Yearly changes in cases of acute acquired comitant esotropia during a 12-year period

Purpose The number of patients with acute acquired comitant esotropia (AACE) has been increasing in Japan. The purpose of this study was to investigate the changes in the number and characteristics of patients with AACE examined in our institution during a 12-year period. Methods We retrospectively reviewed the medical records of patients with AACE aged < 30 years who suddenly developed diplopia or esotropia and were examined in Hyogo College of Medicine Hospital from January 2008 to December 2021. We investigated the association of the yearly changes in the number of patients with the age category, refractive error category, AACE type, esotropia type, and use or nonuse of smartphones. Results The total number of patients with AACE was 171, and this number significantly increased each year (Pearson correlation coefficient, 0.9450; p < 0.0001). Significant increases were found among students in junior high school and beyond, patients with myopia, patients with Bielschowsky type AACE, and patients with basic esotropia (p < 0.0001 for all). We compared two age groups, elementary school students and below versus junior high school students and above, and found that the rate of increase was significantly higher in the junior high school students and above (estimate, 1.951; p < 0.0001), and the non-myopia group and myopia group and found that the rate of increase was significantly higher in the myopia group (estimate, 1.891; p < 0.0001). Excessive use of smartphones was confirmed in 82 of 133 patients, and the rate of the increase in the number of patients with AACE was significantly greater among patients with than without excessive use of smartphones (estimate, 1.098; p = 0.0009). Conclusion This study confirmed a significant increase in the number of patients with AACE in recent years. The excessive use of smartphones may be associated with the increase in AACE.


Introduction
In Asian countries (including Japan), unlike in Western countries, exotropia is much more common than esotropia in patients with comitant strabismus [1]. However, the

Key messages
The number of patients with acute acquired comitant esotropia (AACE) has been increasing in Japan. The present study was performed to investigate the yearly changes in the number of patients with AACE and the characteristics of AACE in our institution during a 12-year period and to evaluate any relationships between AACE and the use of smartphones.

3
frequency of acute acquired comitant esotropia (AACE) has recently shown an increasing tendency, especially in younger generations. Although AACE has been considered a rare condition, recent reports indicate that excessive use of digital devices can trigger AACE [2,3]. With the widespread use of smartphones and other digital devices, the number of patients with AACE is increasing [2,4]. In 2016, Lee et al. [2] described 12 patients with AACE caused by excessive use of smartphones, and the esotropia was significantly improved in 9 of these patients by restriction of smartphone use. This suggests the possibility of a relationship between excessive use of smartphones and development of esotropia.
The present study was performed to investigate the yearly changes in the number of patients with AACE and the characteristics of AACE in our institution during a 12-year period and to evaluate any relationships between AACE and the use of smartphones.

Patients and methods
This retrospective single-center study was performed in compliance with the Declaration of Helsinki and approved by the Research Ethics Review Committee of Hyogo Medical College (Approval No. 202104-756). We reviewed the medical records of patients with AACE examined at the Department of Ophthalmology in Hyogo College of Medicine Hospital from January 2008 to December 2021 and extracted the data of patients who developed onset of diplopia from 2008 to 2019.
The diagnostic criteria for AACE in this study were partially modified from previous reports [2,5] as follows: (1) known date of onset of diplopia or esotropia, (2) no limitation of ocular motility, (3) no particular abnormalities on cranial and orbital computed tomography or magnetic resonance imaging, (4) absence of accommodative component, (5) no history of systemic disease or head trauma, and (6) no history of ocular problems such as strabismus or amblyopia. We included patients who met the following criteria: age of < 30 years, corrected visual acuity of 20/20 in both eyes, and follow-up of ≥ 1 month. We excluded patients who showed a reduction in esotropia when wearing hyperopic glasses, had an unknown date of symptom onset, had convergence spasms, and had decompensated esotropia.
The following background information of the patients was investigated: sex, age at onset, age at first visit to our hospital, period from onset of diplopia to first visit to our hospital, refractive error, angle of esotropia, and type of AACE. We asked the patients about their daily duration of smartphone use and identified excessive use as > 4 h of smartphone use per day.
The angle of esotropia was measured by the alternate prism cover test at near (33 cm) and distance (5 m), and stereopsis for near was measured by the Titmus stereo test (Stereo Optical Inc., Chicago, IL, USA). Spherical equivalent (SE) refractive error (spherical power + 1/2 cylindrical power) was measured after administration of cyclopentolate hydrochloride in patients aged < 12 years and after administration of tropicamide/phenylephrine in patients aged > 13 years. Automated assessment of refraction was performed by an autorefractometer (RC-5000; Tomey Inc., Nagoya, Japan).
We evaluated the yearly changes in the number of patients diagnosed with AACE and the background characteristics of the patients throughout the study period. The age categories were based on the classification of 6 years of elementary school (6-11 years old), 3 years of junior high school (12 to 14 years old), and 3 years of senior high school (15 to 17 years old) in the Japanese educational system. The patients' age at onset was categorized into the following five categories: < 5 years, 6-11 years (elementary school students), 12-14 years (junior high school students), 15-17 years (senior high school students), and > 18 years. Because the smartphone penetration rate in Japan rapidly increases among junior high school students and above, we categorized the patients into two additional groups: elementary school students and below and junior high school students and above.
AACE was classified into three main types as reported previously [6][7][8]: (1) Swan type, which occurs following unilateral occlusion or vision loss; (2) Burian-Franceschetti type, which is thought to be caused by physical and psychological stress in the absence of an accommodative component; and (3) Bielschowsky type, which develops in patients with myopia of − 5.00 D or higher and is characterized by divergence insufficiency esotropia. In this study, patients with refractive error of less than − 5.00 D but with undercorrection or no correction of myopia were also classified as having Bielschowsky type AACE.
The difference between near and distance esodeviation was categorized into the following three types: (1) divergence insufficiency type [≥ 10 prism diopter (PD) larger at distance than at near], (2) basic type (difference of < 10 PD between near and distance), and (3) non-accommodative convergence excess type (≥ 10 PD larger at near than at distance).

Statistical analysis
The two independent variable comparisons in the study population were performed with Student's t-test for continuous variables approaching a normal distribution and with the Mann-Whitney U test for continuous non-normally distributed variables.
Pearson's correlation test was used to identify any correlation between variables, and simple and multiple linear regression analyses were used to predict dependent variables.
Statistical analysis was performed using JMP Pro version 14.0.0 (SAS Institute Inc., Cary, NC, USA). For significance testing, a risk rate of < 5% was considered statistically significant.
The mean age at the first visit to our hospital was 16.9 ± 5.7 years (range, 2-30 years). The mean period from the onset of diplopia to the first visit to our hospital was 18.6 ± 19.7 months (range, 0-105 months). The mean follow-up period at the hospital was 19.0 ± 20.9 months (range, 1-103 months).

3
The amount of time spent using a smartphone per day was confirmed in 112 (65.5%) of 171 patients. Forty-three (38.4%) patients were female, and the mean age at onset was 16.0 ± 5.1 years (range, 2-28 years). Excessive use of smartphones was confirmed in 82 (73.2%) of the 112 patients. Among the remaining 30 patients, 9 patients used their smartphones for 3 h per day, 6 used their smartphones for. 2 hours, 4 used their smartphones for 1 h, and 11 did not use their smartphones.
A similar analysis in each year group subcategory showed significant increases over time in all groups except for patients aged < 5 years . We compared two age groups, elementary school students and below versus junior high school students and above, and found that the rate of increase was significantly higher in the junior high school students and above (estimate, 1.951; p < 0.0001) (Fig. 2).
Among the AACE types, only the Bielschowsky type showed a significant increase [Swan type

Discussion
AACE is a rare condition [9,10] and has been estimated to account for only 0.3% of childhood strabismus [7,10] in the absence of hyperopia or exogeneous causes such as a brain tumor [11,12] or total occlusion therapy [9,11]. The classification of three types of mechanisms underlying the onset of AACE proposed by Burian and Miller [6] has commonly been used. More recently, however, research has indicated that prolonged use of digital devices such as smartphones at closely near may be one cause of AACE, especially in adolescents [2,4]. In 2016, Lee et al. [2]. reported that the onset of AACE in 12 patients with an average age of 13.3 years (range, 7-16 years) was considered to be related to excessive use of smartphones because refraining from smartphone use decreased the degree of esodeviation in 9 of these patients.
In the present study, we retrospectively analyzed patients with AACE aged < 30 years who suddenly presented with diplopia or esotropia from 2008 to 2019 to determine whether the number of patients with AACE (especially younger patients) is increasing with the widespread use of digital devices such as smartphones. Because Ali et al. [13] reported that the mean age of eight patients with decompensated esotropia that caused by AACE was 29 years (range, 20-48 years), we analyzed patients aged ≤ 30 years to exclude those with decompensated esotropia. The purpose of this study was twofold: first, to determine the significance of the increase in patients with AACE, and second, to determine the relationship between excessive use of smartphones and the increase in patients with AACE.
We confirmed a significant increase in the number of patients with AACE over the 12-year study period. This study confirms that the number of patients with AACE, a growing research topic in recent years, has markedly Fig. 3 Yearly changes in number of patients with AACE by refractive error classification. The rate of increase was significantly higher in the myopia group than in the nonmyopia group (estimate, 1.951; p < 0.0001) Fig. 4 Yearly changes in number of patients with AACE by Bielschowsky type. The rate of increase was not significantly different between − 5.00 D or more and less than − 5.00 D among patients with Bielschowsky type (p = 0.8895) 1 3 increased. The peak age at onset in our study was 15 years. Iimori et al. [3] investigated patients with AACE aged 5 to 35 years from 2015 to 2018 and found a peak age at onset of 16 years, followed by 15 years, similar to the present study. The rate of increase in the number of patients with AACE was significantly different between elementary students and below and junior high school students and above, with the greatest increase in the number of patients with AACE in junior high school students (12-14 years), and the junior and senior high school students (12-17 years) accounting for about 60% of the cases.
In Japan, sales of smartphones started in 2008, and the penetration rate was about 10% in 2010; however, it steadily increased to 49.5% in 2012, 72.0% in 2015, and 83.4% in 2019. Digital devices such as smartphones have rapidly become widespread, especially among young people (Trends in Household Ownership of Information and Communication, Equipment, Ministry of Internal Affairs and Communications: https:// www. soumu. go. jp/ johot susin tokei/ white paper/ ja/ r02/ html/ nd252 120. html). The number of patients with AACE is increasing with the widespread use of digital devices such as smartphones [2,4]. The penetration rate of smartphones among 13-to 19-year-olds in Japan increased from just under 60.0% in 2013 to 79.5% in 2017; in comparison, the rate among 6-to 12-year-olds was only about 20.0% in 2013 and 30.3% in 2017 (https:// www. soumu. go. jp/ johot susin tokei/ white paper/ ja/ h30/ html/ nd142 110. html).
A relationship between AACE and myopia has been reported [14,15]. In the present study, the rate of increase in the number of patients with AACE was significantly higher among patients with than without myopia. In terms of the mechanism of AACE onset, Bielschowsky [14] indicated the involvement of uncorrected myopia because of the inability to maintain a balance between the converging and diverging forces of the eyes due to excessively close proximity to the targets. However, the 10 cases of adult-onset AACE described by Spierer [5] in 2003 did not fit into the previous types of AACE, and the common characteristics of these 10 patients were as follows: esotropia had developed after the age of 16 years, the angle of esodeviation was similar for distance and near, myopia was present in all but one patient, and normal stereopsis was regained after surgical correction of the esotropia. Our study also showed that 166 (96.9%) of the 171 patients had Bielschowsky type AACE, 69.3% of which were − 5.00 D or less, and we found no significant difference in the rate of increase in the number of patients with AACE between those with − 5.00 D or more and less than − 5.00 D.
Indeed, in this study, 61 (74.4%) of the 82 patients with AACE whose smartphone use time was confirmed had excessive smartphone use (≥ 4 h per day). In addition, in more recent years, the rate of increase in the number of patients with excessive smartphone use was significantly higher than that of patients without excessive smartphone use (p = 0.0009). Furthermore, remission of entropion was observed in four patients by refraining from using smartphones, suggesting a relationship between excessive smartphone use and the development of AACE, as reported by Lee et al. [2].
Lee et al. [2]. speculated that the excessive use of smartphones at near may overstimulate accommodation and vergence, causing the medial rectus (MR) muscle to become dominant; this in turn may result in low fusional divergence ability and latent esophoria, resulting in the development of manifest esotropia. Our study included an 18-year-old patient who developed AACE after watching Fig. 5 Yearly changes in number of patients with AACE according to excessive smartphone use. Multiple regression analysis showed a significantly higher annual increase in patients with than without excessive smartphone use (estimate, 1.098; p = 0.0009) three-dimensional attractions. We consider that out-ofthe-ordinary dichoptic viewing, such as three-dimensional attractions, triggers vergence-accommodation conflict, and a large parallax stimulus becomes a convergence stimulus that exceeds relative convergence, resulting in not only disruption of fusion but also disruption of vergenceaccommodation regulation. Therefore, the imbalance among vergence, accommodation, and convergence due to excessive use of smartphones at near may be involved in the onset of AACE rather than refractive error, even if uncorrected myopia is involved [3,13].
Cai et al. [15]. first reported that the distance of the MR insertion from the limbus was shorter in patients with AACE than in patients with exotropia. It is assumed that the shorter distance of MR insertion may lead to strengthening of convergence tonus, resulting in an imbalance between convergence and divergence and subsequent esotropia. However, Lai et al. [16]. and Niyaz et al. [17] indicated that the distance of the MR insertion from the limbus was not significantly different among patients with esotropia, patients with exotropia, and control patients. Therefore, whether the shorter distance of the MR from the limbus is characteristically recognized only in patients with AACE needs to be examined in a larger population. Nevertheless, it is considered to be a possible predisposing factor for AACE.
This study has some limitations. First, because of the single-center and retrospective nature of our study, the data were limited to what was available in the patients' records and the small proportions. We excluded patients with decompensated esotropia to focus only on patients with acquired and acute-onset diplopia or esotropia without a congenital element. Second, the duration of smartphone use per day was not confirmed for all patients. In addition, we were unable to confirm whether the distance was extremely close or not during use of the smartphones. Looking at smartphones at extremely close distances may be a risk factor for onset of AACE.
Vagge et al. [18]. described four patients with AACE who presented during the national lockdown due to COVID-19 in Italy. All patients spent 8 to 10 h a day using computers, tablets, and smartphones to play, access school lessons, and navigate social networks. The prolonged school closures and home confinement during the COVID-19 lockdown period resulted in important lifestyle behavioral changes, such as a significant increase in screen time [19], highlighting the risk of an increased myopia burden due to these new lifestyle habits [20]. However, it also indicates that excessive application of near vision might have other detrimental consequences, including the onset of AACE. This study was not affected by COVID-19 because it reviewed patients with AACE from 2008 to 2019. The transition of patients with AACE after 2020 should be noted in future research.
In Japan, multicenter research on AACE began in 2018, and we expect that much information on the relationship between digital devices and the onset of AACE will soon become available.

Declarations
Ethical approval This study was approved by the institutional review board of Hyogo College of Medicine Hospital and was conducted in accordance with the tenets of the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent Informed consent was obtained from all individual participants included in the study.

Conflicts of interest
The authors declare that they have no conflict of interest.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.