examinations should start at birth and continue as part of routine checkups for primary care physicians.

The acronym I-ARM (inspection—acuity, red reﬂex, and motility) can be a helpful reminder of the essential parts of a pediatric screening examination. Table 4-4 summarizes the I-ARM screening eye examination for neonates, babies, and children.

The most important test for the newborn is the red reﬂex test.

If an abnormal red reﬂex is present, then an immediate referral to an ophthalmologist is required. Infant screening examinations take less than a minute, but this brief exam is quite powerful.

If performed properly, it can detect the vast majority of eye pathology, including the important diagnoses mentioned previously. Guidelines for visual acuity referral are presented in Table 4-5.

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Red Reﬂex

The red reflex test is the single best vision screening exam for infants and young children. It is best performed using the Brück- ner modification, which is simply a simultaneous bilateral red reflex. Use the direct ophthalmoscope and view the patient’s eyes at a distance of approximately 2 feet from the patient. Use a broad beam so that both eyes are illuminated at the same time.

Dim the room lights and have the child look directly into the ophthalmoscope light. Start with the ophthalmoscope on low illumination then slowly increase the illumination until a red reflex is seen. You will observe a red reflex that fills the pupil and a small (approximately 1 mm) white light reflex that appears to reflect off the cornea (Fig. 4-12). The white light reflex is actually a reflex coming from just behind the pupil and is called the “corneal light reflex” or the “Hirschberg reflex.” Thus, the Brückner test gives both a red reflex and the corneal light reflex simultaneously.

Blockage of the retinal image or large retinal pathology will result in an abnormal red reﬂex. A cataract can either block the 126 handbook of pediatric strabismus and amblyopia

TABLE 4-4. Screening Eye Examination: I–ARM.

Neonate Babies Children

Steps (Birth–2 months) (3 months–2 years) (3 years and older) Inspection Symmetry Face Face turn or head tilt Face turn or head tilt

& eyes

Acuity Poor ﬁxation Good ﬁxation and Visual acuity: Allen Pupillary response smooth pursuit cards, E-game,

Snellen acuity Red reflex Red reflex test Binocular red reflex Bilateral red reflex test

(Brückner) (Brückner) Motility Gross alignment Good alignment Good alignment

(70% small Light reﬂex and Light reﬂex and exotropia but Brückner (esotropia Brückner (any esotropia probably is abnormal after misalignment is abnormal 2 months of age) abnormal)

TABLE 4-5. Abnormal Red Reﬂex: Symmetry Is the Key.

Cataract May block the red reﬂex (dark or dull reﬂex) or may look white (leukocoria)

Vitreous hemorrhage Blocks red reflex (dark or dull reflex) Retinoblastoma Appears as a yellow or white reflex (leukocoria) Anisometropia Results in an unequal red reflex

Strabismus Causes a brighter red reﬂex in the deviated eye; the corneal light reﬂex will be decentered

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red reflex or reflect light to give a white reflex. Retinoblastoma has a yellowish-white color and will produce a yellow reflex. An- isometropia (difference in refractive error) will result in an unequal red reflex. Strabismus will cause a brighter red reflex in the deviated eye, and the corneal light reflex will be decentered.

The key sign of a normal exam is symmetry. See Figure 4-13 and Table 4-5 for examples of abnormal red reﬂexes.

AMBLYOPIA TREATMENT

Early treatment of amblyopia is critical for best visual acuity results. The basic strategy for treating amblyopia is to ﬁrst provide a clear retinal image, and then correct ocular domi- nanceif dominance is present, as early as possible during the period of visual plasticity (birth to 8 years). Correction of ocular dominance is accomplished by forcing ﬁxation to the amblyopic eye through patching or blurring the vision of the sound eye.

Clear Retinal Image

Patients with bilateral hypermetropia (5.00D) should receive the full hypermetropic correction, as amblyopic eyes do not fully accommodate. Patients who are given partial correction of their high hypermetropia often show very slow or no improvement FIGURE 4-12. Normal Brückner test with symmetrical red reﬂex and centered corneal light reﬂex.

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B A

FIGURE 4-13A,B. Abnormal reﬂex. (A) Cataract: left eye. (B) Ani- sometropia: brighter reﬂex in right eye.

in their amblyopia. Patients with large astigmatism (2.50D) will also have amblyopia secondary to the astigmatism or develop meridional amblyopia. Prescribe the full astigmatic correction to provide a clear retinal image. It is important to con- sider correcting astigmatisms of 2.50 to 3.00 or more in small children, even if the astigmatism is bilateral. Table 4-6 lists guidelines for prescribing spectacles in children. In general, if the patient has anisometropic amblyopia and straight eyes, this author initially prescribes just glasses and waits to start patch-

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ing of the good eye. Most anisometropic amblyopes will respond to glasses alone with no or minimal part-time occlusion of the good eye.¹⁹

Children with media opacities, such as a visually significant cataract, should have immediate surgery with visual rehabilita- tion using a contact lens or intraocular lens. Early treatment is critical; infants with a congenital cataract should undergo surgery within the first month of life, even as early as the first week.

C

FIGURE 4-13C. (C) Strabismus: esotropia with brighter reﬂex from devi- ated left eye. (Note: This is the author’s youngest son. The author sub- sequently performed strabismus surgery on him, and the eyes have remained straight.)

TABLE 4-6. When Should Spectacles Be Prescribed in Children?

Type of refractive error Threshold for prescribing spectacles

Hypermetropic anisometropia 1.50 D

Myopic anisometropia 3.00 D

Astigmatic anisometropia 1.50 D

Bilateral hypermetropia 5.00 D

Bilateral astigmatism 2.50 D

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Correct Ocular Dominance

OCCLUSION

Patching or occlusion therapy is based on covering the sound eye to stimulate the amblyopic eye. Strabismic patients without binocular fusion can be treated with full-time occlusion;

however, full-time occlusion may result in reverse amblyopia in children under 4 to 5 years of age. To prevent reverse amblyopia, do not use full-time occlusion for more than 1 week per the child’s age in years without reexamining the vision of the good eye. For example, a 2-year-old child receiving full-time occlusion should be examined every 2 weeks. In children less than 1 year of age, part-time occlusion may be preferable to avoid reverse amblyopia.

Amblyopic patients with essentially straight eyes (tropias

8 PD) and peripheral fusion (e.g., anisometropic amblyopia and microtropia monoﬁxators) are best treated with part-time patching (3 to 4 h/day) or no occlusion. For anisometropic amblyopia, initially prescribe spectacle correction and follow the patient each month for visual acuity improvement. If vision does not improve on monthly follow-ups, then part-time patching is started. Part-time occlusion or penalization therapy is preferred because these methods help to preserve fusion. If vision does not improve with part-time occlusion, then full-time occlusion should be tried.

PENALIZATION

Penalization is a method for blurring the sound eye to force fixation to the amblyopic eye. Penalization actually switches ocular suppression, which can be demonstrated by a Polaroid vectographic chart or by the Worth 4-dot test. Penalization only works if fixation is switched from the sound eye to the amblyopic eye.⁵⁹Blurring of the sound eye can be achieved by various methods. Optical penalization is based on over-plussing (pre- scribing more plus sphere than needed) the sound eye to force fixation to the amblyopic eye for distance targets; the patient will usually use the sound eye for near targets. Optical penalization works well for mild amblyopia; however, some children will look over the tops of their glasses to use their sound eye.

Atropine penalizationis a stronger form of penalization and is useful even in dense amblyopia so long as the patient has sig- niﬁcant hypermetropia of the good eye.³⁸Atropine at 0.5% or 130 handbook of pediatric strabismus and amblyopia

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1% is placed in the sound eye each day, optical correction is removed from the sound eye, and the amblyopic eye is given full optical correction. If the patient switches ﬁxation to the amblyopic eye under these conditions of penalization, then penalization will improve vision.⁵⁹

Cyclopentolate can be used as an in-office test to predict if penalization will work.⁵⁹The in-office test consists of providing the amblyopic eye with full optical correction while deadening the sound eye with cyclopentolate and removing optical correction from the sound eye. If fixation switches to the amblyopic eye under these conditions, then the patient will improve with atropine penalization. Atropine penalization usually requires

3.00 or more hypermetropia in the sound eye to obtain significant blur to switch ﬁxation. It is important to note that blurring the sound eye to a visual acuity lower than the amblyopic eye does not guarantee a switch in ﬁxation to the amblyopic eye.

Penalization in young children may result in reverse amblyopia (decrease vision in the previously good eye), so patients 4 years of age or younger should be followed closely when undergoing atropine penalization therapy.^50,59

OCCLUSIVECONTACTLENS

Occlusive contact lens can be used in treating amblyopia. A study by Eustis and Chamberlain¹⁵ showed 92% of patients improved at least 1 line of Snellen acuity, but complications limited the usefulness. Complications included conjunctival irritation and poor contact lens ﬁt, and one patient even learned to decenter the lens to peek around the occlusive contact lens.

There was a high recurrence to pretreatment visual acuity, as 55% showed recurrence of amblyopia. The authors concluded that occlusive contact lenses should only be considered as a last resort and that these patients require close follow-up.¹⁵

BILATERALLIGHTOCCLUSION

A preventive treatment of amblyopia may be the use of bilateral light occlusion. Studies on dark-rearing have shown that bilateral total light occlusion prolongs the sensitive period of visual development. In several animal studies, researchers have shown that animals placed in total darkness for several months (or the human equivalent to several years) do not develop dense amblyopia and their visual development is minimally affected.^9,10,11,40 A study by Hoyt²²on neonates with hyperbilirubinemia treated

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under bili-lights who were patched bilaterally from several days to 2 weeks showed that they did not have an increased incidence of amblyopia or strabismus. In a separate report by the author,⁶¹ a neonate received 17 days of bilateral patching after having 2 weeks of dense vitreous hemorrhage and hyphema. Follow-up at 3 years of age showed visual acuity of 20/30 in each eye and a small accommodative esophoria with good fusion. Bilateral light occlusion remains controversial and, in this author’s opinion, should be used only as a temporary measure in neonates 3 months or younger with ocular opacities such as congenital cataracts. Urgent surgery is still required but, for visually sig- niﬁcant cataracts, bilateral occlusion can be used to prevent amblyopia until the retinal image is cleared. The author’s recommendation is to limit bilateral patching to a maximum of 2 weeks.

LEVODOPA/CARBIDOPA IN THETREATMENT OFAMBLYOPIA

Levodopa/carbidopa has been traditionally used to treat Parkin- son’s disease. Levodopa is a precursor for the catecholamine dopamine, a neurotransmitter/neuromodulator known to inﬂu- ence receptive ﬁelds. Levodopa/carbidopa has been studied as an adjunct to patching for the treatment of amblyopia.27,28,29,30The treatment remains controversial, as the visual acuity improvement has been relatively small, not clearly better than with patching alone, and there are questions regarding long-term stability of vision.

PLEOPTICS

Pleopticsis a method of treating eccentric fixation associated with dense amblyopia. A bright ring of light is flashed around the fovea to temporarily “blind” or saturate the photoreceptors surrounding the fovea, which eliminates vision from the eccentric fixation point and forces fixation to the fovea. Pleoptic treat- ments are given several times a week to enhance occlusion therapy. Most practitioners have found pleoptics to be no better than standard occlusion therapy.¹⁶

ACTIVESTIMULATION

Some investigators have suggested active stimulation of the amblyopic eye as a way to improve vision in the amblyopic eye.

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A high-contrast spinning disc with square-wave grading was one method that has been tried (CAM). The CAM treatment has been found to be no better than standard occlusion therapy.⁸

PROGNOSIS OF AMBLYOPIA

The prognosis for amblyopia depends upon the age of the patient, severity of amblyopia, and type of amblyopia. The earlier the amblyopia occurs and the longer it remains untreated, the worse the prognosis. In general, bilateral amblyopia responds better than unilateral amblyopia, and myopic anisometropic amblyopia responds better than hypermetropic anisometropic amblyopia. Each case must be evaluated individually as to whether the child is too old to undergo amblyopia therapy. Visual acuity improvement has been documented when children are treated in late childhood after 8 years of age.^6,33This author reported improvement in vision from legally blind to 20/70 and damping of sensory nystagmus in a 14-year-old who underwent late cataract surgery for bilateral congenital cataracts.⁶⁰Even adults with dense amblyopia can show visual acuity improvement and prolonged plasticity. Signiﬁcant visual acuity improvement of the amblyopic eye has been reported in adults who have lost vision in their good eye and relied on the amblyopic eye for their vision.^14,45

References

1. Atkinson J. Development of optokinetic nystagmus in the human infant and monkey infant: an analogue to development in kittens.

In: Freeman RD (ed) Developmental neurobiology of vision. New York: Plenum Press, 1979.

2. Birch EE, Gwiazda J, Held R. Stereoacuity development of crossed and uncrossed disparities in human infants. Vision Res 1982;22:507.

3. Birch E, Petrig B. FPL and VEP measures of fusion, stereopsis and stereoacuity in normal infants. Vision Res 1996;36(9):1321–1327.

4. Braddick O, et al. Cortical binocularity in infants. Nature (Lond) 1980;288:363–365.

5. Braddick O, Wattam-Bell J. The onset of binocular function in human infants. Hum Neurobiol 1983;2(2):65–69.

6. Brown MH, Edelman PM. Conventional occlusion in the older amblyope. Am Orthopt J 1976;26:54–56.

7. Carney T. Evidence for an early motion system which integrates information from the two eyes. Vision Res 1997;37(17):2361–2368.