Short-Term Vision-Related Ocular Side Effects of Treatment with Dexmethylphenidate for Attention-Deficit/Hyperactivity Disorder

Abstract

Objective:

To evaluate the short-term effect of dexmethylphenidate (D-MPH) on visual acuity (VA), pupil size, anterior chamber depth, and accommodation-convergence reflex in children treated with D-MPH for attention-deficit/hyperactivity disorder (ADHD).

Method:

Prospective cohort study including 15 patients aged 8–16 (11.58 ± 2.39) treated with D-MPH for ADHD. Patients were questioned for subjective complaints such as blurred vision and photosensitivity. An ophthalmic evaluation was performed twice; before and 1.5 hours after D-MPH administration. The examination included evaluation of best corrected visual acuity at distance and near, accommodation range, convergence range, 3D vision test (stereopsis), and anterior segment optical coherence tomography.

Results:

A significant association between change in pupil diameter and D-MPH treatment dose was demonstrated (p = 0.01). In addition, a positive correlation between complaints about blurred vision and pupil's size change was found (p < 0.05). There were no significant changes in VA, convergence range, stereopsis, accommodation range, or anterior chamber measures.

Conclusions:

Our findings provide support for the effect of stimulants on pupil diameter in a dose-dependent manner. No clinically significant differences in visual functions were found 1.5 hours after consumption of D-MPH. Institutional review board clinical trial refference no. 0122-17-TLV.

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder in childhood with a worldwide estimated prevalence of 3.4%–7.2% in children aged 4–18 years (Polanczyk et al, 2015; Thomas et al, 2015). ADHD impacts children, adolescents, and adults in all areas of life, including academic performance, extracurricular activities, and social interactions. The updated guidelines recommend a multidisciplinary treatment that combines parents' and educational team guidance, educational intervention, and pharmacological therapy (Wolraich et al, 2019).

The imbalance of the neurotransmitters norepinephrine (NE) and dopamine (DA) in the prefrontal cortex (PFC) is believed to be the basis of this neurobehavioral problem (Sharma and Couture, 2014). Stimulants, which inhibit the reuptake of DA and NE in the presynaptic area, are the medications of choice for treating ADHD for >60 years. About 75%–80% of children with ADHD will benefit from the use of psychostimulants (Briars and Todd, 2016; Liu et al, 2006).

Methylphenidate (MPH) is the most widely used psychostimulant as a first-line treatment for ADHD. MPH exerts its action on both DA (through DAT-1-DA transporter) and norepinephrine transporters and, thus, increases DA and norepinephrine levels in the PFC (Markowitz et al, 2003).

Dexmethylphenidate (D-MPH) is a relatively new isomeric form of MPH. It comprises only the d-enantiomer (the pharmacologically effective isomer) of racemic MPH. D-MPH also acts through the inhibition of the reuptake of norepinephrine and DA. It was developed to reduce drug load, adverse events, and drug interactions. D-MPH provides effective management of ADHD at half the dose of MPH (Novartis/Celgene, 2002).

D-MPH is a short-acting medication with an effect of 3–5 hours, whereas D-MPH extended-release (D-MPH XR) is a long-acting medication with an effect of 6–8 hours, with a bimodal absorption system that mimics a twice-daily administration (Novartis, 2005). The time to the first concentration peak (t _max1) with D-MPH XR is 1.5 hours (typical range 1–4 hours). After first-pass metabolism, the mean absolute bioavailability of D-MPH in the serum is 22%–25%, and 24 hours after administrating the drug, the plasma concentration was shown to be undetectable (Novartis/Celgene, 2002).

MPH and D-MPH share adverse reactions, including decreased appetite, stomach pain, weight loss, sleep disturbance, and headache (Novartis, 2005; Novartis, 1955). Ocular side effects of MPH are blurred vision and dry eyes, with less frequent reports of diplopia and mydriasis (Jaanus, 1992). Grönlund et al (2007) described the visual function and ocular features of children treated with MPH or amphetamines for ADHD by comparing vision-related functions before and during treatment. They concluded that children with ADHD tend to have a higher frequency of ophthalmological findings such as heterophoria, subnormal stereovision, and abnormal convergence. Remarkably, these abnormalities did not significantly change with stimulants administration (Grönlund et al, 2007). Parameters such as pupil diameter and anterior chamber depth (ACD) were not part of this study scope.

Focusing on near objects is achieved by the ability of the eye to execute three oculomotor responses: miosis, accommodation, and convergence, known as the accommodation reflex or the near response triad. These acts are controlled by the autonomic parasympathetic nervous system both centrally and peripherally. By increasing norepinephrine concentration in the synaptic cleft, stimulants may increase sympathetic tone and affect pupillary near response and pupillary light reflex. Increment of the sympathetic innervation may result in inhibition of the parasympathetic efferent innervation by the Edinger–Westphal nuclei through α₂-adrenergic receptor activation, leading to relaxation of the iris sphincter muscle. In addition to central control, the iris dilator muscle contracts directly by activating α₁-adrenergic receptors with norepinephrine (Gabay et al, 2011; Hall and Chilcott, 2018; Joshi et al, 2016; McDougal and Gamlin, 2015; Spiers and Calne, 1969; Yoshitomi and Ito, 1986).

Although never investigated, there are reports of dilated pupils, blurred vision, and light sensitivity associated with D-MPH treatment in parents' web forums (Anonymous, 2017).

To the best of our knowledge, those side effects of D-MPH have not been investigated previously. The purpose of our study was to investigate whether D-MPH treatment in children with ADHD leads to changes in subjective visual functions, including visual acuity (VA), stereoacuity, accommodation, and convergence, as well as objective measurements within the ocular anterior segment.

Methods

Subjects and methods

All children aged 6–18 years who were diagnosed with ADHD according to the Diagnostic and Statistical Manual for Mental Disorder (DSM-V) by an experienced pediatric neurologist and who were treated with D-MPH XR between July 2017 and February 2019 were offered to participate in this prospective pilot study.

The study protocol was reviewed and approved by the Ethics Committees of the participating medical center in compliance with the Declaration of Helsinki. Written informed consent was obtained from all patients' parents before enrollment in the study.

Exclusion criteria included any neurodevelopmental disturbance other than ADHD/attention-deficit disorder and any current or past ophthalmological disorder or surgery other than simple refractive error, including glaucoma, strabismus, cataract, amblyopia, and VA lower than 20/30 in one eye.

All encounters were scheduled for 8:00 AM. Patients and their parents filled out a structured questionnaire that included questions regarding gender, age, duration of ADHD diagnosis, and dosage and duration of D-MPH XR use. Patients were asked to report if they noticed any phenomena such as blurred vision or dazzling during the treatment period with D-MPH. Body mass index (BMI) was calculated after weight and height measurements. Ophthalmological examination was performed by an experienced pediatric ophthalmologist in all cases and included distance and near-best corrected visual acuity for each eye separately.

Distance vision was measured using a computerized vision testing system (M&S Technologies^®); Near vision was measured using a Jaeger eye chart card. Convergence range was evaluated by the Prism Vergence Test as described by Wesson: in short, the patient is watching a target that is presented 40 cm from him while the examiner is moving a base out prism bar in front of one of the patient's eyes, increasing gradually the convergence effort. When the patient cannot convert enough and sees double, the breakpoint (BP) is documented. Then, the prism is moved back until the patient recovers his convergence and sees again one object, and a recovery point (RP) is documented (Wesson, 1982).

The accommodation was evaluated by a subjective pull-away method: an accommodative target (letter) is slowly moved away from the child's eye until blurring dissolves and the letter can be read. The distance between the eye and the clearing point is then used to calculate the accommodation power of the eye. Each eye was measured separately (Woehrle et al, 1997). Stereoacuity was evaluated by the Randot^© test. Anterior segment optical coherence tomography (OCT) image (Visante^© scanner; Carl Zeiss Meditec, Inc.) was taken for each eye to measure pupil diameter, corneal thickness, and ACD (Fig. 1). After completing those examinations, patients were asked to take their usual daily dose of D-MPH and return after 90 minutes. The second examination was the same as the first one.

FIG. 1.

Imaging of the anterior chamber with Visante Anterior Chamber OCT (Carl Zeiss Meditec©). (a) Pupil diameter was measured as the distance between iris inner borders. (b) Anterior chamber depth was measured as the distance, perpendicular to the angle-to-angle line, between the middle of the pupil and the inner edge of the corneal layer. OCT, optical coherence tomography.

All OCT scans were conducted in identical environmental conditions before and after D-MPH ingestion. A regular fluorescent lamp was turned on, and the room had no windows. Pupil's diameter, ACD, and central corneal thickness (CCT) was calculated after analyzing the scan using Visante™ OCT software (version 3.0.1.8) as previously described by Güell et al (2007). Scan output is demonstrated in Figure 2. All scans were analyzed by one of the authors.

FIG. 2.

Correlation between D-MPH dosage and change in pupil diameter. Kruskal–Wallis H test analysis of pupil diameter change per dosage group of D-MPH treatment, 10 mg (low), 10–20 (moderate), and 25–30 (high). Data are presented as mean ± SD and ANOVA analysis parameters presented hereunder. ANOVA, analysis of variance; D-MPH, dexmethylphenidate; SD, standard deviation.

Statistical analysis

Data were analyzed using Statistical Package for the Social Sciences software version 25 (SPSS, Inc., Chicago, IL, USA). Monocular data such as VA, accommodation, pupil diameter, and ACD were recorded separately for each eye. As systemic drugs can lead to inter-eye correlation, we used the average measurement of both eyes of each participant (N = 15). Binocular functions such as convergence and stereoacuity were recorded for each patient (N = 15). Continuous variables are described as means ± standard deviations (SDs).

The paired T-test was used to compare the means between two continuous variables that had a normal distribution. Kruskal–Wallis H test (one-way analysis of variance [ANOVA] of ranks) was used to test for differences between subgroups of independent variables (i.e., dosage level). The Wilcoxon signed-rank test was used to compare averages of interval variables or those that are not normally distributed according to the Shapiro–Wilk test of Normality. To examine possible correlations between the dependent and independent variables, and between dependent variables, we used Spearman's rank correlation coefficient. For the entire statistical analysis, statistical significance was defined by an α (alpha) error <0.05.

Results

Fifteen children (11 males, 73.3%) aged 8–16 years (mean = 11.58 ± 2.39 years) were included. One child did not complete the second OCT examination as they mistakenly left the clinic immediately after the clinical examination; therefore, his data from the first OCT were disregarded. Two more children left the clinic before their height and weight were taken. The mean BMI was 18.93 ± 4.56 kg/m² (n = 13). The average BMI of the boys was 17.85 ± 3.05 kg/m², and of the girls was 22.5 ± 6.26 kg/m². The duration of D-MPH use was between 1 month and 4 years (mean = 1.26 ± 1.18 years), and the doses were 10–30 mg/day (mean = 19 ± 8.13 mg). Six out of 15 (40%) examinees reported blurred vision and increased sensitivity to light in both eyes after the use of D-MPH. Table 1 summarizes the study population characteristics.

Table 1.

Patients' Characteristics

Variable	N	M	SD
Age	15	11.58	2.39
Gender (M/F)	11/4	—	—
BMI	13	18.93	4.56
D-MPH usage period (years)	15	1.36	1.19
D-MPH dosage (mg)	15	19	8.13
ADHD diagnosis period (years)	15	3.41	1.985
Report of blurred vision (did not report)	15	6 (9)	—
Reported photophobia (did not report)	15	6 (9)	—

ADHD, attention-deficit/hyperactivity disorder; BMI, body mass index; D-MPH, dexmethylphenidate; M, mean; N, number; SD, standard deviation.

Table 2 includes the results of the subjective visual functions of all participants before and after the administration of D-MPH.

Table 2.

Means and Differences of Subjective Examined Variables Before and 1.5 Hours After Taking the Daily Regular Dose of Dexmethylphenidate

Ocular parameter	Before D-MPH			1.5 Hours after D-MPH			Difference
Ocular parameter	N	Mean	SD	N	Mean	SD	Δ^a	SD	p
Accommodation	15	12.74	4.50	15	11.82	3.09	−0.916	3.32	0.440
Convergence break point	15	29.66	8.965	15	30.2	10.044	0.533	8.262	0.837
Convergence recovery	15	22.80	10.379	15	23.2	12.054	−0.071	10.535	0.767
Breakpoint − recovery difference	15	6.86	4.533	15	10	4.225	1.333	14.227	0.811
Stereopsis	15	41.93	19.815	15	36.13	16.986	−5.800	16.50	0.160

p-Value represents significance of Wilcoxon rank sum test.

Δ, Delta = [mean of measurements after D-MPH treatment] − [mean of measurements before D-MPH treatment].

D-MPH, dexmethylphenidate; SD, standard deviation.

No significant change in distance or near VA was observed [distance VA: Wilcoxon test (p = 0.157), near VA: no difference of means before and after treatment].

There was no statistically significant difference in accommodation as evaluated by the Wilcoxon test (p = 0.440). Convergence was estimated by three components: BP, RP, and the difference between the two points. There were no differences in all examined components between the two tests. No correlation was found between convergence parameters and other independent variables. Stratification by gender or D-MPH dosage did not yield a significant change in convergence.

The stereoacuity examination demonstrated a mean improvement of 5.8 ± 16.5 seconds of arc (p = 0.160). The result did not change after stratification by gender or dosage.

OCT-derived data including pupil diameter and ACD are summarized in Table 3.

Table 3.

Means and Differences of Subjective Examined Variables Before and 1.5 Hours After Taking the Daily Regular Dose of Dexmethylphenidate

		Before D-MPH			1.5 Hours after D-MPH			Difference
Variable	Group	N	Mean	SD	N	Mean	SD	Mean Δ	SD	p
Pupil diameter	All patients	14	4.88	1.03	14	4.64	1.00	−0.22	0.64	0.235
	According to dose: dose (5–10 mg) (M/F)	5 (5/0)	4.94	0.90	5	4.33	0.44	−0.61	0.59	0.080
	dose (15–20 mg) (M/F)	5 (3/2)	4.94	1.47	5	4.56	1.61	−0.38	0.43	0.225
	dose (25–30 mg) (M/F)	4 (2/2)	4.77	0.63	4	5.13	0.38	0.475	0.40	0.109
ACD	All patients	14	3.25	0.25	14	3.31	0.28	0.044	0.13	0.074

p-Value represents significance of paired T-test.

ACD, anterior chamber depth; D-MPH, dexmethylphenidate; SD, standard deviation.

Pupil diameter measurement was extracted from OCT images by calculating the distance between the two edges of the iris (Fig. 1). The average pupil diameter before and after the use of D-MPH was 4.88 ± 1.03 and 4.64 ± 1.00 mm, respectively, with a difference of −0.22 ± 0.64 mm (p = 0.235) and is summarized in Table 3.

We found a medium positive correlation between D-MPH dose and positive difference in pupil diameter before and after treatment (ρ = 0.625, n = 14, p = 0.01) that was not conserved after adjustment to BMI (ρ = 0.308, n = 14, p = 0.165) (Table 4).

Table 4.

Spearman's Rho Correlation Between Complaints of Blurred Vision, Photophobia, Dexmethylphenidate Dose, and Dexmethylphenidate Dose/Body Mass Index to Change in Pupils' Size

Variable	Report of blurred vision	Reported photophobia	D-MPH dose	Dose/BMI
Delta^a pupils diameter
Pearson correlation	0.462^*	0.501^*	0.615^**	0.308
Significance (one-tailed)	0.048	0.034	0.010	0.165
N	14	14	14	12
D-MPH dose
Pearson correlation	0.423	0.163	—	—
Significance (one-tailed)	0.058	0.281	—	—
N	15	15	—	—

Delta = [measurement after D-MPH treatment] − [measurement before D-MPH treatment].

Correlation is significant at the 0.05 level (one-tailed).

Correlation is significant at the 0.01 level (one-tailed).

BMI, body mass index; D-MPH, dexmethylphenidate.

We defined three dosing groups: low dose (5–10 mg/day), moderate dose (15–20 mg/day), and high dose (20–30 mg/day). A Kruskal–Wallis H test showed that there was a statistically significant difference in pupil diameter change before and after D-MPH between the different drug dosage groups, χ ²(2) = 6.146, p = 0.046, with a mean rank pupil difference of 5.00 for low-dose group, 6.60 for moderate-dose group, and 11.75 for high-dose group.

A Spearman's rank correlation coefficient was used to evaluate the association between change in pupil diameter and subjective complaints. There was a statistically significant positive correlation between pupil enlargement and reports of blurred vision (ρ = 0.462, n = 14, p = 0.048) and photosensitivity (ρ = 0.501, n = 14, p = 0.034). No statistically significant correlation was found between dosage adjusted to BMI and pupil diameter and between D-MPH dosage and reports on blurred vision and photosensitivity. Data are presented in Table 4.

ACD measurements were normally distributed before as well as after the treatment. Wilcoxon test indicated that the average chamber depth increased after treatment, in a statistically insignificant manner (0.044 ± 0.13, p = 0.074). Subgroup analysis by gender or dosage did not produce a different result.

There were no significant correlations between any of the other variables, such as age, BMI (and, therefore, height and weight), CCT, and duration of ADHD diagnosis.

Discussion

This pilot study aimed to examine if there are significant vision-related ocular side effects of D-MPH use and to characterize them. We decided to focus on D-MPH because of the rising use of this drug among young patients treated for ADHD. Only children with normal vision functions were included. 1.5 Hours after taking D-MPH there was no statistically significant difference in VA (distance or near), convergence, ACD, accommodation, and stereopsis. Anterior segment OCT enabled us to accurately calculate pupil diameter. the main finding of our study was a statistically significant dose-dependent change in pupil diameter 1.5 hours after taking D-MPH.

D-MPH, similar to MPH, is a psychostimulant that blocks the reuptake of norepinephrine and DA; therefore, increasing systemic adrenergic activity, and can lead to pupil diameter enlargement. The change in pupil's size is consistent with the well-known data that stimulants affect the Locus Coeruleus-Norepinephrine (LC-NE) system, which is responsible for arousal and alertness states. The modulation of the LC-NE system by stimulants such as MPH influences pupil's diameter (Siegle et al, 2003). Our finding is of clinical significance as there is a positive correlation between pupil's enlargement after drug administration and complaints of blurred vision and photophobia, which might interfere with daily activities; blurred vision might interfere with near activities such as studying, and photophobia with outdoor activities. Our findings showed a strong correlation between the objective finding of pupil's dilation and subjective complaints.

There still might be a bias as children were directly and specifically asked about those side effects, and we did not have a control group.

Accommodation did not change in a statistically significant manner. A previous study that looked at the accommodative response in children with ADHD also did not find a significant effect of medication for ADHD on accommodation accuracy (Redondo et al, 2020). Change in accommodation might have clinical importance as in pedagogical settings, children are required to activate accommodation for near reading. If accommodation is weakened due to the use of D-MPH, it can clinically disrupt focusing while reading a written text. Indeed, in five cases, the change in accommodation was greater than or equal to 2 Diopters, and although this change can be overlooked in children who have high accommodation reserves, it might be clinically significant in adults who use the medication.

There was a tendency for worse depth vision capacity after taking D-MPH that did not reach clinical significance.

No change in distance or near VA was found. This finding is consistent with previous publications (Grönlund et al, 2007; Larrañaga-Fragoso et al, 2015).

The main weakness of the study is its small number of participants, and there is a possibility that some of the findings and trends that were presented in this study have low statistical power. We could not examine the correlation between ocular side effects to high-dose D-MPH, as most of the study participants were treated with daily doses of 10–20 mg. It is possible that higher doses may have a more significant effect on pupil size and create a refractive effect on close-range visual tasks. Finally, there is also a possibility of gender bias since most patients were male patients. The difference between males and females was evaluated in an animal model of rats treated with d-MPH, l-MPH, and d,l-MPH in early investigations as part of the FDA approval of D-MPH (Teo et al, 2003). In this study, no significant difference in the side effects profile was found between female and male rats. In our study, the group size is very small; therefore, it is difficult to draw a definite conclusion.

Beyond substantiating the fact that D-MPH brings about an objective change in pupil diameter, the results of this study bring to light the possibility that the pupil response is related to the reaction of the nervous system to D-MPH and stimulants in general. The correlation with drug dosage enlightens the need for further investigation of the utility of pupil size measurement and its clinical significance.

Conclusion

Our findings suggest that D-MPH has a dose-dependent effect on pupil diameter, which is correlated with complaints of blurred vision and photophobia. In this study, we used advanced imaging (AS-OCT) alongside thorough clinical examination. We did not find a statistically significant change in visual acuity, accommodation power, convergence ability, and anterior segment parameters (ACD, CCT). D-MPH is an effective and safe treatment for ADHD (Liu et al, 2006). Most of the ocular findings in this study are subclinical and, in most cases, require only the awareness of both patient and physician. Patients and parents of children should be informed about possible ocular-related side effects, which are reversible. As the usage of psychostimulants is increasing among children, adolescents, and adults, we should expect more reports on various side effects, part of which are visually related.

Clinical Significance

Parents, educators, and pediatricians should be aware of vision-related side effects of D-MPH. Increased pupil diameter was found to be related to visual complaints during treatment with D-MPH. Another interesting finding was a decrease in accommodative power. Although this finding was not statistically significant, it may carry clinical significance in adult patients in which accommodative reserve is low.

Footnotes

Disclosures

No competing financial interests exist.

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