Table 6.5  Differential diagnostic considerations of sixth nerve palsy in childhood

Duane syndrome Myasthenia gravis Spasm of the near reflex

Medial orbital fracture with entrapment

Longstanding esotropia with medial rectus muscle contracture Ocular neuromyotonia

Graves’ ophthalmopathy

cocontraction of the lateral rectus muscle and a characteristic retraction of the globe on attempted adduction. The anomalous recruitment of the paretic lateral rectus muscle in attempted adduction can lead to a variety of bizarre motility disturbances, some of which have only recently been recognized as epiphenomena of Duane syndrome.

Clinically, most children with Duane syndrome exhibit the following common features: (1) Limited abduction, (2) widening of the palpebral fissure on attempted abduction, and (3) retraction of the globe with narrowing of the palpebral fissure on attempted adduction.512 Although adduction is always limited because of lateral rectus cocontraction, it often appears to be full because the globe retracts. About 22% of children with Duane syndrome have significant enophthalmos of the involved eye in the primary position, which occasionally is the most disfiguring aspect of the syndrome.512 Children with Duane syndrome rarely complain of diplopia, although they can recognize two images when forced to gaze in the direction of the paretic lateral rectus muscle. About 50% are orthotropic or esotropic in the primary gaze position, adopting a small face turn.9 For this reason, amblyopia is uncommon in Duane syndrome,512 but binocular sensory function and stereoacuity may be reduced.109,522,551 Unilateral Duane syndrome is more common in females and involves the left eye more often than the right.381

Duane syndrome is unilateral in about 86% of cases and bilateral in 14%.277 Bilateral Duane syndrome is associated with a higher prevalence of strabismus in the primary position and, unlike unilateral Duane syndrome, is more common in males.277 The types of Duane syndrome tend to be the same in the two eyes, esotropia appears to be more common than exotropia, and amblyopia is rare in bilateral cases,277 although one series244 found a higher incidence of exotropia. Bilateral Duane syndrome appears to be associated with a lower incidence of multisystem disorders.277

Duane syndrome occurs as a sporadic condition in about 90% of cases and is familial in about 10%,134 although the high rate of systemic malformations in first-degree relatives suggests that the inheritance of Duane syndrome may actually be higher.346 In hereditary cases, it is rare to find more than one other affected family member. Familial cases are commonly bilateral and have associated vertical eye movement abnormalities.392a Some reports of bilateral familial Duane retraction syndrome may represent congenital ocular fibrosis syndrome.621

Genetics

Some forms of familial Duane syndrome is caused by mutations in the gene CHN-1, on chromosome 2q31 that encodes alpha2-chimaerin, a signaling protein implicated in the pathfinding of corticospinal neurons in mice.378 However, the gene loci of Duane syndrome have been mapped on 8q, 2q,17,111,163 and 1q,265 indicating genetic heterogeneity. The transcription factors SALL4 and HOX1A have been iden­ tified as the genes mutated in Duane syndrome with radial anomalies, and in Duane syndrome with deafness, vascular anomalies, and cognitive deficits, respectively.160 SALL4 mutations on chromosome 20q13.13–13.2 have been found in patients with Okihiro syndrome, Holt–Oram syndrome, and acro-renal-ocular syndrome, explaining the considerable clinical overlap of these disorders.7,44,263,289

The distinction between Duane syndrome and sixth nerve palsy can readily be made in a cooperative child but may be difficult in an infant. Jampolsky251 has cautioned that one cannot rely on palpebral fissure changes during sidegaze to identify globe retraction, because the palpebral fissure may normally widen in abduction and narrow slightly in adduction. Rather, one must directly observe the globe from a lateral view as the eye is moved from its position of maximal abduction into a position of adduction. The discrepancy between the primary gaze deviation and the degree of abduction deficit often provides an additional clue to the presence of Duane syndrome in an infant. For instance, it is not uncommon for a patient with Duane syndrome to be orthotropic or almost orthotropic despite the complete absence of abduction in one eye. In contrast, a complete unilateral sixth nerve palsy produces about 35 diopters of esotropia at near fixation. The distinction between Duane syndrome and sixth nerve palsy in infancy is also aided by having the infant view a toy with the affected eye in adduction and performing a quick alternate cover test. The infant with Duane syndrome is exotropic in this position due to cocontraction of the lateral rectus muscle, whereas the infant with a sixth nerve palsy is orthotropic or esotropic.

Other Clinical Features of Duane Syndrome

With rare exceptions,420,422 an innervational abnormality of the lateral rectus muscle is the underlying cause of all of the associated ocular motility disorders, which are summarized as follows:

Upshoots and Downshoots

During adduction of the affected eye, the cocontracting lateral rectus muscle overlies the crest of the globe, and there is maximal retraction. When the eye elevates or depresses

in adduction, many children develop an upshoot or downshoot (or both), which may cause the eye to completely disappear under the upper or lower eyelid (Fig. 6.15). Upshoots or downshoots represent a “retraction escape” or “retraction substitute.” The finding that these movements in Duane syndrome are associated with electromyographic (EMG) activity in the superior and inferior rectus muscles initially led to the belief that they resulted from anomalous superior rectus recruitment. However, it has since been shown that increased EMG activity occurs with any retraction of the eye.250 Presumably, these muscles are “taking up the slack” caused by the origins and insertion of the muscle being brought closer together. Because surgically tenotomizing the superior rectus muscle under local anesthesia does not eliminate the upshoot, one must assume that the EMG activity seen in the vertically acting rectus muscles occurs as a result of (rather than causing) the upshoot or downshoot.251 This supposition is supported by the fact that surgically disinserting the lateral rectus muscle under local anesthesia almost completely eliminates the upshoot or downshoot.

The longstanding notion that the cocontracting horizontal rectus muscles slip superiorly or inferiorly over the globe (the “bridal theory” or “leash effect”) to produce the upshoot or downshoot has been supported by improvement or resolution when the lateral rectus muscle is recessed by a large

amount, recessed and split, or fixated retroequatorially to the globe.446 However, recent cinematic MR imaging studies by Bloom et al59 show little, if any, vertical displacement of the horizontal rectus muscles. von Noorden575 has argued that these findings confirm (rather than refute) the bridal theory by providing indirect evidence that it is the center of rotation of the globe that slips beneath the muscles as the eye elevates or depresses, rather than vice versa.

Y or l Pattern

Some children with Duane syndrome display an abrupt splaying of the eyes into exotropia in upgaze293 (Fig. 6.16). Kommerell and Bach293 described a rare form of Y-pattern Duane syndrome characterized by a unique twitch abduction of the involved eye that was accompanied by a mild retraction of the globe, producing an arc or diamond-shaped trajectory of its rotational path as the patient moves the eyes into upgaze. Abduction remains full in some patients, obscuring the diagnosis of Duane syndrome and simulating primary inferior oblique muscle overaction.310 However, fundus extorsion is absent, and inferior oblique weakening fails to improve the problem. Supraplacement and recession of the misinnervated lateral rectus muscles have been used successfully to normalize ocular rotations.310

Fig. 6.16  Child with left Duane syndrome demonstrating Y pattern secondary to recruitment of lateral rectus muscles in upgaze. Note minimal abduction limitation despite retraction in adduction. Absence of

alternating hypertropia of adducting eye in sidegaze helps distinguish this condition from primary inferior oblique overaction

This phenomenon results from anomalous recruitment of the lateral rectus muscle in upgaze. A similar phenomenon with a l pattern is less commonly seen in downgaze (Fig. 6.17). The finding of horizontal splaying of the eyes in extreme vertical gaze may cause diagnostic confusion when it occurs in the absence of an abduction deficit (Fig. 6.10). Because abduction may be normal or decreased, Kushner311 has suggested that cases without abduction deficits still fall within the spectrum of Duane syndrome. This rare motility pattern can be distinguished from the more common V-pattern associated with inferior oblique muscle overaction by abrupt divergence of the eyes in far upgaze and the absence of alternating hyperdeviations on sidegaze.311 Kushner has treated this condition with recessions and superior transposition of the lateral rectus muscles.312 This variant of Duane syndrome shows that the aberrant innervation of lateral rectus muscle need not always arise from the medial rectus branch of the oculomotor nerve. Rarely, the vertical rectus muscle rarely cocontracts to produce upshoot or downshoot in Duane syndrome.420

Synergistic Divergence

Rarely, recruitment of the lateral rectus muscle in attempted adduction can exceed the force produced by the medial rectus muscle, resulting in a paradoxical abduction of the

affected eye (termed synergistic divergence)579,593 (Fig. 6.17). Most patients with this phenomenon have a large exotropia and simultaneous nystagmoid movements on attempted adduction of the affected eye.134 The condition is usually unilateral, but bilateral cases have been described.80,128,212,548,583,611 The occurrence of synergistic divergence in several patients with congenital fibrosis syndrome77,80,211 reflects the fact that a primary failure to establish normal neuronal-extraocular muscle connections may underlie this disorder (see Chap. 7). Lateral rectus muscle fibrosis in Duane syndrome is seen histopathologically only in areas of lateral rectus muscle lacking innervation.41,374 In congenital fibrosis syndrome, the paradoxically abducting eye simultaneously abducted and depressed, suggesting that this form of synergistic divergence is attributable to aberrant innervation of the superior oblique muscle.72 Synergistic divergence may occur as a surgical complication following medial rectus recession in patients with Duane syndrome who have marked lateral rectus cocontraction. The treatment of synergistic divergence is difficult, because crippling of the cocontracting lateral rectus muscle is usually necessary to abolish the phenomenon.212

Synergistic divergence poses a complex surgical dilemma that can be eliminated only by crippling the misinnervated lateral rectus muscle. To the extent that bilateral lateral rectus muscle recession is necessary to treat the associated exodeviation, recessing the contralateral lateral rectus muscle increases the adduction innervation in the misinnervated eye,

Fig. 6.18  Axial MR scan demonstrating absence of abducens nerve in child with Duane syndrome. Courtesy of Joseph Demer, M.D.

which tends to augment its anomalous abduction. Thus, when bilateral lateral rectus muscle recession is necessary to treat the baseline exotropia, the misinnervated lateral rectus muscle must be weakened to the extent that it provides less force than the normal medial rectus muscle. Rarely, synergistic divergence accompanies other complex syndromic disorders.545

Rare Variants

Kesen et al273 described a 5-year-old girl with Duane syndrome who exhibited synergistic convergence with retraction of the globe in abduction and widening of the palpebral fissure in adduction. Cases of “inverse” Duane syndrome (widening of the palpebral fissure in adduction) may be attributable to excessive tightening of the medial rectus muscle due to excessive diversion of its innervation to the lateral rectus