Clinical profile and magnetic resonance imaging characteristics of Duane retraction syndrome.

PURPOSE: To describe the clinical profile and magnetic resonance imaging findings of the brain in Duane retraction syndrome (DRS) and determine whether there is an association between clinical presentation and magnetic resonance imaging (MRI) brain characteristics.
MATERIALS AND METHODS: This was a cross-sectional study done at a tertiary care center in South India. We recruited and analyzed the clinical characteristics of 54 patients with DRS. MRI of the brain with fast imaging employing steady-state acquisition (FIESTA) was performed in 41 cases, and the cisternal segment of the sixth nerve was studied. Statistical analysis was done to determine any association between the radiological and clinical features.
RESULTS: Type 1 DRS was predominant, followed by Type 3 DRS and Type 2 DRS. 9.3% of cases were bilateral and 11.1% were familial. Orthotropia was most common, followed by esotropia and exotropia. The MRI brain showed the absence of the cisternal part of the sixth nerve on the affected side in 82% of Type 1 and 75% of Type 3 unilateral DRS. Both the abducens nerves were visualized in 19.5% of the patients with unilateral DRS. There was no statistically significant association between MRI brain findings and the clinical features.
CONCLUSIONS: MRI brain with FIESTA shows absent or hypoplastic sixth nerve in most cases of Type 1 and Type 3 DRS. However, around 20% of DRS cases may show the presence of the cisternal part of the sixth nerve. Hence, clinicians must be cautious when ruling out DRS on the basis of MRI brain findings. Although aplasia of the sixth nerve is the most frequent MRI finding, it may not be the sole etiologic factor. Copyright:

Introduction and Background

Duane retraction syndrome (DRS) is a disorder characterized by limited horizontal eye movements with narrowing of the palpebral fissure, retraction of the globe, and overshoots on attempted adduction. Initially, ophthalmologists considered DRS to be a mechanical abnormality because of inextensible recti or anomalous insertion of the recti.[1] Later, electrophysiology and autopsy studies suggested a neurologic pathogenesis for DRS – primarily due to hypoplastia of the sixth cranial nerve (CN6) and misinnervation of the recti.[234] DRS came to be classified as a congenital cranial dysinnervation disorder (CCDD) – a group of diseases with complex strabismus and abnormal ocular movements – the underlying cause being the defective development of the cranial nuclei or cranial nerves.[5]

Parsa et al. were the first to report the absence of the CN6 in the brainstem in DRS using high-resolution magnetic resonance imaging (MRI).[6] The development of fast imaging employing steady-state acquisition (FIESTA, a high-resolution MRI sequence) improved the evaluation of the cisternal segments of the cranial nerves.[7] MRI is clinically useful in diagnosing abduction limitation in young children and abduction limitation with atypical eye movements and in differentiating DRS from posttraumatic CN6 palsy.[8]

There are very few studies addressing the radiological features of DRS and the association between the clinical findings and radiology. Here, we aim to study the clinical profile and radiologic findings of the brain in DRS and to determine if there is an association between the clinical presentation and MRI brain characteristics.

Materials and Methods

Type and duration of study

This was a hospital-based cross-sectional study conducted in the squint clinic of a tertiary care center from January 2015 to January 2020. The study was approved by the institutional review board and research performed in adherence with the tenets of the Declaration of Helsinki.

Inclusion and exclusion criteria

We included all patients with DRS characterized by decreased abduction, adduction, or both along with:

Palpebral fissure narrowing on adduction and/or

Globe retraction and/or

Excessive upshoot or downshoot.

Patients with any history of orbital fractures or orbital diseases were excluded from the study.

Methods

All patients underwent a comprehensive ophthalmologic evaluation. Snellen chart was used to measure the visual acuity in older children and HOTV chart in younger children. Quantification of strabismus was done with an alternate prism cover test. Subjective grading of extraocular movements was done using a grading scale with 0 for full excursion, −3 to − 1 for excursions in 25% decrements, −4 for reaching midline, and − 5 for failure to reach the midline. Binocular single vision (BSV) was assessed with Bagolini striated glasses and the Worth four-dot test in all cooperative patients. The patients were categorized according to Huber classification into three types – Type 1 – DRS with defective abduction, Type 2 – DRS with defective adduction, and Type 3 – DRS with defective adduction and abduction.[9]

All cooperative patients underwent MRI of the brain (1.5 Tesla MRI) with 1 mm thick image planes using T2-weighted FIESTA. The MRI images were examined and the path of both the Abducens nerves was traced from the upper medulla to the upper pons. If the whole cisternal segment of the nerve was traced, it was labeled as “present.” If a limited segment was identified or the nerve was smaller in comparison to the other side, it was considered “hypoplastic.” If the whole cisternal segment of the nerve could not be identified, it was considered “absent.”

The data was analyzed using SPSS software (Statistical Package for Social Sciences for Windows, version 18.0, SPSS Inc., Chicago, USA). The categorical variables were described using frequencies and percentages. The numerical variables were summarized using mean and standard deviation (SD). The association between the categorical variables was analyzed using the Fisher's exact test. We considered a two-tailed P < 0.05 for statistical significance.

Results

There were 54 patients with DRS: mean age 9.9 ± 5.9 years; age range 1–25 years; 26 males and 28 females. Of these, 42 patients had involvement of the left eye and seven in the right eye. Five patients had bilateral DRS. All the patients with bilateral DRS were males. There were 40 patients with Type 1 DRS and 13 with Type 3 DRS. There was one patient with bilateral Type 2 DRS (10 years, male). We have compared the demographic and clinical features of patients with Type 1 and Type 3 DRS in Table 1.

Table 1

Demographic and clinical features of the patients with Type 1 Duane retraction syndrome and Type 3 Duane retraction syndrome

Parameter	Type 1 (n=40), n (%)	Type 3 (n=13), n (%)
Age, mean±SD	8.2±5.2	15.2±4.8
Sex
Male	19 (47.5)	6 (46.8)
Laterality
Right	6 (15)	1 (7.7)
Left	32 (80)	10 (76.9)
Bilateral	2 (5)	2 (15.4)
Ocular deviation
Orthotropia	17 (42.5)	5 (38.5)
Esotropia	15 (37.5)	2 (15.4)
Exotropia	8 (20)	6 (46.2)
Refractive error
Myopia	5 (12.5)	6 (46.2)
Hypermetropia	10 (25	1 (7.7)
Astigmatism	2 (5)	3 (23.1)

SD: Standard deviation

Of the 54 individuals in this study, a family history of DRS was present in six cases (11.1%). The mother of one patient with bilateral Type 3 DRS had bilateral Type 1 DRS. Thus, the disease showed intrafamilial variation. We have summarized the systemic and ocular abnormalities encountered in this study in Table 2.

Table 2

The systemic and ocular abnormalities in patients with Duane retraction syndrome

Case number	DRS type and laterality	Systemic association	Ocular association
4	Type 1-left eye	Equinus deformity	Nil
6	Type 1-right eye	Nil	Congenital glaucoma
25	Type 1-left eye	Maxillary hypoplasia	Microphthalmos
33– (Goldenhar syndrome)	Type 1-left eye	Dextrocardia, cervical vertebral defects, corpus callosal hypoplasia, preauricular skin tags	Limbal dermoid
36	Type 1-right eye	Nil	Nystagmus
38	Type 1-both eyes	Nil	Bilateral keratoconus

Out of the 54 patients, 22 (40.7%) were orthotropic. Most of these patients (12/22) presented due to the cosmetic disfigurement because of the globe retraction or overshoots. Defective vision due to refractive error was the presenting complaint in six patients. Four patients were referred after diagnosis at school ophthalmic screening camps. Abduction limitation ≥−3 was present in 16/22 patients (72.7%).

Strabismus was present in 32/54 patients (59%). Esotropia (17 cases) was more common than exotropia (15 cases). Angle of deviation was more than 30 Prism Diopter (PD) in 12 patients – seven patients with esotropia and five with exotropia. Angle of deviation was less than 30 PD in 20 patients (10 patients with esotropia and 10 with exotropia). Abduction limitation of grade ≥−3 was more frequent in those with deviation <30 PD (15/20, 75%) compared to those with deviation >30 PD (6/12, 50%).

We observed face turn in 15 individuals (27.8%) and overshoots in 14 individuals (25.9%). Downshoot (nine cases) was more common than upshoot (five cases). Most of the overshoots (12/14, 85.7%) were sudden, mechanical overshoots. Two patients (14.3%) had gradual, innervational overshoots. The visual acuity was better than 6/18 in 82% of the eyes. BSV was present in 39/47 (83%) patients. All cases of Ortho-Duane had BSV, but three cases of Eso-Duane and five cases of Exo-Duane had suppression.

We could perform MRI of the brain using FIESTA in 41 patients. The findings are summarized as shown in Figure 1. We analyzed whether there was any association between clinical features and absent cisternal sixth nerve in both Type 1 and Type 3 unilateral DRS. The results are summarized in Tables 3 and 4.

Figure 1

Flowchart showing the magnetic resonance imaging brain findings encountered in this study

Table 3

Clinical manifestations of patients with unilateral Type 1 Duane retraction syndrome (n=28) and Type 3 Duane retraction syndrome (n=8) were compared between patients who had absent/ hypoplastic cisternal part of abducens nerve (absent group) and those with present abducens nerve (present group) on magnetic resonance imaging brain

Clinical characteristic	Absent/hypoplastic group (n=23), n (%)	Present group (n=5), n (%)	P
Gender
Male	10 (43.5)	3 (60)	0.64
Laterality
Right	3 (13)	1 (20)	>0.99
Presence of strabismus	13 (23.5)	2 (40)	0.64
Type of strabismus
Esotropia	7 (30.4)	2 (40)	>0.99
Exotropia	6 (26.1)	1 (20)
Amount of deviation
>30 PD	5 (21.7)	1 (20)	>0.99
Abduction restriction
Grade ≥−3	19 (82.6)	2 (40)	0.52
Overshoots	5 (21.7)	0	0.55
Face turn	6 (26.1)	0	0.55
Binocular single vision
Present	18 (90)*	3 (60)	0.20

*Binocular single vision could not be assessed in three children with absent CN6. PD: Prism Diopter

Table 4

Clinical manifestations of patients with unilateral Type 3 Duane retraction syndrome (n=8) were compared between patients who had absent/ hypoplastic cisternal part of abducens nerve (absent group) and those with present abducens nerve (present group) on magnetic resonance imaging brain

Clinical characteristic	Absent/hypoplastic group (n=6), n (%)	Present group (n=2), n (%)	P
Gender
Male	2 (33.3)	0	>0.99
Laterality
Right	0	0	-
Presence of strabismus	2 (33.3)	2 (100)	0.43
Type of strabismus
Esotropia	1 (16.6)	0	0.21
Exotropia	1 (16.6)	2 (100)
Amount of deviation
>30 PD	1 (16.6)	1 (50)	0.22
Abduction restriction
Grade ≥−3	4 (66.6)	2 (100)	0.52
Adduction restriction
Grade ≥−2	3 (50)	1 (50)	>0.99
Overshoots	2 (33.3)	1 (50)	>0.99
Face turn	1 (16.6)	1 (50)	0.46
Binocular single vision
Present	5 (83.3)	2 (100)	>0.99

PD: Prism Diopter

The nine-gaze photograph of a patient with Duane retraction syndrome and the MRI brain image showing the absent cisternal part of sixth nerve is given in Figures 2 and 3.

Figure 2

Nine-gaze photograph of a patient with unilateral Type 1 Duane retraction syndrome. There is restriction of abduction in the left eye with narrowing and retraction of the globe and upshoot on adduction

Figure 3

Magnetic resonance imaging fast imaging employing steady-state acquisition axial view taken at the level of the pontomedullary junction. The linear dark structure on the right, which the arrow points to, is the right abducens nerve. The left abducens nerve could not be identified

Discussion

This study explored the clinical and radiological characteristics of patients with DRS. Most studies have cited unilateral, left-sided, and female predominance in DRS.[101112] Parsa and Robert hypothesized that emboli causing ischemic injury to the sixth nerve may be involved in the pathogenesis of DRS, which is why it is predominantly left-sided (embolic phenomenon is more on the left as the heart is on the left and common carotid artery arises directly from the aortic arch on the left). The female preponderance may be due to the higher estrogen levels increasing the risk of thrombosis.[11]

In this study, 9.3% of DRS cases were bilateral and all bilateral cases males. Previous reports show a 10–14% prevalence of bilateral DRS and a male predilection.[121314] 11.1% of cases in this study were familial. Most authors have estimated a 10% prevalence of familial DRS.[13] The intrafamilial variation seen in this series has also been previously reported.[13] Similar to previous studies, our study showed Type 1 DRS as the most common, followed by Type 3 DRS, and the least common Type 2 DRS.[101215]

This study reported cases of Duane with Goldenhar syndrome, limb deformities, facial hypoplasia, microphthalmos, nystagmus, congenital glaucoma, and keratoconus. All these associations have been documented.[16171819] We found Ortho-DRS the most common, followed by Eso-DRS and Exo-DRS. Most studies have reported the same.[1020] Similar to other studies, most strabismic patients in this study had small angle deviation and good visual acuity.[21] In this study, 25.9% of DRS cases showed overshoots. Previous studies have reported 39%–43% of overshoots.[51215] BSV was present in 83% of the patients in our study. Sloper and Collins had found BSV in 72.7% of DRS patients.[22] Thus, the clinical characteristics of DRS in this study are consistent with other similar studies.

Magnetic resonance imaging brain findings in Duane retraction syndrome

In this study, 82.1% of patients with unilateral Type 1 DRS and 75% of patients with unilateral Type 3 DRS had absent or hypoplastic cisternal part of CN6. Previous studies have reported absent or hypoplastic cisternal part of CN6 in 85.7%–100% of patients with unilateral Type 1 DRS and 60%–100% of unilateral Type 3 DRS [Table 5].[23242526272829] Except two studies, all others have reported normal cisternal segment of CN6 in Type 2 DRS.[2430]

Table 5

Number and percentage of patients with absent/hypoplastic cisternal part of abducens nerve in unilateral Type 1 and Type 3 Duane retraction syndrome compared to previous studies

Unilateral DRS	Type 1, n (%)	Type 2	Type 3, n (%)
Present study	23/28 (82.1)	0	6/8 (75)
Kim and Hwang, 2005[23]	15/15 (100)	0/2	3/5 (60)
Yonghong et al., 2009[24]	3/3 (100)	1/1	4/4 (100)
Kim and Hwang, 2012[25]	-	0/11	-
Xia et al., 2014[26]	4/4 (100)	0/3	-
Tuzcu et al., 2014[27]	9/10 (90)	-	-
Aggarwal et al., 2016[28]	12/14 (85.7)	0/2	-
Yang et al., 2016[29]	-	-	23/26 (88.5)

DRS: Duane retraction syndrome

Of the five patients with bilateral DRS in this study, one had Type 2 DRS with the cisternal part of sixth nerve present on both sides. The other four patients (2 Type 1 and 2 Type 3 DRS) had absent cisternal part of CN6 on the one side and visible CN6 on the other. In these four cases, the CN6 was absent on the side of more abduction limitation. There is a scarcity of studies on the MRI brain findings in bilateral DRS. Most studies in bilateral Type 1 DRS have reported bilaterally absent cisternal segments of the sixth nerve.[2324] Kim and Hwang have reported bilaterally present sixth nerve in bilateral Type 2 DRS.[25] Yang et al. reported bilaterally absent CN6 in three cases of bilateral Type 3 DRS.[29] Ozkurt et al. have reported three different findings in bilateral Duane (The study does not specify the type of DRS) – one having unilaterally absent CN6, one with bilaterally absent CN6, and one with bilaterally present sixth nerve.[31] An important limitation in our results in bilateral DRS is the lack of a control group to compare the size of the CN6. Establishing reference values for the absolute thickness of CN6 will help in differentiating normal and hypoplastic abducens nerves in bilateral DRS.

We had analyzed the association between the clinical features and MRI findings in unilateral Type 1 and Type 3 DRS. There was no statistically significant association between the absent cisternal part of CN6 and the gender, laterality, presence and amount of squint, the severity of abduction limitation, presence of overshoots, face turn, or BSV. The only other study to analyze this – Yang et al. in Type 3 DRS – also did not find any association between the radiology and the above clinical findings. They, however, observed more adduction limitation in Type 3 DRS with present CN6.[29]

This study has evaluated the utility of the MRI brain in the diagnosis and management of DRS in a real-world setting. Most of the DRS patients have an absent cisternal part of the sixth nerve. In around 20% of cases, the cisternal part of the sixth nerve is present. Hence, clinicians cannot rule out DRS in clinically doubtful cases, relying on the MRI brain findings alone.

The study has the following limitations – the small sample size and the cross-sectional design (hence, no control group for the comparison of the MRI images). We used the 1.5 Tesla MRI and have evaluated only the cisternal segment of the CN6. Further, we do not have electromyographic recordings to support clinical evidence in individual cases.

Conclusion

MRI reveals an absent sixth nerve in most patients with DRS, but the cisternal part of the sixth nerve was present in around 20% of DRS patients. Aplasia of the sixth nerve is the most frequent MRI finding but may not be the sole etiologic factor. There was no significant association between the presence and/or absence of CN6 in the MRI and the clinical findings in both unilateral Type 1 and Type 3 DRS.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.