A randomized trial evaluating efficacy of overminus lenses combined with prism in the children with intermittent exotropia

Background To evaluate the efficacy of overminus lenses combined with prism spectacles in children of 3 to 6 years of age with intermittent exotropia (IXT). Methods Sixty patients with IXT were randomly assigned to the treatment and observation groups. Each group included 30 IXT children aged 3 to 6 years. The treatment group was prescribed overminus lenses of − 2.50 D incorporated with the 2 PD base-in prisms on each side. Ocular alignment, the status of binocular vision, as well as the refraction changes were carried out and followed at 1, 3, 6, and 12 months. A revised form of the Newcastle Control Score (NCS) was used to evaluate the patients’ ability to control their IXT. Results After 12 months, the mean refractive error was 1.42 ± 1.25 D, and 1.43 ± 1.12 D for the observation and the treatment group, respectively (95% CI: − 0.61 to 0.62)); the mean exotropia control score was 5.72 ± 1.28 and 1.75 ± 1.18 in the observation and the treatment group, respectively (95% CI: − 4.63 to − 3.33); the mean near stereoacuity was 2.16 ± 0.42 log arcsec and 1.91 ± 0.26 log arcsec in the observation and the treatment group, respectively (95% CI: − 0.44 to − 0.06). Conclusions In our randomized clinical trial, overminus spectacles with prism significantly improved the control of IXT and stereopsis, by reducing the angle of strabismus in children with IXT. This treatment does not appear to cause myopia, at least in the manner used this series. A further randomized trial is warranted to assess the effect of overminus spectacles with prism after the treatment has been discontinued. Trial registration This study adheres to CONSORT 2010 guidelines. Chinese Clinical Trial Registry, ChiCTR1900025243. Registered 17 August 2019.


Background
Intermittent exotropia (IXT) is a very common form of childhood strabismus, occurring in approximately 0.5 to 1% of the general population [1,2]. It accounts for approximately 25% of pediatric strabismus in Caucasians and that of 44.9% in Chinese children [3]. Early onset of IXT, within the age of 2 to 5 years, is common, but it may also present shortly after birth [4]. Patients with IXT are characterized by an intermittent outward deviation of one or both eyes when fixating on a target at a distance or when fatigued. Surgery is considered to be an effective method for the correction of exotropia and restoration of binocular vision. However, there are some arguments regarding the optimal surgical timing for children. Overminus lenses, as an alternative non-surgical intervention treatment, are often used for children.
Studies suggest that overminus therapy stimulates accommodative convergence and helps reduce the angle of exodeviation [5,6]. Another hypothesis is that the fusional convergence is exerted to control the exodeviation, inducing convergence accommodation and distance blur, and that overminus lenses may allow clear distance vision, facilitating fusion [7]. Prism has also been used to treat IXT as it maintains fusion, alleviates symptoms, and reinforces binocular functions, both alone and in conjunction with orthoptic exercises [8,9]. Previous studies of IXT conservative therapy were mainly focused on overminus lenses, it appear to be well controlled in the regular refractive correction. Nevertheless, these studies have been limited to retrospective case series without comparison groups and few studies reported the outcomes of overminus lenses combined with prism. Therefore, in this study, we evaluated the efficacy of overminus lenses combined with prism for children aged 3 to 6 years.

Methods
Sixty patients with IXT were recruited for this study. The inclusion criteria were as follows: (1) Exodeviation angle was more than 15 prism diopters (PD) at a distance measured by prism and alternate cover test (PACT); (2) The difference was within 10 PD between the near and distance deviations; (3) The spherical equivalent (SE) ranged from + 0.50 to + 5.00 D; (4) The Newcastle Control Score (NCS) was ≥3. Patients with neurological disorders who could not cooperate well for ocular examinations, oblique muscle overaction, disassociated vertical deviation or vertical deviations > 5 PD, anisometropia > 2 D, and follow-up time < 12 months, were excluded.
The treatment group was prescribed with overminus lenses of − 2.50 D incorporated with base-in prisms of 2 PDs on each side after cycloplegic refraction. The observation group was supposed to wear spectacles if refractive error met any of the following criteria: SE anisometropia ≥1.00 D; astigmatism ≥1.00 D in either eye; and SE hyperopia ≥ + 1.00 D [10]. The others who did not need refractive correction were prescribed plano lens spectacles that were to be worn at each follow-up visit but were not to be worn in the interim.
Ocular alignment, status of the binocular vision, and refractive changes were evaluated regularly for each patient at 1 month, 3 months, 6 months, and 12 months. Distance visual acuity (VA) was measured using the Amblyopia Treatment Study HOTV testing protocol and near VA testing using the Amblyopia Treatment Study 4 test (Precision Vision, La Salle, IL). The NCS incorporates subjective (home control) and objective (clinic control at near and in the distance) criteria ( Table 1). The home control section asks the parent/guardian to rate the frequency with which the strabismus is noticed to be present, while the clinic components rate the ease with which binocular single vision is regained after a cover test. The exodeviation angle was measured with PACT at both 6 m and 33 cm using an accommodative target. Stereoacuity was assessed using the Randot Preschool Stereoacuity test (Stereo Optical Co., Inc., Chicago, IL) at 40 cm. All patients were assessed by the same studycertifified masked examiner (a pediatric ophthalmologist) at primary and 1-, 3-, 6-, and 12-month outcomes in all cases.

Data analysis
The sample size was 55 participants using a 1-sided test with alpha = 0.05, assuming 10% loss to follow up. A priori the study had 80% power to detect a treatment group difference in mean 12-month near stereoacuity, assuming a true difference of − 0.25 points or larger (Overminus and prism minus observation) with a standard deviation of 0.50 (based on prior studies). A 1-sided hypothesis test using alpha = 0.05 was used to determine whether the overminus and prism group had better 12- Table 1 The Revised Newcastle Control Score The scale below applies to both distance and near separately.

Home control Score
XT or monocular eye closure seen never 0 < 50% of time fixing at distance 1 > 50% of time fixing at distance 2 > 50% of time fixing at distance + seen at near 3

Clinical control
Near Immediate realignment after dissociation 0 Realignment with aid of blinking or re-fixation 1 Remains manifest after dissociation or prolonged fixation 2

Manifest spontaneously 3
Distance Immediate realignment after dissociation 0 Realignment with aid of blinking or re-fixation 1 Remains manifest after dissociation or prolonged fixation 2

Manifest spontaneously 3
Total NCS = home + near+ distance. month mean near stereoacuity than the observation group in this pilot study. Outcome variables were tested for departures from a normal distribution with the Shapiro-Wilk test. If significant departures were found, appropriate nonparametric tests were also used to assess for a treatment effect. Statistical analysis was performed to compare the differences between the treatment and observation groups in terms of refractive changes, control of IXT, exodeviation, and stereoacuity (converted from seconds of arc to log arcsec values). The comparison of the treatment and observation groups was performed using an analysis of covariance (ANCOVA) model that was adjusted for baseline control, baseline refractive error, baseline stereoacuity, baseline distance, and near PACT. The parameters before and after the treatment were compared using parametric (paired ttest) analysis. All statistical analyses were performed using SPSS 20.0 (SPSS Inc., Chicago, IL, USA). A p value < 0.05 was accepted as significant.

Baseline characteristics
Sixty Asian patients with IXT were recruited for this study during 2019-2020, 30 of which received the overminus lenses combined with prism treatment and 30 were under observation. The average patient age was 4.75 ± 1.03 years; 28 (46.7%) were female, and 32 (53.3%) were male. The baseline clinical characteristics are shown in Table 2.

Visit completion
The 1-month and 3-month visits were completed by all 60 patients, and 29 patients (96.7%) and 30 patients (100%) in the treatment and observation groups, respectively, completed the 6-month visit. Twenty-eight of 30 (93.3%) and 30 (96.7%) patients in the treatment and observation groups, respectively, completed the 12-month visit.

Analysis of the baseline and final follow-up measurements between the treatment and observation groups
The mean refractive error, exotropia control, deviation magnitude by the PACT, and near stereoacuity for the participants who completed the 1-, 3-, 6-, and 12-month visits are listed in

Discussion
The management of IXT is unlike other types of childhood onset strabismus as the timing and method of intervention are controversial. Many studies have advocated for a delayed management because it may help in avoiding a higher overcorrection rate and poor sensory outcomes caused by early surgery while also allowing for more accurate measurements and better results [11,12]. It has been suggested that surgical outcomes of IXT are optimized if combined with non-surgical treatment, which may be more effective in preschool children.
Hence, conservative options have been deemed useful in this "delay" period. The use of prisms has been primarily focused on preor postsurgical applications to facilitate binocular sensory fusion, but there are few studies on its management of IXT. In our study, we prescribed 2 D base-in prism spectacles OU instead of base-out prism because the base-out prism would be used as an "exercise" for fusional convergence, which might seem useful for the treatment of exotropia. However, the base-out prism, in effect, increases the size of the deviation and thus, makes fusion more difficult. It may not only be useful for dedicated exercise sessions but also result in frequent manifestation of the deviation. The prescribed base-in prisms (relieving or demand-reducing prisms) could neutralize a certain amount of exodeviation, reducing the "demand" on fusional vergence and making its control easier. Additionally, reduced deviation allows sensory fusion even while the visual axes remain diverted (neutralizing prisms). Both of these approaches are intended to partially compensate for an exodeviation in an effort to attain a continuous binocular sensory fusion. Overminus lenses were often used alone in previous studies [13][14][15][16]; their prescription ranged from 0.50 D to 5.00 D considering the children's adaptability and the risk of myopia caused by overcorrection [15,17,18]. In our clinical trial, we chose −2.50 D incorporated with the 2 PD base-in prisms as the initial power of overminus lenses, as it allowed the children to adapt to the lenses to maintain a constant accommodative demand and clear visual quality. We calculated that 4 D of the base-in prism could provide as many accommodative convergence benefits as would 1 D of additional overminus, assuming a normal accommodative convergence to accommodation ratio. Thus, − 2.5 D of overminus with 4 D of base-in prism could achieve the same effect as that of 3.5 D of overminus; this is theoretically less likely to cause asthenopia, especially at near work.
It has been reported that the accommodative efforts of overminus lenses may induce myopia or enhance myopic progression [19]. Some studies have suggested that myopic patients overminused for exotropia became more myopic, and demonstrated that the shift toward myopia is greater in initially myopic than in hyperopic children [20][21][22]. Considering these hypotheses, we chose children with hyperopia as subjects. After 12 months of follow-up, 92% of the patients had no change in their refractive error, 5% of the children had a small decrease, which was less than + 0.5 D. The refractive error was not significantly different between the treatment and observation groups, and before and after treatment in the treatment group. In fact, previous studies on children with intermittent exotropia have suggested that overminus lenses treatment does not cause myopic progression [5,14]. Our research further provided evidence that overminus lenses combined with prism do not cause myopia, at least in the manner used in this series at 12 months follow-up.
In previous studies, overminus treatment significantly improved exotropic control [13][14][15][16]. Watts et al. reported that patients with a baseline NCS of ≤4 showed a slightly better exotropic control (75%) compared to patients with a baseline NCS of ≥5 (62.5%) [16]. In our study, we found that 28 of 30 (93.3%) and 20 of 28 (75.4%) patients with a baseline NCS ≥4, showed an NCS ≤ 3 or less after 12-month follow-up in the treatment group, which suggests a significant improvement. Therefore, we consider that even in patients with high NCS, overminus and prism lenses may be an effective method for improving the control of exotropia.  Most studies on overminus focused on the changes in refractive error, magnitude of the exodeviation, and control score, but there were few assessments of binocular visual function. However, it is intuitive to consider that better stereopsis must be associated with good control of IXT and a smaller angle of deviation. In our study, we evaluated exodeviation and stereoacuity in the treatment and observation groups as well as self-control in the treatment group. The decrease in exodeviation is significant, which may be attributed to the overminus and neutral prism. Caltrider and Jampolsky [23] reported that 26% of 35 subjects (aged 2 to 13 years) had a decrease of at least 15PD of exodeviation when wearing overminus lenses (2.00. 4.00 D). In our study, the deviation angle was 25.13 ± 6.84PD and 16.25 ± 7.03PD before and after treatment, respectively (p < 0.001). The near stereoacuity in the treatment group was 1.91 ± 0.26 log arcsec versus 2.16 ± 0.42 log arcsec in the observation group at 12 months (95% CI: − 0.25 (− 0.44 to − 0.06)). The improvement of near stereoacuity was also observed in the treatment group (p < 0.001). Thus, we think that an overminus-lens combined with prism can reduce the angle of deviation and improve the quality of fusion, and increase binocular visual function.
There are a number of limitations to our study. We only chose children with hyperopia as subjects and did not include the effects of overminus lens and prism in myopic patients. A further randomized clinical trial needs to be conducted. We used the Newcastle Control Score to evaluate exotropia control, which incorporates parental observations of the deviation, which may have an influence on management decisions. This is a clinical study involving patients aged 3 years; therefore, there are limitations in patients' response to cooperative testing.

Conclusions
The overminus lenses combined with prism may be a safe initial therapy in children aged 3 to 6 years with IXT. The results show better control of IXT and improved stereoacuity in the treatment cohort, relative to the observational cohort. A further randomized trial is warranted to assess the effect of overminus spectacles with prism after the treatment has been discontinued.