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Correlation Between AC/A Ratio and Ciliary Muscle Morphology in School-Age Children THESIS Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in the Graduate School of The Ohio State University By Haind Fadel, M.D. Graduate Program in Vision Science The Ohio State University 2011 Master's Examination Committee: Melissa D. Bailey, OD PhD and Jeffrey J. Walline, OD PhD, Advisors Lisa A. Jones-Jordan, PhD Copyright by Haind Fadel, MD 2011 Abstract Purpose: To examine how the morphology of the ciliary muscle varies as a function of AC/A ratio and to investigate the difference between the thickness of the ciliary muscle during accommodation and during cycloplegia. Methods: Measurements were performed on the right eye only of thirty children aged 6 to 12 years. Height and weight were measured. Accommodative response was measured by autorefraction through habitual correction. Axial length was measured with the IOLMaster. Temporal ciliary muscle images from anterior segment Vistante OCT at 1mm (CMT1), 2mm (CMT2), and 3mm (CMT3) posterior to the scleral spur at 0D and 4D stimulus levels and under cycloplegia were measured four times each. Accommodative response and pupil size data were simultaneously recorded by the PowerRefractor during ciliary muscle measurements. Result: There were no significant correlations between AC/A ratio and the changes in ciliary muscle thicknesses, CMT1 (P= 0.8), CMT2 (P= 0.8), CMT3 (P=0.9), or CMT MAX (P=0.9). Axial length has an inverse correlation with the changes in ciliary muscle thicknesses at CMT1 (P=0.004), CMT2 (P=0.04), and CMT MAX (P= 0.03), but not with CMT3 (P= 0.07). However, when the extreme changes in CMT measures were removed, there was not a significant correlation with axial length at any location. Age was not ii significantly correlated with changes in CMT1 (P=0.18), CMT2 (P=0.4), CMT3 (P=0.5), or CMT MAX (P= 0.4). Conclusions: The AC/A ratio did not appear to be significantly correlated with the changes in ciliary muscle thicknesses with accommodation in this study. Increased axial length was correlated with thinning of the ciliary muscle, possibly due to the positive correlation between axial length and ciliary muscle thickness. Further investigation is necessary to determine whether the association truly exists and the potential reason for the relationship. iii Dedication “Dedicated to my family specially my beloved parents for encouraging and instilling the important of hard work and high education, to my sincere husband for his understanding and support, and to all Libyans who paid their lives for our beloved homeland” Haind Fadel iv Acknowledgments It is an honor for me to thank who made this thesis possible: Dr. Melissa Bailey and Dr. Jeffrey Walline who were abundantly helpful and offered invaluable assistance, support and guidance as my advisers. Deepest gratitude for Austen Tanner who teaches me how to read tapes and for his support. Special thanks for Dr. Karla Zadnik for guidance, support and for acceptance to be my first adviser. Dr. Lisa Jones-Jordan for serving on the thesis committee. Thank you! v Vita 1998................................................................Aligelat High School 2006................................................................M.D. Zawia Medical School 2010 to present ..............................................Graduate Student, Department of Vision Science, The Ohio State University Fields of Study Major Field: Vision Science vi Table of Contents Abstract ............................................................................................................................... ii Dedication .......................................................................................................................... iv Acknowledgments............................................................................................................... v Vita..................................................................................................................................... vi List of Tables ..................................................................................................................... ix List of Figures ..................................................................................................................... x Chapter 1: Introduction ....................................................................................................... 1 1.1 Accommodation ........................................................................................................ 1 1.2 AC/A Ratio ............................................................................................................... 5 1.3 Binocular Dysfunction and AC/A Ratio ................................................................... 6 1.4 Ciliary Muscle .......................................................................................................... 7 1.5 Ciliary Muscle Innervation ....................................................................................... 9 1.6 Accommodation, Ciliary Muscle, and Refractive Error ......................................... 10 1.7 AC/A Ratio and Myopia ......................................................................................... 12 vii Chapter 2: Methods .......................................................................................................... 14 2.1 Subjects ................................................................................................................... 14 2.2 Measurments ........................................................................................................... 14 2.3 Acoommdative Response........................................................................................ 16 2.4 Ciliary Muscle Image Analyses .............................................................................. 17 2.5 Data Analyses.......................................................................................................... 17 Chapter 3: Results ............................................................................................................. 19 Chapter 4: Discussion ......................................................Error! Bookmark not defined.3 References......................................................................................................................... 46 viii List of Tables Table 1. Demographic characteristics of the study sample Error! Bookmark not defined.6 Table 1. Demographic characteristics of the study example. ........................................... 26 Table 2. Demographic characteristic of the changes of ciliary muscle thicknesses per unit of accommodation............................................................................................................. 27 Table 3. Multivariate linear regression models for changes in each of the ciliary muscle thickness locations. ........................................................................................................... 28 Table 4. Multivariate linear regression model for changes in ciliary muscle thickness at each location without the outliers. .................................................................................... 29 ix List of Figures Figure 1. Relationship between changes in CMT1 and axial length. ...................................... 30 Figure 2. Relationship between changes in CMT2 and axial length. ...................................... 31 Figure 3. Relationship between changes in CMT3 and axial length. ...................................... 32 Figure 4. Relationship between changes in CMTMAX and axial length. ............................... 33 Figure 5. Relationship between changes in CMT1 and age . ................................................. 34 Figure 6. Relationship between changes in CMT2 and age ............................................. ….35 Figure 7. Relationship between changes in CMT3 and age ............................................. ….36 Figure 8. Relationship between changes in CMTMAX and age ...................................... ….37 Figure 9. Relationship between changes in CMT1 and AC/A ratio .................................. ….38 Figure 10. Relationship between changes in CMT2 and AC/A ratio ................................ ….39 Figure 11. Relationship between changes in CMT3 and AC/A ratio ................................ ….40 Figure 12. Relationship between changes in CMTMAX and AC/A ratio ......................... ….41 Figure 13. Relationship between changes in CMT1(without outliers) and axial length ........... 42 Figure 14. Relationship between changes in CMT2(without outliers) and axial length ........... 43 Figure 15. Relationship between changes in CMT3(without outliers) and axial length ........... 44 Figure 16. Relationship between changes in CMTMAX(without outliers) and axial length ......45 x Chapter 1: Introduction The mechanism and components of accommodation are fundamental to understanding the pathophysiology of the eye. As it is well known, the ciliary muscle is the most active component in accommodation. It is significant to know changes of morphology of the ciliary muscle with accommodation. In the other words, ciliary muscle thickness might be considered as a significant anatomical measurement for accommodation dysfunction in some ocular problems, such as refractive error. The data from this study provide ciliary muscle thickness and accommodation values for a variety of refractive errors in school-age children. They also help to understand AC/A ratio through ciliary muscle function. 1.1 Accommodation Accommodation is the process by which a dioptric change in power of crystalline lens of the eye allows it to focus on objects at different distances. The accommodation apparatus includes the ciliary muscle contraction, the release of the zonular fiber tension, the increase in the crystalline lens curvature (particularly the front surface), the increase in lens thickness, the decrease in equatorial diameter, and the decrease in pupil size.1,2 Despite its seeming simplicity, the mechanism of accommodation is still a subject for 1 debate. Helmholtz’s theory, as proposed by Von Helmholtz in 1855, is the most widely accepted theory and concludes that during accommodation the diameter of the inner ring of the ciliary muscle decreases due to muscle contraction, which reduces the tension on the lens zonules. By loosening the zonular tension, the crystalline lens responds only to capsular tension which results in increasing vertex curvatures and decreasing diameter of the crystalline lens.1, 3, 4 Schachar provided an equatorial tension theory which proposed that contraction of ciliary muscle during accommodation decreases the tension on the equatorial zonular fibers which increases the equatorial crystalline lens diameter toward the sclera.5 In addition, releasing tension on the anterior and posterior zonular fibers makes the lens radii steepen.5 Near accommodation is associated with changes in convergence and miosis, which is termed as the near triad. The association is a result of the synkinetic combination of nerves that innervate the medial recti, iris and ciliary muscles.6 Convergence provides the correct position of the near object image in relation to the fovea to eliminate diplopia. The association between pupil constriction and accommodation provides appropriate depth of focus. Kasthurirangan and co-workers investigated the pupil response during accommodation in subjects aged 14-45 years. As a result of the study, they found that with increasing age, the amount of pupil constriction increases per diopter of accommodative response regardless of the amount of accommodative stimulus amplitude.7 Kasthurirangan and co-workers concluded that the increase of pupil 2 constriction with age increased the depth focus, which might potentially compensate for inaccurate accommodation.7 There are many studies discussing the development of accommodation. Braddick and co-workers investigated the ability of accommodation among infants with different ages.8 They suggest that although infants under one month of age tend to over accommodate at distance targets, they are able to change their accommodation in the right direction. Furthermore, the accuracy of accommodation range increases over the first six months of life.8 The link between accommodation and vergence has been suggested to be dependent upon the development of accommodation in infancy.9 Hainline and co-workers investigated the development of simultaneous binocular accommodation and vergence in infants.10 They found little lags of accommodation with appropriate convergence and concluded that this link between accommodation and convergence in infancy is still not completely developed.10 In 1912, Duane presented the data of the accommodative amplitude for subjects aged 8 to 70 years that are still used as standard values to determine the amplitude of accommodation according to age.11 According to the data, he created the standard formulas: minimum amplitude = 15 – 0.25 * age, maximum amplitude = 25 – 0.4 * age, and expected amplitude = 18.5 – 0.3 * age. However, even though these formulas were widely accepted, the reliability of these data for the age group between 8 to 12 years is still under discussion, as it only includes 35 subjects.11 3 As it is well known, accommodation has been considered in terms of four components: (1) tonic accommodation, (2) convergence accommodation, (3) proximal accommodation, and (4) reflex accommodation. Reflex accommodation represents accommodation response and its stimulus by automatic adjustment of the refractive state to maintain a clear retinal image.12 Proximal accommodation is the influence of the object distance in the visual field upon accommodation and convergence. Tonic accommodation occurs when there is no specific innervation or adequate stimulus for accommodative response, and this state tends to maintain a particular accommodative value other than zero regardless of accommodative stimulus. Interestingly, the association between myopia and tonic accommodation has been investigated in many studies.12 Convergence accommodation is the amount of accommodation associated with convergence in the absence of blur.13 In addition to the association between accommodation and convergence systems, the crosslink components of both systems are considered an important issue to focus on how these components would affect AC/A and CA/C ratios. On the other hand, there are many types of accommodative dysfunctions, such as accommodative insufficiency, accommodative fatigue, accommodative infacility, accommodative spasm and accommodative paralysis. Accommodative insufficiency is a sensory motor condition where the patient is unable to sustain focus at near and his accommodative amplitude is lower than age expected norms.14 When the patient is unable to sustain focus at near, but still has normal age expected accommodative amplitudes, this condition called accommodative fatigue.15 This condition is a result of the inability of the ciliary muscle to maintain contraction for near 4 accommodation and the accommodation shifts to the far target accommodation value.16 Accommodative spasm results from overstimulation of the parasympathetic system, so the accommodative response remains constant regardless of the distance of stimulus. Accommodative spasm often occurs as a part of a spasm of near reflex (SNR) triad.17 Paralysis of accommodation is an uncommon condition resulting from the inability of the accommodation system to respond to any stimulus. This condition can be unilateral or bilateral, depending on the cause, such as trauma or local cycloplegic drugs or bilateral as a result of systemic diseases or toxicity.18 1.2 AC/A Ratio Normal viewing condition requires adequate accommodation and convergence systems. The response of the two systems depends on the crosslink components that are measured by AC/A and CA/C ratios.19 The accommodative convergence accommodation (AC/A) ratio is defined as the amount of accommodative convergence induced per unit of accommodative response.20 AC/A ratio is considered as a method to determine the association between the convergence and accommodation system and as an important component of the near reflex mechanism. Although many studies agree that accommodative amplitude decreases with age, age- related AC/A ratio changes are still a controversial topic.21 The AC/A ratio can be measured by different methods. The AC/A ratio by the Heterophoria method equals the summation of interpupillary distance in centimeters and the difference between eye deviation while looking at optical infinity and the deviation while looking at near 5 with full refractive error correction divided by accommodative stimulus at near in diopters. (AC/A = PD + (∆n - ∆o) ⁄ D). In the gradient method, ophthalmic lenses are used as the accommodation stimulus instead of viewing distance. In the gradient method, the AC/A ratio equals the difference between the original deviation and the deviation with lens divided by the power of the lens. 1.3 Binocular Dysfunction and AC/A Ratio Convergence insufficiency (CI) is one of the most common binocular vision disorders and muscular asthenopias.22 CI is defined as inability to maintain appropriate binocular convergence. As a result, the accommodation system for patients with CI works more in order to maintain normal binocular convergence.23 CI is often associated with a variety of symptoms such as diplopia, eyestrain, headache, blurred vision, inability to read for long time or lack of comprehension after reading, and difficulty concentrating.24-28 Convergence insufficiency has five common clinical characteristic: near exophoria greater than distance phoria; reduced convergence at near (NPC); reduced positive fusional amplitude, particularly at near; low AC/A ratio as a result of low convergence; and low or absent accommodative lag as a result of excessive accommodative effort.28 There are still debates as to the exact effect of CI on AC/A ratio. Brautaset and Jennings suggest that accommodative adaptation would rapidly replace reflex accommodation at near. Furthermore, it reduces accommodative vergence which is responsible for near exophoria and low AC/A ratio.28 However, the changes in AC/A ratio are considered as an outcome criterion to evaluate the efficacy of convergence 6 insufficiency treatments. Brautaset and Jennings found that there has no change in AC/A and CA/C ratios after 12 weeks period of home- based orthoptic treatment.23 Convergence excess (esotropia) is defined as eso-deviation of the eyes for near fixation greater than distance fixation. Accommodative demand is considered as one of direct causes of excessive convergence which leads to increasing AC/A ratio as a diagnostic findings. Although, for some patients who have a normal accommodative response, the AC/A ratio has been found within normal range.29 Accommodative esotropia is the most common type of misalignment and it is also about 50% of convergence deviations. Accommodative esotropia is the result of excessive accommodation required in order to overcome the blur which is produced by uncorrected hyperopia.30, 31 1.4 Ciliary Muscle The ciliary muscle is a well-developed, multi-unit smooth muscle that has been subdivided into three fibers, differentiated according to their positions and orientation within ciliary body: circular, radial, and longitudinal.32 The ciliary muscle is considered as the most active force responsible for changing the crystalline lens shape in the accommodation process. According to the orientation of smooth muscle bundles, the outer or longitudinal portion starts from the epi-choroid, runs longitudinally along the inner layers of sclera, and finally attaches to the scleral spur and the trabecular meshwork. The intermediate or radial portion fans out from the anterior chamber angle 7 posteriorly toward the ciliary processes. And the inner, circular portion arranges parallel with the margin of the cornea. 32, 33 In other words, the ciliary muscle attaches anteriorly to the scleral spur and the trabecular meshwork, which are considered as a fixed anchor against the ciliary muscle contraction. The ciliary muscle inserts posteriorly into the stroma of the choroid by elastic tendons.32According to positions of the ciliary muscle fibers, the longitudinal fibers are immediately under the sclera. Radial fibers are located under the longitudinal fibers toward the vitreous. The circular fibers are located most anteriorly which are the closest fibers to the lens equators.32 The ciliary muscle is not a typical smooth muscle. Ciliary muscle has features from all three muscle types: smooth, striate, and cardiac. 34 The ciliary muscle, like other smooth muscles, has a single central nucleus for each fiber, with an axis parallel to the longitudinal axis of the cell. Unlike other smooth muscles, the cell of the ciliary muscle has a well-developed Golgi apparatus and more mitochondria.28 The ciliary muscle also has systematic arrangement of endoplasmic reticulum framework that resembles the endoplasmic reticulum of the striated muscle. Although the three layers of muscle fibers are not truly separate, they have different cellular composition. The radial fibers contain more mitochondria than others and fewer numbers of myofibrils than circular fibers. On the other hand, the tips of the longitudinal fibers have more myofibrils and fewer mitochondria.32 In spite of some debates about which muscle fiber layer has the most significant role in accommodation, ciliary muscle contraction during accommodation reduces ciliary 8 muscle diameter, shifts the muscle anteriorly, and displaces the surrounding ciliary processes and the zonular fiber antero-inward toward the lens equator. 28, 35 There is not enough information on the morphology of the ciliary muscle in children. Most of the studies focus on the role of the ciliary muscle in presbyopia, so they investigate the morphology and aging effect on the ciliary muscle function in prepresbyopic and presbyopic adults. 36, 37 By age of 24 months in children, the ciliary body length was found to be three-quarters of the ciliary body length in adults.38 1.5 Ciliary Muscle Innervation The ciliary muscle is innervated mainly by the parasympathetic branch of autonomic nervous system, which originates in the Edinger-Westphal nucleus and runs with the third cranial nerve to form a synapse in the ciliary ganglion to innervate the ciliary muscle via short ciliary nerves. The main role of the parasympathetic nervous system is to mediate rapid focusing accommodation by releasing the acetylcholine into muscarinic receptors. It is also known that the sympathetic nervous system supplies the ciliary muscle via the first division of the trigeminal nerve by releasing noradrenaline into α1 and β2 inhibitory adrenoreceptors. It is thought that the role of the sympathetic nervous system might be significant during tasks that require sustained accommodation rather than rapid focusing accommodation. However, the exact role of the sympathetic nervous system in accommodation is still unclear.24 However, the ciliary muscle is innervated by the autonomic nervous system (mainly parasympathetic axons of the oculomotor nerve). The fine structure of the ciliary muscle has more mylinated and unmylinated nerve fibers than 9 other types of smooth muscle.39 Isbikaw suggests that each ciliary muscle cell might have its own innervation.34 In order to understand morphological changes and the exact function of ciliary muscle during accommodation, much research has focused on pharmacologically affecting accommodation, whether by using parasymathomimetics or parasympatholytics drugs. While pharmacological research helps to understand the mechanism of accommodation, accommodative response is not the same as the physiological condition, because it does not stimulate the Edinger-Westphal nucleus to recognize the physiological changes and function of the ciliary muscle.40 Accommodation is considered as a part of the three physiologic functions called the accommodative triad or near triad: accommodation, convergence, and pupil constriction. It is generally agreed that these three events are neurophysiologically coupled in the brain.32 The Edinger-Westphal (EW) nucleus is located dorsal to the oculomotor nucleus where its neurons supply the extraocular muscles. The EW nucleus innervates the iris and the ciliary muscles via the ciliary ganglion. These anatomical and neurophysiological associations help to understand this triad.32 1.6 Accommodation, Ciliary Muscle and Refractive Error The association between myopia and near work suggests that accommodation and crystalline lens might be involved in the development and progression of myopia. Many measurements such as amplitude of accommodation, tonic accommodation, accommodative facility, adaptation and accommodative stimulus response curves have 10 been investigated to determine the association between myopia development and progression and changes in these measurements. Significant correlations between myopia progression and lag of accommodation and high AC/A ratio have been found, but whether or not accommodation changes before or after myopia onset is still unclear.41,42 Tonic accommodation has also attracted interest as a risk factor for myopia.43 Gwiazda and co-workers have found that tonic accommodation varies with highest values in hyperopes, intermediate values in emmetropes, and the lowest values in juvenile-onset myopia.44 Early theories have widely focused on the mechanical forces of ciliary muscle contraction on the sclera rather than its effects on the quality of the retinal image. Mutti and co-workers examined the differences in global shape of the eye in children.45 They suggest that the equatorial restriction of the eye might be the direct cause of the prolate shape of the eye. There are studies investigating the morphology and configuration of ciliary muscle during accommodation in order to understand how these parameters influence myopia.46 It was reported that during near accommodation there were significant increases in the thickness of the anterior part of the ciliary body with an anterior inward shift of the ciliary body.46 Oliveira and co-workers reported negative correlation between axial length and ciliary body thickness in non-growing eye in adulthood.47 In addition, Bailey and co-workers determined a thicker nasal ciliary body in the myopic eye than the non-myopic eye in childhood.48 On the other hand, Sheppard and Davies examined nasal and temporal ciliary muscle diameters and axial length in prepresbyopic subjects, and they found there was a significant positive correlation 11 between length of ciliary muscle and axial length, but there is no significant association between axial length and the thickness.49Animal studies that focus on hyperopic defocus to induce axial myopia suggest that lag of accommodation as a result of prolonged accommodation might explain the association between near work and axial myopia development. 1.7 AC/A Ratio and Myopia By definition, myopia is condition of refraction where the parallel rays of light are focused in front of the retina when the eye is in the resting state.50 Measurements for myopia are done by using the spherical power, measured in diopters. The diverging lens makes the light focus on the retina.51 Clinically, patients with myopia present with blurred far vision, headaches, rubbing of the eyes, and even it could present as squinting,52 especially when the patients are trying to see objects from a very long distance. Myopia has been subclassified according to its etiology, whether physiological or pathological. The first type usually occurs as a result of axial length greater than normal, but without associated ocular pathology. The second type is basically caused by abnormal length increase in the eyeball which is usually associated a decrease in the thickness of the scleral wall.50 Another subclassification was added recently for myopia. This new subclassification was based on the age-related prevalence. Congenital or infantile myopia occurs at birth and in newborns. Adult-onset, also named late-onset myopia, as described by Grosvenor, consists of patients who became myopic after the age of 17 years.53 12 Environmental factors may play an important role in the etiology of the late-onset myopia. Some investigators have mentioned in many studies the positive correlation between myopia pathogenesis and near work (Bear and Richler).54 This has been hypothesized to the increase the convergence and accommodation levels by near work leading to induce this kind of error of refraction.55 It is widely accepted that myopia is a result of the inability of anterior segment components to compensate for posterior vitreous chamber growth.56 Some researchers have investigated the relationship between ocular structures, such as ciliary muscle thickness and the development and progression of myopia, while others have investigated the correlation between some accommodative measurements and myopia development and progression. The elevation of AC/A ratio is considered risk factor for developing myopia.20 Furthermore, after the onset of myopia, accommodative response becomes less accurate, which indicates that more convergence is required and the AC/A ratio increases. There are some studies investigating the correlation between myopia onset and changes of AC/A ratio in adults. One of these studies found that the AC/A ratio was higher among the early-onset myopia group than emmetropes and late-onset myopia group.57 In addition, AC/A ratio was higher among the late-onset myopia in comparison to emmetropes. Furthermore, the AC/A ratio increased in emmetropes who became myopic later. All of these findings suggest that changes in AC/A ratio may help predict myopia onset among adults.5 13 Chapter 2: Methods 2.1 Subjects Thirty children between 6 to 14 years, regardless of refractive error, were recruited within the Ohio State University College of Optometry. Children who had any other ocular disease, history of strabismus or eye surgery, or used of medications affecting the ciliary body were excluded from the study. After discussing the procedures of the study, all children and their parents provided written informed consent. The protocol was approved by the Ohio State University Biomedical Institution Review Board. 2.2 Measurements The right eyes were examined regardless of what children wore for correction. Children who did not wear their prescribed lens during tests were considered as uncorrected subjects. In normal examination room illumination, high contrast visual acuity was measured monocularly at 4 meters by using logMAR charts. If the subject got 3 or more letters correct credit was given for that line of acuity. If three or more letters were incorrectly identified on a line, the visual acuity test was stopped, and the total number of letters read correctly was recorded. 14 Near horizontal phoria was measured using Modified Thorington Card at d 40 cm with a Maddox rod over the right eye. The horizontal phoria was recorded while the subject was looking at the light in the center of the card. Convergence eye movement was recorded simultaneously with accommodation response data collection. The infrared light produced Purkinje images I and IV, which were recorded and analyzed for the convergence response. Monocular (right eye) accommodative response was measured by using the Grand Seiko WR-5100K (Grand Seiko Co., Hiroshima, Japan) autorefractor. Accommodative response was measured on the right eye at 0.00 D and 4.00 D of stimulus levels while subjects were wearing their habitual correction. Five readings for each stimulus were recorded and the spherical equivalent mean was calculated for data analysis. The temporal ciliary muscle of the right eye was measured by using the Zeiss Visante Anterior segment OCT at 0D and 4D stimulus levels. Accommodative response was measured by using an infrared optometry PowerRefractor (Multichannel System, Reutlingen, Germany) in order to determine the actual accommodative value. For each accommodative stimulus level, accommodative measurements and pupil size were measured while four ciliary muscle images were obtained by using the Zeiss Visante Anterior Segment OCT. During collection of ciliary muscle and simultaneous accommodative response data, a special trial frame was used for children who wore spectacle correction. The right eye was covered with a gel filter (Wratten 89B; Kodak, Rochester, New York) that was used to occlude vision, to transmit only light with wavelengths longer than 680 nm, and to take 15 images for the eye without disturbing the ciliary muscle images. In addition, PowerRefractor data were collected for the left eye through the appropriate trial lens for correction that reflected accommodative response and not refractive error. For children with spectacle correction, a special trial frame was used during data collection for ciliary muscle and simultaneous accommodative response. The spherical equivalent was measured and the appropriate trial lens was used for the left eye Intra ocular pressure was measured with the Tonopen after instilling one drop of 0.5% proparacaine in the right eye. The data for the height and weight for each child were collected by using a standard medical scale and stadiometer. The central axial length of the eye was measured by using the IOLMaster (Carl Zeiss Meditec, Dublin, CA). High-confidence measurements, which were defined as measurements with a signal to noise ratio greater than 2.0 for five axial lengths were obtained. The mean of the five measurements was used for data analysis. Cycloplegic measurements were collected 25 minutes after the second drop of tropicamide was instilled in the eye. Cycloplegic refractive error was measured by using the Grand Seiko autorefractor and the mean of 10 reading was used for data analysis. Four images of cycloplegic measurements of the temporal ciliary muscle of the right eye were collected by using the Zeiss Visante Anterior Segment OCT. 2.3 Accommodative Response PowerRefractor data were collected simultaneously with the ciliary muscle images for the 0D and 4D stimulus levels. The OCT software automatically created time stamps for 16 each ciliary muscle image and then matched those time stamps to the time in seconds from the PoweRefractor spreadsheet. For each ciliary muscle image, five seconds of accommodative data were selected and the mean of each five second interval was taken for both pupil size and accommodative response. The data of the right eye were used for analysis unless the data of the left eye were the only available data. Left eyes of all subjects were corrected with spectacles during ciliary muscle imaging for both eyes. The mean of the right and left eye data was exceptionally taken when data were sparse. 2.4 Ciliary Muscle Image Analyses Data of all ciliary muscle imaging were analyzed by using a semi-automatic algorithm. The scleral spur, which is the anterior insertion point of the ciliary muscle was used as an anatomical landmark and its location was manually selected. The ocular structures were identified in the images and the ciliary muscle boundaries were generated. Refractive index corrections were considered to obtain accurate measurements. A refractive index of 1.41 was used for the scleral measurements and a refractive index of 1.38 for ciliary muscle measurements. Four ciliary muscle thicknesses were taken; the thickest portion (CMTMAX) was collected under non-cycloplegic conditions. 17 2.5 Data Analyses The data of accommodative response for three subjects were excluded from the PowerRefractor as a result of equipment malformation. Accommodative response was calculated for each subject with the following equation: ACC = Poweref – (M – spectsph), where ACC is the corrected accommodative response, Poweref is the mean reading of the powerRefractor for at specific stimulus level, M is the cycloplegic spherical equivalent refractive error, and spectsph is the spherical equivalent refractive error. According to the ciliary muscle imaging data, one subject was excluded from regression modeling for only cycloplegic muscle thickness analysis, because this subject did not have usable cycloplegic ciliary muscle images. This subject was included in all other regression models. Nine subjects were excluded from AC/A ratio data due to inability to find clear Purkinji images in the video tape. Descriptive statistics and linear regression analyses were used to analyze the data and determine the association between the changes in ciliary muscle thickness and AC/A ratio data. Data were analyzed by using IMB SPSS version 19 statistical software. The response of AC/A ratio (in prism diopters per diopter) was determined by following this formula 18 where 0.1745 equals radians ⁄10°, AC4D and AC 0D are the average eye positions at 4.37 D and 0.0 D stimulus levels in pixels, calibration is pixels / 10°, and AR4D and AR0D are the average accommodative responses at 4.37 D and 0.0 D stimulus levels.20 19 CHAPTER 3: RESULTS 3.1 General Sample Characteristics The general characteristics of the study sample are listed in Table 1. The mean ± standard deviation (SD) age of the subjects was 8.9 ± 2.0 years, and the mean ± SD AC/A ratio was 6.9 ± 4.4. The average spherical equivalent was + 0 .40 ± 2.28 D with a range of −7.40 to +5.43 D. The mean ± SD axial length was 23.10 ± 1.10 mm. General characteristics of changes of ciliary muscle thickness per unit of accommodation are summarized in Table 2. The mean ± SD changes in CMT1, CMT2, CMT3, and CMTMAX were 0.15 ± 0.40 mm, 0.07 ± 0.24 mm, 0.04 ± 0.15 mm, and 0.13 ± 0.40 mm, respectively. 3.2 Graphical Analysis of Univariate Relationships In the univariate linear regression model for axial length and changes in ciliary muscle thicknesses in each location, there were no significant correlations between axial length and the changes in ciliary muscle thickness at each location. The univariate regression between axial length change and CMT1 was not significant (R2 = 0.12, p = 0.9, Figure 1). The univariate regression between axial length and changes in CMT2 (R2 =0.06, p= 0.17, Figure 2), CMT3 (R2 = 0.04, p= 0.24, Figure 3), and CMTMAX (R2= 0.07, p= 0.14, Figure 4) were also not significant. There were no significant univariate 20 correlations between age and changes in ciliary muscle thickness at any location (CMT1, R2 = 0.014 , p =0.57, Figure 5; CMT2, R2 = 0.006 , p = 0.67, Figure 6; CMT3, R2 = 0.006 , p =0.68, Figure 7; and CMTMAX. R2 = 0.01 , p =0.59, Figure 8), respectively. There were no significant univariate correlations with AC/A ratio and changes in ciliary muscle thickness at each location (CMT1, CMT2, CMT3, CMTMAX which were (CMT1, R2 = 0.003, p =0.85, Figure 9; CMT2, R2 = 0.004, p = 0.79, Figure 10; CMT2, R2 = 0.001, p =0.89, Figure 11; and CMTMAX, R2 = 0.01, p =0.9, Figure 12), respectively. We found some outliers in changes in ciliary muscle thickness data. Data points at least two standard deviations above the mean were excluded. There were two outliers for changes in CMT1, CMT2, CMT3, and CMTMAX. After the outliers were excluded, the univariate correlation between axial length and the changes in CMT1, CMT2, and CMT3 were not statistically significant, were (R2 = 0.001, p =0.8, Figure 13), (R2 = 0.006, p = 0.6, Figure 14), (R2 = 0.01, p =0.6, Figure 15) (R2 = 0.001, p =0.8, Figure 16), respectively. 3.3 Multivariate Analyses Multivariate regression models of the relationship between predictive variables(age, axial length, and AC/A ratio) and changes in ciliary muscle thickness in each location are described below. Table 3 shows the linear regression model. Age and AC/A ratio did not have statistically significant correlations with any ciliary muscle thickness location. Axial length was significantly negatively correlated with accommodative ciliary muscle thickness change. In other words, larger changes in CMT1 (p = 0.004), CMT2 (p = 0.04) 21 and CMTMAX (p = 0.03) were significantly associated with a shorter axial length, but there was no significant association between the change in CMT3 and axial length. The Multivariate linear regression equations were modeled as follows: Changes in CMT1 = 5.955 + 0.05 (age) – 0.267 (axial length) – 0.002 (AC/A ratio) Changes in CMT2= 2.230 + 0.002 (age) – 0.103 (axial length) + 0.002 (AC/A ratio) Changes in CMT3= 1.07 + 0.009 (age) – 0.04 (axial length) + 0.000 (AC/A ratio) Changes in CMTMAX = 3.74 + 0.02 (age) – 0.16 (axial length) + 0.001 (AC/A ratio) The multivariate linear regression model for the accommodative ciliary muscle thickness (CMT1, CMT2, CMT3, and CMTMAX) without the outliers and the predictive variables (age, axial length, and AC/A ratio) are shown in Table 4. There were no significant correlations after the outliers in accommodative ciliary muscle thickness change were removed. The linear regression equations without the outliers were modeled as follows: Changes in CMT1 = 1.34 + 0.02 (age) - 0.06 (axial length) – 0.001 (AC/A ratio). Changes in CMT2 = 0.05 + 0.013 (age) – 0.004 (axial length) – 0.008 (AC/A ratio). Changes in CMT3 = -0.9 + 0.005 (age) + 0.004 (axial length) – 0.005 (AC/A ratio). Changes in CMTMAX = 0.67 + 0.017 (age) - 0.02 (axial length) – 0.01(AC/A ratio). 22 CHAPTER 4: DISCUSSION Our study found that the response AC/A ratio was not statistically significantly associated with the changes in ciliary muscle thickness at any location. There was no statistically significant association between age and the changes in ciliary thickness at any location. There was a statistically significant negative association between axial length and changes in ciliary muscle thicknesses (CMT1, CMT2, and CMTMAX) respectively, but there was no significant correlation with the changes in CMT3. After the outliers were excluded, there was no statistically significant correlation between axial length and the changes in ciliary muscle thicknesses at any location. Although the changes in ciliary muscle thicknesses were not significantly correlated with AC/A ratio in this study, there are some factors that might affect the reliability of this result. The accommodative response data for this study were not perfectly reliable. In other words, in order to determine the changes of ciliary muscle thickness or ciliary muscle morphology during accommodation, we should use similar accommodative responses for all children instead of simply measuring accommodative response while we are imaging the ciliary muscle with OCT. All children responded differently to the accommodative target, so some accommodated more than 4.00 D and some 23 accommodated only 2.00 D or less, providing varying levels of accommodative response that may confound the results. AC/A ratio depended on the combination of accommodation and convergence, many components that affect both, and the feedback loop that affect the reliability of data collection. The correlation between ciliary muscle morphology and its function during accommodation might be affected by convergence as a result of the synkinetic combination of nerves that innervate the medial recti and ciliary muscle. We found some negative values of AC/A ratio in this study which might be as a result of improper accommodative response in children and noise in the measurements. Furthermore, the parasympathetic innervation of the different portions of the ciliary muscle is still unclear. Interestingly, not all portions of the ciliary muscle respond to parasympathetic stimulation,58,59 which might be one of the other causes that led to an insignificant association between the changes in ciliary muscle morphology and AC/A ratio. This study has shown no association between age and changes in ciliary muscle thickness, which was expected since this study does not include a wide range of ages. However our study found there was a negative correlation between axial length and the changes in ciliary muscle thickness (CMT1, CMT2, and CMTMAX), which is different from another previous study that found the ciliary muscle thickness increased with increasing axial length.60 One explanation for the difference between that study and ours might be that it focused on abnormal (myopic) axial length only. In addition, OCT, which has been used for ciliary muscle imaging in this study, does not give clear information 24 about the length of the ciliary muscle. Since the ciliary muscle length increases with increasing axial length, it gives us a clue that the thinner ciliary muscle might change more than a thicker muscle. As long as there was no statistically significant correlation between AC/A ratio and the changes in ciliary muscle thickness as we expected in the current study, some limitations should be considered. The number of subjects in this study might be not enough to determine this correlation. The accommodative response data, which are important to calculate an accurate AC/A ratio, were not exactly reliable. In addition, measuring the ciliary muscle thicknesses at different accommodative stimuli might give more information about the changes in ciliary muscle morphology during accommodation. In other words, we measured the AC/A ratio in the cycloplegic condition and at 4D stimulus level. It might be more helpful to measure AC/A ratio at different stimulus levels to determine the ciliary muscle morphology association with it. In the current study, we measured the ciliary muscle thicknesses perpendicular to the scleral spur posteriorly at different distances. Since the circular portion is considered the part most responsible for accommodation and it is located anteriorly,32,33, 35 35 it might be more useful to measure the distance of the ciliary muscle from the scleral pure attachment to the maximum thickness of the muscle. 25 Measurement Mean SD Minimum Maximum Age (Y) 8.88 2.03 6.00 12.98 135.56 13.73 106.7 161.3 AC/A ratio (∆/D) 6.93 4.38 1.59 14.35 Axial length (mm) 23.10 1.10 20.13 24.76 Refractive error (D) +0.40 2.28 -7.409 +5.438 Weight (lbs) 70.01 20.66 36.1 128.2 Height (cm) Table 1. Demographic characteristics of the study example. 26 Measurement Mean SD Minimum Maximum Change in CMT1 (mm) 0.154 0.398 -0.067 1.545 Change in CMT2 (mm) 0.070 0.244 -0.080 1.011 Change in CMT3 (mm) 0.038 0.145 -0.048 0.634 Change in CMTMAX (mm) 0.138 0.400 -0.104 1.771 CMT1 = ciliary muscle thickness 1 mm posterior to scleral spur; CMT2 = ciliary muscle thickness 2 mm posterior to scleral spur; CMT3 = ciliary muscle thickness 3mm posterior to scleral spur; CMTMAX = maximum ciliary body thickness Table 2. Demographic characteristic of the changes of ciliary muscle thicknesses per unit of accommodation. 27 Variables Changes in CMT1 (mm) Changes in CMT2 (mm) Changes in CMT3 (mm) Changes in CMTMAX (mm) Coefficient Pvalue Coefficient Pvalue Coefficient Pvalue Coefficient Pvalue Constant 5.955 0.003 2.230 0.03 1.07 0.05 3.74 0.019 Age (Y) 0.050 0.18 0.022 0.41 0.009 0.50 0.02 0.45 AC/A ratio (∆/D) -0.002 0.883 0.002 0.84 0.000 0.94 0.001 0.95 Axial length (mm) -0.267 0.004 -0.103 0.04 -0.04 0.07 -0.16 0.03 CMT1 = ciliary muscle thickness 1 mm posterior to scleral spur; CMT2 = ciliary muscle thickness 2 mm posterior to scleral spur; CMT3 = ciliary muscle thickness 3mm posterior to scleral spur; CMTMAX = maximum ciliary body thickness Table 3. Multivariate linear regression models for changes in each of the ciliary muscle thickness locations. 28 Variables Changes in Changes in Changes in Changes in CMT1 (mm) CMT2 (mm) CMT3 (mm) CMTMAX (mm) Coeff P-value Coeff P-value Coeff P-value Coeff P-value Constant 1.34 0.5 0.05 0.9 -0.93 0.8 0.67 0.6 Age (Y) 0.02 0.4 0.013 0.4 0.005 0.6 0.01 0.5 -0.001 0.3 -0.08 0.2 -0.005 0.2 -0.013 0.2 AC/A ratio (∆/D) -0.06 0.5 -0.004 0.9 0.004 0.2 -0.02 0.6 Axial length (mm) CMT1 = ciliary muscle thickness 1 mm posterior to scleral spur; CMT2 = ciliary muscle thickness 2 mm posterior to scleral spur; CMT3 = ciliary muscle thickness 3mm posterior to scleral spur; CMTMAX = maximum ciliary body thickness Table 4. Multivariate linear regression model for changes in ciliary muscle thickness at each location without the outliers. 29 Figure 1. Relationship between the changes in CMT1 and axial length. 30 Figure 1. Relationship between the changes in CMT2 and axial length. 31 Figure 2. Relationship between the changes in CMT3 and axial length. 32 Figure 3. Relationship between the changes in CMTMAX and axial length. 33 Figure 4. Relationship between the changes in CMT1 and age. 34 Figure 5. Relationship between the changes in CMT2 and age. 35 Figure 6. Relationship between the changes in CMT3 and age. 36 Figure 7. Relationship between the changes in CMTMAX and age. 37 Figure 8. Relationship between the changes in CMT1 and AC/A ratio. 38 Figure 9. Relationship between the changes in CMT2 and AC/A ratio. 39 Figure 10. Relationship between the changes in CMT3 and AC/A ratio. 40 Figure 11. Relationship between the changes in CMTMAX and AC/A ratio. 41 Figure 12. Relationship between the changes in CMT1 (without outliers) and axial length. 42 Figure 13. Relationship between the changes in CMT2 (without outliers) and axial length. 43 Figure 14. 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