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Convergence excess consecutive esotropia associated with 0.01% atropine eye drops usage in patients operated for intermittent exotropia

To report convergence excess esotropia (CEET) following 0.01% atropine eye drops (Low dose atropine [LDA]). Children who developed CEET that resolved promptly after discontinuation of LDA are described. Three myopes aged 5.3 ± 1.2 years and mean sphere -4.5D were included. All were operated for intermittent exotropia earlier. Mean esotropia was +28.3PD for near and 10.6PD for distance. LDA induced high AC/A ratio and fusion normalized in 3 weeks after discontinuation of LDA. LDA should be used with caution in patients with esophoria or previously operated for intermittent exotropia. Any evidence of the emergence of a CEET should warrant discontinuation of LDA.

According to recent studies, 0.01% atropine eye drop (LDA) has become popular first-line treatment for progressive childhood myopia. [1,2] In spite of +3D to +6D decrease in accommodation with LDA, hypoaccommoadtion is seldom of any clinical concern. [3,4] In this study, we present hitherto unreported complication of LDA induced convergence excess esotropia (CEET) due to hypoaccommodation following its application once at night. The esotropia promptly normalized and the fusion was restored in all the children after discontinuation of LDA.

Case Reports
Patient 1: A 6-year-old boy, who underwent bilateral lateral rectus recession of 7.5 mm and inferior oblique weakening for basic type intermittent exotropia with V-pattern, a year prior to starting LDA, developed CEET following its use. His esotropia measured +18PD for distance and +35 PD for near that reduced to +14PD esophoria for distance and +16 PD esophoria for near after discontinuing LDA [ Fig. 1 and Table 1]. Peripheral fusion was found to be restored on Bagolini striated glasses. Prior to the use of LDA, he had orthotropia for the near, flick esotropia (+4PD) for the far, and peripheral fusion was present.
Patient 2: A 6-year-old girl, already on LDA, underwent bilateral lateral rectus recession of 7 mm for intermittent exotropia with tenacious proximal fusion. She was orthotropic for near and +8PD esotropic for distance postoperatively. The LDA was discontinued on the day of surgery and resumed 2 weeks post-surgery; post 1 month of following she developed +2PD esotropia for distance and +25PD for near that recovered to orthotropia after its discontinuation [ Fig. 2 and Table 1]. Her fusion was also restored.
Patient 3: A 4-year-old girl using LDA for 3 months, underwent left eye lateral rectus recession of 7.5 mm and medial rectus resection of 5 mm with bilateral inferior oblique weakening for basic type intermittent exotropia with V-pattern. Postoperatively she had orthotropia for distance and +4PD esotropia for near. She resumed LDA 2 weeks after surgery. One month later, she developed +12PD esotropia for distance and +25PD esotropia for near. Three weeks after stopping LDA, her near esotropia was reduced to +12PD [ Fig. 3] and peripheral fusion was restored. This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.  Accommodation improved in patient 1 and patient 2 after stopping LDA [ Table 2]. However, binocular and monocular accommodative functions could not be measured in patient 3.

Discussion
A modest reduction in accommodation in children using LDA is common and generally well tolerated. [2][3][4][5][6] However, the accommodative abnormalities induced due to long-term use of LDA may affect accommodation and convergence relationship resulting in CEET in children, especially with pre-existing fusional anomalies.
In our study, bedtime instillation of LDA in the patients, who were monofixators postoperatively, resulted in hypoaccommodation induced excessive innervational drive to accommodate, leading to manifest esotropia with an increased AC/A ratio causing decompensation of their tenuous fusion. Similarly, a previous study by Lyu, et al. [7] reported a median increase of +10PD in 38% of children with pre-existing esodeviation under the effect of partial cycloplegia using 0.5% tropicamide and 0.5% phenylephrine. A maximum increase of +25PD was reported which recovered after the effect of cycloplegia subsided. A similar phenomenon (CEET) was observed with the use of systemic anticholinergics viz. scopolamine patch for sialorrhoea in cerebral palsy, [8] amitriptyline and oxybutynin for nocturnal enuresis, [9][10][11] and haloperidol and benzatropine mesylate for Tourette syndrome. [12] The AC/A ratio is believed to be inborn and remains constant throughout life but varies greatly amongst individuals. [13] Cycloplegic agents interfere with accommodation but if it is retained due to incomplete cycloplegia, it induces a reflex convergence by excessive innervational accommodative effort, thus increasing esodeviation. [14] Conversely, if cycloplegia is complete and present for an extended duration, accommodative efforts are suspended causing complete abolition of an accommodative component of esotropia. This is typically seen with the use of 1% atropine drops in patients with fully refractive accommodative esotropia [ Fig. 5]. [15] Some factors that were common in all our patients and previous studies were 1) pre-existing esophoria and 2) prompt reduction in esotropia after discontinuation of the drops. Although two patients in our study were left with significant esotropia, future follow-ups may show a further reduction of esotropia provided their LDA is stopped. Inability to recognize this side effect of LDA could cause permanent contracture of medial rectus leading to incomplete resolution of esotropia despite its discontinuation. Such a phenomenon is often reported in presbyopes, which could happen due to defects in vergence adaptation (neurologic) or muscle length adaptation (anatomic). [16] Because the children were young, no forced duction test (FDT) was performed on medial rectus. Inference of a positive FDT is that the long-term use of LDA caused muscle length adaptation (medial rectus shortening) in response to increased accommodative effort induced convergence excess.
Although none of our patients had convergence excess type of intermittent exotropia preoperatively, it is advisable to discontinue LDA in such patients scheduled for squint surgery.
The last point of contention is possible therapeutic use of LDA for patients with low AC/A ratio viz. convergence insufficiency. Similar to once used cholinergic agents viz echothiopate, carbachol, and isfoflurophate for convergence excess esotropia, it is possible that LDA may improve AC/A ratio in patients with convergence insufficiency. This question is best left for future research.
To summarize, LDA should be used cautiously and after a detailed discussion with the parents regarding it's off label use for retardation of myopia progression more so in the patients having pre-existing fusional anomalies (or other ocular comorbidity). Any evidence of the development of a CEET or any other side effect should warrant immediate discontinuation of LDA. Further research is needed to determine whether bifocal glasses or progressive addition lenses with LDA or switching to 1% atropine eye drops could prevent a recurrence of CEET while retaining the therapeutic benefits of atropine. [17,18]

Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients  understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship
Nil.

Conflicts of interest
There are no conflicts of interest.
Myopia is one of the commonest causes of visual impairment worldwide. The global prevalence of myopia is on a rise. A study conducted at our center has shown the prevalence of myopia to be 13.1% in urban school children in Delhi. [1] Not only does it translate to a huge economic and social burden but also predisposes the affected individuals to a host of sight-threatening conditions such as retinal detachment, choroidal neovascularization, myopic maculopathy, and amblyopia. Due to the magnitude of the prevalence of myopia, it has become an important public health issue. A lot of scientific work is being done on myopia to provide more insight into its etiopathogenesis and treatment. [2] A number of environmental as well hereditary factors have been found to be associated with this disease entity. In the Asian populations, this epidemic in a way seems to be a result of rapid education revolution and increased near work like reading.
Most infants are hyperopes. A fast phase of emmetropisation occurs from age 3 to 12 months which is followed by a slow phase which lasts up to the age of 5 years. [3] During this process, the axial length gets adjusted to the optical nature of the cornea and the lens. Myopia can be attributed to the overshooting of this process of emmetropisation. The corrective treatment options for myopia involve use of spectacles, contact lenses, and various refractive procedures. However, in order to target this significant public health problem, various measures are being studied to stop and thwart myopia progression. One of the most important areas under study is the use of atropine eye drops to slow down progression. Till date, atropine and pirenzepine are the only pharmaceutical agents that have shown consistent efficacy in this regard. [2] Other treatments modalities include orthokeratology and soft contact lenses with peripheral defocus modifying designs. [4] However, these are inconvenient to use and have unwanted side effects. The mechanism through which atropine stops myopia progression is not clearly understood. An up and down regulation of retinal and scleral muscarinic receptors has been postulated as possible mechanism. Some studies also contribute the direct influence of atropine on the scleral fibroblast as a possible apparatus to myopia curbing effect. Low-dose atropine (0.01%) has emerged as an effective approach, as proven by Atropine in the Treatment of Myopia studies (ATOM1 and ATOM2). [5] Although ATOM studied Asian patients, involving other populations have been conducted as well and have supported the use of atropine.
Low-dose atropine has very less impact on accommodation, and near vision and pupil size. Most patients receiving low-dose atropine do not require bifocals or sunglasses. Systemic side effects appear to be rare with 0.01% atropine use. Serious anticholinergic side effects such as tachycardia, altered mental status, dry mouth, urinary retention, constipation, and