Introduction

Intermittent exotropia (IXT) is one of the most common types of strabismus. The binocular abnormal vision mechanism and pathogenesis of exotropia have not been fully known1. Previous study reported that IXT with normal visual acuity and binocular vision was supposed to have normal macular perfusion by SD-OCT2. However, recent studies indicated that macular morphology has changed in strabismic patients whose outer ganglion layer increased meantime, they speculated that strabismus may be associated with brain cortex structure alterations3,4,5,6. Yun Wen et al. indicated that the thickness of nasal intraretinal layers increased in esotropia strabismus patients, particularly in ganglion cell layer and inner nuclear layer. Besides, retinal circulation in healthy adults is available by OCT scanning7. To date, no study was reported about comparison between basic IXT and age-matched healthy subjects, analyzing the relationship of different strabismus deviations with optical coherence tomography angiography (OCTA) parameters alterations. OCTA is a noninvasive quick imaging technique, and has been extensively used to supply the diagnosis of retinal disease by quantify various parameters including superficial capillary plexus (SCP), deep capillary plexus (DCP), foveal avascular zone (FAZ), choroid capillary density and so on8,9. It has benefited for diagnosis and evaluation of many retinal vascular disorders, such as retinal vascular occlusive diseases, diabetic retinopathy, uveitis, inherited diseases, age-related macular degeneration, glaucoma, and myopia10,11. By means of observation of vascularity in macular and specific retinal zones, the association between binocularity and changes of retinal structure was unclear and ambiguous in IXT patients. The study aims to compare retinal thickness and microvascular features in basic IXT with moderate and large angles of deviation, and evaluate the efficacy of OCTA parameters in management of IXT.

Methods

The observational cross-sectional study was conducted at the clinic from August 2021 to June 2022. Written informed consent was obtained from all parents of participants in the study. The study adhered to the Declaration of Helsinki and the study protocol was approved by the ethics committee board of the First Affiliated Hospital of Soochow University.

Patients with IXT who prepared to undergo surgical therapy for strabismus were enrolled. Basic IXT was defined as the near and distance deviations are almost equal. IXT subjects recruited in this study satisfied the following criteria: (1) aged from 7 to 17 years old, (2) a Newcastle Control Score of 3 or more, (3) an axial length from 22.5 mm to 25.5 mm, (4) a refractive spherical error < − 6.0 diopters (D) and a cylindrical error < 2.0 D, (5) a best corrected visual acuity (BCVA) of 20/25 or better. Healthy subjects were enrolled from patients who presented at the clinic with no other types of strabismus or ocular abnormalities. The excluded criteria included amblyopia, hyperopia (> + 3.0D), degenerative macular disease or retinal deterioration, poor OCT image quality resulting from unstable fixation, history of ocular surgery, non-surgical treatments, severe cataracts, glaucoma, or systemic disease like diabetes mellitus, and other types of strabismus.

Participants were divided into two groups, IXT group, and control group. We defined the healthy subjects as participants with no strabismus, amblyopia, and other ocular disease by prisms and the alternate-cover test after 1 h of monocular occlusion. All the procedures were performed by trained ophthalmologists and optometrists. We evaluated by ocular movements, distant and near magnitude of exodeviation, distant and near control, distant and near stereoacuity, not simply for vision screening. Meanwhile, we performed two additional comparisons, moderate (20 < PD ≤ 40) and large (40 < PD ≤ 60) angles of deviation IXT groups, and dominant eye versus deviated eye included in participants in IXT group. Binocular vision, detected by Titmus, refers to near stereoacuity. Non-binocular vision was defined as > 3000 s. In the IXT group, the non-dominant eye was defined as the most frequently deviated eye. In the control group, the right eye was selected as the analyzed eye.

All patients underwent complete examinations including evaluation of visual acuity [logarithm of the minimal angle of resolution (logMAR)], subjective refraction (spherical equivalent), axial length (Intraocular Lens Master 700, Carl Zeiss Meditec, Jena, Germany), slit-lamp examination, fundus photography, eye movement, binocular vision (Titmus), suppression test (Worth-4 dot), complete ocular motility examination using the alternat prism cover test at near (33 cm) and at distance (6 m), and OCTA evaluation.

OCTA scanning

OCTA images were obtained using RTVue XR Avanti device (Optovue Inc., Fremont, CA, USA) by orthogonal registration and merging of two consecutive scans centered on the fovea. Both standard 6 mm × 6 mm and 3 mm × 3 mm scanning of the macular region were used for all patients with undilated pupil. Automatic segmentation was performed by the viewing software to generate en face projection images of the SCP and DCP. The SCP consists of retinal capillaries ranging from the internal limiting membrane (ILM) to the posterior boundary of the inner plexiform layer (IPL). The DCP was defined by the capillaries between the posterior boundary of the IPL and the posterior boundary of the outer plexiform layer (OPL). FAZ parameters were measured in the 3 mm × 3 mm scan. FAZ parameters included the FAZ area, FAZ perimeter, and circularity index. The actual 3 mm and 6 mm circles were cropped and the parafoveal and perifoveal region were divided into 4 quadrants (superior, inferior, temporal, and nasal). Data were obtained from all these regions to determine the differences between two groups in this study. Each scan was repeated for three times, and patients were instructed to close their eyes for 30 s at the interval. The scan with the best signal strength was used for analysis. All procedures were performed under the same illumination by one trained examiner, and only images with signal strength of ≥ 6 points (full score is 10 points) were included in the analysis (Fig. 1).

Fig. 1
figure 1

OCTA macular perfusion in deviated eyes. (A) and (C) are SCP measurement in various regions, superior, inferior, nasal, and temporal. (B) and (D) are DCP measurement and FAZ zone. OCTA optical coherence tomography angiography, SCP superficial capillary plexus, DCP deep capillary plexus.

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Statistical analysis

Data analysis was performed using SPSS 26.0 (SPSS, Inc., Chicago, IL). Categorical variables are shown as numbers and percentages like sex; quantitative variables are described as mean ± standard deviation like age. T-tests was used for comparison between IXT and control groups, and Pearson’s correlation was used to analyze associations between variables for OCTA parameters. For non-normally distributed data, the Wilcoxon signed-rank test and Spearman’s rank-order correlation were used. Analysis of variance (ANOVA) with the Bonferroni method was performed to analyze the intergroup and intragroup differences for OCTA parameters. The chi-square or Fisher’s exact test was used to compare categorical data like Titmus. P values of < 0.05 was considered statistically significant.

Results

A total of 74 participants (109 eyes) were recruited in this study, including 35 (70 eyes) basic intermittent exotropia patients and 39 (39 eyes) healthy subjects. Of all participants, 55.4% were male. All patients showed no monocular suppression by suppression test. For IXT, only 5% of the participants showed no near stereopsis. The complete IXT duration was 13.27 (5.08) months. The angle of deviation in basic IXT patients was 32.86 (10.38) PD at near and 35.57 (8.11) PD at distance. No statistical difference was found (p > 0.05) between groups as shown in Table 1.

Table 1 Demographic characters of IXT patients and normal controls.
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In terms of overall comparison in OCTA parameters, we detected no statistically significant difference in any scanning regions between basic IXT and normal controls (p > 0.05). Table 2 summarizes OCTA findings. For macular vessel density of SCP and DCP, all of regions including superior, inferior, nasal, and temporal quadrants showed lower microvascular perfusion in basic youth IXT group except for the foveal SCP, which was larger comparing with normal controls. In contrast, the macular DCP was 36.41 ± 6.86 (%) and 37.58 ± 6.83 (%), respectively (p > 0.05).

Table 2 Comparisons of OCTA parameters between patients with IXT and normal controls.
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Besides, we identified OCTA metrics in deviated eyes and dominant eyes together in IXT patients.

In basic IXT patients, no difference was found between dominant eyes and deviated eyes shown in Table 3 (p > 0.05) Although RT in deviated eyes was thinner in foveal region and other quadrants. Except for that whole layer was 286.74 ± 10.77 μm in deviated eyes and 284.97 ± 1.78 μm in dominant eyes (p > 0.05). Besides, macular perfusion for SCP and DCP were higher in deviated eyes. The foveal SCP and DCP were 22.96 ± 5.16 (%), and 37.46 ± 6.69 (%) in deviated eyes, 21.85 ± 5.65 (%), and 36.41 ± 6.86 (%) in dominant eyes (p > 0.05).

Table 3 Comparison of OCTA parameters between dominant eyes and deviated eyes in IXT.
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Subgroup analysis

Various angle of deviation in IXT patients had no effect on OCTA parameters comparing with healthy controls (Table 4). P-values mean interaction groups comparison (P1: Moderate angle IXT group vs Normal controls; P2: Large angle IXT group vs Normal controls; P3: Moderate angle IXT group vs Large angle IXT group). There was no statistically significant difference in age, onset of strabismus, BCVA, IOP, SE, AL, and strabismus size at near and distance (p > 0.05). By means of strabismus size, IXT patients were divided into two groups, including moderate (20 ≤ PD < 40) and large (40 ≤ PD ≤ 60) angles of deviation IXT groups. Then we performed subgroup analysis according to different strabismus size of youth IXT in contrast to normal controls. No significant difference was identified in three groups for any OCTA parameters after correction for AL and SE using Bonferroni evaluation.

Table 4 Comparison of OCTA parameters among moderate and large angle IXT patients and normal controls.
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Discussion

We found macular microvasculature had no alterations by means of basic IXTs and age-matched healthy subjects. The retinal microvasculature of strabismus may be the same as the normal controls. IXT simply did not change the vessel density of the capillary completely. No matter in RT, the vessel density of SCP and DCP, or FAZ. This could be related to the intensive control competence of IXT patients when they underwent ocular examination, and keep their eyes in central position simultaneously12. The situation could be alleviated by cranial fusional mechanism. It could be explained by the retinal circulation function supplying optic nerve pathway. The retinal blood serves for the inner, and middle retina and is divided into the following two capillary beds: a superficial plexus located within the nerve fiber or ganglion cell layers, and a deeper plexus in the inner nuclear and outer plexiform layers13. However, these vascular circularity did not provide for the metabolic needs in IXT youth patients14. Meanwhile, the result showed that increased macular SCP in youth IXTs, which may be related to the visual suppression in youth IXTs. The alterations were corresponding to the anomalies of binocular visual perception in immature cortex development.

When it comes to the interocular difference in basic youth IXT, that is the deviated eyes and dominant eyes by using OCTA scanning. There was also no statistically obvious difference in any quadrants of parameters. Although macular perfusion in superficial and deep layer was lower in deviated eyes than that of dominant eyes.

In our study, when both eyes of IXT patients were analyzed as a self-control, OCTA illustrated no statistically significant decrease in the macular perfusion for deviated eyes. This finding may be associated with the chronic onset of IXT as well as variable exodeviation which depends on their mental state. For IXT participants, especially basic youth, they are capable of controlling the deviated eye who manifest strabismus only in some situations, like fatigued or ill, the rare change in retinal morphology was due to the same stimulation received by two eyes at the same time. These findings are consistent with those of one previous study showing no correlation between retinal topographical changes in the macular and the angle of deviation in concomitant strabismic patients3.

Meanwhile, OCTA parameters of different strabismus size in basic IXTs were nearly similar, which indicated that macular vessel density and retinal thickness were not correlated with the severity and the disease onset of IXT. Hence, we investigated whether abnormal retinal microvasculature existed in addition to retinal thickness changes in basic IXT patients. In general, IXT was common in strabismus, patients were able to control eye position by brain cortex. The alterations in microvasculature may play a key role in the binocular visual abnormality of IXTs. Further study needed to be performed to evaluate whether correlation existed between these potential retinal macular capillary plexus changes and the corresponding segmented retinal thickness or abnormal binocular visual function in other types of strabismus.

Several studies also found strabismus surgery may cause transient alterations both in retinal and choroidal microcirculation in the early postoperative period15,16,17. Zahid Huseyinhan et al. found significant increased VD values in SCP of operated eyes in patients who underwent horizontal rectus surgery (p = 0.037). Donghun Lee indicated that foveal VD in the SCP was significantly lower in the paralysis eye (P = 0.034) of paralytic strabismus patients. Besides, the lower foveal VD was corresponding to the greater deviation angle and the more severe eye movement restriction. By means of OCTA, ischemic factors and transitory hemodynamic changes could be examined following muscle recession procedures, which affect intraocular blood flow.

Strengths and limitations

In this study we explored retinal macular density perfusion in basic IXT patients and assessed changes of various strabismus size using OCTA. The retinal thickness and macular perfusion were almost consistent between deviated eyes and dominant eyes by means of IXT youth even comparing with age-matched normal subjects.

Our study has some limitations. First, the sample size of the study is small. This may be contributed to large angle deviation of basic IXT and rigorous inclusion criteria. Second, the data accuracy was affected by the misalignment of exodeviation detected by OCTA in children. We examined each participant with patching one eye to keep fixed in the distance for three times. Third, the effects of spherical equivalent and axial length on retinal vessel density retinal thickness cannot be excluded. We firstly chosen the age-matched controls and IXT patients to control bias. Last, the current OCTA technique cannot detect the vessel velocity of retinal microcirculation and the elasticity and diameter of the capillaries.

The macular microvasculature was similar between basic IXT and healthy controls.

The exodeviation and onset of IXT patients have no effect on retinal vessel perfusion.

The deviated eyes and dominant eyes showed no difference on macular perfusion in different regions.

Conclusions

In conclusion, OCTA shows no changes in patients with intermittent basic exotropia. The fusional control ability of basic IXT may yield the same retinal macular perfusion as the normal subjects. The clinical application of OCTA may have less value in the pathogenesis, diagnosis and treatment of basic intermittent exotropia.