Clinical background
Duane retraction syndrome is a congenital cranial dysinnervation disorder characterized by uni- or bilateral abduction deficit, narrowing of the palpebral fissure on adduction, and globe retraction with occasional upshoot or downshoot in adduction ( Box 57.1 ). 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.
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Limited ab- and/or adduction
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Globe retraction on adduction
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Palpebral fissure narrowing on adduction
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Up- and downshoots in adduction (common but not universal)
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 ab- and adduction. 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, 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 deceleration 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. 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 unilateral and another bilateral autopsy case of Duane syndrome. Parsa et al 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, and later correlated with the presence of residual abduction in multiple cases. Kim and Hwang have emphasized the frequent absence of the subarachnoid abducens nerve ipsilateral to Duane syndrome type 1 and type 3, but the presence of the subarachnoid abducens nerve ipsilateral to type 2. 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. 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.
Etiology
Most cases of Duane syndrome are sporadic. Some of these are clearly teratogenic, associated with intrauterine exposure to drugs such as thalidomide. Other cases have well- characterized genetic causes. Dominant Duane syndrome has been linked to chromosome 2, the DURS2 locus. 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. 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 the dominant association of uni- or bilateral Duane syndrome with uni- or bilateral dysplasia of the radial bone, artery, and thumb ( Figure 57.4 ). DRRS results from heterozygous mutations in SALL4 , a zinc finger transcription factor. The developmental expression profile and functional 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. 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, as well as their peripheral and subarachnoid motor innervation ( 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 locus. 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. 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 ).
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Abnormality of abducens innervation to superior zone of lateral rectus muscle
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Misrouting of inferior division of oculomotor nerve to inferior zone of lateral rectus muscle
Other abnormalities of orbital motor innervation may be present in Duane syndrome, and may explain coexisting vertical pattern strabismus, as well as up- or downshoots in adduction. 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 co-innervated 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.
