muscle.330 Khan275 described a patient with bilateral “inverse” globe retraction on abduction, and two siblings with ptosis and abnormal synkinetic lid elevation associated with ipsilateral abduction276 have been described. Other bizarre examples of ocular motor synkinesis in combination with insertional abnormalities of the extraocular muscles have also been described.416

Systemic Associations

Duane syndrome may be associated with one or more additional systemic findings in about 33% of cases.72,217 Associated conditions most commonly involve the ears, spinal column, kidneys, heart, and upper limbs.578 High-tone hearing loss or sensorineural deafness is found in about 10% of patients with Duane syndrome.285,456,512,513 Conversely, Duane syndrome was found in seven of 500 deaf children, and a horizontally noncomitant strabismus was found in an additional four.6 Crocodile tears (gustatory tearing) can accompany unilateral or bilateral Duane syndrome and are often overlooked.51,520,619,620

Wildervanck syndrome (cervico-oculo-acoustic syndrome) comprises bilateral Duane syndrome, a cervical malformation known as the Klippel–Feil anomaly, and deafness.142 Female predominance is much more marked in Wildervanck syndrome than in Duane syndrome.86 Hypoplasia and other anomalies of the brainstem and cerebellum often accompany this condition.36,76 Other systemic associations include Okihiro syndrome (an autosomal dominant disorder consisting of Duane syndrome,44 radial ray anomaly [manifesting as congenital thenar hypoplasia], and variable sensorineural deafness),110 Holt–Oram syndrome (Duane syndrome with cardiac anomalies),134 acro-renal- ocular syndrome (radial ray defects, renal anomalies, and ophthalmological abnormalities such as coloboma, microphthalmia, and Duane syndrome,44,288,290,366,546 and bran- chio-oto-renal syndrome).453

Duane syndrome may also occur as part of the Goldenhar sequence,89 as well as in arthrogryposis multiplex congenita.352,375 The association of familial Duane syndrome and urogenital abnormalities with a defect in chromosome 22 was recently described.129 Numerous other ocular and systemic anomalies have been described with Duane syndrome, most notably Marcus Gunn jaw winking and iris heterochromia.134,512 A contiguous gene syndrome resulting from a de novo 8q12.2–21.2 deletion is characterized by branchio- oto-renal syndrome, Duane syndrome, hydrocephalus, and aplasia of the trapezius muscle.453,570 The autosomal recessive HOXA1 variant of bilateral Duane syndrome may be accompanied by autism, carotid artery hypoplasia or agenesis, and deafness.61

Etiology of Duane Syndrome

For many years after its initial description, Duane syndrome was attributed to mechanical factors (a tight, paretic lateral rectus muscle that does not abduct and restricts adduction, producing retraction of the globe). Indeed, it is well recognized that contraction of a medial rectus muscle against a tight lateral rectus muscle can produce visible retraction of the globe and simulate Duane syndrome. It is also recognized clinically and histopathologically that the lateral rectus muscle in Duane syndrome tends to be tight and fibrotic. However, EMG studies237,477,506 have conclusively shown that the lateral rectus muscle shows minimal electrical activity in its normal field of action, but that it cocontracts with the medial rectus muscle on attempted adduction, thus explaining retraction of the globe and narrowing of the palpebral fissure. Autopsy studies of two patients with Duane syndrome have demonstrated a total absence of the sixth nerve on the involved side, with innervation of the lateral rectus muscle by an aberrant branch of the third cranial nerve.235,374 In both cases, the lateral rectus muscle was fibrotic in areas lacking innervation but appeared relatively normal where innervated. The portion of the sixth nerve nucleus corresponding to the abducens cell bodies was also deficient.

High-resolution MR imaging can now confirm the absence or hypoplasia of the intracranial abducens nerve in vivo

(Fig. 6.18).137,140,263,423,427

One study by Demer et al139 found that, in contrast to the severe lateral rectus atrophy that accompanies chronic sixth nerve palsy, aberrant innervation allows for sparing of the normal lateral rectus size in Duane syndrome.263 However, a subsequent study by the same authors137 found absence of the abducens nerves, hypoplasia of the oculomotor nerve, and hypoplasia of many of the involved extraocular muscles. Although the diagnosis of Duane syndrome does not warrant neuroimaging, exceptional reports of tumors with possible causal associations have been reported.75,517

The degree to which sporadic mutations in the signaling proteins such as SALL4,160 HOX1A,160 and CHN-1,378 which underlie many hereditary and syndromic forms of Duane syndrome, play a causal role in isolated cases is unknown.

Classification of Duane Syndrome on the Basis of Range of Movement

Huber237 classified Duane syndrome into types I, II, and III, depending on the pattern of horizontal movement abnormality that accompanied the anomalous lateral rectus innervation. Type I Duane syndrome, which is by far the most common form, is characterized by severely limited abduction with

mildly limited adduction with retraction of the globe and narrowing of the lid fissure on attempted adduction. Type II (the rarest) has limited or absent adduction, with relatively normal abduction and retraction of the globe, with narrowing of the lid fissure on attempted adduction. The adduction deficit in type II Duane syndrome can superficially resemble a partial third nerve palsy (Table 6.2). Patients with type III Duane syndrome demonstrate reduced abduction and adduction and have retraction of the globe and narrowing of the lid fissure on attempted adduction. These three types have recently been shown to have differing mean age at presentation, primary position horizontal deviation, upshoot and downshoot, and associated systemic abnormalities.381 Nevertheless, surgical management is predicted on para­ meters that generally fall outside the realm of this classification system.

Embryogenesis

The embryogenesis of Duane syndrome is yet to be elucidated.552 It is not known (1) what circumstances unique to embryogenesis allow for axonal sprouting of the third nerve to innervate the lateral rectus muscle, (2) what is the critical time period in embryogenesis for this type of misinnervation to occur, (3) why neural misdirection occurs preferentially from the medial rectus branch of the third nerve, (4) where along the course of the sixth nerve the injury occurs, and (5) why decreased lateral rectus muscle innervation in utero leads to muscle fibrosis.

There is strong circumstantial evidence to suggest that at least some cases of Duane syndrome are caused by a brainstem injury. Such an injury would have to involve the fascicular portion of the nerve, because affected patients have no evidence of a horizontal gaze palsy (i.e., normal adducting saccades in the opposite eye). Furthermore, autopsy studies have demonstrated the selective absence of the cell bodies corresponding to abducens motoneurons with selective preservation of rostral cell bodies believed to represent internuclear neurons.374 Jay and Hoyt253 found a high incidence of abnormal latencies of brainstem auditory evoked responses (BAER) in Duane syndrome. The hearing loss noted in a significant number of patients with Duane syndrome would seem to fit with the abnormalities in BAER. However, auditory function testing and otolaryngologic examination have also implicated associated middle ear disease and cochlear abnormalities in some patients, indicating that a thorough auditory evaluation should be undertaken in all children with Duane syndrome.454

Ramsay and Taylor445 found a high incidence of Duane syndrome in patients with crocodile tears (which is caused

by seventh nerve misdirection). Miller371 found classic Duane syndrome in 31% of patients with thalidomide embryopathy, while other exposed patients had horizontal gaze palsies, facial weakness, and VIII nerve deficits. The clustering of these effects in patients with early thalidomide exposure suggests teratogenic injury involving the dorsal pons. However, experimental denervation of peripheral cranial nerves in the cavernous sinus of kittens has also led to peripheral misdirection with retraction movements,596 suggesting that an extra-axial sixth nerve fascicular injury can also eventuate in Duane syndrome.

Two theories exist as to the early events in the ontogenesis of the extraocular muscles. One holds that the anlagen of each muscle condenses from one of three distinct myogenic precursors, separately and at different times.186 The alternative theory509,510 is that the extra-ocular muscles develop concurrently from a single mesenchymal condensation that subsequently divides into separate superior and inferior mesodermal complexes. According to this theory, individual extra-ocular muscles may receive contributions from both mesodermal complexes or may arise from only one complex. During organogenesis, the developing brainstem also is segmented into regions known as rhombomeres that give rise to the cranial nerves.336 Each of the ocular motor nerves arise from particular rhombomeres, thereby establishing the segmental nature of the cranial nerves. A caudal-to-rostral internuclear gradient for the genesis of oculomotor motoneurons has been described in rats.10,11

Most motoneurons in abducens, trochlear, and oculomotor nuclei are postmitotic by the time the eye muscles are forming. Recent studies suggest that aggregates of myoblasts may be contacted by oculomotor nerves prior to migration and carry their innervation with them into the developing orbit. Whether innervation first occurs in the orbit or while myoblasts are still adjacent to the neural tube, the close proximity of the anlagen of the extraocular muscles may actually facilitate development of anomalous innervation of eye muscles. Taken together, these developmental sequences set the stage for the pattern of malformation of which Duane syndrome is the prototype. Specifically, the muscle anlagen are very close to each other and to the nuclei of the brainstem at the time of their innervation, so an oculomotor neural growth cone would have a very short distance to travel to innervate the lateral rectus anlage. Furthermore, the lateral rectus may receive myoblasts from both an upper and a lower anlage, rendering at least partial innervation by the third nerve, which also supplies upper and lower anlagen, more likely. A similar outcome has been seen in a transgenic mouse model in which the oculomotor and trochlear nuclei are absent and the abducens nerve sprouts to innervate extraocular muscles other than the lateral rectus.438