Stimulus Phoria versus Response Phoria in a Prepresbyopic Population at COSI (Center of Science and Industry)

THESIS

Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in the Graduate School of The Ohio State University

By

Dix Hale Pettey

Graduate Program in Vision Science

The Ohio State University

2015

Master's Examination Committee:

Melissa D. Bailey, OD, PhD, Advisor

Donald O. Mutti, OD, PhD

G. Lynn Mitchell, MAS

Copyright by

Dix Hale Pettey

2015

Abstract

Background: Phoria measurement is a useful clinical tool in the diagnosis of binocular vision disorders and several methods of phoria measurement have been described. A common weakness of many of these methods is the exact amount of accommodation at the time of measurement must be assumed, which may lead to erroneous results in those who accommodate inaccurately.

Purpose: This study evaluated if the Purkinje image technique using a Grand Seiko

Autorefractor with an attached video camera could be used as an effective and accurate method for heterophoria measurement. The level of agreement between 4-D stimulus phoria (SP) and 4-D response phoria (RP) measurements obtained from the modified autorefractor was compared to those obtained from the Modified Thorington (MT) test.

Methods: Subjects included 20 emmetropic children and adults with a mean age of 12.2 ±

4.5 years who were recruited from the population visiting the Center of Science and

Industry (COSI) in Columbus, Ohio. Horizontal near phoria was first measured using the

MT method. Accommodative response and refractive error were measured using a modified Grand Seiko autorefractor, with accommodation being stimulated by letter targets at distance (0.00 D stimulus), 4-D stimulus (25 cm) and 4-D response (≤ 25 cm) levels. Convergence was measured simultaneously by monitoring the relative movement of Purkinje images I and IV. Bland Altman methods were used to determine agreement between measurements. ii

Results: When measured with MT at 40 cm, the mean ± SD horizontal phoria was −1.24Δ

± 3.28 (exophoria). When measured with the autorefractor, the mean phoria was more esophoric than MT for all three stimulus levels: 1.26Δ ± 5.75 (esophoria) at distance,

3.09Δ ± 6.86 (esophoria) for SP at 25 cm, and 5.80Δ ± 5.94 (esophoria) for RP at ≤25 cm.

The mean of the differences was significantly different between SP and MT [4.60Δ ± 9.09

(esophoria), p = 0.04], RP and MT [7.30Δ ± 7.91 (esophoria), p = 0.001], and between RP and SP [2.71 ± 3.83Δ (esophoria), p = 0.005]. The difference between phoria measurements for both SP vs MT and RP vs MT was found to be dependent upon the mean. The mean ± SD gradient AC/A ratio for the entire sample was 4.59 ± 7.20 Δ/D. A significant correlation was found between the difference in RP and SP versus the RP – SP

Response AC/A ratio (R2 = 0.98, p = <0.0001), suggesting subjects become more esophoric when forced to accommodate fully to a 4-D target.

Conclusion: Video and still frames taken with the autorefractor and secondary CCD camera produced phoria measurements that were more esophoric than those obtained with Modified Thorington or reported in previous studies, but it is beneficial that the amount of accommodation at the time of measurement was known. Further investigation is necessary to determine if efficiency in this methodology could be improved and to explore the level of repeatability. These methods have potential to be useful both in the clinic and as a screening tool in diagnosing and monitoring binocular vision disorders.

iii

Dedication

This document is dedicated to my beautiful wife Lacey and our children Shailey,

Cambria, and Dax, who constantly make me laugh and whose support and

encouragement have been priceless.

iv

Acknowledgments

The work presented here would not have been possible without the tremendous contributions of:

1. Melissa Bailey for her encouragement, guidance, and expertise as my advisor

2. Don Mutti for his wise counsel and for serving on my thesis committee

3. Lynn Mitchell for her statistical expertise and for serving on my thesis committee

4. Danielle Orr, Morgan Garczyk, Landon Perry, Bradley Daugherty, and Nidhi

Satiani for their assistance in recruitment and data collection at COSI.

5. Joe Lehman for the hours of assistance analyzing videos, pictures, and numbers

All of your help and support are deeply appreciated. Thank you!

v

Vita

2010...... B.S. (Hons) Exercise & Sports Science,

University of Utah

2011 to present ...... Optometry Doctoral Student, College of

Optometry, The Ohio State University

Publications

Pettey D. Palmitate evokes ceramide-dependent reactive oxygen species (ROS) generation from sources other than NADPH oxidase in bovine aortic endothelial cells (BAECS). Thesis (Honors)-

-Dept. of Exercise and Sport Science, University of Utah, 2010.

Zhang QJ, Holland WL, Wilson L, Tanner JM, Kearns D, Cahoon JM, Pettey D, Losee J, Abel

ED, Symons JD (2012). Ceramide mediates vascular dysfunction in diet-induced obesity by

PP2A-mediated dephosphorylation of the eNOS-Akt complex. Diabetes, 61(7), 1848-59.

Pettey JH, Mifflin MD, Kamae K, McEntire MW, Pettey DH, Callegan MC, Brown H, Olson RJ

(2013). The impact of short-term topical gatifloxacin and moxifloxacin on bacterial injection after hypodermic needle passage through human conjunctiva. J Ocul Pharmacol Ther, 29(5), 450-5.

vi

Fields of Study

Major Field: Vision Science

vii

Table of Contents

Abstract ...... ii

Dedication ...... iv

Acknowledgments...... v

Vita ...... vi

List of Tables ...... x

List of Figures ...... xi

Chapter 1: Introduction ...... 1

1. Horizontal Movement of the Eyes ...... 2

1.1 Vergence Eye Movements ...... 2

1.2 Disorders of the Vergence System ...... 3

1.3 Anatomy and Innervation of Extraocular Muscles ...... 5

2. The Heterophoria ...... 8

3. Heterophoria Measurement ...... 11

4. Accommodative Convergence / Accommodation (AC/A) Ratio ...... 16

Chapter 2: Methods ...... 20

Chapter 3: Results ...... 29

viii

Chapter 4: Discussion ...... 32

References ...... 55

ix

List of Tables

Table 1. Innervation and actions of the extraocular muscles from the primary position.

Adapted from Adler’s Physiology of the Eye.34 ...... 39

Table 2. Demographic description of the 20 subjects in study sample...... 40

Table 3. Mean, standard deviation, and distance to target of four different phoria measurements across 20 subjects...... 41

Table 4. Agreement between three different near phoria measurements across 20 subjects...... 42

x

List of Figures

Figure 1. Muscle Imbalance Measure Card used for measurement of heterophoria...... 43

Figure 2. Example photo of Grand Seiko Autorefractor measurement of right eye...... 44

Figure 3. View from above the apparatus used to measure accommodation and vergence...... 45

Figure 4. Example photo of Purkinje images I and IV produced by infrared light source.

...... 46

Figure 5. Difference versus mean plot for the agreement in phoria between 4D Stimulus

Phoria (SP) and Modified Thorington (MT)...... 47

Figure 6. Difference versus mean plot for the agreement in phoria between 4D Response

Phoria (RP) and Modified Thorington (MT)...... 48

Figure 7. Difference versus mean plot for the agreement in phoria between 4D Response

Phoria (RP) and 4D Stimulus Phoria (SP)...... 49

Figure 8. Difference versus standard measurement for the agreement in phoria between

4D Stimulus Phoria (SP) and Modified Thorington (MT)...... 50

Figure 9. Difference versus standard measurement for the agreement in phoria between

4D Response Phoria (RP) and Modified Thorington (MT)...... 51

Figure 10. Lack of correlation (p = 0.5) between difference in SP and MT versus DP –

SP Response AC/A ratio...... 52

xi

Figure 11. Lack of correlation (p = 0.17) between difference in RP and MT versus DP –

RP Response AC/A ratio...... 53

Figure 12. Correlation (p = <0.0001) between difference in RP and SP versus RP – SP

Response AC/A ratio...... 54

xii

Chapter 1: Introduction

Binocular vision disorders, such as convergence insufficiency, have been associated with a variety of visual symptoms including eyestrain, headaches, sleepiness, difficulty concentrating, blurred vision, diplopia, swimming of text while reading, and poor comprehension after short periods of reading or near work.1-5 The measurement of the heterophoria (phoria) position is an important part of a complete optometric examination as it is commonly used to aid in the diagnosis of binocular vision disorders.6

There have been several methods described for the clinical measurement of the phoria position, the most common method currently being the alternating cover test.6-8 One weakness of many clinical methods of phoria measurement in pre-presbyopic populations is the examiner must assume the subject is accommodating fully and consistently to a fixation stimulus, while the actual amount of the accommodative response is unknown.

This may be particularly problematic in young populations as some children have been shown to accommodate inaccurately.9,10 Mutti and co-workers (2000) described a method of simultaneously measuring accommodation and convergence using the Grand Seiko

Autorefractor with an attached video camera to obtain the accommodative convergence / accommodation (AC/A) ratio.11 Using this system, the AC/A ratio was calculated on the basis of the measured accommodative response, rather than the accommodative stimulus and assumed response. To our knowledge there has not been a study published using this methodology to determine heterophoria. The overall purpose of the present study was to 1 determine if the Grand Seiko Autorefractor with an attached video camera could be used to produce a more effective, repeatable measurement of the phoria position when accommodative response was known. Additionally, phoria measurements made with the

Grand Seiko Autorefractor will be compared with measurements taken with Modified

Thorington.

1. Horizontal Movement of the Eyes

1.1 Vergence Eye Movements

When an object is fixated with both eyes in a correctly functioning visual system, there are two retinal images produced, yet we experience a single, clear perception of our surroundings.12 For this to occur, there are a number of psychological and physiologic processes that must function properly, including a clear line of sight in both eyes, higher- order processing to produce sensory fusion, and a correct balance of muscle tension and neural control to result in motor fusion. One of the components of fusion and the normal means through which we maintain a fused and single percept of an object moving in depth is via the vergence eye movements.13

The classic model of the vergence system was initially described by Maddox,14 and later reiterated by Heath15 and Morgan,16,17 as having four distinct components, namely tonic vergence, accommodative vergence, proximal vergence, and fusional or disparity vergence. According to this classification, tonic vergence, or the eyes’ physiological position of rest, results from extraocular muscle tonus and is an estimate18 of the distance heterophoria. Tonic vergence is not to be confused with the anatomical

2 position of rest which is the resting position of the eyes if all innervation were to cease, such as via death or anesthesia.19,20 Accommodative vergence is said to be “blur driven”, and is a change in the horizontal alignment of the eyes resulting from accommodative effort.13 Proximal vergence occurs as a result of the psychological awareness of nearness of a fixation target. Fusional vergence, or disparity vergence, is induced when there is a difference between similar targets seen by the two eyes, or in other words, it acts to keep a target single as a result of non-zero retinal disparity signals.21 Of the four components of vergence eye movements, proximal and tonic vergence have been shown to play a relatively minor role in the overall vergence system compared to disparity and accommodative vergence.21 The magnitude of the disparity vergence is determined by dissociating the eyes, thereby eliminating fusion, and measuring the heterophoria. The magnitude of accommodative vergence may be established by determining the accommodative convergence to accommodation (AC/A) ratio.22 Numerically the AC/A ratio is the amount of vergence change per unit of accommodation.

1.2 Disorders of the Vergence System

An imbalance of the vergence system may lead to binocular vision disorders that ultimately cause symptoms of ocular discomfort. Oculomotor imbalances may be categorized in a number of different ways. Firstly, they may be described as either manifest (heterotropia or strabismus) or latent (heterophoria). Either of these may be further broken down into comitant, in which the amplitude of deviation remains constant in all directions of gaze, or incomitant, where the amplitude changes according to the

3 direction of gaze.23 Incomitant deviations occur when an over-action or under-action of a specific extraocular muscle is present. Strabismus may be constant or intermittent, and may also be the result of decompensated heterophoria.24

If a patient does present with symptoms such as asthenopia, headache, blur, diplopia, or light sensitivity, it is important clinically to obtain accurate data to determine if one or more components of the vergence system are contributing so that effective treatments may be recommended. Vergence system anomalies are typically categorized based upon the Duane-White25 classification, which was later modified by Tait (1951)26 to include the magnitude and direction of the heterophoria, along with the measured

AC/A ratio. Briefly, divergence insufficiency describes a condition where a patient with a low AC/A has a poorly compensated esophoria at distance with either no or a lesser amplitude of well-compensated esophoria at near. Divergence excess occurs when a patient with a high AC/A ratio has a poorly compensated exophoria at distance with less exophoria at near that is well-compensated. Convergence excess is a condition where a patient with a high AC/A ratio is orthophoric or esophoric at distance and has a poorly compensated esophoria at near.25

One of the most common causes of ocular discomfort is convergence insufficiency (CI), which is characterized by a low AC/A ratio and exophoria greater at near than at distance.25,27 CI has also been described as an eye muscle alignment issue in which the eyes tend to drift outward when doing near work.28 Symptoms specific to CI generally occur with reading or near work and may include eyestrain, headaches, blurred vision, double vision, sleepiness, difficulty concentrating, movement of print while

4 reading, and loss of comprehension after short periods of reading or performing close activities.28 Additional symptoms may include dull orbital pain, pulling sensation, and short attention span. There has been some disputation as to the prevalence of symptomatic CI, with a range of 1.75% to 50%.27,29 This variability has been attributed to variations in criteria for the definition of CI and to differences in subpopulations within the data.30

Most criteria for the diagnosis of CI consist of clinical signs that include greater exophoria at near than at distance and a low AC/A ratio, along with a reduced positive fusional vergence range and a receded near point of convergence. The Convergence

Insufficiency Treatment Trial (CITT) was a randomized clinical trial of convergence insufficiency, and their study group, along with Rouse et al,29 applied a criterion of 4∆ greater exophoria at near than at distance.27,31 When considering the AC/A ratio, a ratio less than 3/1 is expected in CI patients.25 Clearly an accurate measurement of both the distance and near heterophorias and accommodative capacity is vital in the diagnosis of

CI patients as inaccurate values could mask the underlying cause of patient complaints.

1.3 Anatomy and Innervation of Extraocular Muscles

Vergence eye movements are achieved via manipulation of the eye by the extraocular muscles (EOMs). In order for accurate positioning of the visual world on the fovea, and to maintain balance of the vergence system, activity of each EOM must be tightly coordinated. Table 1 includes a summary of the innervation and actions of the

EOMs from the primary position. The following is a brief overview of the anatomy of the

5

EOMs. The eyeball is suspended in the bony orbit by fascia, fibrous septa, and six EOMs, namely the lateral rectus, medial rectus, superior rectus, inferior rectus, superior oblique, and inferior oblique.32 The overall function of the EOMs is to move the eyes. The origin of the four rectus muscles includes the bones at the apex of the bony orbit along with the

Annulus of Zinn. These four muscles then course anteriorly to insert into the sclera anterior to the equator of the globe.33 The superior oblique has its origin just superior and medial to the Annulus of Zinn. Coursing anteriorly, it becomes tendinous and passes through the trochlea before changing direction and coursing posteriorly to insert posterior to the equator of the globe. The inferior oblique originates from the anteromedial orbital floor, then courses posteriorly and inserts into the sclera posterior to the equator of the globe.34

The orientation of the EOMs from origin to insertion is responsible for the function and direction of the eye movements that result from their contraction.34,35

Contraction of the lateral rectus and medial rectus muscles produce horizontal eye movements, with their primary actions being abduction and adduction, respectively.35

Abduction is the lateral rotation of the anterior pole of the globe around the vertical axis, while adduction is medial rotation of the anterior pole about the vertical axis. The remaining four EOMs manifest both primary (1°) and secondary actions. In primary gaze, both the superior and inferior recti are angled laterally at approximately 23° from the sagittal plane.36 The superior rectus is responsible for elevation (1°), adduction and intorsion. The primary action of the inferior rectus muscle is depression, but it also adducts and extorts the eye. Intorsion is where the superior pole (12 o’clock position) of

6 the eye rotates medially, while extorsion is lateral rotation of the superior pole of the eye.

The superior oblique and inferior oblique muscles are angled at approximately 55° from the sagittal plane in primary gaze.37 The superior oblique mainly intorts (1°) the eye, and secondarily depresses and abducts the eye. The inferior oblique muscle parallels the superior oblique, but inserts on the inferior surface of the globe, its primary function is extorsion, along with elevation and abduction.36

While the coordinated movements of all extraocular muscles are critical to maintain single, clear, binocular vision, EOMs of particular interest in this study are the lateral and medial recti as these muscles are exclusively involved in eye movements along the horizontal plane. The following is a brief overview of the cranial nerve (CN) innervation for these two EOMs. The medial rectus muscle is innervated by the oculomotor nerve (CN III), which carries somatic motor fibers to the medial, superior, and inferior rectus muscles, the inferior oblique muscle, and to the levator palpebrae superioris muscle.38 As a side note, CN III also carries parasympathetic fibers to the intrinsic muscles of the eye,39 and sensory neurons from proprioceptive receptors in the

EOMs. Motor neurons of CN III arise in the somatic portion of the oculomotor nucleus of the midbrain, just ventral to the aqueduct of Sylvius.38 Bundles of fibers called rootlets converge in the interpenduncular fossa to form the oculomotor nerve trunk which lies between the superior cerebellar and posterior cerebral arteries. The nerve eventually passes through the cavernous sinus just above the trochlear nerve, within the deep layer of the lateral wall of the sinus.38,40 CN III enters the orbit through the superior orbital fissure and divides into superior and inferior divisions that pass through the Annulus of

7

Zinn. Parasympathetic fibers from the Edinger-Westphal nucleus accompany other oculomotor fibers into the orbit where they terminate in the ciliary ganglion.39 Axons then pass through the short posterior ciliary nerves to supply the sphincter pupillae and the ciliary muscle.34,41

The lateral rectus muscle is innervated by the abducens nerve (CN VI), which contains somatic motor and sensory (proprioceptive) fibers.42 These motor neurons arise in the paired motor nuclei which lie in the pons, immediately ventral to the floor of the fourth ventricle.42 The nerve eventually passes through the cavernous sinus. Conversely, unlike the oculomotor nerve, the abducens nerve does not lie within the lateral wall of the sinus, but rather runs within the body of the sinus just lateral to the internal carotid artery.40 The abducens nerve enters the orbit through the superior orbital fissure and the oculomotor foramen of the annulus of Zinn, adjacent to the origin of the lateral rectus muscle.36 Within the orbital apex, the nerve may run as a single trunk, but more frequently it splits into 2–7 branches. These branches course laterally and penetrate the sheath of the lateral rectus muscle shortly after leaving the annulus of Zinn.34,41

When determining if ocular discomfort is related to the phoria position, mechanical and neurologic deficiencies should first be ruled out. An understanding of the underlying anatomy and innervation involved in horizontal eye movements is beneficial as a dysfunction of either of these systems may independently lead to symptoms of ocular discomfort unrelated to the phoria position.

2. The Heterophoria

8

The heterophoria position, also known as the physiological position of rest or functional position of rest, has been described as the position that the visual axes take with respect to one another in the absence of all stimuli to fusion.43 Some research suggests it is mostly tonic vergence, whereas others suggest it has other aspects.18 There are three types of horizontal phoria categories including orthophoria, esophoria and exophoria. Esophoria is present when the visual axes cross closer than the object of regard in the absence of fusional stimuli, exophoria is the condition when the visual axes intersect beyond the object of regard, and orthophoria occurs when the visual axes cross at the object of regard.44 The deviation from the ortho position is measured in prism diopters (∆), with 1∆ = 0.57 degrees.45

The etiology of heterophoria was addressed by Lyle and Bridgemann46 who suggested four main categories of potential causes of heterophoria including anatomical causes, refractive causes, uniocular activity, and trauma. Possible anatomical causes they suggest include relative exophthalmos or enophthalmos, which may produce an exo- or esophoric tendency respectively; an abnormality of orbital fascia or ligaments may be a cause of an imbalance, an abnormal interpupillary distance, and/or the distance between the centers of the pupils may contribute. For example, hypertelorism, an abnormally wide interpupillary distance, might predispose a patient to a tendency for exophoria.47 In a study of 133 normal Arab males aged 20-67 years, a weak, positive correlation was found between near phoria and near interpupillary distance (r2 > 0.04; p < 0.03), and overall, there was a predominance of exophoria for near interpupillary distances > 63 mm, and esophoria for near interpupillary distances < 62 mm.47 In a 10 year study of 114 myopic

9 children, Anderson and coworkers (2011) found that near phoria became more exophoric

(4∆ in 10 years, p <0.001) while distance interpupillary distance increased 3 mm over the same 10 year period (p <0.001), although it is unclear whether a direct correlation between phoria and interpupillary distance was determined.48 Refractive causes relate to the relationship between accommodation and convergence with, for example, uncorrected hyperopia having a tendency to induce a shift towards esophoria or esotropia,49 although the magnitude of the esophoria and potential for symptoms are directly related to the

AC/A ratio.50 An example of uniocular activity, the repeated and prolonged use of one eye, which was hypothesized to be a cause of heterophoria, is the visual activity of a watchmaker.46

The phoria position is typically measured at distance (target greater than or equal to 20 feet from patient representing optical infinity) and near (target 40 cm from patient).

At distance, it is generally accepted that for the majority of people the visual axes are parallel or slightly divergent.13 Multiple studies have demonstrated a high prevalence of distance orthophoria in the population despite a large number of mechanical, neural, and sensory variables, with the average heterophoria for a distance target being 0 to 1∆ of exophoria with a standard deviation of 2∆.26,51 Dowley (1990) looked at a sample of 925 subjects and demonstrated a significantly non-normal (p = < 0.05) leptokurtic frequency distribution centered on orthophoria.52 When distance phoria was measured with

Modified Thorington, Lyon & Rainey (2005) found the mean distance phoria to be orthophoria in 453 children in the first grade (SD = 2∆) and 426 children in the fourth grade (SD = 1∆).7

10

When an individual switches fixation from a distance target to a near target, both their vergence and accommodative demands increase and so the heterophoria for the near demand is a result of the new combination of cues and responses. There has been less agreement on the average magnitude of the near heterophoria, particularly when comparing age and results from different methods of heterophoria measurement. In a study using Maddox rod and Risley prisms,53 Eames (1933) found the average near phoria was 0.2∆ exophoria in 212 non-presbyopes (SD = 0.7∆), and 7.0∆ exophoria in 90 presbyopic subjects (SD = 0.5∆).51 When measured via Modified Thorington, Lyon &

Rainey found a mean near phoria of 1.0∆ exophoria (SD = 4.0∆) in both children in the first grade and fourth grade.7 Additionally, when evaluating near phoria, an increase in exophoria with age has been described.47,48,51,54 It is apparent that the magnitude of the phoria can be variable depending on a number of factors including the method of measurement used, age of subjects, and potentially the attentiveness and accommodative accuracy of the individual being tested. The ability to obtain accurate measurements of the distance and near phoria of a patient is important as these values are key factors when clinically identifying a particular binocular vision disorder.

3. Heterophoria Measurement

There are many methods used clinically to evaluate the phoria position of a patient. These can be divided into methods of determining the associated phoria (a measure of fixation disparity),12 or the dissociated phoria, where fusion must be eliminated to achieve dissociation of the eyes. The associated phoria measurement has

11 been shown to be helpful in determining the amount of prism correction to prescribe in some binocular vision disorders,55 but this thesis will focus solely on dissociated phoria measurement. Most methods of phoria measurement are subjective, meaning they require subjective feedback from the patient during testing. There are also methods that clinically are considered objective, relying upon the expertise of the practitioner to determine the magnitude of the phoria. With each of these methods, dissociation may be accomplished with occlusion of one eye (i.e. the cover test, eye tracking methods), by distortion of one image (i.e. Maddox rod or Modified Thorington), by displacement of the image perceived by one eye (i.e. the von Greafe technique), or by dissimilar targets (i.e. stereoscopes).

An objective method that is most commonly utilized clinically to determine the presence of a heterophoria is the alternating cover test. For this test, the practitioner places an occluder in front of one eye while the other eye fixates a proper target at a given test distance. The occluder is then quickly moved to the fixating eye without giving any time for binocular vision to occur and the examiner observes the eye that has just been uncovered as it takes up fixation.43 If no motion of the occluded eye is noted at the instant of exposure, no phoria is considered to exist, and this is known as orthophoria. If the eye that has just been uncovered turns inward, this implies an exophoria exists, or that the eye was deviating outward when under cover. Similarly, if the eye turns outward when uncovered, this implies an esophoria exists, or that the eye must have been deviating inward when under cover. If the eye turns upwards under occlusion and downward when exposed, hyperphoria is evident, whereas opposite movements would

12 exhibit hypophoria.56 Prisms can then be used to neutralize the movement of the eye to determine the magnitude of the deviation.

Multiple studies have been performed to determine the inter-examiner and intra- examiner reliability of the alternating cover test. A study performed by Rainey and co- workers, comparing inter-examiner repeatability of the prism-neutralized objective cover test between two experienced faculty optometrists, found the mean difference between the measurements was −1.0∆ and the 95% limits of agreement were −2.6∆ to 4.6∆.6

Similarly, Johns and co-workers compared the reliability of the alternating cover test between two experienced optometrists who had been in practice for 20 years, and found a mean difference of −0.53∆ with the 95% limits of agreement being −4.51∆ to 3.45∆.57

More recently, Hrynchak and co-workers compared the reliability of the alternating cover test between experienced and novice examiners in 50 non-strabismic participants.58 They found the mean difference among experienced examiners was 0.7∆ with 95% limits of agreement of −2.3∆ to 3.7∆, among novice examiners the mean difference was −0.1∆ with

95% limits of agreement of -4.5∆ to 4.3∆, and the mean difference between the experienced and novice examiners was 0.8∆ with 95% limits of agreement of −2.7∆ to

4.3∆. While the mean differences were not found to be clinically meaningful, the 95% limits of agreement were quite high (between ±3.0–4.4∆ per comparison), demonstrating the potential for variability of results with a given patient. Despite the potential for variability with the prism-neutralized alternating cover test, it is still commonly used for heterophoria testing and widely accepted as a means of investigating binocular vision disorders in research and in the clinic.

13

A common subjective method of phoria measurement is the Modified Thorington test, which dissociates the eyes using visual distortion. This test consists of a card on which a horizontal and vertical scale has been printed so that the distances between the individual markings are equivalent to the displacement of 1∆ at the test distance. The card has a fine hole positioned at the center of the target and this hole is illuminated from behind. Dissociation is achieved by placing a Maddox rod over the subject’s right eye to produce a vertical streak before one eye of the patient and the patient is asked through which number the streak intersects on the tangent scale. Vertical phoria may be measured by rotating the Maddox rod to produce a horizontal streak. The Modified Thorington may be used to measure the phoria at distance or near, with a different card being used for each scenario.

Despite its simplicity in administering the test, the Modified Thorington test has been shown to be repeatable and comparable to both subjective and objective techniques of phoria measurement.7 Casillas and Rosenfield compared repeatability of the Modified

Thorington test to Maddox rod and Von Graefe techniques and found Modified

Thorington to be the most repeatable of the three techniques at distance and near in 60 visually normal 20-34 year-old subjects.59 Cebrian and co-workers investigated the repeatability of the distance Modified Thorington card in 110 subjects aged 18 to 32 years by comparing it with three additional phoria tests: the cover test, Von Graefe, and

Maddox rod.60 The mean time interval between sessions was 1 week. The Modified

Thorington test showed best inter-examiner repeatability (coefficient of repeatability

[COR] = ±1.43∆), followed closely by cover test (COR = ±1.65∆), whereas best intra-

14 examiner repeatability was observed for cover test (COR = ±1.28∆) followed by Modified

Thorington (COR = ±1.51∆). Among the different combinations of tests, Modified

Thorington and cover test showed the best agreement between measurements with a mean difference of 0.63∆ and 95% limits of agreement of −1.6∆ to 2.86∆.

Rainey and co-workers assessed inter-examiner reliability of seven clinical tests of phoria measurement, using correlational and mean difference analyses.6 In their study, two experienced optometrists performed seven phoria tests on 72 healthy adult subjects ranging from 22 to 40 years old. The seven tests employed were the estimated cover test, the prism neutralized objective cover test, the prism neutralized cover test with subjective reporting of target movement, von Graefe with continuous target presentation, von

Graefe with flashed target presentation, the Thorington and Modified Thorington. All tests were performed in the same way by both examiners in a random sequence. Of the seven methods of phoria measurement, The Modified Thorington had the highest inter- examiner correlation coefficient (0.92), the smallest mean difference (+0.1∆) and the smallest 95% limits of agreement (−2.2∆ to 2.4∆) of all tests and was considered the most reliable. As a side note, the prism neutralized cover test with subjective reporting of target movement had the largest mean difference of all the tests and was considered the least repeatable. As the Modified Thorington is relatively easy to perform and has been shown to be repeatable in school-aged children and adults, this technique was chosen to be used for comparison in this study.

Repeatability is clearly important in clinical testing of heterophoria, but there are weaknesses that should be considered. In practice, the results of a heterophoria test can

15 vary depending on the test used.59 These variations may be due to differences in the central or peripheral stimulus to fusion, the size and complexity of the visual field or the fixation targets, the nature of the borders in the field of view, luminance differences, proximal vergence effects, and the length of time fusion is disrupted.45,61

One additional weakness of many methods of phoria measurement is the examiner must assume the subject is accommodating fully and consistently to a fixation stimulus, while the actual amount of the accommodative response is unknown. This may be particularly problematic in young populations as some children have been shown to accommodate inaccurately.9 Also, a recent study by Anderson and co-workers (2014) exploring the accuracy of accommodation demonstrated that the subjective push-up test substantially overestimates accommodative amplitude, particularly in young children.10

This finding is alarming as it demonstrates that the practitioner may not recognize when a patient is accommodating inaccurately during testing, including tests of heterophoria. A lack of information regarding the patient’s accommodative status was also one of the motivating factors for the present study.

4. Accommodative Convergence / Accommodation (AC/A) Ratio

It has been demonstrated that each diopter of accommodation of an individual is accompanied by a specific amount of convergence.11,43 The relationship between accommodative convergence and accommodation is known as the AC/A ratio. The magnitude of the AC/A ratio is particularly important clinically in patients with binocular vision abnormalities, especially when they are associated with an inappropriate

16 accommodative response (i.e. accommodative esotropia and divergence excess intermittent exotropia).62 In an emmetropic or individual with fully-corrected refractive error, the stimulus to accommodation at distance is zero, and if orthophoric at distance, the stimulus to convergence is also zero. When that individual fixates on an object at 40 cm, the stimulus to accommodation will be 1/.40 meters or 2.50 diopters (D). The stimulus to convergence at 40 cm for that individual, assuming an interpupillary distance of 60 mm, will be 15∆. Therefore, the normal stimulus AC/A ratio for an individual with an interpupillary distance of 60 mm is 6∆ /D (calculation: 15∆ / 2.50D = 6/1 = 6∆ /D).

Normal stimulus AC/A ratios in adults are obtained clinically and have been reported to range from 2/1 to 6/1.63 In an attempt to establish normal stimulus AC/A values in children age 6-12 years, Jimenez and co-workers (2004) provided a reference mean of 5

± 0.9 and 2.2 ± 0.8 for the calculated AC/A and gradient AC/A methods, respectively.64

They also agree with Mutti and co-workers (2011) in that the AC/A ratio did not change according to age in children.11

Two commonly used methods of measuring the stimulus AC/A ratio include

Gradient AC/A and Far-Near AC/A. The gradient AC/A is determined by direct measurement, in which fixation is held constant at some distance, usually 40cm.

Convergence is then determined for two different levels of accommodation induced by lenses (i.e. +/- 1.00D lenses). The change in convergence divided by the change in accommodation will disclose the accommodative convergence-accommodation ratio. The

Far-Near AC/A is determined by utilizing the subject's distance and near heterophoria and the convergence necessary for binocular fixation at near.16 In the far-near AC/A

17 method, the assumption is made that when there is near fixation the distance heterophoria is overcome by accommodative convergence and that this function is equal to or exceeds the required convergence by the amount of the near heterophoria. The further assumption is made that proximity, i.e., proximal accommodation, has little or no effect on the value of the near heterophoria.

The stimulus AC/A ratio is defined as the ratio of accommodative convergence to the stimulus to accommodation. Conversely, the response AC/A ratio is determined only when it is possible to measure the exact amount of accommodation (e.g. using an autorefractor, MEM or Nott) during convergence testing, and is defined as the ratio of accommodative convergence to the accommodative response.43 The stimulus AC/A ratio is what is measured most often clinically, as the stimulus to accommodation is easily determined by either the test object distance or the use of minus lenses, or both. Because children may accommodate inaccurately,9 it is preferable to calculate the AC/A ratio on the basis of the measured accommodative response rather than the accommodative stimulus and assumed response.11

A newer method of determining the response AC/A ratio has been described based on Purkinje image evaluation for the quantitative assessment of ocular alignment.11,62 This technique uses an autorefractor, an infrared CCD camera and an eye monitor to provide simultaneous measurement of mean accommodation and accommodative convergence. It also allows the measurement of horizontal eye movements to fixation targets that can be presented at any distance. Specific procedures for this method are discussed in Methods section below.

18

This videographic technique monitors the position of the first and fourth purkinje images to determine the magnitude and direction of eye movement and to assess ocular alignment under natural viewing conditions.62,65 Purkinje images are reflections of light from the front and back surfaces of the cornea (Purkinje images I and II, respectively), and from the front and back surfaces of the crystalline lens (Purkinje images III and IV, respectively). Purkinje I is bright, virtual, erect and lies at the pupillary plane, while

Purkinje II is much dimmer and almost coincides with Purkinje I. The third image lies in the vitreous and changes its site with accommodation. The fourth image lies almost exactly in the same plane as Purkinje I, but is almost impossible to be seen by the naked eye. Flash photography or infrared videography may be used to visualize Purkinje IV.

These images have been used previously to measure the AC/A ratio. Theoretically, we should also be able to use changes in position of Purkinje images I and IV to obtain a phoria measurement. The main value of this method of phoria measurement is the ability to monitor accommodation throughout testing, thereby allowing for both stimulus phoria and response phoria measurements that will hopefully lead to better treatment decisions.

The overall purpose of this study is to determine the level of agreement between phoria measurements taken with the Purkinje image technique using a Grand Seiko

Autorefractor with an attached video camera and the Modified Thorington. It is hypothesized that the phoria measurements obtained from the Grand Seiko’s video output will be similar to those obtained from the Modified Thorington Test. Stimulus phoria versus response phoria will also be compared.

19

Chapter 2: Methods

Subjects

Subjects enrolled in this study were children and adults 2-40 years of age.

Participants were recruited from the population visiting the Center of Science and

Industry (COSI) in Columbus, Ohio on a given day, as well as from an email advertisement to students of the Optometry Services Clinics at The Ohio State

University. Participants had one visit lasting approximately 30 minutes. Subjects could have any refractive error, i.e., myopia, hyperopia, or astigmatism, as long as their habitual visual acuity was at least 20/35 with a logMAR visual acuity or 20/40 with a Lea Acuity

Chart. Exclusion criteria were habitual visual acuity measurements that were 20/40 or worse in either eye, any subject with more than 0.50 D of uncorrected myopia, or any subject who was unable or unwilling to complete study testing procedures for any reason, especially for reasons such as a mental disability or general physical or emotional immaturity that prevented the subject from understanding and following investigators’ instructions. After a presentation and discussion of the study procedures, all subjects provided written informed consent and/or assent. The study was approved by the

Institutional Review Board of the Ohio State University and the tenets of the Declaration of Helsinki were followed throughout this study.

A pilot study of four subjects was performed to determine the amount of time required to analyze data for each subject. Due to the excessive time required during data 20 analysis, it was determined that twenty subjects in this data set should be selected from the overall pool of 199 participants using a random number generator (Excel 2013,

Microsoft Corporation, Redmond, WA). To ensure maximum viewing ability of Purkinje images when viewing video recordings of the eyes, only subjects who were not wearing correction (glasses or contact lenses) were entered into the random number generator.

The first twenty subjects listed on the random number generator who were not wearing refractive correction were used.

Visual Acuity

For adults and children able to read a letter chart, visual acuity was measured using a logMAR chart (Bailey Lovie Chart, National Vision Research Institute of

Australia). Multiple versions of the logMAR visual acuity chart were available and the visual acuity chart was changed between each measurement of the right eye and left eye.

The luminance of the visual acuity charts was calibrated to 75 -110 cd/m2. Testing was performed at a distance of 6 meters and the total number of letters correct was recorded.

Guessing was encouraged and patients were required to provide responses for all five letters on each line he or she began to read. Only when three or more letters on a given line were called incorrectly was the test completed and results recorded.

If a child was too young to read a letter chart, the letter chart was substituted with an age-appropriate Crowded Lea Symbols VA screening test (Good-Lite CO., Elgin, IL) administered according to manufacturer instructions.66 This test was designed to use presentation of single, crowded Lea symbols at a distance of 5 feet. Symbols were

21 surrounded on all four sides by a crowding bar at 0.5-optotype width and printed on a disk that had an overlay mask with a window, allowing presentation of single crowded symbols.

The disk was presented on a lighted stand (True Daylight Illuminator with Easel;

Richmond Products, Inc, Boca Raton, FL) that provided standardized illumination and positioning. The screener monitored the child’s responses on a disk-specific score sheet that listed all the symbols in the order presented to the child. When the child incorrectly identified two symbols on a line (or optotype size on the disk) or provided responses for all symbols at the smallest optotype level, measurement was complete for that eye. The same procedure was repeated for the left eye.

Modified Thorington Phoria

Modified Thorington phoria measurements were performed using a Muscle

Imbalance Measure Card (Figure 1) from Bernell (Bernell VTP, Mishawaka, IN, USA).

Near lateral phoria, was measured first, followed by near vertical phoria. The cards were calibrated for testing at 40 cm, with the subjects wearing their habitual prescription. A

Maddox rod was placed over the subject’s right eye with the grooves oriented in the appropriate direction to measure either the lateral or vertical phoria. The subjects were instructed to look at the zero in the center of the card and to keep it clear. For lateral phoria, they then stated if the line was to the right or left of the zero (subjects could also point to the side of the card on which the line fell). The examiner asked the subjects which number was closest to the red line and this number was recorded. For vertical

22 phoria, the subject was asked if the line was above or below the zero (subjects could also point to the portion of the card on which the line fell), and then the examiner asked the subjects which number was closest to the red line and this number was recorded.

Negative numbers corresponded to exophoria or hypophoria.

Demographic Data Collection

Study data were collected verbally during the visit and managed using REDCap electronic data capture tools hosted at the Ohio State University.67 REDCap (Research

Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies, providing 1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for importing data from external sources. Variables collected during the survey included gender, vision history, personal medical history, family medical history, current medications (over-the-counter and prescribed). First, middle, and last name, along with date of birth were collected only to determine if someone completed study testing twice.

Autorefraction

The accommodative stimulus was a 4 x 4 grid of letters, with each letter and space between letters subtending 38.75 minutes of arc at the eye (20/155 equivalent). The print was chosen to be similar in size to that found in children’s books and was found by Mutti,

23 et.al11 to be an adequate size for testing at all ages. Distance and near targets were illuminated by ambient room lighting. A distance target was placed at 12 meters to simulate optical infinity. An accommodative stimulus level of 4.00 D relative to optical infinity was produced by placing the letter target 25 cm from the eye on a track positioned in front of the right eye. The letter target was then moved either towards or away from the eye until a 4.00 D response was achieved. The 4.00 D stimulus and response were chosen to coincide with ciliary body measurements (with and without accommodation) which were taken during the same visit but are not discussed in this thesis. A Badal lens was not used during this procedure as the subject’s eyes needed to be associated to view real targets seen binocularly during portions of the testing.

Accommodative response was measured at each stimulus level using a binocular auto refractor/keratometer WR-5100K (Grand Seiko Co., Ltd.). At least five autorefractor readings were taken with the right eye in primary gaze. Fixation was monitored by viewing eye movements on the screen built into the autorefractor (Figure 2). Any unsteady fixation resulted in invalid measurements that could be identified by cylinders that differed from the mode value for cylinder by more than 1.00 D. Rejecting these readings also eliminated most erroneous sphere values, but remaining readings with spheres differing by at least ±5.00 D from the mode value for sphere readings, were also rejected.

The amount of convergence of the left eye was monitored via a second camera. A focused infrared LED light source (SFH 484-2; Siemens, Munich, Germany) was mounted on top of a CCD camera (XC-77RR; SONY, Tokyo, Japan) and aimed at the

24 left eye of the subject by way of an infrared-reflecting mirror (Figure 3). The CCD camera was fitted with a 50-mm focal length F1.4 C-mount lens on a 20-mm extension tube with the camera’s stock infrared filter removed. The infrared LED produces Purkinje images I and IV (Figure 4). Eye rotation was monitored by measuring the relative lateral movement of these two images. The two data channels, accommodative response from the right eye and convergence eye movement from the left eye, were recorded simultaneously by Eyeline Video Surveillance Software (NCH Software, Inc.,

Greenwood Village, Colorado, USA).

The protocol for measurement was as follows. A subject was placed behind the autorefractor, and the subject given a pair of modified glasses frames. The left side of the frame held a gel filter (Wratten 89B; Kodak, Rochester, NY). This filter passes only wavelengths longer than 680 nm, disrupting fusion by appearing opaque to the observer, but remaining transparent to the CCD camera. The right side of the frame remained empty and this modified frame was placed over the habitual correction of the subject. The subject was instructed to keep the letters clear at all stimulus levels and accommodative response was measured at each stimulus level while eye position was recorded on the second channel. For distance measurements the subject was instructed to look at an eye chart 12 meters across the room and five measurements were taken. The track was then placed in front of the right eye with the near letter target placed at 25 cm (4 D stimulus) and five measurements were taken. The letter target was moved either towards or away from the subject’s eye until a 4-D response was achieved (mean distance reading of 4-D), and five readings were taken. The 4-D response distance from eye to letter target was

25 recorded in cm. The modified glasses frames were then removed (habitual correction remained) and the subject was instructed to view the same letter target binocularly for at least five seconds, keeping it single and clear, at both the 4 diopter response distance and the 4 diopter stimulus distance. The track was removed and the subject was instructed to view the distance target binocularly for five seconds.

Calibration was then performed after the right eye was occluded, the track replaced, and the letter target exchanged for the 10° calibration target. Calibration was achieved by making a 10° eye movement with the left eye, alternating fixation two times between a green dot and two red circles printed on a card.

Data Analysis

Videos and still frames were analyzed to extract eye position information using

MatLab 2013b (The MathWorks, Inc., Natick, MA). As there was a 1-2 second delay between recording start times in the two videos, simultaneous frames were matched by finding a corresponding blink and calculating the difference in frame number. This difference was used to ensure vergence images matched accommodation data. One still image was extracted from the left eye video for calibration and monocular and binocular viewing at each stimulus level. Measurements were taken of the lateral and vertical separation from the center of Purkinje images I and IV and recorded in Excel 2013

(Microsoft Corporation, Redmond, WA). Pixel values were converted into degrees of separation, which were then converted into prism diopters for distance phoria, near phoria with 4-D stimulus, and near phoria with 4-D response using the following formulae:

26

10° 1.745∆ ∆ 푥 = # 푝푖푥푒푙푠 푑푒푔푟푒푒 푝푖푥푒푙

푟푎푑푖푎푛푠 휋 = 100 ∗ tan ( ) = 1.745 푑푒푔푟푒푒 180

Where Δ = prism diopters and 1.745 is radians per degree.

AC/A ratios were calculated using the difference in calculated vergence response in the numerator and the difference in measured accommodative response in the denominator. The AC/A ratio was calculated in three different ways corresponding to differences in accommodative stimuli. The three formulae used are:

DP-SP DP– SP Response AC/A Ratio = ARDP - ARSP

DP-RP DP– RP Response AC/A Ratio = ARDP - ARRP

RP-SP RP– SP Response AC/A Ratio = ARRP - ARSP

Where DP = Distance Phoria, SP= 4-D Stimulus Phoria measured with autorefractor, RP

= 4-D Response Phoria measured with autorefractor, ARDP = Accommodative Response at distance, ARSP = Accommodative Response when 4-D stimulus presented, ARRP =

Accommodative Response when 4-D response achieved, and AC/A = Accommodative

Convergence / Accommodation ratio.

Statistical Methods

27

All analyses were performed using SPSS software (IBM SPSS Statistics Version

22). To assess the agreement of phoria measurements taken with the Grand Seiko autorefractor with the standard of the Modified Thorington, the method described by

Bland and Altman was used.68 The mean of the differences between the measurements at different levels of accommodation (i.e., the difference between the 4-D stimulus and 4-D response) characterizes the bias of the method. This mean of the differences was compared to zero using a 1-sample t-test to determine whether the bias was statistically significant. The mean of the differences and its standard deviation were used to construct

95% limits of agreement (LoA) (mean ± [1.96 × standard deviation]). The 95% LoA characterize the expected differences between phoria measurements. The difference between autorefractor measurements and Modified Thorington was also compared to the standard measurement, which is being considered as the Modified Thorington, using the method described by Bland and Altman.69

Three Pearson correlations were calculated to assess the difference between phoria measurements vs the AC/A ratio. The SP – MT phoria difference was compared to the DP – SP response AC/A ratio, the RP – MT phoria difference was compared to the

DP – RP response AC/A ratio, and the RP – SP phoria difference was compared to the

RP – SP response AC/A ratio. R2 values were calculated for each comparison.

28

Chapter 3: Results

The mean ± SD age of the 20 participants in this study was 12.2 years ± 4.5

(range 8 to 25 years). Eleven (55%) subjects were female, 19 (95%) subjects were

Caucasian, and 19 (95%) subjects were non-Hispanic (See Table 2). The mean ± SD number of pixels for the two 10° eye movements used for calibration was 33.80 ± 3.50.

Medications reported as being used by subjects in this sample have not been shown to have ocular side-effects.

Means of Refractive Error and Phoria Measurements among participants

The mean ± SD uncorrected distance refractive error of the participants was +0.69

D ± 0.57, suggesting that the participants were mostly emmetropic. This is not surprising given that the subjects were selected from the general population at COSI, and not a clinical population. Additionally, we selected subjects who were not wearing contact lenses or glasses to allow for maximum viewing ability of Purkinje images. Means and standard deviations were determined for each of the four measurements of phoria for the

20 participants and are presented in Table 3. The mean ± SD phoria when measured via

Modified Thorington (MT) at 40 cm was −1.24Δ ± 3.28 (exophoria). When phoria was measured with the autorefractor, on average, subjects were increasingly relatively more esophoric as the distance between the target and the subject decreased. The distance phoria measured with the autorefractor at 12 meters had a mean of 1.26Δ ± 5.75 29

(esophoria). The mean phoria with a 4-D stimulus, or the stimulus phoria (SP), when measured with the autorefractor was 3.09Δ ± 6.86 (esophoria) and with a 4-D response, or the response phoria (RP), was 5.80Δ ± 5.94 (esophoria).

Agreement between Near Phoria Measurements

The mean differences between near phoria measurements are shown in Table 4. For both SP and RP, the phoria measurements were significantly more esophoric than those of the MT. This is not surprising given that the test distance for the

MT was 40 cm and the test distance for the SP was 25 cm and the test distance for the RP was ≤25 cm. The mean difference between SP and MT was 4.60Δ ± 9.09 (esophoria), p =

0.04, and mean difference between RP and MT was 7.30Δ ± 7.91 (esophoria), p = 0.001.

The mean difference between RP and SP was also significantly different from zero [2.71

± 3.83Δ (esophoria), p = 0.005].

Figures 5 through 9 show the level of agreement between phoria measurements taken with Modified Thorington and those taken with the autorefractor. When examining the scatter of data points in Figures 5, 6, 8 and 9, distinct patterns emerged. Note that the difference between phoria measurements for both SP vs MT and RP vs MT is dependent upon the mean (Figures 5 and 6). Additionally, the difference between phoria measurements for both SP vs MT and RP vs MT is related to the standard Modified

Thorington measurement (Figures 8 and 9). A regression model was fitted to the data and a reasonably strong R2 value was found showing a relationship between the mean of the phoria measurements and the difference between measurements. The Bland Altman

30

95% LoA are not a valid metric of agreement in this comparison. Because the difference between MT and phoria measurements taken with the autorefractor is a function of the mean phoria, the LoA will vary in proportion to the mean phoria.

AC/A Ratio

The mean ± SD gradient AC/A ratio for the entire sample was 4.59 ± 7.20Δ/D when using the equation for RP – SP response AC/A ratio. Mutti and coworkers (2000) suggested excluding subjects with an accommodative response of less than 1.00 D to avoid the problem of inflating the AC/A ratio by including very small denominators.11

This eliminated a significant number of subjects (9 out of 20 or 45%) and reduced the mean AC/A ratio for this sample to 2.37 ± 3.01Δ/D. The mean DP – SP response AC/A ratio for the sample was 1.77 ± 1.51Δ/D and the mean DP – RP response AC/A ratio for the sample was 1.46 ± 0.97Δ/D.

As the difference between MT and the various phoria measurements taken with the autorefractor was found to be a function of the mean phoria above, Pearson correlation coefficients were calculated to investigate a relationship in the differences between near phoria measurements and the AC/A ratio. The difference in SP and MT versus the DP – SP Response AC/A ratio was not found to be correlated (R2 = 0.02, p =

0.5, Figure 10), nor was the difference in RP and MT versus DP – RP Response AC/A ratio found to be correlated (R2 = 0.10, p = 0.2, Figure 11). There was a significant correlation found between the difference in RP and SP versus the RP – SP Response

AC/A ratio (R2 = 0.98, p = <0.0001, Figure 12).

31

Chapter 4: Discussion

The measurement of the phoria position has been shown to be a useful clinical tool in the diagnosis of binocular vision disorders and several methods of phoria measurement have been described. A common weakness of many of these methods is the exact amount of accommodation at the time of measurement must be assumed, which may lead to erroneous results in those who accommodate inaccurately. The first objective of this study was to determine if vergence and accommodation measurements taken with the 2-camera setup of the Grand Seiko autorefractor could be used as a feasible method of determining the heterophoria with the benefit of knowing the accommodative response. This methodology had been used in previous literature to measure a stimulus

AC/A ratio and a response AC/A ratio,11 but not specifically to determine the phoria. In this thesis, three phoria measurements were taken with the autorefractor, including one at distance (12 meters) and two at near (4-D stimulus at 25cm and 4-D response at less than

25cm).

The mean ± SD distance phoria as measured with the autorefractor in this study was +1.26Δ ± 5.75 esophoria. This appears to agree well with the reported findings of

Gwiazda and coworkers (2005) who found a mean distance phoria of +1.8∆ (esophoria) in emmetropes using a modified autorefractor with attached cover-test.70 Still, this result is slightly more esophoric compared to values published previously with common methods of clinical phoria measurement, as multiple studies have demonstrated orthophoria or up 32 to –1.0∆ ± 2.0 of exophoria when measured with both the distance Modified Thorington technique and the alternating cover test.7,26,51 The current study did not use any distance phoria test other than the autorefractor so it is difficult to determine if this difference in and of itself is the result of methodology or a sample who is more esophoric than what has been found traditionally. Additionally, although this difference appears to be significant, its clinical importance must be considered. The question of the minimum deviation observable by the examiner on the cover test has been evaluated previously and it was concluded that under ideal conditions, movements of less than 2∆ cannot be reliably perceived by the examiner, and that 2Δ should be considered the smallest deviation routinely detected by cover test under ideal conditions.71,72 Thus, although more esophoric that what has been reported previously, the distance phoria measurement obtained by the autorefractor seems to be clinically reasonable and acceptable.

Near phoria measurements in this study included Modified Thorington (MT), 4−D stimulus phoria (SP) and 4−D response phoria (RP). The mean phoria for MT was slightly exophoric, while the mean SP and RP produced phoria values that were more esophoric than those published previously at near (Table 3). Lyon and Rainey (2005) reported the average near phoria in their sample to be slightly exophoric (−1.0Δ ± 4.0),7 matching very closely with the mean MT (−1.50Δ ± 3.13) in our sample. Gwiazda and coworkers (2005) found a mean near phoria of -2.9Δ exophoria in emmetropic subjects.70

Conversely, the mean SP and RP phoria values in this thesis sample were both esophoric

(+3.09Δ ± 6.86 and +5.80Δ ± 5.94, respectively). One discrepancy in SP and RP measurements that must be taken into account when comparing these mean values is the

33 stimulus distance. The typical distance at which near phoria is measured clinically and in research is 40 cm (2.5 D), Gwiazda and coworkers used a stimulus distance of 33 cm (3.0

D),70 while a distance of 25 cm (4.0 D) was chosen in the current study to coincide with ongoing research in the lab exploring changes to ciliary body thickness with accommodation.73 This closer stimulus distance increases the amount of accommodation required to fixate the target, increasing the amount of accommodative convergence, and would be expected to increase the amount of esophoria or decrease the amount of exophoria. Additionally, with the subject looking through a viewing window directly in front of the eyes, it is possible that proximal accommodation could have played an additive role in the increase in esophoria at both distance and near. While the mean phoria at distance and near as measured with the autorefractor proved to be more esophoric than what may be expected clinically (Table 3), it is promising that these mean values are still clinically reasonable, and videos and still images taken with the autorefractor appear to have potential as a useful tool in determining the stimulus and, in particular, the response phoria. Still, the large amounts of esophoria at near as found by the autorefractor will require further research to determine validity.

A further objective of the current study was to compare the level of agreement in near phoria values in our sample when measured via the autorefractor versus the

Modified Thorington method. The phoria measurements made with the autorefractor for both the 4-D stimulus and the 4-D response were significantly more esophoric than measurements taken with the Modified Thorington (+4.60Δ and +7.30Δ, respectively).

Both of these differences would be clinically meaningful. This bias was dependent upon

34 the mean phoria (Figures 5 and 6), so results from this study would suggest that no single correction factor could be used to adjust for the differences in phoria between the autorefractor and Modified Thorington. Additionally, phoria measurements made at the

RP level were significantly more esophoric than SP measurements [+2.71Δ, (one-sample t-test; p = 0.005)] and this was also clinically meaningful.

When the difference between SP – MT and RP – MT were compared to the standard measurement (MT), Figures 8 and 9 appear to show that the MT has a much smaller range closer to orthophoria than the near phoria tests performed with the autorefractor. Additionally, those subjects who are orthophoric on MT appear to also be orthophoric on the autorefractor measurements, while most subjects with a non-zero phoria are different on the two tests. These figures further demonstrate that subjects are more esophoric when measured with the autorefractor.

The finding that the SP and RP measurements are both more esophoric than those found with the MT may be a result of a lack of full accommodation to the 2.50 D stimulus presented during the MT test, which would result in a more exophoric measurement. Mutti and coworkers (2000) found that a substantial proportion of children did not accommodate by more than 1.00 D at the 2.25-D stimulus level (311/847, 36.7%), while all but 13 of the children in their study accommodated by more than 1.00 D at the

4.37-D stimulus level. The accommodative stimulus for the MT test is 2.50 D, similar to the 2.25 D stimulus level presented in the study by Mutti and coworkers. It may be the case that if the stimulus is too low (2.50 D or less), people do not put forth an ample effort to accommodate, which may be a weakness of the MT test and phoria tests at a

35 similar test distance. Further investigation is necessary to determine if a closer accommodative stimulus (greater than 2.50 D) leads to more esophoric results with the

MT test.

The magnitude of the mean AC/A ratio of the entire sample was comparable to the mean AC/A found by Mutti and coworkers (2000). When subjects with an accommodative response of less than 1.00 D were excluded, however, the mean AC/A of the sample was lower than what has been reported previously, but that sample of subjects was also very small (N = 11). Pearson correlations were performed to determine if the

AC/A ratio was related to the differences between near phoria measurements of each subject. As measured with the autorefractor, the AC/A was not correlated with either RP

– MT or SP – MT (Figure 10 and Figure 11, respectively), which may be due to a high amount of noise in MT measurements. This noise may have been due to the subjective nature of the MT test, along with the potential for inaccurate or variable accommodation during MT testing as discussed earlier. When comparing the AC/A ratio to non- subjective near phoria testing with the autorefractor, there was a significant correlation found between the difference in RP and SP versus the RP – SP Response AC/A ratio

(Figure 12). This correlation suggests that subjects become more esophoric when forced to accommodate fully to a 4-D target, and that the amount of change between the stimulus versus response measurements is not the same for all subjects. It is dependent upon an individual’s AC/A. This was demonstrated by the fact that subjects with higher

AC/A ratios were considerably more esophoric when fully accommodating (Figure 12).

The trend for all correlations between near phoria measurements and AC/A ratios were in

36 the same direction, and if we had tested more subjects, the analyses related to MT may have been statistically significant.

Limitations of this study include a small sample size, which was in large part due to the amount of time required to analyze the two videos and extract usable data for each subject. Additionally, as has been discussed previously, the closer and somewhat untraditional distance to stimulus target for SP and RP makes it difficult to compare phoria findings in this study with those published previously. Perhaps in future studies a distance of 40 cm to SP could be used to make it more directly comparable to Modified

Thorington, alternating cover test, and other methods. One important limitation which did not have an effect on this sample but should be considered in future studies using this methodology is the necessity of acquiring high quality images during data gathering.

While sampling ten videos from the larger COSI study population, 2/10 (20%) of the videos sampled showed long stretches where Purkinje images I and IV were not visible.

It is unclear if this may have been due to a lack of training for technicians assisting in data collection or a lack of cooperation on the part of the subject, but this would obviously hinder the ability of researchers or clinicians to obtain meaningful data from the subject or patient.

Furthermore, we did not occlude one of the subject’s eyes for a specific amount of time prior to measuring the phoria in this study. It has been shown that vergence adaptation can occur after as little as 5 minutes of dissociation.74,75 Video length in this sample ranged from 3.63 minutes to 13.53 minutes, and while subjects were occluded for only a portion of the time, this disparity in video length may have impacted results via

37 differences in slow fusional vergence. Finally, while there were procedures in place to reduce the likelihood of a participant being strabismic (questionnaire, stereoacuity, minimum visual acuity), there was no direct measurement to distinguish a tropia from a phoria, which could have impacted current findings. If this methodology were to be used clinically, it may be useful to incorporate testing to distinguish between a strabismus and a phoria.

Video and still frames taken with the autorefractor and secondary CCD camera produced phoria measurements that were more esophoric than those obtained with the

Modified Thorington or reported in previous studies, but these results may be more accurate as the amount of accommodation at the time of measurement was known. The current methodology is also time-prohibitive, in its current structure, to be used with regularity. Further investigation is necessary to determine if the reported results are repeatable and if these methods could be performed in a more efficient manner, perhaps using video multiplexing during data collection instead of two separate videos. If so, this could be useful both in the clinic and as a screening tool in diagnosing and monitoring binocular vision disorders.

38

Muscle Primary Secondary Motor innervation Action Action

Lateral rectus Abduction None Abducens nerve (CNVI)

Medial rectus Adduction None Oculomotor nerve (CNIII, inferior division) Superior rectus Elevation Adduction, Oculomotor nerve (CNIII, superior Intorsion division) Inferior rectus Depression Adduction, Oculomotor nerve (CNIII, inferior Extorsion division) Superior oblique Intorsion Depression, Trochlear nerve (CNIV) Abduction Inferior oblique Extorsion Elevation, Oculomotor nerve (CNIII, inferior Abduction division)

Table 1. Innervation and actions of the extraocular muscles from the primary position. Adapted from Adler’s Physiology of the Eye.34

39

Characteristic: Number or %

Number of Participants: 20

Age (mean ± SD): 12.20 ± 4.54 yrs

Gender (% Female): 55 %

Race (% Caucasian): 95 %

Ethnicity (% Non-Hispanic): 95 %

Stereoacuity: 40ʺ = 65 % 60ʺ = 30 % 100ʺ = 5 % Visual Acuity (20/32 or better): 100%

Table 2. Demographic description of the 20 subjects in study sample.

40

Measure Mean SD Range Distance to Target

MT -1.50Δ 3.13 -8.00, +6.50 40 cm

DP 1.26Δ 5.75 -9.21, +15.13 12 m

SP 3.09Δ 6.86 -7.48, +14.96 25 cm

RP 5.80Δ 5.94 -5.19, +16.00 <25cm

Distance to 20.1 cm 1.59 15.0, 22.0 --- RP Target

Table 3. Mean, standard deviation, and distance to target of four different phoria measurements and distance to RP target across 20 subjects. Negative numbers signify exophoria. MT = Modified Thorington Phoria at 40 cm. DP = Distance Phoria measured with autorefractor. SP = 4-D Stimulus Phoria measured with autorefractor. RP = 4-D Response Phoria measured with autorefractor. Distance to RP target = distance from eye to letter target (in cm) that elicited a full 4 D response

41

Measure Difference (Δ) 95% LoA R2 Value p value

SP - MT +4.60Δ N/A +0.54 0.04

RP - MT +7.30Δ N/A +0.38 0.001

RP - SP +2.71Δ −4.80, 10.22 N/A 0.005

Table 4. Agreement between three different near phoria measurements across 20 subjects. Negative numbers signify exophoria. The Bland Altman 95% LoA are not a valid metric of agreement in the comparison between phoria measurements for both SP – MT and RP – MT as the difference was found to be dependent upon the mean. MT = Modified Thorington. SP = 4-D Stimulus Phoria measured with autorefractor. RP = 4-D Response Phoria measured with autorefractor. N/A = Not applicable.

42

Figure 1. Muscle Imbalance Measure Card (Bernell VTP, Mishawaka, IN, USA). Modified Thorington test card used for measurement of heterophoria.

43

Figure 2. Example photo of Grand Seiko Autorefractor measurement of right eye of Subject 171. Sphere (S), cylinder (C), axis (A), and pupil diameter (P. Diam) are displayed in lower left corner.

44

Figure 3. View from above the apparatus used to measure accommodation and vergence. Eye movements were recorded using an accessory CCD camera (A). Purkinje images were generated by an infrared light source (B) directed at a semisilvered mirror (C). The track with the letter target (D) was placed in front of the right eye. Subjects wore frames containing a gel filter (E) over the left eye and an empty aperture (F) over the right eye. The track was then moved in front of the left eye and the letter target was replaced with a dot and circle target (G). Calibration was achieved by the subject’s alternately fixating the dot and circle target. Accommodative response was measured by the autorefractor (H). The two video channels were recorded simultaneously using the Eyeline Video Surveillance Software computer program (I), with one channel for accommodative response and one for Purkinje images I and IV.

45

Figure 4. Example photo of Purkinje images I and IV produced by infrared light source (photo from Subject 057).

46

Figure 5. Difference versus mean plot for the agreement in phoria between 4D Stimulus Phoria (SP) and Modified Thorington (MT).

47

Figure 6. Difference versus mean plot for the agreement in phoria between 4D Response Phoria (RP) and Modified Thorington (MT).

48

Figure 7. Difference versus mean plot for the agreement in phoria between 4D Response Phoria (RP) and 4D Stimulus Phoria (SP).

49

Figure 8. Difference versus standard measurement for the agreement in phoria between 4D Stimulus Phoria (SP) and Modified Thorington (MT).

50

Figure 9. Difference versus standard measurement for the agreement in phoria between 4D Response Phoria (RP) and Modified Thorington (MT).

51

Figure 10. Lack of correlation (p = 0.5) between difference in SP and MT versus DP – SP Response AC/A ratio. The equation for DP – SP Response AC/A Ratio is [(DP - SP) / (ARDP – ARSP)]. MT = Modified Thorington. SP = 4-D Stimulus Phoria measured with autorefractor. DP = Distance Phoria. AC/A = Accommodative Convergence / Accommodation ratio.

52

Figure 11. Lack of correlation (p = 0.17) between difference in RP and MT versus DP – RP Response AC/A ratio. The equation for the DP – RP Response AC/A Ratio is [(DP - RP) / (ARDP – ARRP)]. MT = Modified Thorington.RP = 4-D Response Phoria measured with autorefractor. DP = Distance Phoria. AC/A = Accommodative Convergence / Accommodation ratio.

53

Figure 12. Correlation (p = <0.0001) between difference in RP and SP versus RP – SP Response AC/A ratio. The equation for the RP – SP Response AC/A Ratio is [(RP - SP) / (ARRP – ARSP)]. RP = 4-D Response Phoria measured with autorefractor. SP = 4-D Stimulus Phoria measured with autorefractor. AC/A = Accommodative Convergence / Accommodation ratio.

54

References

1. Group CITTS. Randomized clinical trial of treatments for symptomatic convergence insufficiency in children. Arch Ophthalmol. 2008;126(10):1336- 1349. 2. Porcar E, Martinez-Palomera A. Prevalence of general binocular dysfunctions in a population of university students. Optometry & Vision Science. 1997;74(2):111- 113. 3. Borsting EJ, Rouse MW, Mitchell GL, et al. Validity and reliability of the revised convergence insufficiency symptom survey in children aged 9 to 18 years. Optometry & Vision Science. 2003;80(12):832-838. 4. Pickwell LD, Hampshire R. The significance of inadequate convergence. Ophthalmic & Physiological Optics: The Journal Of The British College Of Ophthalmic Opticians (Optometrists). 1981;1(1):13-18. 5. Davis W. Esophoria and exophoria as the cause of obstinate asthenopia: Cure by surgical and other means. Archives of Ophthalmology. 1933;10(4):455-464. 6. Rainey BB, Schroeder TL, Goss DA, Grosvenor TP. Inter-examiner repeatability of heterophoria tests. Optom Vis Sci. 1998;75(10):719-726. 7. Lyon DW, Goss DA, Horner D, Downey JP, Rainey B. Normative data for modified Thorington phorias and prism bar vergences from the Benton-IU study. Optometry-Journal of the American Optometric Association. 2005;76(10):593- 599. 8. Barnard NA, Thomson WD. A quantitative analysis of eye movements during the cover test--a preliminary report. Ophthalmic & Physiological Optics: The Journal Of The British College Of Ophthalmic Opticians (Optometrists). 1995;15(5):413- 419. 9. Gwiazda J, Thorn F, Bauer J, Held R. Myopic children show insufficient accommodative response to blur. Invest Ophthalmol Vis Sci. 1993;34(3):690-694. 10. Anderson HA, Stuebing KK. Subjective versus Objective Accommodative Amplitude: Preschool to Presbyopia. Optometry And Vision Science: Official Publication Of The American Academy Of Optometry. 2014;91(11):1290-1301. 11. Mutti DO, Jones LA, Moeschberger ML, Zadnik K. AC/A ratio, age, and refractive error in children. Invest Ophthalmol Vis Sci. 2000;41(9):2469-2478. 12. Ogle KN, Mussey F, De HPA. Fixation disparity and the fusional processes in binocular single vision. American journal of ophthalmology. 1949;32(8):1069- 1087.

55

13. Schor CM, Ciuffreda KJ. Vergence eye movements: basic and clinical aspects. Butterworth-Heinemann; 1983. 14. Maddox EE. Investigations in the Relation between Convergence and Accommodation of the Eyes. Journal Of Anatomy And Physiology. 1886;20(Pt 4):565-584. 15. Heath GG. Components of accommodation. American journal of optometry and archives of American Academy of Optometry. 1956;33(11):569-579. 16. Morgan M. Relationship between accommodation and convergence. AMA archives of ophthalmology. 1952;47(6):745-759. 17. Morgan MW. The Maddox classification of vergence eye movements. American journal of optometry and physiological optics. 1980;57(9):537-539. 18. Rosenfield M. Tonic Vergence and Vergence Adaptation. Optometry and vision science : official publication of the American Academy of Optometry. 1997;74(5):303. 19. Stutterheim NA. The divergence of the primary position of the eyes. British Journal of Ophthalmology British Journal of Ophthalmology. 1934;18(5):256- 260. 20. Prajmovsky Meyers M. The Position of Eyes Under General Anesthesia. American journal of ophthalmology. 1951;34(12):1749-1752. 21. Stark L, Kenyon RV, Krishnan VV, Ciuffreda KJ. Disparity vergence: a proposed name for a dominant component of binocular vergence eye movements. American journal of optometry and physiological optics. 1980;57(9):606-609. 22. Rainey BB, Goss DA, Kidwell M, Feng B. Reliability of the response AC/A ratio determined using nearpoint autorefraction and simultaneous heterophoria measurement. Clinical and Experimental Optometry. 1998;81(5):185-192. 23. Oystreck DT, Lyons CJ. Comitant strabismus: Perspectives, present and future. Saudi journal of ophthalmology : official journal of the Saudi Ophthalmological Society. 2012;26(3):265-270. 24. Schiavi C. Comitant strabismus. Current Opinion In Ophthalmology. 1997;8(5):17-21. 25. Scheiman M, Wick B. Clinical management of binocular vision : heterophoric, accommodative, and eye movement disorders. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins; 2014. 26. Tait EF. Accommodative convergence. American journal of ophthalmology. 1951;34(8):1093-1107. 27. Scheiman M. The Convergence Insufficiency Treatment Trial: Design, Methods, and Baseline Data. Ophthalmic Epidemiology. 2008;15(1):24-36. 28. Scheiman M, Gwiazda J, Li T. Non-surgical interventions for convergence insufficiency. Cochrane Database of Systematic Reviews. 2011(3). 29. Rouse MW, Hyman L, Hussein M, Solan H. Frequency of convergence insufficiency in optometry clinic settings. Convergence Insufficiency and Reading Study (CIRS) Group. Optometry and vision science : official publication of the American Academy of Optometry. 1998;75(2):88-96.

56

30. Daum KM. Characteristics of convergence insufficiency. American journal of optometry and physiological optics. 1988;65(6):426-438. 31. Scheiman M, Mitchell GL, Cotter S, et al. A randomized clinical trial of treatments for convergence insufficiency in children. Archives of ophthalmology. 2005;123(1):14-24. 32. Demer JL, Kono R, Wright W. Magnetic resonance imaging of human extraocular muscles in convergence. Journal of neurophysiology. 2003;89(4):2072-2085. 33. de Gottrau P, Gajisin S, Roth A. Ocular Rectus Muscle Insertions Revisited: An Unusual Anatomic Approach. Cells Tissues Organs. 1994;151(4):268-272. 34. Adler FH, Kaufman PL, Levin LA, Alm A. Adler's Physiology of the Eye. Elsevier Health Sciences; 2011. 35. Wei Q, Sueda S, Pai DK. Physically-based modeling and simulation of extraocular muscles. JPBM Progress in Biophysics and Molecular Biology. 2010;103(2):273-283. 36. Remington LA, Remington LA. Clinical anatomy and physiology of the visual system. St. Louis, Mo.: Elsevier/Butterworth Heinemann; 2012. 37. Krewson WE. Comparison of the oblique extraocular muscles. Archives of Ophthalmology Archives of Ophthalmology. 1944;32(3):204-207. 38. Brazis PW. Localization of lesions of the oculomotor nerve: recent concepts. Mayo Clinic proceedings. 1991;66(10):1029-1035. 39. Kozicz T, Bittencourt JC, May PJ, et al. The Edinger-Westphal nucleus: a historical, structural and functional perspective on a dichotomous terminology. The Journal of comparative neurology. 2011;519(8):1413-1434. 40. Amemiya S, Aoki S, Ohtomo K. Cranial nerve assessment in cavernous sinus tumors with contrast-enhanced 3D fast-imaging employing steady-state acquisition MR imaging. Neuroradiology. 2009;51(7):467-470. 41. Dutton JJ. Atlas of Clinical and Surgical Orbital Anatomy: Expert Consult. Elsevier Health Sciences; 2011. 42. Yamaguchi K, Honma K. Development of the human abducens nucleus: A morphometric study. Brain and Development. 2012;34(9):712-718. 43. Grosvenor T, Grosvenor TP. Primary care optometry. Elsevier Health Sciences; 2007. 44. MacDonald AE. Exophoria and Esophoria. Canadian Medical Association Journal. 1931;25(3):306. 45. Babinsky E, Sreenivasan V, Candy TR. Near heterophoria in early childhood. Investigative ophthalmology & visual science. 2015:IOVS-14-14649. 46. Bridgeman GJO, Lyle TK, Worth CA, Chavasse FB. Worth and Chavasse's Squint : the binocular reflexes and the treatment of strabismus. London: Baillière, Tindall & Cox; 1959. 47. Alanazi SA, Alanazi MA, Osuagwu UL. Influence of age on measured anatomical and physiological interpupillary distance (far and near), and near heterophoria, in Arab males. Clinical ophthalmology (Auckland, N.Z.). 2013;7:711-724. 48. Anderson H, Stuebing KK, Fern KD, Manny RE. Ten-year changes in fusional vergence, phoria, and nearpoint of convergence in myopic children. Optometry 57

and vision science : official publication of the American Academy of Optometry. 2011;88(9):1060-1065. 49. Stidham DB, Borissova O, Borissov V, Prager TC. Effect of hyperopic laser in situ keratomileusis on ocular alignment and stereopsis in patients with accommodative esotropia1. Ophthalmology. 2002;109(6):1148-1153. 50. Rutstein RP. Update on accommodative esotropia. Optometry (St. Louis, Mo.). 2008;79(8):422-431. 51. Eames TH. Physiologic exophoria in relation to age. Archives of Ophthalmology Archives of Ophthalmology. 1933;9(1):104-105. 52. DOWLEY D. Heterophoria. Optometry & Vision Science. 1990;67(6):456-460. 53. Eames TH. A Comparison of the Ocular Characteristics of Unselected and Reading Disability Groups. The Journal of Educational Research The Journal of Educational Research. 1932;25(3):211-215. 54. Freier BE, Pickwell L. Physiological exophoria. Ophthalmic and Physiological Optics. 1983;3(3):267-272. 55. Yekta AA, Pickwell LD, Jenkins TC. Binocular vision, age and symptoms. Ophthalmic & Physiological Optics: The Journal Of The British College Of Ophthalmic Opticians (Optometrists). 1989;9(2):115-120. 56. Benjamin WJ. Borish's clinical refraction. Vol 2: Butterworth-Heinemann St. Louis; 2006. 57. Johns HA, Manny RE, Fern K, Hu Y-S. The intraexaminer and interexaminer repeatability of the alternate cover test using different prism neutralization endpoints. Optometry And Vision Science: Official Publication Of The American Academy Of Optometry. 2004;81(12):939-946. 58. Hrynchak PK, Herriot C, Irving EL. Comparison of alternate cover test reliability at near in non-strabismus between experienced and novice examiners. Ophthalmic & Physiological Optics: The Journal Of The British College Of Ophthalmic Opticians (Optometrists). 2010;30(3):304-309. 59. Casillas Casillas E, Rosenfield M. Comparison of subjective heterophoria testing with a phoropter and trial frame. Optometry And Vision Science: Official Publication Of The American Academy Of Optometry. 2006;83(4):237-241. 60. Cebrian JL, Antona B, Barrio A, Gonzalez E, Gutierrez A, Sanchez I. Repeatability of the modified Thorington card used to measure far heterophoria. Optometry And Vision Science: Official Publication Of The American Academy Of Optometry. 2014;91(7):786-792. 61. Daum KM. Analysis of seven methods of measuring the angle of deviation. American Journal Of Optometry And Physiological Optics. 1983;60(1):46-51. 62. Asakawa K, Ishikawa H, Shoji N. New methods for the assessment of accommodative convergence. Journal of pediatric ophthalmology and strabismus. 2008;46(5):273-277. 63. Morgan MW. The clinical aspects of accommodation and convergence. American Journal of Optometry. 1944;21:301-313. 64. Jiménez R, Pérez MA, García JA, González MD. Statistical normal values of visual parameters that characterize binocular function in children. Ophthalmic & 58

Physiological Optics: The Journal Of The British College Of Ophthalmic Opticians (Optometrists). 2004;24(6):528-542. 65. Barry JC, Effert R, Reim M, Meyer-Ebrecht D. Computational principles in Purkinje I and IV reflection pattern evaluation for the assessment of ocular alignment. Investigative Ophthalmology & Visual Science. 1994;35(13):4205- 4218. 66. VIP Group ViPSG. Preschool vision screening tests administered by nurse screeners compared with lay screeners in the vision in preschoolers study. Investigative Ophthalmology & Visual Science. 2005;46(8):2639-2648. 67. Harris PT, R; Thielke, R, Payne, J; Gonzalez, N; Conde, JG. Research electronic data capture (REDCap) - A metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377-381. 68. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet. 1986;1(8476):307-310. 69. Bland JM, Altman DG. Comparing methods of measurement: why plotting difference against standard method is misleading. The Lancet. 1995;346(8982):1085-1087. 70. Gwiazda J, Thorn F, Held R. Accommodation, accommodative convergence, and response AC/A ratios before and at the onset of myopia in children. Optom Vis Sci. 2005;82(4):273-278. 71. Ludvigh E. Amount of eye movement objectively perceptible to the unaided eye. American journal of ophthalmology. 1949;32(5). 72. Romano PE, von Noorden GK. Limitations of cover test in detecting strabismus. American Journal Of Ophthalmology. 1971;72(1):10-12. 73. Lewis HA, Kao CY, Sinnott LT, Bailey MD. Changes in ciliary muscle thickness during accommodation in children. Optometry and vision science : official publication of the American Academy of Optometry. 2012;89(5):727-737. 74. Rosenfield M, Chun TW, Fischer SE. Effect of prolonged dissociation on the subjective measurement of near heterophoria. Ophthalmic & physiological optics : the journal of the British College of Ophthalmic Opticians (Optometrists). 1997;17(6):478-482. 75. Toole AJ, Fogt N. The forced vergence cover test and phoria adaptation. Ophthalmic & Physiological Optics: The Journal Of The British College Of Ophthalmic Opticians (Optometrists). 2007;27(5):461-472.

59