Ординатура / Офтальмология / Английские материалы / Ocular Disease Mechanisms and Management_Levin, Albert_2010

Growing evidence for the involvement of TSHR and IGF-1R autoantibodies in the pathogenesis of GO has led to the concept that rituximab may be an attractive therapeutic agent to consider in the treatment of GO. This anti-B-cell monoclonal antibody targets the CD20 antigen and impacts antigen presentation and early steps in B-cell maturation.6 Trials of rituximab in the treatment of systemic lupus erythematosus and rheumatoid arthritis have shown significant improvement in active disease concomitant with decreases in serum activity markers.66,67 Results of uncontrolled trials of this agent in GO are promising and have paved the way for randomized controlled trials now underway.68,69

The participation of proinflammatory cytokines and chemokines in the development of GO suggests that monoclonal antibodies targeting these molecules might hold therapeutic promise. In particular, biological agents that block TNF-α (infliximab, adalimumab, etanercept) or IL-1 receptor (anakinra) are attractive theoretical choices that should be evaluated in randomized controlled trials.

Other approaches to GO therapy might include targeting early phases of adipogenesis in orbital preadipocytes to prevent the disease manifestations resulting from increased adipose tissue volume within the orbit. PPAR-γ ligation plays an important role in the initiation of adipogenesis and PPAR-γ agonists have been shown to stimulate both adipogenesis and TSHR expression in cultured orbital preadipocytes.58 Therefore, agents that specifically block PPAR-γ ligation may be of benefit in GO.

Useful information regarding the efficacy of any drug (or combination of therapeutic agents) in the treatment or pre-

vention of GO can be gained only through randomized controlled trials, several of which are currently under way. Equally important will be the continued study of GO pathogenesis and mechanisms of immune dysregulation. Information gained through these studies will be important in the development of novel approaches to prediction, prevention, and treatment of this debilitating condition.

Conclusion

Graves’ hyperthyroidism is an autoimmune disease in which unregulated production of thyroid hormone results from the stimulation of the TSHR on thyroid follicular cells by circulating autoantibodies. While the pathophysiology of GO is less well understood, the condition likely stems from an autoimmune process directed against the TSHR within the orbit. Environmental factors, including mechanical pressures within the nonyielding bony orbit, smoking, and radio­iodine treatment for hyperthyroidism, may also play a role in disease development. The mechanical pressures result from an increase in both the orbital fat and extraocular muscle volumes due to new fat cell development and excess accumulation of hydrated GAG, respectively. Orbital fibro­ blasts are thought to be the primary target cell in GO; these cells express TSHR, produce GAG, and a subset have the ability to differentiate into mature adipocytes. Novel therapies aimed at abrogating the initial stages of both B- and T-cell activation or the initiation of adipogenesis within the orbit may be of therapeutic benefit in the disease.

1.Khoo TK, Bahn RS. Pathogenesis of Graves’ ophthalmopathy: the role of autoantibodies. Thyroid 2007;17:1013– 1018.

2.Bahn RS. Pathophysiology of Graves’ ophthalmopathy: the cycle of disease. J Clin Endocrinol Metab 2003;88:1939– 1946.

6.Garrity JA, Bahn RS. Pathogenesis of Graves’ ophthalmopathy: implications for prediction, prevention, and treatment. Am J Ophthalmol 2006;142:147–153.

32.Eckstein A, Quadbeck B, Meuller G, et al. Impact of smoking on the response to treatment of thyroid associated ophthalmopathy. Br Ophthalmol 2003; 87:773–776.

40.Bartalena L, Marcocci C, Bogazzi F, et al. Relation between therapy for hyperthyroidism and the course of Graves’ ophthalmopathy. N Engl J Med 1998;338:73–78.

42.Wiersinga WM, Bartelena L. Epidemiology and prevention of Graves’ ophthalmopathy. Thyroid 2002;12:855–860.

43.Perros P, Kendall-Taylor P, Frewin S,

et al. A prospective study of the effects of radioiodine therapy for hyperthyroidism in patients with minimally active Graves’ ophthalmopathy. J Clin Endocrinol Metab 2005;90:5321–5323.

44.Smith TJ, Koumas L, Gagnon A, et al. Orbital fibroblast heterogeneity may determine the clinical presentation of thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 2002;87:385– 392.

52.Heufelder AE, Dutton CM, Sarkar C,

et al. Detection of TSH receptor RNA in cultured fibroblasts from patients with Graves’ ophthalmopathy and pretibial dermopathy. Thyroid 1993;3:297–300.

54.Starkey KJ, Janezic A, Jones G, et al. Adipose thyrotrophin receptor expression is elevated in Graves and thyroid eye diseases ex vivo and indicates adipogenesis in progress in vivo. J Mol Endocrinol 2003;30:369–380.

59.Kumar S, Coenen MJ, Scherer PE, et al. Evidence for enhanced adipogenesis in the orbits of patients with Graves’ ophthalmopathy. J Clin Endocrinol Metab 2004;89:930–935.

60.Kumar S, Leontovich A, Coenen MJ, et al. Gene expression profiling of orbital adipose tissue from patients with Graves’ ophthalmopathy: a potential role for secreted fizzled-related protein-1 in orbital adipogenesis. J Clin Endocrinol Metab 2005;90:4730–4735.

S E C T I O N   8

Pediatrics

C H A P T E R 57

Duane syndrome

Clinical background

Duane retraction syndrome is a congenital cranial dysinnervation disorder characterized by unior bilateral abduction deficit, narrowing of the palpebral fissure on adduction, and globe retraction with occasional upshoot or downshoot in adduction (Box 57.1).1 Unlike the large esotropia in abducens paralysis with which Duane syndrome shares the typical feature of abduction deficit, in Duane syndrome there is typically little to no esotropia in central gaze.

Huber’s commonly used clinical classification of Duane syndrome consists of three groups: type 1, with limitation of abduction only; type 2, with limitation of adduction only; and type 3, with limitation of both aband adduction.2,3 Type 1 Duane syndrome is most commonly encountered (Figure 57.1), followed by type 3. Type 2 Duane syndrome is rare, and often associated with exotropia. While there is wide agreement that unilateral Duane syndrome is more common than bilateral, the former is inconsistently reported to be more common sometimes on the left, and other times on the right, and sometimes with an inconsistent gender preponderance. Taken together, asymmetries of laterality and gender are probably artifacts of sampling and ascertainment in small studies.

An essential element of Duane syndrome is globe retraction in adduction, which is best recognized by examining the patient in profile view (Figure 57.2). As the globe translates posteriorly in the orbit, the lids slide passively together over the curvature of the globe, narrowing the palpebral fissure. The degree of globe retraction and palpebral fissure narrowing varies among affected individuals with Duane syndrome.

Pathology

The key element in the pathogenesis of Duane syndrome is abnormal innervation of the lateral rectus muscle. Limited abduction in Duane syndrome types 1 and 3 is associated with slowing of the abducting saccade,4 a sign of deficiency in lateral rectus force generation. Normal saccades are brief, high-velocity eye movements reaching 400–700 degree/ second; abducting saccades in Duane syndrome types 1 and 3 have reduced peak velocities, are visibly prolonged on physical examination, and have a lengthy terminal decelera-

tion to final position. Electromyographic studies suggest that this abduction deficiency in Duane syndrome type 1 is due to absence of normal abducens innervation to the lateral rectus muscle, and suggest that the retraction is due to paradoxical lateral rectus innervation in adduction.2,5 Thus, in adduction, the paradoxical lateral rectus contraction counters the physiologic medial rectus contraction, increasing net posterior muscle force that causes the globe to retract against the elasticity of the orbital connective tissues. It seems plausible that the limitation of both abduction and adduction in type 3 Duane syndrome may simply be due to greater paradoxical lateral rectus contraction in attempted adduction, overcoming physiologic medial rectus contraction altogether. Duane syndrome of relatively rare type 2 may be explained by co-innervation of the lateral rectus by a normal abducens nerve, plus a strong projection of the medial rectus motor nerve to the lateral rectus that substantially or completely opposes the adducting effect of the medial rectus.

Absence of the abducens nerve and motor neurons has been confirmed in one sporadic unilateral6 and another bilateral autopsy case of Duane syndrome.7 Parsa et al8 first used magnetic resonance imaging (MRI) to demonstrate absence of the subarachnoid portion of the abducens nerve in Duane syndrome, a finding that has been confirmed in six of 11 additional cases,9 and later correlated with the presence of residual abduction in multiple cases.10,11 Kim and Hwang have emphasized the frequent absence of the subarachnoid abducens nerve ipsilateral to Duane syndrome type 111,12 and type 3,11 but the presence of the subarachnoid abducens nerve ipsilateral to type 2.11 Examples of absence of the subarachnoid portion of the abducens nerve are illustrated in Figure 57.3. Innervation of the lateral rectus muscle by the abducens nerve is deficient in both type 1 Duane syndrome and abducens palsy, although, unlike abducens palsy, the eyes in central gaze are frequently aligned in Duane syndrome.13 This evidence for contractile tonus in the lateral rectus muscle suggests that the involved lateral rectus is either solely, or co-innervated by a branch of the oculomotor nerve, as supported by the autopsy studies.6,7

Etiology

Most cases of Duane syndrome are sporadic. Some of these are clearly teratogenic, associated with intrauterine exposure to drugs such as thalidomide.14 Other cases have well-

characterized genetic causes. Dominant Duane syndrome has been linked to chromosome 2, the DURS2 locus.15 Individuals with DURS2 exhibit unilateral or bilateral Duane syndrome types 1 or 3, or sometimes Duane syndrome type 1 in one eye and type 3 in the fellow eye.16 This phenotypic variability indicates that the mutation causing DURS2 has variable expressivity or is modified by another genetic or environmental factor.

Duane radial ray syndrome (DRRS, also known as Okihiro syndrome, online mendelian inheritance in man 607323) is

Box 57.1  Clinical features of Duane  

retraction syndrome

•Limited aband/or adduction

•Globe retraction on adduction

•Palpebral fissure narrowing on adduction

•Upand downshoots in adduction (common but not universal)

A

Figure 57.2  (A, B) Left globe retraction in Duane syndrome.

Etiology

the dominant association of unior bilateral Duane syndrome with unior bilateral dysplasia of the radial bone, artery, and thumb17 (Figure 57.4). DRRS results from heterozygous mutations in SALL4, a zinc finger transcription factor.17,18 The developmental expression profile and func-

Figure 57.1  Versions in left Duane retraction syndrome type 1, showing limited abduction, with palpebral fissure narrowing in adduction.

B

tional role of SALL4 in normal and abnormal ocular motor development are not yet elucidated, and SALL4 mutations have not been identified in individuals with isolated sporadic Duane syndrome.19 However, investigation of the role of SALL4 in this rare form of Duane syndrome may provide important clues to its pathogenesis generally.

Pathophysiology

Imaging evidence of dysinnervation

High-resolution MRI enables direct demonstration of the size and contractility of extraocular muscles,20 as well as their peripheral and subarachnoid motor innervation16,21,22 (Figure 57.5A). Such MRI has shown that a branch of the inferior division of the oculomotor nerve abuts and probably enters the inferior zone of the lateral rectus muscle in dominant Duane syndrome linked to chromosome 2, the DURS2

440

Box 57.2  Peripheral neuroanatomy of Duane

retraction syndrome

•Abnormality of abducens innervation to superior zone of lateral rectus muscle

•Misrouting of inferior division of oculomotor nerve to inferior zone of lateral rectus muscle

locus.16 The lateral rectus muscle in such cases frequently exhibits a prominent longitudinal fissure (Figure 57.5B), extending the anteroposterior length of the muscle, that divides it into superior and inferior zones.23 When the abducens nerve is present, it innervates the superior zone of the lateral rectus muscle; innervation of the lateral rectus muscle by the oculomotor nerve is limited to the inferior zone only (Box 57.2).16

Other abnormalities of orbital motor innervation may be present in Duane syndrome, and may explain coexisting

vertical pattern strabismus, as well as upor downshoots in adduction.16 The foregoing are common in DURS2, where MRI shows that orbital motor nerves are typically small, and the abducens nerve often undetectable. Hypoplasia of the superior oblique, superior rectus, and levator is variably observed within the same families. Only the medial and inferior rectus and inferior oblique muscles have consistently normal structure.

Most cases of DURS2 exhibit evidence of oculomotor nerve innervation from axons normally targeting vertical rectus muscles leading to A or V patterns of strabismus. While MRI cannot directly image this innervation, paradoxical contractile changes in the deep belly of the lateral rectus muscle with vertical gaze changes allow secure inferences about sources of anomalous lateral rectur innervation. For example, contractile thickening of the lateral rectus muscle

in upgaze associated with V-pattern exotropia allows the inference that the lateral rectus muscle is innervated or coinnervated by an oculomotor branch normally targeting the superior rectus muscles (Figure 57.6). In DURS2, the misrouted oculomotor nerve may also be hypoplastic in its subarachnoid segment, perhaps reflecting more generalized oculomotor nerve pathology.

Horizontal rectus co-contraction

While upand downshoots of the affected eye in Duane syndrome may be due to misdirection of oculomotor nerve branches to vertically acting extraocular muscles in some cases, in other cases these phenomena are the mechanical consequences of medial and lateral rectus muscle cocontraction leading to a bridle effect mechanism (Box 57.3).24 Normally, connective tissue pulleys prevent significant vertical sideslip over the globe of the horizontal rectus muscles, resisting muscle tendency to follow the shortest path over the globe.25−27 In the bridle effect mechanism, the connective tissue suspensions of these pulleys presumably become weakened by aging and the abnormal forces chronically generated by horizontal rectus co-contraction. Horizontal rectus muscle paths then tend toward shortest paths, which are displaced superiorly in upgaze, and inferiorly in downgaze, relative to the normal situation. The forces exerted by horizontal rectus muscles thus vertically displaced include vertical components in the direction of displacement.

442

Box 57.3  Pathophysiology of Duane  

retraction syndrome

•Types 1 and 3: insufficient or absent abducens innervation to lateral rectus muscle limits abduction

•Type 2: oculomotor misinnervation causes lateral rectus contraction to oppose medial rectus in attempted adduction

•Medial and lateral rectus co-contraction causes globe retraction and narrows palpebral fissure

•Upand downshoots in adduction may be due to vertical sideslip of co-contracting horizontal rectus muscles, or misinnervation of vertical rectus muscles

Duane syndrome with superimposed neuropathy

Binocular alignment in central gaze is nearly normal in many cases of Duane syndrome, or can be made normal by a small face turn toward the unilaterally affected side. Affected individuals frequently do not seek medical attention for this condition. Due to facultative strabismic suppression in deviated gaze positions, affected individuals seldom complain of diplopia. In infants and toddlers, Duane syndrome may go unnoticed for an extended interval before recognition. When Duane syndrome is suspected in this setting, it is important to distinguish it from the potentially ominous condition of abducens palsy. The hallmark signs

of globe retraction and palpebral fissure narrowing in adduction may either not be developed in early infancy, or be unrecognizable due to the child’s limited cooperation. If near orthotropia in central gaze is not present or clinically convincing in the young child with an abduction defect, orbital imaging can distinguish Duane’s syndrome from abducens palsy. Chronic abducens palsy is reliably associated with lateral rectus muscle atrophy, whereas Duane syndrome is not.20

In patients suspected of having Duane syndrome, large angles of esotropia should motivate alternative consideration of abducens palsy, an entity in which abducens innervation to the lateral rectus muscle by the abducens nerve is also deficient and abducting saccades also slowed. However, while Duane syndrome is congenital and benign, abducens palsy may be progressive due to a growing structural lesion. A progressive mass lesion may have clinically grave consequences. Orbital imaging, by MRI or by computed X-ray tomography, may be valuable in distinguishing abducens palsy from Duane syndrome. Palsied extraocular muscles develop prominent denervation atrophy that is not observed in Duane syndrome.20 Presumably even oculomotor innervation of the lateral rectus muscle in Duane syndrome prevents denervation atrophy in typical cases. In rare cases in which a mass compresses the oculomotor nerve, the lateral rectus will develop atrophy diagnostic of denervation.28

Associations with Duane syndrome

Duane syndrome may occasionally be associated with hearing defects, perhaps indicating abnormality of cochlear nerve or central hearing function.29 A plethora of other neurological and somatic abnormalities, syndromic and nonsyndromic, has been occasionally reported in association with Duane syndrome.30

Duane radial ray (Okihiro) syndrome

Duane syndrome may have other syndromic associations. As noted above, DRRS due to SALL4 mutation is associated with unior bilateral dysplasia of the radial bone, artery, and thumb, as well as pectoral musculature.17,31 Despite these prominent extraocular abnormalities, DRRS is not associated with a high frequency of A- or V-pattern strabismus, structural abnormality of extraocular muscles, oculomotor nerve hypoplasia, optic nerve hypoplasia, or significant amblyopia.31 One case of DRRS was associated with vertical saccade initiation failure, historically termed oculomotor apraxia, and is a central finding associated with metabolic disease and structural lesions of the cortex, brainstem, and cerebellum.32

Heritable forms of Duane syndrome

While the mutation or mutations causative for DURS2 has not been identified, its syndromic associations clearly differ from DRRS. In contrast to its relative absence in DRRS, DURS2 is associated with frequent A or lambda strabismus31 similar to that observed in another congenital cranial dysinnervation disorder, congenital fibrosis of the extraocular muscles type 1 (CFEOM1)21 resulting from heterozygous missense mutations in KIF21A.33 In DURS2, optic nerve

Pathophysiology

cross-sections are subclinically reduced about 25% from normal,16 while CFEOM1 due to KIF21A mutation is associated with 30–40% reduction in optic nerve cross-section.21 In contrast, optic nerve size is normal in DRRS, suggesting that SALL4 is not involved in optic nerve development or maintenance. There is little or no significant amblyopia associated with DURS2.

Moebius syndrome

Moebius syndrome is a heterogeneous clinical disorder whose clinical definition has evolved in the recent literature. The minimum criteria include congenital facial palsy with impairment of ocular abduction consistent with Duane syndrome type 1.34−36 Thus Moebius syndrome may be considered minimally to consist of congenital facial palsy plus Duane syndrome. Other cranial nerves, orofacial malformations, limb malformations, and gross motor disturbance are also often present.34,36 A family has been reported exhibiting complete ophthalmoplegia and bilateral facial paralysis consistent with autosomal-recessive inheritance.37 In all three cases from that family, MRI of the brainstems and contiguous cranial nerves 3, 6, 7, and 8 exiting the brainstem were normal. All motor nerve branches, however, were abnormally small in the orbit, and the extraocular muscles were all hypoplastic. These findings suggest that Moebius syndrome includes some aspects of the pathophysiology of Duane syndrome.

Pathophysiology influences treatment of Duane syndrome

Indications for surgical treatment of Duane syndrome include central gaze strabismus, unacceptable compensatory head posture, and severe globe retraction. Since Duane syndrome is mainly due to peripheral misinnervation in the affected orbit, Hering’s law of equal central innervational effort is not applicable, so strabismus surgery on the unaffected orbit of unilateral cases is generally useless in altering the innervation to the affected orbit. In cases of Duane syndrome type 1 with mild central gaze esotropia, ipsilateral medial rectus muscle recession (retroplacement on the sclera) often provides satisfactory reduction of esotropia, compensatory face turn, and may also reduce globe retraction and upor downshoot in adduction. The affected medial rectus muscle is uniformly stiff and relatively inelastic, consistent with limited stretching due to the limited abduction. However, medial rectus recession may limit adduction to the degree that a postoperative exotropia may occur in extreme adduction of the unilaterally affected eye. Patients may develop a new and potentially disturbing diplopia when such consecutive exotropia occurs. Furthermore, medial rectus recession does little to increase the range of abduction of the affected eye.

An alternative approach to treating Duane syndrome type 1 may be particularly appropriate when a larger esotropia is present in central gaze. The superior and inferior rectus tendons may be partially or completely transposed to the edges of the affected lateral rectus insertion, along with posterior fixation of the transposed tendons to the underlying sclera to displace the vertical rectus pulleys further temporally.38 Such an approach can increase the degree of abduc-

tion and the field of single binocular vision, but may require additional medial rectus recession simultaneously or as a later procedure if the medial rectus is excessively stiff. To avoid anterior-segment ischemia, caution may be appropriate in avoiding simultaneous disinsertion of three rectus muscles of the same eye in adults.

Surgical treatment of upand downshoots, as well as pattern strabismus, is more complex and must be individualized to the clinical situation. Some of these signs may be due to significant structural abnormalities that may be impossible to recognize preoperatively without high-resolution orbital imaging by MRI or computed X-ray tomography. Structural abnormalities commonly include extraocular muscle dysplasia, rectus and oblique muscle hypoplasia or aplasia, and pulley heterotopy causing abnormal rectus muscle pulling directions. Surgery in such cases is tailored to the individual pathologic functional anatomy.

Upand downshoots due to the bridle effect may respond to medial rectus recession alone. Resection of any rectus muscle is generally to be avoided, as this will increase total forces causing lid retraction, palpebral fissure narrowing, and the bridle effect. Upand downshoots and patterns due to anomalous lateral rectus innervation will not respond to medial rectus recession. Some of these cases may respond to Y-splitting of the lateral rectus insertion, shifting the superior

half superiorly on the sclera, and the inferior half inferiorly.39

Summary

Duane retraction syndrome is a congenital cranial dysinnervation disorder of the extraocular muscles in which the inferior zone of the lateral rectus muscle is misinnervated by the oculomotor nerve, with or without innervation of the superior zone of the lateral rectus muscle by the abducens nerve. The trochlear and optic nerves may also be abnormal, and the deep bellies of the extraocular muscles may exhibit structural anomalies. While most cases of Duane syndrome are sporadic, genetic evidence supports the concept that the condition is a developmental cranial neuropathy, leading secondarily to abnormalities of extraocular muscle structure and function.

Acknowledgment

This work was supported by NEI grants EY08313 and EY13583. Joseph L Demer is Leonard Apt Professor of Ophthalmology.

1.Duane A. Congenital deficiency of abduction associated with impairment of adduction, retraction movements, contraction of the palpebral fissure and oblique movements of the eye. Arch Ophthalmol 1905;34:133–159.

2.Huber A. Electrophysiology of the retraction syndromes. Br J Ophthalmol 1974;58:293–300.

6.Miller NR, Kiel SM, Green WR, et al. Unilateral Duane’s retraction syndrome (type 1). Arch Ophthalmol 1982;100: 1468–1472.

11.Kim JH, Hwang JM. Presence of abducens nerve according to the type of Duane’s retraction syndrome. Ophthalmology 2005;112:109–113.

13.DeRespinis PA, Caputo AR, Wagner RS, et al. Duane’s retraction syndrome. Surv Ophthalmol 1993;38:257–288.

14.Miller MT. Thalidomide embryopathy: a model for the study of congenital incomitant horizontal strabismus. Trans Am Ophthalmol Soc 1991;89:623–674.

15.Engle EC, Andrews C, Law K, et al. Two pedigrees segregating Duane’s retraction syndrome as a dominant trait linked to the DURS2 genetic locus. Invest Ophthalmol Vis Sci 2007;48:189–193.

16.Demer JL, Clark RA, Lim KH, et al. Magnetic resonance imaging evidence for widespread orbital dysinnervation in dominant Duane’s retraction syndrome linked to the DURS2 locus. Invest Ophthalmol Vis Sci 2007;48:194–202.

21.Demer JL, Clark RA, Engle EC. Magnetic resonance imaging evidence for widespread orbital dysinnervation in congenital fibrosis of extraocular muscles due to mutations in KIF21A. Invest Ophthalmol Vis Sci 2005;46:530–539.

28.Silverberg M, Demer JL. Duane’s syndrome with compressive denervation of the lateral rectus muscle. Am J Ophthalmol 2001;131:146–148.

29.Chung M, Stout T, Borchert MS. Clinical diversity of hereditary Duane’s retraction

syndrome. Ophthalmology 2000;107: 500–503.

31.Demer JL, Clark RA, Lim K-H, et al. Magnetic resonance imaging of innervational and extraocular muscle abnormalities in Duane-radial ray syndrome. Invest Ophthalmol Vis Sci 2007;48:5505–5511.

36.Verzijl HT, van der Zwaag B, Cruysberg JR, et al. Mobius syndrome redefined: a syndrome of rhombencephalic maldevelopment. Neurology 2003; 61:327–333.

38.Britt MT, Velez FG, Velez G, et al. Vertical rectus muscle transposition for bilateral Duane syndrome. J AAPOS 2005;9:416– 421.

39.Rao VB, Helveston EM, Sahare P. Treatment of upshoot and downshoot in Duane syndrome by recession and Y-splitting of the lateral rectus muscle. J AAPOS 2003;7:389–395.

Clinical background

Classification

From a traditional clinical perspective, amblyopia is defined as a loss of visual acuity of three lines or more on a clinical letter chart that is not optically correctable and is not due to an ophthalmoscopically observable pathological cause. Amblyopia is classified by its underlying etiologic association with one or more of the following: strabismus, anisometropia, or form deprivation. Approximately onethird of amblyopes have a strabismus (eye deviation), onethird have anisometropia (unequal refractive error), and one-third have a mixture of the two. Deprivation amblyopia is rare (incidence 0.1%).

Initially amblyopia was conceptualized as a single condition resulting from one of these three types of disruption to normal visual development (Figure 58.1). Since then two more complicated classifications have been suggested, one based on the detailed properties of the behavioral deficit in small samples of amblyopes1 that suggested a classification in terms of the presence or absence of a strabismus and the other based on a few summary measures conducted on a large sample of around 400 amblyopes, suggesting a classification based on whether binocular function has been preserved.2 According to the summary measures of McKee et al,2 only around 10% of strabismics have binocular function as opposed to 80% of anisometropes, so these two different dichotomies are very similar. However, what is neglected by all these classifications is that there is considerable variation from patient to patient even within one class. Amblyopia can be associated with disrupted vision at a variety of different ages and it is known from animal models that there are different critical periods for different visual functions.

Even if one were to consider amblyopia simply in terms of a monocular visual loss (which would be misleading, as argued above) it is still much more than simply a loss in visual acuity. Amblyopia is a complex syndrome in which many seemingly unrelated visual functions are impaired. Letters presented in a row with other letters adjacent are much harder to discriminate than isolated letters, a phenomenon known as crowding. Subtle spatial distortions are also a part of an amblyope’s perception: the edges of letters close to the fovea are less blurred3 and simple repetitive patterns

Amblyopia

Robert F Hess and Nigel Daw

with a fine structure (i.e., high spatial frequencies) are seen to be distorted within central vision.4,5 Further anomalies for spatial and motion processing are detailed below. In addition, under normal binocular viewing conditions, the two eyes of an amblyope do not work together correctly. Therefore, with both eyes open amblyopes are effectively monocular as most of the information seen by the fellow amblyopic eye is suppressed. The site and nature of this suppressive mechanism, thought to be cortical, are largely unknown but its importance, from both etiologic and treatment perspectives, is immense. Indeed, the visual deficit in the amblyopic eye that occurs under binocular viewing may include several components, including full monocular amblyopia, reduced peripheral function of the amblyopic eye’s visual field in a region corresponding to the fovea of the fellow fixing eye (anomalous retinal correspondence owing to the strabismus), and suppression or masking from the fellow fixing eye (Box 58.1).6

Treatment

The traditional treatment for amblyopia has been to occlude the good eye with the intention of forcing the amblyopic eye to function.7 If the child has a significant amount of hyperopia, atropine penalization can be used to blur the good eye by paralyzing its accommodation. In the case of emmetropia, an opaque occluder can be worn in front of the good eye. In the late 1980s it was generally accepted that such occlusion had to be complete and fulltime for it to be effective. This produced great psychological and social hardship for young children, most of whom were of school age, and consequently the compliance was never what it should have been.8 Owing to a number of innovative treatment approaches,9–13 it is now generally accepted that part time occlusion, if associated with an intensive, attention-demanding task, can be just as successful as fulltime occlusion with none of the associated psychosocial side-effects. The recovery of vision is believed to be agedependent, with little recovery possible from occlusion beyond 12 years,14 but see PEDIG.15 However, active training regimes11 based on the principle of perceptual learning have recently been shown to be effective in restoring at least some visual function in adult amblyopes.16

Interestingly, the rationale behind both the standard treatment for amblyopia and perceptual training approaches is that amblyopia is a monocular problem and, until the

monocular function of the amblyopic eye is restored, one cannot expect the two eyes to work together in a binocular and/or stereoscopic sense.17 What has been ignored10–13 is that the monocular loss could be the consequence of disrupted binocular mechanisms that have to be rectified prior to monocular recovery and that the amblyopia per se may not be the limiting impediment to binocular function.18 Accordingly, any therapeutic approach should involve binocular stimulation and an attempt to reduce not only the monocular acuity loss, but also any additional suppressive influences exerted by the good eye on the amblyopic eye.6 Recent results suggesting that a reduction of intracortical inhibition in animals deprived of vision early in life leads to acuity improvement further highlight the importance of cortical suppressive mechanisms (Box 58.2).19

Laboratory perspective

Psychophysics

One observation20–22 that has stood the test of time is that amblyopes require more contrast to detect stimuli with their amblyopic eyes, particularly those at higher spatial frequencies. Peak contrast sensitivity is often reduced to some extent but contrast sensitivity at higher spatial frequencies shows a more pronounced reduction. Unfortunately this has little diagnostic utility because similar losses are seen for all types of amblyopes as well as for many different types of optical, retinal, and cortical pathology. It does, however, provide a more sensitive way of monitoring recovery from treatment than the more conventional acuity measures simply because

446

Figure 58.2  Contrast sensitivity measurements from the central and peripheral visual field for a representative strabismic amblyope and nonstrabismic anisometropic amblyope showing the selective loss of foveal function in the case of the former. (Redrawn with permission from Hess R, Campbell F, Zimmerman R. Differences in the neural basis of human amblyopias: the effect of mean luminance. Vis Res 1980;20:295−305.)

of the steeper than unity slope of the contrast sensitivity fall off. On log/log axes this is usually between 3 and 4, giving a corresponding contrast sensitivity magnification.

The way that the contrast deficit is distributed across the visual field has some diagnostic value and suggests an important difference in the underlying mechanisms responsible for strabismic and nonstrabismic amblyopia.1 The contrast sensitivity deficit is confined to central vision for strabismics, whereas it is more evenly distributed across the visual field in nonstrabismic anisometropes (Figure 58.2). This provides an explanation for another curious finding, that the contrast sensitivities of the two eyes of a strabismic amblyope normalize (i.e., are equated in sensitivity) under conditions of low light levels whereas those of nonstrabismic anisometropes do not.23

At suprathreshold levels, contrast is perceived normally by the amblyopic eye, as the deficit is confined to threshold. Again strabismics and nonstrabismic amblyopes show subtle differences in the way their visual systems go from obvious contrast deficits at threshold to normal contrast perception above threshold. For strabismics, this transition is abrupt, whereas for nonstrabismic anisometropes it is gradual.24 For suprathreshold conditions, even though contrast is perceived normally, visual perception is quite abnormal for amblyopes for two other, possibly related, reasons that seem to have