Synergistic Divergence: A Distinct Ocular Motility Dysinnervation Pattern

Abstract

Purpose.: To summarize the clinical, neuroradiologic, and genetic observations in a group of patients with unilateral synergistic divergence (SD).

Methods.: Five unrelated patients with unilateral SD underwent ophthalmic and orthoptic examinations; three of them also had magnetic resonance imaging of the brain and orbits. Three patients underwent genetic evaluation of genes known to affect ocular motility: KIF21A, PHOX2A, HOXA1, and ROBO3.

Results.: The patients did not meet the clinical criteria for CFEOM types 1, 2, or 3. Each patient had severe adduction weakness on the affected side and large-angle exotropia in primary gaze that increased on attempted contralateral gaze because of anomalous abduction. Magnetic resonance imaging revealed a much smaller medial rectus muscle in the involved SD orbit. Oculomotor cranial nerves were present in the one patient imaged appropriately. Genetic sequencing in three patients revealed no mutations in KIF21A, PHOX2A, HOXA1, or ROBO3.

Conclusions.: SD should be classified as a distinct congenital ocular motility pattern within congenital cranial dysinnervation disorders. It may be caused by denervation of the medial rectus with dysinnervation of the ipsilateral lateral rectus by the oculomotor nerve precipitated by genetic abnormalities (some currently identified) or by local environmental, teratogenic, or epigenetic disturbances.

Synergistic divergence (SD) is a congenital ocular motility pattern characterized by paradoxical abduction during attempted horizontal gaze to the contralateral side. ¹ This rare condition is generally unilateral and is always associated with limited adduction of the affected eye. The pathophysiology of anomalous abduction remains unclear but has been variously attributed to mechanical factors, anomalous innervation of the ipsilateral medial and lateral recti muscles, ^2,3 and even anomalous cross innervation between the two lateral recti. ⁴ SD is usually an isolated ocular motility abnormality, but it has been described several times in conjunction with ocular motility phenotypes consistent with congenital fibrosis of the extraocular muscles types 1 (CFEOM1) ⁵ and 3 (CFEOM3). ⁶  

This report summarizes clinical, radiologic, and genetic observations in a group of patients with unilateral SD. 

Methods

Five unrelated patients of Middle Eastern ethnicity had complete orthoptic and ophthalmic examinations, including dilated funduscopy. Ocular motility was assessed visually and by videotaping. Fusion was measured using the Worth 4-Dot Test and the Lang Stereo Test. 

Standard brain MR pulse sequences were acquired in one patient by a 1.5-Tesla scanner (Signa; GE Medical Systems, Waukesha, WI) and in two patients by a 3.0-Tesla scanner (Magneton Allegral; Siemens Medical Systems, Germany), including sagittal T₁-weighted spin-echo, coronal fluid-attenuated inversion recovery, axial dual echo, and axial proton density inversion recovery sequences in all patients and axial 3D FT constructive interference in steady state (CISS) of the brain stem in one patient. One patient had brain computed tomography performed on another scanner (Sensation 4; Siemens Medical Systems). 

Five milliliters of peripheral blood was collected in EDTA tubes from three patients and high-molecular-weight DNA was extracted with a blood kit (Puregene; Qiagen, Hilden, Germany), quantified spectrophotometrically, and stored at −20°C in aliquots until required. PHOX2A (MIM *602753), ⁷ HOXA1 (MIM *142955), ⁸ and KIF21A (MIM *608283) ⁹ (Mendelian Inheritance in Man, provided in the public domain by the National Institutes of Health, Bethesda, MD; http://www.ncbi.nlm.nih.gov/Omim/) coding exons and exon–intron boundaries were amplified using polymerase chain reactions (PCR) with Taq DNA polymerase (Hotstar; Qiagen). Two patients also had ROBO3 (MIM *608630) ¹⁰ sequenced. All resulting amplicons for PHOX2A, HOXA1, and ROBO3, and the amplicons for KIF21A exons 8, 20, and 21 were direct sequenced on a sequence analyzer (3730; Applied Biosystems, Inc. [ABI], Foster City, CA). The remaining KIF21A amplicons were analyzed by denaturing high-performance liquid chromatography (DHPLC; Transgenomic, Inc., Omaha, NE). All screening conditions were as previously published, and primers are available on request. Study protocol adhered to the tenets of the Declaration of Helsinki, and patients signed consent forms approved by the King Khaled Eye Specialist Hospital, Riyadh, or the Children's Hospital, Boston. 

Results

Birth, general medical history, and family history were unremarkable, although two patients were from consanguineous families (a typical prevalence in the Middle East). Figure 1 illustrates the eye movements of patients 1, 2, and 3, whereas Table 1 presents clinical details. All patients were male, and all had unilateral SD, with the right eye involved in four. No family member of patients 1 to 4 reported an ocular motility, ophthalmic, or neurologic abnormality. A brother and sister of patient 5 had congenital ptosis. 

Figure 1.

 

Montage of ocular alignment and motility Horizontal ocular motility montage of patients 1 (A–C), 2 (D–F), and 3 (G–I). Primary position (B, E, H) included a large-angle right exotropia in each patient. Right gaze (A, D, G) resulted in good but not complete abduction of the right eye in each patient. Right exotropia increased on left gaze (C, F, I) in each patient because of an abducting movement of the right eye (i.e., synergistic divergence). Patient 1 also had a motility pattern in the left eye compatible with DRS type 3. Patients 2 and 3 had a small right hypotropia in primary position that was exaggerated by a downshoot of that eye on attempted left gaze. None of these three patients had globe retraction on the right.

Table 1.

 

Clinical Details

Patient	Age (y)	SD Eye	Fellow Eye	Ocular Alignment	Horizontal Ocular Motility (%)*				Vertical Ocular Motility SD Eye†
					SD Eye		Fellow Eye
					ABD	ADD	ABD	ADD
1	2	Right	DRS type 3	XT 85	75	0‡	25	25	Full
2	9	Right	Normal	XT 55	75	0‡	100	100	Mild elevation deficiency; Down shoot during attempted adduction
				RHypoT 8 with AHP; X 2
3	1	Right	Normal	XT 60	85	0‡	100	100	Full; down shoot during attempted adduction
				RHypoT 10
4	5	Left	Normal	XT 70	90	0‡	100	100	Mild elevation and depression deficiency
5	3	Right	DRS type 1	XT 70	75	0‡	0§	100	Full

 Age, age at first examination; SD eye, eye with synergistic divergence; ABD, abduction; ADD, adduction; DRS, Duane retraction syndrome; XT, exotropia; X, exophoria; RhypoT, right hypotropia.

*  Duction movement scored as a percentage of normal excursion where 100% = full movement and 0% = no movement into field of action.

†  Contralateral (non-SD eye) had full vertical ocular motility in all patients.

‡  Eye unable to reach midline (i.e. straight ahead position) and remains in an abducted position.

§  Eye unable to reach midline (i.e. straight ahead position) and remains in an adducted position.

Ocular motility patterns did not meet clinical criteria for CFEOM1, ¹¹ CFEOM2, ¹² and CFEOM3, ⁶ horizontal gaze palsy and progressive scoliosis, ¹³ or the HOXA1 clinical spectrum. ¹⁴ All patients had large-angle exotropia with the SD eye fixed in an abducted position and unable to adduct sufficiently to reach the midline. On attempted gaze contralateral to the SD eye, the SD eye of each patient abducted incompletely rather than adducting, so that both eyes abducted simultaneously. Ipsilateral abduction of the SD eye was also incomplete in all patients. No patient had globe retraction of the SD eye during horizontal gaze or anomalous lid movement on either side with ocular or jaw movement. Additional SD eye motility anomalies included primary position hypotropia which increased during attempted adduction (i.e., coincident with anomalous abduction; patients 2 and 3); mild elevation and depression deficiency (patient 4); and a mild elevation deficiency only (patient 2). 

Two patients had Duane retraction syndrome (DRS) in the contralateral eye. Patient 1 had a DRS type 3 with characteristic marked limitation of abduction and adduction of the left eye associated with marked lid fissure narrowing and globe retraction on right gaze. He also had reduced hearing bilaterally. Patient 5 had DRS type 1 on the left with absent abduction, normal adduction, and globe retraction, with narrowing of the palpebral fissure during attempted right gaze. All five patients preferred fixation with the non-SD eye, and amblyopia was present in the SD eye of three patients (patients 1, 4, and 5). Fixation was exclusively monocular in four patients, whereas patient 2 adopted an anomalous head position with face turned left to obtain fusion documented by Worth 4-Dot Test responses at near and distance and measurable stereopsis on the Lang Stereo Test. However, this marked head position was too uncomfortable to maintain for prolonged periods, and he would typically revert to fixing monocularly with the non-SD eye. 

Only patient 2 had a surgical correction to reduce his exotropia and eliminate the anomalous divergence movement. Right lateral rectus extirpation eliminated the anomalous divergence movement; however, a large exotropia persisted. Three months later he underwent vertical recti transpositions to the medial rectus, at which time the medial rectus muscle was found to be thin and fibrotic. 

Patients 1, 2 and 3 had brain imaging performed. Orbits, skull base, brain stem, and supratentorial brain appeared normal. Figure 2 shows images of patient 1, documenting a small right medial rectus (Figs. 2A, 2B) and the presence of oculomotor nerves (Fig. 2C). The maximum cross section size of the right medial rectus was approximately 30% of that on the left in all three imaged patients, whereas other extraocular muscles appeared symmetric in size. 

Figure 2.

 

Montage of brain imaging. Images of patient 1. (A) Axial CT image of orbit showing smaller medial rectus muscle on right. (*) Right optic nerve; arrows: medial recti. (B) Coronal T2W MRI image of orbits again showing smaller medial rectus muscle on right. Arrows: medial recti. (C) Axial CISS MRI image showing normal-appearing oculomotor nerves (arrows) bilaterally. Images did not adequately demonstrate the presence or absence of the abducens nerves.

Three subjects had genetic screening for known CCDD genes. KIF21A, PHOX2A, and HOXA1 sequencing in patients 2, 3, and 5 revealed no mutations. ROBO3 sequencing in patients 2 and 5 also showed no mutations. 

Discussion

We describe five unrelated patients of Middle Eastern ethnicity with unilateral synergistic divergence, an unusual congenital ocular motility pattern consisting of exotropia due to unilateral absent adduction and bilateral abduction during attempted gaze contralateral to the affected eye. ¹ Two patients had DRS contralaterally, and three others had mild vertical motility abnormalities in the SD eye. A small medial rectus muscle was observed in the SD eye of patients who underwent brain imaging. We did not find a mutation in any gene currently identified to cause a congenital ocular motility abnormality. 

Patients reported previously ⁵ and all three patients with brain imaging reported herein had small medial recti on the affected side, perhaps due to maldevelopment of the medial rectus muscle, and surgical observation of our patient 2 and others ^1,15 noted fibrosis and/or hypoplasia of the medial and sometimes the lateral rectus muscles. However, hypoplasia of the affected medial rectus alone would not explain abduction of the affected eye on attempted contralateral gaze. 

Recently, certain congenital ocular motility disorders formerly thought due to congenital fibrosis of the extraocular muscles have been reclassified as congenital cranial dysinnervation disorders (CCDDs). ¹⁶ These disorders result from the congenital absence or misdirection of specific brain stem lower motor neurons, leading to the loss of correct innervation of certain extraocular and/or cranial muscles, often with subsequent anomalous innervation (dysinnervation) by other nerves. ^7–9  

SD has certain similarities to DRS, the most common CCDD ocular motility pattern. Both SD and DRS affect predominantly horizontal ocular muscles, they both occur unilaterally or bilaterally, ¹⁷ and they sometimes coexist. ¹⁸ However, the SD clinical phenotype differs from DRS in several ways. It involves a different motility pattern from all three DRS types; the muscle most involved is the medial rectus rather than the lateral rectus; and it does not include the DRS clinical hallmarks of globe retraction and lid fissure narrowing. DRS is more common in females for unclear reasons, ¹⁷ whereas SD is more common in males in currently reported patients. ^19–22  

A likely scenario is that a developmental anomaly in SD prevents the inferior branch of the oculomotor nerve from correctly innervating the medial rectus. The presence of synergistic divergence of the affected globe suggests that oculomotor fibers that should innervate the medial rectus actually innervate the lateral rectus, causing anomalous abduction on attempted contralateral gaze. Medial rectus denervation would explain a small medial rectus and absence of adduction on the affected side, and electromyographic studies in SD have documented reduced or absent firing in the medial rectus compatible with denervation. ¹ One of our patients underwent extirpation of the lateral rectus in the SD eye but that eye remained exotropic with no apparent adduction, implying complete denervation of the medial rectus. 

SD is sometimes associated with other evidence of miswiring such as Marcus Gunn jaw winking ^20,23 and anomalous innervation of the medial rectus by the motor branch of the trigeminal nerve. ¹⁹ In fact, SD has been reported in patients with CFEOM1, ⁵ a genetic abnormality that typically causes widespread extraocular muscle dysinnervation, ²⁴ and another previously reported patient with eye movements characteristic of SD had linkage to the CFEOM3 locus. ⁶ Two of our patients had contralateral DRS, and three others had mild anomalous vertical eye movements. These observations indicate that miswiring extended beyond the horizontal rectus muscles in the SD eye in all our patients. The negative genetic results reported herein prove that SD is not exclusively associated with currently identified CCDD genes but also may be due to currently unrecognized genetic abnormalities or to local environmental, teratogenic, or epigenetic disturbances during development. 

SD deserves recognition as a distinct ocular motility pattern of CCDD, comparable to DRS but much less common. It is possibly caused by congenital denervation of the medial rectus with dysinnervation of the ipsilateral lateral rectus, resulting in the characteristic anomalous abduction bilaterally on attempted contralateral gaze. Future studies may elucidate the genetic and/or teratogenic factors during development that cause this CN misdirection pattern. 

Footnotes

 Supported in part by the National Eye Institute (ECE, WMC) and NEI Grant R01 EY15298, EY012498, and EY013583 (EE).

Footnotes

 Disclosure: D.T. Oystreck, None; A.O. Khan, None; A.A. Vila-Coro, None; O. Oworu, None; N. Al-Tassan, None; W.-M. Chan, None; E.C. Engle, None; and T.M. Bosley, None

Footnotes

 The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked “advertisement” in accordance with 18 U.S.C. §1734 solely to indicate this fact.

The authors thank the study participants and the staff of the Research Department of the King Khaled Eye Specialist Hospital.