Pediatr Clin N Am 50 (2003) 189 196

Amblyopia
David Mittelman, MDa,b,c,*
Department of Ophthalmology, University of Illinois at Chicago, UIC Eye Center, 1855 W. Taylor, Chicago, IL, USA b Department of Pediatric Ophthalmology, Lutheran General Childrens Hospital, 1775 W. Dempster, Park Ridge, IL, USA c Pediatric Ophthalmology, Adult Strabismus Center, Ltd., 1875 West Dempster Street, Suite 610, Park Ridge, IL 60068, USA
a

The term amblyopia refers to an abnormality of visual development characterized by decreased visual acuity, not correctable by glasses or other optical means, which is generally unilateral but may occasionally be bilateral, for which no obvious pathologic basis can be detected by the physical examination of the eye or visual pathway. Amblyopia is associated with form deprivation and/or abnormal visual interaction and is usually reversible if treatment is instituted in a timely manner [1]. The word amblyopia comes from the Greek and literally means dull sight. The diagnosis of amblyopia is made when a complete ophthalmologic examination reveals reduced visual acuity that is not explained by any obvious organic lesion of the eye or optic nerve. Amblyopia should be considered if strabismus is present, if there is a large refractive error, especially in one eye, or if organic pathology is present in an infant or young child. Over a century ago, von Graefe formulated the classic description of amblyopia: it is the condition in which the observer sees nothing and the patient sees very little [2]. Amblyopia is common; it affects approximately 2% to 2.5% of the general population or nearly 6 million Americans. This disorder is responsible for loss of vision in more people under 45 years of age than all other forms of eye disease or trauma combined. Indeed, one large study by the National Eye Institute showed that amblyopia remains the number one cause of monocular vision loss in people ages 70 years or younger [1,3].

* Pediatric Ophthalmology, Adult Strabismus Center, Ltd., 1875 West Dempster Street, Suite 610, Park Ridge, IL 60068. E-mail address: mittelmd@yahoo.com 0031-3955/03/$ see front matter D 2003, Elsevier Science (USA). All rights reserved. PII: S 0 0 3 1 - 3 9 5 5 ( 0 2 ) 0 0 1 0 7 - 4

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Clinical findings The most important clinical feature of amblyopia is reduced vision. The extent of this visual loss varies greatly. The loss may be as little as one or two lines difference in Snellen acuity, or vision may be reduced to the level of legal blindness or worse. This decrease in visual acuity is of greater magnitude when the patient is asked to read a complete line on the eye chart rather than individual letters or symbols. This finding has been termed the crowding phenomenon. Testing done with single optotypes may fail to disclose the full extent of vision loss in amblyopic individuals and may indeed mask the presence of significant amblyopia. Therefore, when the clinician measures visual acuity, it is important always to present children with full lines of letters or symbols to avoid overlooking some cases of amblyopia. In addition, vision loss from amblyopia can be differentiated from vision loss secondary to organic reasons by the patients response to neutral density (ie, dark) filters. The amblyopic eye is much more resistant to further degradation of vision when dense filters are placed before the eye, so that vision does not decrease in very dim light, as it does in nonamblyopic eyes. The amblyopic eye seems to behave in a manner similar to the dark-adapted normal eye [1]. The diagnosis of amblyopia in preverbal infants and children requires special examination techniques, because they are unable to respond to standardized eye charts. Although complex techniques to measure visual acuity in infants such as forced preferential looking or visual evoked responses are of value in the research setting, they are not readily available to most clinicians. Therefore, in the clinical setting, fixation pattern is the most commonly used parameter to diagnose amblyopia in nonverbal children. A penlight or other interesting object is presented before the child. If strabismus is present, the examiner then occludes the fixating eye and observes the childs ability to fixate and follow with the deviating eye. When no amblyopia exists, the childs deviating eye quickly moves centrally to take up fixation and maintains that position for quite a while, even after the occluder is removed from the fellow eye. If the patient is unable to fixate centrally or maintains that fixation only briefly when the dominant eye is re-exposed, amblyopia can be presumed to exist. Fixation pattern is more difficult to evaluate when little or no strabismic deviation is present. In that case, a prism is placed before one eye, simulating a strabismus, allowing the experienced clinician to estimate fixation ability. Forced preferential looking tests [4] utilize infants innate tendency to gaze at sharply contrasting objects rather than at blank surfaces. A hidden observer watches as two paddles designed with either black and white stripes or a blank gray field are presented before the infant. The observer records which of the two paddles the baby prefers to look at. As the stripes become finer, the difference in the appearance of the paddles diminishes, until eventually the subject can no longer differentiate between the two. Visual acuity can be extrapolated from the size of the stripes producing a fixation preference.

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Visual evoked potentials may also be used to determine infant visual acuity. A series of checkerboard or striped patterns is presented before the child while scalp electrodes record the pattern of cortical responses elicited from the brain. Again, the minimum magnitude of the target producing a distinct electrical response in the brain indicates threshold visual acuity.

Classification There are three major types of amblyopia: strabismic amblyopia, anisometropic amblyopia, and deprivation amblyopia [1]. Patients with strabismus who strongly favor fixation with one eye, rather than alternating fixation between both eyes, are at risk for developing amblyopia. Strabismic amblyopia results from abnormal binocular interaction that develops from misalignment of the optical axes. When the eyes are not parallel, images fall on disparate parts of the retina, resulting in double vision or optical confusion. To avoid this uncomfortable situation, the patient unconsciously suppresses the image from the nonpreferred eye. In a young child, this chronic suppression of the visual stimulus from one eye leads to loss of vision (amblyopia). Amblyopia is much more likely to occur in esotropia than from any other form of strabismus. Anisometropia refers to a difference in refractive error between the two eyes. If this refractive error is not properly corrected, one of the retinal images will be out of focus compared with the other. The clearer image will then be favored, resulting in vision loss from amblyopia in the fellow eye. This form of amblyopia is particularly difficult to diagnose in the preverbal child, because there may be no associated strabismus or other external manifestation to alert the pediatrician. Anisometropic amblyopia is usually diagnosed following a routine screening examination either in the primary care physicians office or in the school setting. Finally, deprivation amblyopia results when the eyes fail to receive clearly formed images on the retina. Opacities of the optical system such as cataract or corneal opacity are often precipitating factors. Deprivation amblyopia can be quite profound in the newborn period. For example, if visually significant congenital cataracts or other media opacities are not removed in the first few months of life, visual loss from amblyopia is usually irreversible [5]. A special form of deprivation amblyopia is termed occlusion amblyopia. This type of amblyopia results most commonly from the iatrogenic occlusion of one eye to treat amblyopia in the fellow eye. As a result of treatment, the eye being patched, that is, the sound eye, becomes amblyopic as the previously amblyopic eye improves in vision. This problem can often be avoided by frequent monitoring of the vision in each eye during amblyopia therapy. Very young infants may have to be seen as often as weekly to guard against the development of this condition. Occlusion amblyopia can also occur any time the pupillary axis is obstructed, such as after a black eye, acquired ptosis, and so forth. Likewise, the primary care doctor should be aware that the seemingly harmless practice of

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patching an infant or toddler for a corneal abrasion or other eye injury can result in amblyopia and therefore should be undertaken with care. A fourth, somewhat lesser form of amblyopia also exists. This condition is termed ametropic or refractive amblyopia. In this situation, a large, uncorrected, fairly symmetrical refractive error is present in both eyes, leading to poorly formed images bilaterally. The childs visual acuity does not improve with the placement of glasses initially, but generally does get better over time, eventually reaching relatively normal levels.

Pathophysiology Much of what is known at this time about the physical basis of amblyopia comes from the pioneering work of Hubel and Wiesel, who studied the effects of normal and abnormal visual experience in kittens. Flynn nicely summarized their Nobel Prize winning work in his 1991 Costenbader lecture [3]. In their initial experiment, the investigators sutured one eyelid shut shortly after birth, simulating form deprivation, and assessed the effect this had on vision when they surgically opened the eye 10 weeks later. They discovered that there was little or no electrical response in the cerebral cortex when images were viewed with the previously sutured eye, whereas the electrical response from those cortical cells driven by the normal eye were as expected. Histologically, marked shrinkage was noted in the lateral geniculate nucleus of those cells associated with the deprived eye. Similar results were obtained when the experiment was repeated in monkeys. These findings did not occur when single eyelids of adult cats were sutured shut or when both eyelids of the kittens were sewn shut. This finding led them to postulate that, in the developing brain, there is a competition between both eyes for cells in the visual cortex. Unequal visual input results in abnormal development of the brain, with cells anatomically destined to serve the closed eye responding only to input from the open eye. This results in a reduction in the number of cells receiving input from the deprived eye, as well as a reduction in the number of binocularly driven visual cortical cells. No anatomic changes were found in the retina or optic nerve. Timing and duration of closing were critical; the earlier the manipulation occurred and the longer it lasted, the more severe the cortical damage. In addition, if the lids were simply opened afterwards in the affected kittens, and nothing else was done, no recovery resulted. If, however, the eyelids of the fellow eye were then sutured closed, recovery of vision could be seen in the previously closed eye. This finding led to the development of the concept of the critical period of visual development. The critical period of visual development also applies to the human experience [6]. Form deprivation, strabismus, and anisometropia can all cause amblyopia in the infant and young child, but if the onset of these abnormalities occurs after age 7 to 8 years old, vision loss from amblyopia is no longer seen. The period during which recovery from amblyopia can be obtained is somewhat longer in humans,

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and may, in some individuals, last into the teen-age years or even later [7 9]. The earlier amblyopia is recognized and treated, however, the more certain the result.

Treatment The treatment of amblyopia involves forcing the patient to fixate with the amblyopic eye rather than the sound eye. This treatment is accomplished by providing optimal conditions for use of the amblyopic eye: correcting any underlying organic pathology, such as a cataract or corneal scar, and furnishing the appropriate glasses or contact lenses, if a refractive error is present. Following this correction, some form of artificial deprivation is employed to blur the image in the good eye, forcing the patient to use the amblyopic one. In strabismic amblyopia, however, aligning the eyes is not necessary before initiating amblyopia therapy. In fact, most clinicians feel that just the opposite is true; that is, the elimination of amblyopia is the first step to treating strabismus successfully. The mainstay of amblyopia therapy is occlusion of the sound eye with either an opaque patch or contact lens or with a translucent filter over the fixing eye. Reports of patching to treat strabismic amblyopia date back to at least 900 AD. In a well-known treatise on the subject, Count de Buffon, a French naturalist and botanist, recommended patching the fixating eye in strabismic amblyopia in 1743. This treatment was later abandoned, however, because amblyopia was considered to be a fixed, congenital anomaly. It was not until the 1930s, when the concept of amblyopia as a sensory adaptation to strabismus was developed, that patching was once again reinstituted as a therapeutic modality [1,2]. Occlusion can be prescribed either full time or for part of the day, depending on such factors as the age of the patient, visual needs such as school or sports, and degree of amblyopia. In general, the older the patient and the more severe the depth of vision loss, the longer the duration and intensity of patching that is required. As previously discussed, the patient must also be carefully monitored during this therapy because of the possibility that the patching itself might induce occlusion amblyopia in the good eye. Thus frequent visits to the ophthalmologist are required, especially in infants, to monitor the vision in both eyes. Another potential complication of patching occurs in the treatment of anisometropic amblyopia when there is little or no strabismus present. Occasionally, the long-term application of a patch might adversely affect binocular fusion in these patients, producing strabismus as an unintended consequence. Most clinicians feel strongly that the benefit of restoration of vision warrants the risk involved. Penalization is another method of treating amblyopia. Penalization involves the instillation of a cycloplegic agent that paralyzes accommodation, such as atropine 1% or cyclopentolate ophthalmic solution, into the good eye to blur vision and induce the child to fixate with the amblyopic eye. This technique is not

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as effective as full-time patching but can be successful if the fixating eye is hypermetropic, and there is a mild to moderate vision deficit to overcome. Penalization may also be of benefit in those children who are reluctant to comply with occlusion therapy [10].

Prevention and screening Successful treatment of amblyopia depends on timely recognition of amblyopia and those factors that may produce amblyopia. For this reason, the American Academy of Ophthalmology, the American Association for Pediatric Ophthalmology and Strabismus, the American Academy of Pediatrics, the American Academy of Family Physicians, and others recommend early vision screening to detect treatable eye disease, notably amblyopia, in infancy and childhood [11]. A summary of the recommendations of the American Academy of Pediatrics [12] regarding vision screening and detection of amblyopia and other eye disease is provided in another article. Despite these recommendations, the American Academy of Pediatrics believes that only 21% of preschool and younger children in this country are adequately screened for amblyopia [13]. Many difficulties are encountered when performing vision screening in the pediatric population. Infants and preverbal children are unable to provide subjective responses to visual acuity testing and do not easily cooperate with testing of ocular alignment or stereoacuity. The same is often true of older children who are nonverbal or have developmental delay. Some populations, particularly in underserved areas, might be difficult to reach for vision screening. Therefore developing better techniques to screen large populations of children remains a public health challenge. The ideal screening approach must be accurate, with both high sensitivity and specificity. It should be easy to administer to large groups of children and should also be reasonably inexpensive. One possible technologic answer to this problem is photoscreening [13]. In this technique, a camera or video system is used to capture the image of the pupil and red reflex. The child need only fixate on a target for a few seconds to obtain an adequate photograph. The quality of the image is then analyzed, either on site by the tester or at some remote location by trained technicians or computerized analysis. Abnormal reflexes might indicate the presence of amblyogenic factors, such as strabismus, media opacities, and significant refractive errors. The technology is still in the developmental phase, however, and most techniques still exhibit relatively low sensitivity with high false-positive rates. In addition, the equipment is still too expensive at this time to be cost effective in the ophthalmologists or pediatricians office [14]. It is hoped that advances in technology will lead to more accurate, cost-effective techniques to screen preverbal children for those factors that could predispose them to the development of amblyopia. Once a child is old enough to cooperate with visual acuity and stereopsis testing, however, carefully administered subjective tests are far

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superior in detecting vision defects than mass screening techniques and remain the standard of care for the diagnosis of amblyopia.

Future developments There is much room for improvement in the diagnosis and management of patients with amblyopia. Better screening methods are being formulated for the timely recognition of patients who are at risk for or who have already developed amblyopia. Public health initiatives will be required to make this screening available to all segments of society. In addition, large-scale clinical trials are currently underway to determine the best method for treating established amblyopia. For example, a recent study compared atropine to patching for the treatment of moderate amblyopia and found no significant differences in efficacy [10]. Improved techniques to ensure patient compliance will increase success rates [9]. Finally, basic science research is looking at the molecular basis for the neurophysiologic changes seen in amblyopia. The goal will be to modulate the neuronal responses to abnormal visual input, either to prevent amblyopia when known predisposing conditions are present or to treat long-established amblyopia [15]. Pharmacologic agents such as levodopa and cytidine-50-diphosphocholine have been shown to produce temporary improvement in vision in patients with amblyopia [16 18]. Psychophysical perceptual learning techniques are also currently being investigated as a means to correct amblyopia in adults [19]. It is hoped that earlier and better treatment options will markedly reduce the incidence of this serious ocular disorder.

Summary Amblyopia is a serious medical condition affecting tens of millions of individuals around the world. For the most part it is correctable, assuming that it is promptly recognized and vigorously treated. Amblyopia may result from form deprivation, anisometropia, or strabismus in infants and young children. Basic research in animal models has shown that the major pathologic changes in amblyopia occur in the visual cortex of the brain. The mainstay of treatment remains patching, although penalization has a role to play in the management of moderate degrees of amblyopia. Better methods for early identification of patients with amblyopia are being developed, along with newer novel methods of treatment.

References
[1] Von Noorden GK. Amblyopia. In: Binocular vision and ocular motility: theory and management of strabismus. St. Louis: CV Mosby; 1995. p. 206 45. [2] Duke Elder S, Wybar K. Amblyopia. In: System of ophthalmology, vol VI, ocular motility and strabismus. London: H Kimpton; 1973. p. 292 317.

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[3] Flynn JT. 17th annual Frank Costenbader lecture: amblyopia revisited. J Pediatr Ophthalmol Strabismus 1991;28(4):183 201. [4] Quinn GE, Berlin JA, James M. The Teller acuity card procedure. Ophthalmology 1993;100(4): 488 94. [5] Birch EE, Stager DR. The critical period for surgical treatment of dense congenital unilateral cataract. Invest Ophthalmol Vis Sci 1996;37(8):1532 8. [6] Daw NW. Critical periods and amblyopia. Arch Ophthalmol 1998;116(4):502 5. [7] Levi DM. Pathophysiology of binocular vision and amblyopia. Curr Opin Ophthalmol 1994; 5(5):3 10. [8] El Mallah MK, Chakravathy U, Hart PM. Amblyopia: is vision loss permanent? Br J Ophthalmol 2000;84(9):952 6. [9] Mintz-Hittner HA, Fernandez MA. Successful amblyopia therapy initiated after age 7 years: compliance cures. Arch Ophthalmol 2000;118(11):1535 41. [10] Pediatric Eye Disease Investigator Group. A randomized trial of atropine vs patching for treatment of moderate amblyopia in children. Arch Ophthalmol 2002;120(3):268 78. [11] American Association for Pediatric Ophthalmology and Strabismus. American Academy of Ophthalmology. Policy statement on vision screening for infants and children. San Francisco: American Association for Pediatric Ophthalmology and Strabismus. American Academy of Ophthalmology; 2001. [12] American Academy of Pediatrics. Committee on Practice and Ambulatory Medicine and Section on Ophthalmology. Eye examination and vision screening in infants, children, and young adults. Pediatrics 1996;98(1):153 7. [13] American Academy of Pediatrics. Committee on Practice and Ambulatory Medicine and Section on Ophthalmology. Use of photoscreening for childrens vision screening. Pediatrics 2002; 109(3):524 5. [14] Wright MC, Colville DJ, Oberklaid F. Is community screening for amblyopia possible, or appropriate? Arch Dis Child 1995;73(3):192 5. [15] Campos E. Amblyopia. Surv Ophthalmol 1995;40(1):23 39. [16] Gottlob I, Charlier J, Reineke RD. Visual acuities and scotomas after one week of levodopa administration in human amblyopia. Invest Ophthalmol Vis Sci 1992;33(9):2722 8. [17] Leguire LE, Rogers GL, Bremer DL, et al. Levodopa/cardidopa for childhood amblyopia. Invest Ophthalmol Vis Sci 1993;34(11):3090 5. [18] Porciatti V, Schiaci C, Benedetti P, et al. Cytidine-50-diphosphocholine improves visual acuity, contrast sensitivity, and amplitude of visual evoked potentials in adult patients with amblyopia. Curr Eye Res 1998;17(2):141 8. [19] Polat U, Ma-Naim T, Belkin M. Treatment of adult amblyopia by perceptual learning. Invest Ophthalmol Vis Sci 2001;42(4):S400.