Duane Retraction Syndrome

Etiology

Though the condition was first described in the literature as early as 1887, the etiology remains elusive. The advent of muscle electrophysiology and modern neuroimaging techniques such as MRI aided in the understanding that underlying abnormality in DRS is the absence or partial development of the abducent nucleus and nerve, resulting in aberrant innervation of the lateral rectus by the oculomotor nerve.[2][3][4]

Myofibers of extraocular muscles (EOMs) are developed by a condensation of the mesoderm around the eye. When the embryo is 7 mm long, the EOMs form one mass supplied by the oculomotor nerve. When the embryo is 8–12 mm long, this mass divides into separate muscles. It is at this stage that the fourth and sixth nerves arrive. Due to disturbing influences of unknown origin, the abducent nerve fails to develop, causing branches of the oculomotor nerve to remain in contact with the muscle mass that would later become the lateral rectus.[4]

Considering the other ocular and systemic anomalies associated with DRS, these disturbing influences are believed to affect the developing structures of the body between the 4 and 8 weeks of gestation.[5] Pfaffenbach et al. showed that sporadic forms of DRS are at 10 to 20 times greater risk of having other congenital malformations divided into mainly four categories: skeletal, auricular, ocular, and neural.[6] 

Skeletal abnormalities include cleft palate, limb deformities, phocomelia, vertebral anomalies, and spina bifida. Auricular abnormalities include preauricular tags, pinna defects, and sensorineural deafness. Neural defects involve the third, fourth, and sixth cranial nerves. Ocular associations of DRS are numerous and include epidermal dermoids, ptosis, dysplasia of the iris stroma, iris heterochromia, pupillary anomalies, cataracts, colobomas, optic nerve hypoplasias, morning glory disk, and nystagmus.[2]

DRS is commonly a sporadic disorder, but in 10% of cases, it may be familial. Both autosomal dominant and recessive forms of DRS have been documented. In cases of isolated DRS, the DURS1 gene on chromosome 2q31 has been identified.[7] The autosomal dominant pattern of DRS is associated with mutations in the CHN1 gene, which affects the guidance of the growing abducent nerve axons to the lateral rectus.[8][9] In DRS with associated malformation syndromes, the spalt-like transcription factor 4 (SALL4) gene on chromosome 20 has been implicated.[10] These syndromes include Okihiro syndrome, Duane-radial ray syndrome, and acro-renal-ocular syndrome.

DRS is also associated with mutations in the homeobox A1 (HOXA1) gene, which affects the creation or survival of cranial nerve neurons.[9] Associated syndromes include Bosley-Salih-Alorainy Syndrome (BSAS) and Athabascan Brainstem Dysgenesis syndrome (ABDS).

Epidemiology

DRS is found in 1% to 4% of the strabismic population.[11] Most cases are sporadic and unilateral; however, 10% are bilateral. Females are predominantly affected, and the left eye is more frequently affected than the right.[12] It has been hypothesized that higher estrogen levels in females during embryogenesis, together with a greater risk of inflammation, and lead to a higher risk of venous thromboembolic events. Furthermore, right to left shunts cause embolic phenomena affecting the left carotid artery more often, causing dysregulated apoptosis along with misinnervation affecting the left eye.[13]

Though DRS is a congenital anomaly, the average age at presentation in types I, II, and III is 13.5, 23.0, and 21.9 years respectively.[12]

Pathophysiology

An understanding of the pathogenesis of characteristic features of DRS, such as globe retraction and shoots, is essential in the evaluation and management of the condition. Paradoxical innervation of the LR by oculomotor nerve leads to co-contraction of lateral rectus (LR) and medial rectus (MR) on attempted adduction. This leads to globe retraction, which is usually accompanied by a narrowing of the palpebral aperture.

Another characteristic feature is shoots, which can be explained by mechanical factors as well as innervational anomalies. The mechanical cause of these vertical movements is due to a “bridle effect” or “leash effect” of the tight LR.[14] As the globe adducts and moves above or below the horizontal plane, there is sudden slippage of the tight LR, causing an upshoot or downshoot. In severe cases, this has been described to manifest even with the slightest of movement in adduction, known as the “knife-edge effect”. In contrast, innervational upshoots and downshoots are due to abnormal synergistic innervation between the medial rectus muscle and the superior, inferior rectus, or oblique muscles.[15]

History and Physical

Parents may seek medical attention for a child with DRS due to abnormal head posture, pseudoptosis when the affected eye adducts, limitation of eye movement, and abnormal eye movements. Clinical features of DRS include:

1. Abduction limitation – One of the prominent features of DRS is due to subnormal innervation of the LR. The amount of abduction limitation is disproportionately larger than the amount of primary position deviation. This is most likely due to an underlying adduction deficit present in varying amounts in DRS. This helps distinguish it from sixth nerve palsy, where the abduction limitation and primary position deviation are in proportion to each other.[16]
2. Abnormal head posture (AHP) – Commonly seen in unilateral cases, the AHP aims to center, enlarge and maintain binocular single vision and compensate for the duction deficit. The head turn will be toward the side of the affected eye in esotropic DRS and away from the affected eye in exotropic DRS.
3. Globe retraction - A characteristic feature of DRS and is usually accompanied by a narrowing of the palpebral fissure on adduction. According to Jampolsky, in some patients, globe retraction is replaced by retraction escapes or equivalents. Examples are 1) knife-edge LR/globe slip with upshoot or downshoot, 2) deficient inward rotation in opposite gaze, and 3) exotropic DRS with the “splits.”
4. Upshoots and downshoots - As aforementioned, shoots may be mechanical or innervational. While mechanical shoots are characterized by a sudden abrupt movement following a small vertical movement in adduction, innervational shoots are characterized by gradual elevation or depression of the eye as it adducts. Mechanical shoots usually do not have a primary gaze vertical tropia, whereas innervational shoots may be associated with vertical tropia in the primary position.[2]
5. Alphabet patterns – Alphabet patterns are due to the co-contraction of the vertical and lateral recti when the patient is looking toward the affected field of gaze. V pattern is the most common, while A and no pattern are found less frequently.[17]
6. Strabismus – Last but not least, patients of DRS may present with esotropia, orthotropia, or exotropia. This is discussed further in subsequent sections.

Evaluation

Evaluation of a patient with DRS is similar to any case of strabismus. This includes assessment of vision and cycloplegic refraction, inspection, motor evaluation, assessment of binocularity, and other supplemental tests.

A significant proportion (30% to 70%) of DRS patients has hypermetropia or hypermetropic astigmatism of more than 1.5D.[2] Some of these patients may also have an accommodative component; hence, cycloplegic refraction is essential for treatment planning.[18]

As patients adopt a compensatory head posture, strabismic amblyopia is not a common feature in patients with unilateral DRS. In contrast, up to 25% of patients with bilateral DRS have been found to have amblyopia.

Inspection and motor evaluation aids in determining the type of DRS. Based on electromyography, Huber classified the condition into three types:[19]

Type 1 – Marked limitation of abduction with minimally defective or normal adduction. This is the most common type, accounting for 70-80% of cases. EMG recordings showed paradoxical innervation of LR on adduction and reduced impulses on attempted abduction, while MR had normal electrical activity.

Type 2 - Limitation of adduction with normal or slightly limited abduction. This is the least common type, accounting for 7% of the cases. EMG recordings showed innervation of LR in both abduction and adduction, while MR was innervated normally.

Type 3 - Limitation or complete absence of adduction and abduction. EMG recordings showed simultaneous innervation of LR and MR in primary position, adduction, and abduction.

Ahluwalia et al. modified the Huber classification by dividing each type based on the primary position deviation found. This classification is more useful in terms of surgical planning and management.[20] Usually, patients with unilateral type I DRS have esotropia more frequently than exotropia, while type II DRS patients have exotropia, and type III DRS patients have esotropia, exotropia, and orthotropia occurring in an equal proportion.[17] Overall, the most common primary position deviation is esotropia, followed by orthotropia.

Bilateral DRS is less frequent than unilateral DRS, with a reported incidence between 10% and 24%. Zanin et al. classified bilateral DRS into three types based on the works of Jampolski: 1) Bilateral DRS with fusion – usually bilateral type I with a small angle of deviation or orthotropia with minimal eye movements, often without retraction or its equivalents, 2) Bilateral DRS without fusion – characterized by prominent eso- or exodeviation and 3) Bilateral DRS with an alphabet pattern.[14]

As aforementioned, DRS is associated with many ocular and systemic anomalies. Hence, a thorough multi-disciplinary evaluation is necessary.

Treatment / Management

Non-surgical management of DRS consists of spectacles or contact lenses for refractive error, prism glasses to improve the compensatory head position, and treatment of amblyopia with standard therapy. The efficacy of botulinum toxin has also been investigated. In most patients, the results of injection have been relative and short-term.[21](B2)

Indications for surgical management of DRS include 1) significant ocular deviation in primary position, 2) marked anomalous head posture, 3) disfiguring retraction of the globe on attempted adduction, and 4) upshoots and downshoots of the globe in adduction.

Patients should be informed that no treatment or surgical procedure will restore normal ocular movements in all gaze positions, as the underlying abnormality of paradoxical innervation cannot be corrected. Also, before operating any case of DRS, a forced duction test (FDT) is necessary to rule out MR or LR contracture in the affected eye.[22]

Surgical options for esotropic DRS include:

1. Medial rectus recession (MRc) – In cases with a tight MR and minimal co-contraction, MRc is generally indicated. Unilateral MRc of the DRS eye can correct up to 20 prism diopters (PD) of esotropia. It is recommended that MRc of the DRS eye should be limited to less than 6 mm. This is because a larger MRc increases the likelihood of an iatrogenic adduction limitation, which compromises the field of binocular single vision by causing an exotropia in the contralateral gaze.[23] It may also lead to the limitation of convergence.
2. Bilateral MRc – It is considered in certain situations.[23] First, in cases of esotropia with a primary position deviation of more than 20 PD, a single MRc of less than 6 mm is unlikely to be sufficient. Second, in cases with severe globe retraction, LR may have to be recessed along with the MR, conversely increasing the esotropia; hence, recessing the contralateral MR in such cases may also help correct the total esotropia. Finally, bilateral MRc may help prevent contracture of the MR on the affected side by creating “fixation duress” in the contralateral eye. After surgery, MR of the fixing eye receives increased innervation to maintain fixation, which reduces innervation to its LR. This, in turn, reduces the innervational tone of the MR of the affected eye, lowering the risk of its contracture.
3. MRc with LR recession (LRc) - In cases of esotropic DRS with moderate to severe co-contraction, MRc may be combined with LR recession. This reduces the anomalous innervation of the LR during adduction.[24]
4. Transposition of vertical muscles (VRT) - This surgery aims to create active abduction vector forces by creating a tone for LR through the transposed muscle.[25] It is indicated in cases of esotropic DRS with minimal co-contraction. However, the transposition of both vertical muscles has several limitations. New vertical deviations have been described in 6-30% of patients after VRT, the most common being hypotropia.[26] Co-contraction may worsen after VRT. Nearly fifty percent of patients require a secondary procedure involving recession of the ipsilateral MR to achieve acceptable eye alignment and head position. Also, when VRT needs to be combined with MRc, the risk of anterior ischemia syndrome increases.[27]
5. Transposition of superior rectus (SRT) – Transposition of superior rectus eliminates the risk of iatrogenic vertical limitation and anterior segment ischemia. It is recommended in esotropia of less than 15 PD with minimal co-contraction. In esotropias of 15 to 25 PD, SRT combined with unilateral or bilateral MRc is recommended.[2]
6. Recess-resect procedures – Lateral rectus resection of the concerned eye is usually not advised as globe retraction may be worsened. However, combined MR recession and LR resection may be considered in cases of esotropic DRS of less than 25 PD, with normal adduction and severely limited abduction. Globe retraction and shoots should also be absent.
(B2)

For exotropic DRS, LR recession (LRc) is advocated when there is normal LR activity in abduction. Unilateral LRc corrects up to 20 PD of exotropia. For exotropia of more than 20 PD, bilateral LRc may be considered. Recessing LR may worsen abduction limitation if present; therefore if bilateral LR recession is required, the larger recession should be done in the contralateral eye.[23]

Conversely, if the anomalous activity of LR is present, periosteal fixation of the LR may be considered. In this procedure, the insertion of LR is moved from the globe to the lateral orbital wall, eliminating the effect of paradoxical innervation and co-contraction in adduction. The resultant absence of abduction is correctable with transposition procedures, which may increase the risk of anterior segment ischemia. As a relatively new procedure, there is limited literature data on its efficacy.[22]

Surgical options to correct shoots and globe retraction include:

1. Y-split of the LR – This procedure has been advocated to treat mechanical shoots. In this procedure, LR is divided into two horizontal limbs as far posteriorly as possible and inserted 20 millimeters apart. Thus, when the eye elevates in adduction, the lower half of the LR contracts prevent the globe from slipping upwards.[28]
2. Periosteal fixation of the LR[22]
3. Vertical rectus muscle recession or inferior oblique myectomy – This procedure has been advocated to treat innervational shoots.[29][30][29]
(B3)

Differential Diagnosis

Differential diagnoses of DRS include disorders that cause or may appear to cause abduction deficits, such as sixth nerve palsy, infantile esotropia, Mobius syndrome, and congenital ocular motor apraxia. Most of these conditions can be differentiated from DRS on the basis of associated clinical features. For example, in infantile esotropia, abduction saccades and cross fixation are usually present; patients with Mobius syndrome may have associated feeding and speech difficulties; in congenital ocular motor apraxia, there is an inability to generate horizontal saccades. However, there is full retention of eye movements, and gradual improvement with time occurs.

Esotropic DRS and congenital sixth nerve palsy may be differentiated based on the following clues: 1) globe retraction in adduction is present in cases of DRS, while it is absent in sixth nerve palsy, 2) the esotropic angle is usually smaller in DRS patients compared with sixth nerve palsy patients who have the same limitation of abduction, and 3) the amount of abduction deficit varies in upgaze and downgaze in patients with DRS, whereas it is similar in patients with sixth nerve palsy.[16]

Duane et al. described certain mechanical and neurogenic conditions that lead to globe retraction in adduction and limitation of abduction but are etiologically distinct from classical DRS. These conditions are collectively termed “Acquired retraction syndrome.”[31] Mechanical conditions include fracture of the medial orbital wall, orbital inflammation, thyroid myopathy, and bony orbital metastasis. Neurogenic conditions include head injury, intracranial metastases, and brainstem tumors such as glioma. These can be differentiated from true DRS based on the history of systemic illness, diplopia, trauma, or surgery.[2]

Prognosis

Isolated DRS leads to an excellent long-term prognosis for vision if managed appropriately. With a motley of non-surgical and surgical options available, features of DRS such as abnormal head posture, globe retraction, shoots, and misalignment of the visual axes can be improved. Advances in surgery such as transposition of vertical muscles also aid in improving ductions in patients of DRS.

Complications

1. Undercorrection and residual esotropia – Residual esotropia may result if a) an inadequate amount of horizontal muscle recession is performed, b) if contracture of MR occurs with time, or c) if inadequate vector force is generated by muscle transposition.[26]
2. Consecutive exotropia – This may result if a) excess tension is created by vertical muscle transposition, b) if ipsilateral MR is weak, or c) if co-contraction is worsened by transposition.[23]
3. Induced vertical deviation – This may result in a restrictive imbalance between the transposed muscles or if recession or slippage of the transposed muscle occurs. If excess muscle belly is used for transposition, vertical action of the muscle may also be weakened, leading to induced vertical deviation.[23]