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Purpose: Although the three-step test (3ST) is typically used to diagnose superior oblique palsy (SOP), sagging eye syndrome (SES) has clinical similarities. We sought to determine if alignment measurements can distinguish unilateral SOP from hypertropia in SES., Methods: We studied hypertropic subjects who underwent surface-coil magnetic resonance imaging (MRI) demonstrating either SO cross-section reduction indicative of congenital or acquired palsy (SOP group) or lateral rectus muscle sag (SES group). Alignment was measured by Hess screen and prism-cover testing. Multiple supervised machine learning methods were employed to evaluate diagnostic accuracy. Rectus pulley coordinates were determined in SES cases fulfilling the 3ST., Results: Twenty-three subjects had unilateral SOP manifested by SO atrophy. Eighteen others had normal SO size but MRI findings of SES. Maximum cross-section of the palsied SO was much smaller than contralaterally and in SES (P < 2 × 10-5). Inferior oblique cross-sections were similar in SOP and SES. In both SOP and SES, hypertropia increased in contralateral and decreased in ipsilateral gaze and was greater in ipsilateral than contralateral head tilt. In SES, nine subjects (50%) fulfilled the 3ST and had greater infraplacement of the lateral than medial rectus pulleys in the hypotropic orbit. Supervised machine learning of alignment data distinguished the diagnoses with areas under the receiver operating curves up to 0.93, representing excellent yet imperfect differential diagnosis., Conclusions: Because the 3ST is often positive in SES, clinical alignment patterns may confound SES with unilateral SOP, particularly acquired SOP. Machine learning substantially but imperfectly improves classification accuracy.

Purpose: To determine whether structural protein composition and expression of key regulatory genes are altered in strabismic human extraocular muscles., Methods: Samples from strabismic horizontal extraocular muscles were obtained during strabismus surgery and compared with normal muscles from organ donors. We used proteomics, standard and customized PCR arrays, and microarrays to identify changes in major structural proteins and changes in gene expression. We focused on muscle and connective tissue and its control by enzymes, growth factors, and cytokines., Results: Strabismic muscles showed downregulation of myosins, tropomyosins, troponins, and titin. Expression of collagens and regulators of collagen synthesis and degradation, the collagenase matrix metalloproteinase (MMP)2 and its inhibitors, tissue inhibitor of metalloproteinase (TIMP)1 and TIMP2, was upregulated, along with tumor necrosis factor (TNF), TNF receptors, and connective tissue growth factor (CTGF), as well as proteoglycans. Growth factors controlling extracellular matrix (ECM) were also upregulated. Among 410 signaling genes examined by PCR arrays, molecules with downregulation in the strabismic phenotype included GDNF, NRG1, and PAX7; CTGF, CXCR4, NPY1R, TNF, NTRK1, and NTRK2 were upregulated. Signaling molecules known to control extraocular muscle plasticity were predominantly expressed in the tendon rather than the muscle component. The two horizontal muscles, medial and lateral rectus, displayed similar changes in protein and gene expression, and no obvious effect of age., Conclusions: Quantification of proteins and gene expression showed significant differences in the composition of extraocular muscles of strabismic patients with respect to important motor proteins, elements of the ECM, and connective tissue. Therefore, our study supports the emerging view that the molecular composition of strabismic muscles is substantially altered.

Purpose: In order to better understand whether white matter structural deficits are present in strabismic amblyopia, we performed a survey of the tissue properties of 28 major white matter tracts using diffusion and quantitative magnetic resonance imaging approaches., Methods: We used diffusion-based tensor modeling and a new quantitative T1 protocol to measure fractional anisotropy (FA), mean diffusivity (MD), and myelin-sensitive T1 values. We surveyed tracts in the occipital lobe, including the vertical occipital fasciculus (VOF)-a newly rediscovered tract that bridges dorsal and ventral areas of the occipital lobe, as well as tracts across the rest of the brain., Results: Adults with long-standing strabismic amblyopia show tract-specific elevations in MD. We rank-ordered the tracts on the basis of their MD effect-size. The four most affected tracts were the anterior frontal corpus callosum (ACC), the right VOF, the left inferior longitudinal fasciculus (ILF) and the left optic radiation., Conclusions: The results suggest that most white matter tissue properties are relatively robust to the early visual insult caused by strabismus. However, strabismic amblyopia does affect MD, not only in occipital tracts, such as the VOF and optic radiation, but also in long range association tracts connecting visual cortex to the frontal and temporal lobes (ILF) and connecting the two hemispheres (ACC).

Purpose: Unilateral treatment with sustained release IGF-1 to one medial rectus muscle in infant monkeys was performed to test the hypothesis that strabismus would develop as a result of changes in extraocular muscles during the critical period of development of binocularity., Methods: Sustained release IGF-1 pellets were implanted unilaterally on one medial rectus muscle in normal infant monkeys during the first 2 weeks of life. Eye position was monitored using standard photographic methods. After 3 months of treatment, myofiber and neuromuscular size, myosin composition, and innervation density were quantified in all rectus muscles and compared to those in age-matched controls., Results: Sustained unilateral IGF-1 treatments resulted in strabismus for all treated subjects; 3 of the 4 subjects had a clinically significant strabismus of more than 10°. Both the treated medial rectus and the untreated ipsilateral antagonist lateral rectus muscles had significantly larger myofibers. No adaptation in myofiber size occurred in the contralateral functionally yoked lateral rectus or in myosin composition, neuromuscular junction size, or nerve density., Conclusions: Sustained unilateral IGF-1 treatment to extraocular muscles during the sensitive period of development of orthotropic eye alignment and binocularity was sufficient to disturb ocular motor development, resulting in strabismus in infant monkeys. This could be due to altering fusion of gaze during the early sensitive period. Serial measurements of eye alignment suggested the IGF-1-treated infants received insufficient coordinated binocular experience, preventing the establishment of normal eye alignment. Our results uniquely suggest that abnormal signaling by the extraocular muscles may be a cause of strabismus.

Purpose: To determine variations in eye volume, surface area, and shape with refractive error in young children using a three-dimensional magnetic resonance imaging (MRI) model., Methods: A subset of Singaporean Chinese boys enrolled in the population-based Strabismus, Amblyopia, and Refractive Error in Singapore (STARS) study underwent MRI using a 3-Tesla whole body scanner with a 32-channel head coil. Eye volume and surface area were measured. Eye shape was assessed qualitatively from the three-dimensional models and quantitatively by measurement of the longitudinal axial length (LAL), horizontal width, and vertical height along the cardinal axes., Results: One hundred thirty-four eyes of 67 subjects (mean age, 77.9 ± 3.9 months) were analyzed. The mean spherical equivalent (SE) refraction was 0.65 ± 0.92 D (range, -2.31 to 4.13 D). More myopic SE was associated with larger surface area (-20.59 [-37.09 to -4.10] mm²/D; P = 0.01) but not volume. In age-height adjusted models, more myopic SE was associated with longer LAL (-1.94 [-2.47 to -1.41] mm/D; P < 0.001) and greater width (-1.12 [-1.26 to -0.99] mm/D; P < 0.001) but not height (0.64 [-2.55 to 3.82] mm/D; P = 0.70). In nonmyopic subjects, less hyperopic SE was associated with longer AL (-0.40 [-0.71 to -0.10] mm/D; P = 0.01), width (-0.59 [-0.84 to -0.34] mm/D; P < 0.001), and height (-0.40 [-0.64 to -0.17] mm/D; P = 0.001). In three-dimensional models, myopic eyes conformed to an axial elongation model with a prolate profile in the axial plane, whereas nonmyopic eyes showed global expansion., Conclusions: Eye surface area increases with myopia in young children. Eye shape is different in myopia, even in its early stages. Axial globe enlargement occurs in myopic eyes leading to a prolate shape, whereas nonmyopic eyes enlarge globally in length, width, and height.

Purpose: The goal of this study was to determine whether the medial rectus muscles of patients with a history of medial rectus underaction or overaction show alterations in the process of satellite cell activation when compared with normal age-matched control muscles., Methods: Medial rectus muscles were obtained with consent from adult patients undergoing surgical resection due to medial rectus underaction or overaction and were prepared for histologic examination by fixation and paraffin embedding. Control muscles were obtained from cornea donor eyes of adults who had no history of strabismus or neuromuscular disease. Cross sections were obtained and stained immunohistochemically for the presence of activated satellite cells, as identified by MyoD immunoreactivity, and the presence of the total satellite cell population, as identified by Pax7 immunoreactivity. The percentages of MyoD- and Pax7-positive satellite cells per 100 myofibers in cross section were calculated., Results: As predicted from results in the literature, MyoD-positive satellite cells, indicative of activation, were present in both the control and resected muscles. In the underacting medial rectus muscles, the percentages of MyoD- and Pax7-positive satellite cells, based on the number of myofibers, were approximately twofold higher than the percentages in the control muscles. In the overacting medial rectus muscles, the percentage of MyoD-positive satellite cells was twofold less than in the control muscles, whereas the percentage of Pax7-positive satellite cells significantly increased compared with that in the control specimens., Conclusions: The presence of an increased number of activated satellite cells in the resected underacting medial rectus muscles and the decreased numbers of activated satellite cells in the overacting muscles was unexpected. The upregulation in the number of MyoD-positive satellite cells in underacting muscles suggests that there is potential for successful upregulation of size in these muscles, as the cellular machinery for muscle repair and regeneration, the satellite cells, is retained and active in patients with medial rectus underaction. The decreased number of activated satellite cells in overacting MR muscle suggests that factors as yet unknown in these overacting muscles are able to affect the number of satellite cells and/or their responsiveness compared with normal age-matched control muscles. These hypotheses are currently being tested.

Purpose: Strabismus is an oculomotor disorder in which there is a misalignment of the visual axes of the eyes. Inferior oblique muscle (IOM) overaction is a common finding in comitant horizontal strabismus, but its origin is unclear. Recent studies have demonstrated that myogenic satellite cells (SCs) are still activated in adult extraocular muscles, with continuous myonuclear addition in normal uninjured muscles. The objective of this study was to determine whether there are differences in the processes of activation and proliferation of SCs in IOMs of patients with strabismus and IOM overaction and in patients with no history of strabismus., Methods: Cross sections of IOMs from strabismic and control groups were analyzed immunohistochemically for the presence of MyoD1 and myogenin, specific markers of activated SCs, and for c-Met, which is expressed in quiescent, activated, and proliferating SCs., Results: In overacting IOMs of 26 patients in the strabismic group and 10 patients in the control group, 28.8% and 3.0% of the myofibers, respectively, were associated with MyoD1-positive SC. The frequency of myogenin-positive SC was 30.8% in the strabismic group and 3.6% in the control group, and the frequency of presumptive SCs immunostained for c-Met was 33.6% in the strabismic group and 34.1% in the control group., Conclusions: The presence of an increased number of activated SCs in overacting IOMs of the strabismic group in contrast to the frequency in the control group resembles the findings detected in developing, regenerating, or hypertrophic muscle tissue. High levels of MyoD1- and myogenin-positive SC in overacting IOMs support the hypothesis that these cells may be involved in alterations in IOM structure correlated with the overaction observed clinically.

Purpose: The paths of the rectus extraocular muscles (EOMs) are constrained by pulleys, connective tissue sleeves mechanically coupled to the orbital walls. This study sought to investigate, using high-resolution magnetic resonance imaging (MRI), the location and stability of EOM pulleys in normal subjects and those with strabismus., Methods: Multiple contiguous coronal MRI scans spanning the anterior-to-posterior extent of the orbit during primary gaze, upgaze, downgaze, adduction, and abduction were analyzed digitally to determine the paths of the rectus EOMs. Pulley locations were inferred from EOM paths., Results: Data for 10 orbits of six normal subjects established the normal paths of the rectus extraocular muscles in primary gaze. Muscle paths in primary position were highly uniform across normal subjects. In secondary gaze positions, rectus muscle paths at the level of the pulleys exhibited small but consistent shifts, relative to the orbit, opposite the direction of gaze, consistent with the expected mechanical effects of the intermuscular connective tissue suspensions of the pulleys. Twelve orbits of seven subjects with strabismus showed, as a group, no significant difference from normal in rectus muscle paths in primary gaze and no significant difference from normal in changes of muscle paths in secondary gaze. Two subjects with incomitant strabismus wer found to have grossly abnormal rectus muscle paths in primary gaze, suggesting heterotopic pulleys. Computer simulations of these heterotopic pulley locations accounted for the observed patterns of incomitant strabismus in both., Conclusions: High-resolution MRI can determine the location and sideslip of rectus EOM pulleys. Pulley position is highly uniform across normal subjects, consistent with the notion that musculo-orbital tissue connections determine the pulling direction of the rectus EOMs. In normal subjects and subjects with strabismus, pulleys exhibit small shifts with eccentric gaze that are consistent with secondary intermuscular, but not musculo-global, mechanical couplings. Heterotopic pulley position is a potential cause of incomitant strabismus.

Cell shrinkage in monkey lateral geniculate nucleus (LGN) layers supplied by the amblyopic eye have been described in experimental amblyopia caused by visual deprivation, anisometropia, and strabismus. A human brain from a strabismic amblyope became available for study and the authors compared cell sizes in LGN layers receiving input from the normal and the amblyopic eye. Significant cell shrinkage was present in layers connected with the amblyopic eye, and was most evident in the ipsilateral LGN. These findings support the validity of the monkey model for the study of strabismic amblyopia by showing, for the first time, changes in the brain from a human strabismic amblyope that are similar to those previously described in monkeys.

We conducted anatomic dissections of macaque monkey orbits and made a quantitative assessment of the orbital geometry of the accessory lateral rectus muscle. Our results show that the expected effect of this muscle on rotations of the globe is to produce elevation and abduction. The abducting component could counteract nasal drifts, and thus our findings provide support for the hypothesis that this muscle could render monkeys resistant to the development of esodeviations. Dissections of the orbits from two naturally esotropic monkeys also are consistent with this hypothesis. The accessory lateral rectus muscle was absent in one of them and abnormally small in the other. Humans do not have an accessory lateral rectus muscle, and we speculate that the high prevalence of esodeviations in humans may be related to an evolutionary loss of this muscle system.

The capillaries of overacting inferior oblique muscles from children with strabismus and of dog inferior oblique muscles were ultrastructurally described. Biopsy material was used in all instances. The mean diameter of the capillary lumen was 2.03 microns for the human inferior oblique and 2.76 microns for the dog inferior oblique. Quantitative estimates of capillary basement membrane width were obtained by two different methods of measurement. The capillaries of human and dog inferior oblique muscles were compared with capillaries of human gastrocnemius muscle and of dog quadriceps muscle. The data were statistically evaluated. It was found that the mean basement membrane width of capillaries of overacting inferior oblique muscles is quite similar to that of the dog normal inferior oblique muscles, showing 2,049 A in overacting muscles and 1,976 A in normal muscles. With both methods of measurement, the mean basement membrane width of inferior oblique muscles appeared thicker than the mean basement membrane of capillaries of the leg muscles in man and in dog as well. It is suggested that the thickening of the capillary basement membrane of inferior oblique muscles represents a regional characteristic. Marked variation in the thickness of the basement membrane was encountered in all muscles.

The presence of nerve terminals in the tendinous insertions of human eye muscles was investigated histologically in adult human eye muscles obtained from donor eyes and in muscle pieces resected from juvenile patients undergoing surgical correction for strabismus. Lateral and medial recti, superior and inferior oblique muscles from adults, were stained "en bloc" using a silver impregnation method. Numbers of nerve terminals were isolated that resembled "palisade endings" previously described in other species. A single palisade ending usually appeared as an interwoven network of fine neural filaments that cupped the inserting tip of a single extrafusal fiber. A collection of palisade endings on several neighboring muscle fibers were supplied by a single myelinated axon that branched from a nerve bundle in the muscle mass. The presence of nerve terminals at the distal musculotendinous interface of juvenile muscle also was observed when some resected specimens of lateral and medial recti were sectioned and stained using Holmes' silver method with a picrofuschin counterstain. No conventional Golgi tendon organs were seen.

The reduced visual sensitivity of strabismic amblyopes is often accentuated when they view vertical as opposed to horizontal gratings ("vertical effect"). Earlier attempts to show neurophysiological correlates of the vertical effect in strabismic cats have yielded controversial findings. We now report the results of experiments in the lateral geniculate nucleus (LGN) that clearly demonstrate the reduced sensitivity of X-cells in strabismic cats to vertical gratings as compared to horizontal ones. We conclude that the neural basis for the vertical effect is present at least at the level of the LGN.

Experimental esotropia was produced surgically in infant rhesus monkeys (Macaca mulatta) for brief periods of time. Electrophysiological studies of the visual cortex showed that esotropia of only 2 weeks duration in an infant monkey is sufficient to cause a marked shift of dominance in favor of the fixating eye and to virtually extinguish cortical neuronal responses from the esotropic eye. In the lateral geniculate nucleus cell (LGN), shrinkage of 6% to 8% occurred in the parvocellular layers connected with the esotropic eye, the magnocellular layers showing no changes. After the fixating eye had been sutured for 3 weeks, a complete reversal of the cortical physiology in favor of the esotropic eye occurred, whereas no recovery in cell size was observed in the LGN. Surgical realignment of an esotropic eye caused recovery of cortical neuronal responses from the formerly esotropic eye, but the number of binocularly responsive cells remained reduced.

A fluorescent antiserum against myosin from chicken anterior latissimus dorsi muscle, which stains specifically the multiply innervated slow fibers of birds and amphibians, was applied to frozen sections of human extraocular muscles. A proportion of fibers in oculorotatory muscles were labeled by the antiserum. In contrast, no labeled extrafusal fiber was present in the levator palpebrae or in other body muscles. Serial study of sections stained for acetylcholinesterase and myosin ATPase showed that the labeled fibers in human oculorotatory muscles are multiply innervated and display acid-stable myosin ATPase activity.