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1.  Differential Lateral Rectus Compartmental Contraction during Ocular Counter-Rolling 
The lateral rectus (LR) and medial rectus (MR) extraocular muscles (EOMs) have largely nonoverlapping superior and inferior innervation territories, suggesting functional compartmental specialization. We used magnetic resonance imaging (MRI) in humans to investigate differential compartmental activity in the rectus EOMs during head tilt, which evokes ocular counter-rolling, a torsional vestibulo-ocular reflex (VOR).
MRI in quasi-coronal planes was analyzed during target-controlled central gaze in 90° right and left head tilts in 12 normal adults. Cross sections and posterior partial volumes of the transverse portions of the four rectus EOMs were compared in contiguous image planes 2 mm thick spanning the orbit from origins to globe equator, and used as indicators of contractility.
Horizontal rectus EOMs had significantly greater posterior volumes and maximum cross sections in their inferior compartments (P < 10−8). In orbit tilt up (extorted) compared with orbit tilt down (intorted) head tilts, contractile changes in LR maximum cross section (P < 0.0001) and posterior partial volume (P < 0.05) were significantly greater in the inferior but not in the superior compartment. These changes were not explainable by horizontal or vertical eye position changes. A weaker compartmental effect was suggested for MR. The vertical rectus EOMs did not exhibit significant compartmental contractile changes during head tilt. Mechanical modeling suggests that differential LR contraction may contribute to physiological cyclovertical effects.
Selective activation of the two LR, and possibly MR, compartments correlates with newly recognized segregation of intramuscular innervation into distinct compartments, and probably contributes to noncommutative torsion during the VOR.
Magnetic resonance imaging of extraocular muscles during ocular counter-rolling demonstrates selective activation of the lateral rectus inferior but not superior compartment. This is novel functional evidence that differential rectus compartmental activation contributes to a vestibulo-ocular reflex.
PMCID: PMC3367472  PMID: 22427572
2.  Independent Passive Mechanical Behavior of Bovine Extraocular Muscle Compartments 
Intramuscular innervation of horizontal rectus extraocular muscles (EOMs) is segregated into superior and inferior (transverse) compartments, while all EOMs are also divided into global (GL) and orbital (OL) layers with scleral and pulley insertions, respectively. We sought evidence of potential independent action by examining passive mechanical coupling between EOM compartments.
Putative compartments of each of the six whole bovine anatomical EOMs were separately clamped to a physiologically controlled, dual channel microtensile load cell (5-mN force resolution) driven by independent, high-speed, linear motors having 20-nm position resolution. One channel at a time was extended or retracted by 3 to 5 mm, with the other channel stationary. Fiducials distributed on the EOM global surface enabled optical tracking of local deformation. Loading rates of 5 to 100 mm/sec were applied to explore speeds from slow vergence to saccades. Control loadings employed transversely loaded EOM and isotropic latex.
All EOM bellies and tendons exhibited substantial compartmental independence when loaded in the physiologic direction, both between OL and GL, and for arbitrary transverse parsings of EOM width ranging from 60%:40% to 80%:20%. Intercompartmental force coupling in the physiologic direction was less than or equal to 10% in all six EOMS even for saccadic loading rates. Coupling was much higher for nonphysiologic transverse EOM loading and isotropic latex. Optical tracking demonstrated independent strain distribution between EOM compartments.
Substantial mechanical independence exists among physiologically loaded fiber bundles in bovine EOMs and tendons, providing biomechanical support for the proposal that differential compartmental function in horizontal rectus EOMs contributes to novel torsional and vertical actions.
Dual-channel tensile loading demonstrates that adjacent extraocular muscle (EOMs) regions have marked mechanical independence. This finding supports the active pulley hypothesis and the proposal that topographic innervation within horizontal rectus EOMs could command torsional and vertical actions.
PMCID: PMC4113332  PMID: 23188730
3.  Functional Imaging of Human Extraocular Muscles In Head Tilt Dependent Hypertropia 
High-resolution MRI shows heterogeneous extraocular muscle features in strabismus, typical of superior oblique palsy. Rectus pulley counterrotations in response to head tilt may be paradoxical and depend on the presence of superior oblique atrophy, which is detected in half of patients.
Although alteration in hypertropia induced by head tilt is considered a clinical criterion for diagnosis of superior oblique (SO) palsy, the mechanism of this head-tilt–dependent hypertropia (HTDHT) is unclear. In this study, magnetic resonance imaging (MRI) was used to study extraocular muscle (EOM) responses to head tilt in HTDHT.
Orbital MRI was used to study 16 normal subjects and 22 subjects with HTDT, of whom 12 had unilateral SO atrophy and 10 had “masquerading” SO palsy with normal SO size. Sizes and paths of all EOMs were compared in 90° roll tilts.
Normal subjects exhibited the expected 3° to 7° physiologic extorsion of all four rectus pulleys in the orbit up-versus-down roll positions, corresponding to ocular counterrolling. In orbits with SO atrophy, the lateral (LR) and inferior rectus (IR) pulleys paradoxically intorted by approximately 2°. Subjects with HTDHT but normal SO size exhibited reduced or reversed extorsion of the medial, superior, and LR pulleys, whereas pulley shift was normal in nonhypertropic fellow orbits in HTDHT. In normal subjects and in SO atrophy, the inferior oblique (IO) muscle contracted in the orbit up-versus-down roll position, but paradoxically relaxed in HTDHT without SO atrophy.
The ipsilesional IR and LR pulleys shift abnormally during head tilt in HTDHT with SO atrophy. In HTDHT without SO atrophy, the ipsilesional MR, SO, and LR pulleys shift abnormally, and the IO relaxes paradoxically during head tilt. These widespread alterations in EOM pulling directions suggest that complex neural adjustments to the otolith–ocular reflexes mediate HTDHT.
PMCID: PMC3109014  PMID: 21282574
4.  Intramuscular Innervation of Primate Extraocular Muscles: Unique Compartmentalization in Horizontal Recti 
Segregation of intramuscular motor nerves indicates distinct superior and inferior zones within the horizontal but not vertical rectus extraocular muscles in humans and monkeys, supporting a potential functional role for differential innervation that might mediate oculorotary actions.
It has been proposed that the lateral rectus (LR), like many skeletal and craniofacial muscles, comprises multiple neuromuscular compartments subserving different physiological functions. To explore the anatomic potential of compartmentalization in all four rectus extraocular muscles (EOMs), evidence was sought of possible regional selectivity in intramuscular innervation of all rectus EOMs.
Whole orbits of two humans and one macaque monkey were serially sectioned at 10 μm thickness and stained with Masson's trichrome. Three-dimensional reconstruction was performed of the intramuscular courses of motor nerves from the deep orbit to the anterior extents of their arborizations within all four rectus EOMs in each orbit.
Findings concorded in monkey and human orbits. Externally to the global surface of the lateral (LR) and medial rectus (MR) EOMs, motor nerve trunks bifurcated into approximately equal-sized branches before entering the global layer and observing a segregation of subsequent arborization into superior zones that exhibited minimal overlap along the length of the LR and only modest overlap for MR. In contrast, intramuscular branches of the superior and the nasal portion of the inferior rectus were highly mixed.
Consistent segregation of intramuscular motor nerve arborization suggests functionally distinct superior and inferior zones within the horizontal rectus EOMs in both humans and monkeys. Reduced or absent compartmentalization in vertical rectus EOMs supports a potential functional role for differential innervation in horizontal rectus zones that could mediate previously unrecognized vertical oculorotary actions.
PMCID: PMC3088565  PMID: 21220556
5.  Functional Anatomy of the Extraocular Muscles During Vergence 
Progress in brain research  2008;171:21-28.
Magnetic resonance imaging (MRI) now enables precise visualization of the mechanical state of the living human orbit, enabling inferences about the effects of mechanical factors on ocular kinematics. We used 3-dimensional magnetic search coil recordings and MRI to investigate the mechanical state of the orbit during vergence in humans. Horizontal convergence of 23° from a remote to a near target aligned on one eye was geometrically ideal, and was associated with lens thickening and extorsion of the rectus pulley array of the aligned eye with superior oblique muscle relaxation and inferior oblique muscle contraction. There was no rectus muscle cocontraction. Subjective fusion through a 1° vertical prism caused a clockwise (CW) torsion in both eyes, as well as variable vertical and horizontal vergences that seldom corresponded to prism amount or direction. MRI under these conditions did not show consistent torsion of the rectus pulley array, but a complex pattern of changes in rectus extraocular muscle (EOM) crossections, consistent with co-contraction. Binocular fusion during vergence is accomplished by complex, 3D eye rotations seldom achieving binocular retinal correspondence. Vergence eye movements are sometimes associated with changes in rectus EOM pulling directions, and may sometimes be associated with co-contraction. Thus, extraretinal information about eye position would appear necessary to interpret binocular correspondence, and to avoid diplopia.
PMCID: PMC2881303  PMID: 18718278
active pulley hypothesis; extraocular muscles; magnetic resonance imaging; pulleys; vergence
6.  Sagging Eye Syndrome 
JAMA ophthalmology  2013;131(5):619-625.
Recognition of sagging eye syndrome (SES) as the cause of chronic or acute acquired diplopia may avert neurologic evaluation and imaging in most cases.
To determine whether SES results from inferior shift of lateral rectus (LR) extraocular muscle (EOM) pulleys and to investigate anatomic correlates of strabismus in SES.
Design and Setting
We used magnetic resonance imaging to evaluate rectus EOMs, pulleys, and the LR– superior rectus (SR) band ligament at an eye institute.
Patients with acquired diplopia suspected of having SES. We studied 56 orbits of 11 men and 17 women (mean [SD] age of 69.4 [11.9] years) clinically diagnosed with SES. Data were obtained from 25 orbits of 14 control participants age-matched to SES and from 52 orbits of 28 younger controls (23[4.6] years).
Main Outcome Measures
Rectus pulley locations compared with age-matched norms and lengths of the LR-SR band ligament and rectus EOMs. Data were correlated with facial features, binocular alignment, and fundus torsion.
Patients with SES commonly exhibited blepharoptosis and superior sulcus defect. Significant infero-lateral LR pulley displacement was confirmed in SES, but the spectrum of abnormalities was extended to peripheral displacement of all other rectus pulleys and lateral displacement of the inferior rectus pulley, with elongation of rectus EOMs (P < .001). Symmetrical LR sag was associated with divergence paralysis esotropia and asymmetrical LR sag greater than 1mm with cyclovertical strabismus. The LR-SR band was ruptured in 91% of patients with SES.
Conclusions and Relevance
Widespread rectus pulley displacement and EOM elongation, associated with LR-SR band rupture, causes acquired vertical and horizontal strabismus. Small-angle esotropia or hypertropia may result from common involutional changes in EOMs and orbital connective tissues that may be suspected from features evident on external examination.
PMCID: PMC3999699  PMID: 23471194
7.  Compartmentalized Innervation of Primate Lateral Rectus Muscle 
Innervation to monkey and human lateral rectus muscles is segregated into well-defined superior and inferior zones, so that the lateral rectus may function as two parallel muscles under separate control. Differential activation of the two lateral rectus zones could impart previously unrecognized torsional and vertical actions to this nominally “horizontal” rectus muscle, potentially resolving an important paradox in ocular kinematics.
Skeletal and craniofacial muscles are frequently composed of multiple neuromuscular compartments that serve different physiological functions. Evidence of possible regional selectivity in LR intramuscular innervation was sought in a study of the anatomic potential of lateral rectus (LR) muscle compartmentalization.
Whole orbits of two humans and five macaque monkeys were serially sectioned at 10-μm thickness and stained with Masson trichrome. The abducens nerve (CN6) was traced anteriorly from the deep orbit as it branched to enter the LR and arborized among extraocular muscle (EOM) fibers. Three-dimensional reconstruction was performed in human and monkey orbits.
Findings were in concordance in the monkey and human orbits. External to the LR global surface, CN6 bifurcated into approximately equal-sized trunks before entering the global layer. Subsequent arborization showed a systematic topography, entering a well-defined inferior zone 0.4 to 2.5 mm more posteriorly than branches entering the largely nonoverlapping superior zone. Zonal innervation remained segregated anteriorly and laterally within the LR.
Consistent segregation of intramuscular CN6 arborization in humans and monkeys suggests functionally distinct superior and inferior zones for the LR. Since the LR is shaped as a broad vertical strap, segregated control of the two zones could activate them separately, potentially mediating previously unappreciated but substantial torsional and vertical oculorotary LR actions.
PMCID: PMC2941164  PMID: 20435590
8.  Evidence of an Asymmetrical Endophenotype in Congenital Fibrosis of Extraocular Muscles Type 3 Resulting from TUBB3 Mutations 
Mutations producing single amino acid substitutions in neuron-specific β-tubulin isotype III cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3), a variable and frequently asymmetrical congenital cranial dysinnervation disorder with ophthalmic findings that include blepharoptosis and strabismus. Magnetic resonance imaging demonstrates oculomotor and abducens nerve hypoplasia with misinnervation and secondary hypoplasia of multiple extraocular muscles and hypoplasia of the optic nerve.
Orbital magnetic resonance imaging (MRI) was used to investigate the structural basis of motility abnormalities in congenital fibrosis of the extraocular muscles type 3 (CFEOM3), a disorder resulting from missense mutations in TUBB3, which encodes neuron-specific β-tubulin isotype III.
Ophthalmic examinations in 13 volunteers from four CFEOM3 pedigrees and normal control subjects, were correlated with TUBB3 mutation and MRI findings that demonstrated extraocular muscle (EOM) size, location, contractility, and innervation.
Volunteers included clinically affected and clinically unaffected carriers of R262C and D417N TUBB3 amino acid substitutions and one unaffected, mutation-negative family member. Subjects with CFEOM3 frequently had asymmetrical blepharoptosis, limited vertical duction, variable ophthalmoplegia, exotropia, and paradoxical abduction in infraduction. MRI demonstrated variable, asymmetrical levator palpebrae superioris and superior rectus EOM atrophy that correlated with blepharoptosis, deficient supraduction, and small orbital motor nerves. Additional EOMs exhibited variable hypoplasia that correlated with duction deficit, but the superior oblique muscle was spared. Ophthalmoplegia occurred only when the subarachnoid width of CN3 was <1.9 mm. A-pattern exotropia was frequent, correlating with apparent lateral rectus (LR) muscle misinnervation by CN3. Optic nerve (ON) cross sections were subnormal, but rectus pulley locations were normal.
CFEOM3 caused by TUBB3 R262C and D417N amino acid substitutions features abnormalities of EOM innervation and function that correlate with subarachnoid CN3 hypoplasia, occasional abducens nerve hypoplasia, and subclinical ON hypoplasia that can resemble CFEOM1. Clinical and MRI findings in CFEOM3 are more variable than those in CFEOM1 and are often asymmetrical. Apparent LR innervation by the inferior rectus motor nerve is an overlapping feature of Duane retraction syndrome and CFEOM1. These findings suggest that CFEOM3 is an asymmetrical, variably penetrant, congenital cranial dysinnervation disorder leading to secondary EOM atrophy.
PMCID: PMC2941178  PMID: 20393110
9.  Magnetic Resonance Imaging of the Effects of Horizontal Rectus Extraocular Muscle Surgery on Pulley and Globe Positions and Stability 
Magnetic resonance imaging (MRI) was used to determine the effect of recessions and resections on horizontal extraocular muscle (EOM) paths and globe position.
Four adults with horizontal strabismus underwent contrast-enhanced, surface-coil MRI in central, secondary, and tertiary gazes, before and after horizontal EOM recessions and/or resections. EOM paths were determined from 2-mm thickness, quasicoronal MRI by analysis of cross-sectional area centroids in a normalized, oculocentric coordinate system. Globe displacement was determined by measuring the apparent shift of the bony orbit in eccentric gaze.
In all subjects, the anteroposterior positions of the horizontal rectus pulleys shifted by less than 2 mm after surgery, indistinguishable from zero within measurement precision. In three subjects who underwent medial rectus (MR) recession or resection, postoperative globe position was similar in central gaze, but globe translation during vertical gaze shift changed markedly. There was no effect on globe translation in the subject who underwent only lateral rectus (LR) resection.
Recessions and resections of horizontal EOMs have minimal effect on anteroposterior EOM pulley positions. Because the pulley does not shift appreciably despite large alterations in the EOM insertion, the proximity of a recessed EOM to its pulley would be expected to introduce torsional and vertical actions in tertiary gazes. Connective tissue dissection during MR surgery may destabilize the globe’s vertical translational stability within the orbit, potentially changing the effective pulling directions of the rectus EOMs in vertical gazes. These changes may mimic oblique muscle dysfunction. LR surgery may avoid globe destabilization.
PMCID: PMC1850672  PMID: 16384961
10.  Mechanics of the Orbita 
Developments in ophthalmology  2007;40:132-157.
The oculomotor periphery was formerly regarded as a simple mechanism executing complex behaviors explicitly specified by innervation. It is now recognized that several fundamental aspects of ocular motility are properties of the extraocular muscles (EOMs) and their associated connective tissue pulleys. The Active Pulley Hypothesis proposes that rectus and inferior oblique EOMs have connective tissue soft pulleys that are actively controlled by the direction action of the EOMs’ orbital layers. Functional imaging and histology have suggested that the rectus pulley array constitutes an inner mechanism, similar to a gimbal, that is rotated torsionally around the orbital axis by an outer mechanism driven by the oblique EOMs. This arrangement may mechanically account for several commutative aspects of ocular motor control, including Listing’s law, yet permits implementation of noncommutative motility as during the vestibulo-ocular reflex. Recent human behavioral studies, as well neurophysiology in monkeys, are consistent with mechanical rather than central neural implementation of Listing’s law. Pathology of the pulley system is associated with predictable patterns of strabismus that are surgically treatable when the pathologic anatomy is characterized by imaging. This mechanical determination may imply limited possibilities for neural adaptation to some ocular motor pathologies, but indicates greater potential for surgical treatments.
PMCID: PMC2268111  PMID: 17314483
11.  Magnetic Resonance Imaging Evidence for Widespread Orbital Dysinnervation in Dominant Duane’s Retraction Syndrome Linked to the DURS2 Locus 
High-resolution, multipositional magnetic resonance imaging (MRI) was used to demonstrate extraocular muscles (EOMs) and associated motor nerves in Duane retraction syndrome (DRS) linked to the DURS2 locus on chromosome 2.
Five male and three female affected members of two autosomal dominant DURS2 pedigrees were enrolled in the study. Coronal T1-weighted MRI of the orbits was obtained in multiple gaze positions, as well as with heavy T2 weighting in the plane of the cranial nerves. MRI findings were correlated with motility.
All subjects had unilateral or bilateral limitation of abduction, or of both abduction and adduction, with palpebral fissure narrowing and globe retraction in adduction. Orbital motor nerves were typically small, with the abducens nerve (cranial nerve [CN]6) often nondetectable. Lateral rectus (LR) muscles were structurally abnormal in seven subjects, with structural and motility evidence of oculomotor nerve (CN3) innervation from vertical rectus EOMs leading to A or V patterns of strabismus in three cases. Four cases had superior oblique, two cases superior rectus, and one case levator EOM hypoplasia. Only the medial and inferior rectus and inferior oblique EOMs were spared. Two cases had small CN3s.
DRS linked to the DURS2 locus is associated with bilateral abnormalities of many orbital motor nerves, and structural abnormalities of all EOMs except those innervated by the inferior division of CN3. The LR may be coinnervated by CN3 branches normally destined for any other rectus EOMs. Therefore, DURS2-linked DRS is a diffuse congenital cranial dysinnervation disorder involving but not limited to CN6.
PMCID: PMC1850629  PMID: 17197533
12.  High-Resolution Magnetic Resonance Imaging Demonstrates Abnormalities of Motor Nerves and Extraocular Muscles in Patients With Neuropathic Strabismus 
Although the ocular motility examination has been used traditionally in the diagnosis of strabismus that is a result of cranial nerve (CN) abnormalities, magnetic resonance imaging (MRI) now permits the direct imaging of lesions in CN palsies.
Prospectively, nerves to extraocular muscles (EOMs) were imaged with T1 weighting in orbits of 83 orthotropic volunteers and 96 strabismic patients in quasicoronal planes using surface coils. Intraorbital resolution was 234–312 microns within 1.5- to 2.0-mm thick planes. CNs were imaged at the brainstem using head coils and T2 weighting, yielding 195 micron resolution in planes 1.0-mm thick in 6 normal volunteers and 22 patients who had oculomotor (CN3), trochlear (CN4), or abducens (CN6) palsies and Duane syndrome.
Oculomotor (CN3) and abducens (CN6) but not trochlear (CN4) nerves were demonstrable in the orbit and skull base in all normal subjects. Patients with congenital CN3 palsies had hypoplastic CN3s both in orbit and skull base, with hypoplasia of involved EOMs. Patients with chronic CN6 and CN4 palsies exhibited atrophy of involved EOMs. Patients with Duane syndrome exhibited absence or hypoplasia of CN6 in both orbit and brainstem regions, often with mild hypoplasia and apparent misdirection of CN3 to the lateral rectus muscle. Unlike CN6 palsy, patients with Duane syndrome exhibited no EOM hypoplasia. Patients with congenital fibrosis exhibited severe hypoplasia of CN3, moderate hypoplasia of CN6, and EOM hypoplasia, particularly severe for the superior rectus and levator muscles.
High-resolution MRI can directly demonstrate pathology of CN3 and CN6 and affected EOM atrophy in strabismus caused by CN palsies. Direct imaging of CNs and EOMs by MRI is feasible and useful in differential diagnosis of complex strabismus.
PMCID: PMC1847327  PMID: 16678748
13.  Enhanced Vertical Rectus Contractility by Magnetic Resonance Imaging in Superior Oblique Palsy 
Archives of Ophthalmology  2011;129(7):904-908.
To seek evidence for causative secondary changes in extraocular muscle volume, cross-sectional area, and contractility in superior oblique (SO) palsy using magnetic resonance imaging, given that vertical deviations in SO palsy greatly exceed those explained by loss of SO vertical action alone.
High-resolution, quasi-coronal orbital magnetic resonance images in target-controlled central gaze, supraduction, and infraduction were obtained in 12 patients with chronic unilateral SO palsy and 36 age-matched healthy volunteers using an 8-cm field of view and 2-mm slice thickness. Digital image analysis was used to quantify rectus extraocular muscle and SO cross-sectional areas and volumes. Measurements were compared with those of controls in central gaze to detect hypertrophy or atrophy and during vertical gaze changes to detect excess contractility.
In central gaze, the paretic SO was significantly atrophic (P<.001) and the contralesional superior rectus (SR) was significantly hypertrophic (P=.02). Across the range of vertical duction from supraduction to infraduction, both the contralesional SR (P=.04) and inferior rectus (P=.001) exhibited significantly supernormal contractile changes in maximum cross-sectional area. Contractile changes in the ipsilesional SR and inferior rectus exhibited a similar but insignificant trend (.08
Central gaze hypertrophy of the contralesional SR may be secondary to chronic excess innervation to compensate for relative hypotropia of this eye. Supernormal contralesional SR and inferior rectus contractility suggests that dynamic patterns of abnormal innervation to vertical rectus extraocular muscles may contribute to large hypertropias often observed in SO palsy.
PMCID: PMC3286651  PMID: 21746981
We explored multiple quantitative measures of horizontal rectus extraocular muscle (EOM) morphology to determine the magnetic resonance imaging (MRI) measure best correlating with duction and thus contractility.
Surface coil coronal MRI was obtained in target-controlled central gaze and multiple positions of adduction and abduction in 26 orbits of 15 normal volunteers. Duction angles were determined by position changes of the globe-optic nerve junction. Cross-sectional areas, partial volumes, and location of peak cross-sections of the horizontal rectus EOMs were computed in contiguous image planes 2-mm thick spanning the EOM origins to the globe equator.
All measures correlated significantly with duction angle (P < 0.0001). The best measures obtainable in single image planes were the maximum change in the cross-sectional area between equivalent image planes, with coefficients of determination R2 = 0.92 for medial rectus (MR) and 0.91 for lateral rectus (LR), and percentage change in maximum cross-section with R2 = 0.79 for MR and 0.78 for LR. The best partial volume measure of contractility was the change in partial volumes in four contiguous posterior planes (R2 = 0.86 MR and for 0.89 LR), particularly when combined with the corresponding change in partial volume for the antagonist EOM (R2 = 0.95 for MR and LR).
EOM morphologic changes are highly correlated with degrees of duction and thus contractility. Both changes in single-plane maximum cross-sectional areas and posterior partial volumes provide accurate, quantitative measures of EOM contractility.
Magnetic resonance morphometry of horizontal rectus extraocular muscles is highly correlated with duction angle in normal subjects, suggesting that local volume and cross-section muscle features reflect contractile state.
PMCID: PMC3481603  PMID: 22997285
Divergence insufficiency is generally regarded as a neurological event. While high myopia is not a well-known cause of divergence insufficiency, we frequently encounter divergence insufficiency in high-myopia patients. Thus, the purpose of this study was to report detailed information on such cases and examine mechanisms that might potentially be responsible for this disorder.
We investigated 20 cases of high myopia (>−6 D) with divergence insufficiency, 20 cases of high myopia without double vision, and 10 normal cases as controls. Using magnetic resonance imaging (MRI), a coronal image 6 mm anterior to the eyeball–optic nerve junction was measured and used to examine the extraocular muscle (EOM) path shift and angle of the eye. Higher angles in each patient were used for statistical comparison.
In high-myopia patients with divergence insufficiency, ocular axis measurements ranged from 24.8 to 31.0 (mean ± SD: 27.6 ± 1.6) mm. In high-myopia patients without double vision, the ocular axis length was 27.6 ± 1.3 mm. In normal cases, the ocular axis length was 23.5 ± 1.0 mm. The EOM angles in these patients ranged from 100 to 140 (112.9 ± 9.7) degrees, which was significantly higher (P < 0.05) than that seen in the high-myopia patients without double vision (average EOM angle, 99.2 ± 2.8 degrees) and normal cases (average EOM angle, 97.9 ± 3.8 degrees). However, orbital lengths in the patients were 41.0 to 48.9 (44.6 ± 2.3) mm, which also differed from the high-myopia patients without double vision (average orbital length, 49.9 ± 2.0 mm) significantly (P < 0.05). In normal cases, average orbital length was 45.5 ± 1.6 mm.
In high-myopia patients with divergence insufficiency, nasal shift of the superior rectus and an inferior shift of the lateral rectus were observed, but the orbital lengths were normal. Divergence insufficiency may be caused mechanically by shifts of the EOM due to the presence of a long axis. Therefore, high myopia with a long axis can be considered to be a risk factor for the occurrence of divergence insufficiency.
PMCID: PMC3032998  PMID: 21311651
divergence insufficiency; high myopia; MRI; extraocular muscle
Connective tissue pulleys inflect the extraocular muscles (EOMs) and receive insertions from some fibers. The authors investigated insertions and anatomic relationships of fiber fascicles within rectus EOMs to clarify the relationship to their pulleys.
Two human and two monkey orbits were removed intact, serially sectioned in the coronal plane, histologically stained, and digitally photographed. The authors traced representative fascicles in the human medial rectus (MR) and inferior rectus and monkey lateral rectus and superior rectus muscles. In the human MR, the authors computed average collagen fractions in the orbital layer (OL) and the global layer (GL).
In human and monkey, OL fascicles remained distinct from each other and from the GL throughout. Most OL fascicles were inserted into the pulley through short tendons. Most GL fascicles bypassed the pulley without insertion. Collagen content in the human MR OL increased from 29% ± 5% (SD) in midorbit to 65% ± 9% in the anterior orbit but slightly decreased from 26% ± 6% to 23% ± 1% in the GL. Tracing of every fiber in a human MR OL fascicle demonstrated terminations on pulley tendons without myomyous junctions.
Fibers in the primate rectus OL lack myomyous or GL junctions, but nearly all insert on the pulley through a broad distribution of short tendons and dense intercalated collagen. Fibers in the GL generally do not insert on pulley tissues and are associated with less collagen. These features support the distinct role of the OL in anteroposterior positioning of connective tissues proposed in the active pulley hypothesis and substantial mechanical independence of the OL and GL.
PMCID: PMC1978188  PMID: 17591878
Chronic progressive external ophthalmoplegia (CPEO) is characterized by slowly progressive bilateral ophthalmoplegia and blepharoptosis. Molecular diagnosis is problematic because sporadic mitochondrial DNA deletions can be causative. We sought findings using magnetic resonance imaging (MRI) that might support the diagnosis of CPEO.
Two men (ages 31 and 47 years) and 3 women (ages 40–49 years) with CPEO and symptom durations of 8 months to 28 years underwent high-resolution (2-mm slice thickness, 312 micron pixels), surface coil, T1-weighted orbital MRI in coronal planes. Images were analyzed quantitatively to determine extraocular muscle (EOM) sizes and were compared with 10 age- and gender-matched normal volunteers, one subject with myasthenia gravis, and with 30 subjects having EOM paralysis caused by oculomotor, trochlear,0 and abducens neuropathies.
EOM function was clinically diminished in CPEO, most markedly for the superior rectus (SR) and levator muscles. All EOMs in CPEO exhibited unusual qualitative T1 MRI signal abnormalities. Unlike the profound EOM atrophy typical of neurogenic paralysis, anterior volumes of medial rectus, lateral rectus, and inferior rectus muscles in CPEO were not smaller than normal ( p > 0.003). Anterior volumes of the SR muscle-levator complex and superior oblique were significantly reduced ( p < 0.003). Denervated EOMs exhibited statistically significant volume reduction when compared with normal and CPEO groups. Volume of the SR muscle-levator complex was the same in subjects with CPEO and oculomotor palsies.
CPEO is associated with minimal EOM volume reduction despite clinically severe weakness. This combination of findings may be specific for CPEO and could resolve the diagnostic dilemma in difficult cases.
PMCID: PMC1850670  PMID: 17070475
The EOMs are particularly adaptive to changes induced by recession and tenotomy surgery, responding with modulations in fiber remodeling and myosin expression and also with changes in antagonist and contralateral muscles. These results suggest the possibility that these processes are manipulated immediately after surgery to improve surgical success rates.
Surgical recession of an extraocular muscle (EOM) posterior to its original insertion is a common form of strabismus surgery, weakening the rotational force exerted by the muscle on the globe and improving eye alignment. The purpose of this study was to assess myosin heavy chain (MyHC) isoform expression and satellite cell activity as defined by Pax7 expression in recessed EOMs of adult rabbits compared with that in muscles tenotomized but not recessed and with that in normal control muscles.
The scleral insertion of the superior rectus muscle was detached and sutured either 7 mm posterior to its original insertion site (recession surgery) or at the same site (tenotomy). One day before euthanatization, the rabbits received bromodeoxyuridine (BrdU) injections. After 7 and 14 days, selected EOMs from both orbits were examined for changes in fast, slow, neonatal, and developmental MyHC isoform expression, Pax7 expression, and BrdU incorporation.
Recession and tenotomy surgery resulted in similar changes in the surgical EOMs. These included a decreased proportion of fast MyHC myofibers, an increased proportion of slow MyHC myofibers, and increased BrdU-positive satellite cells. Similar changes were seen in the non-operated contralateral superior rectus muscles. The ipsilateral inferior rectus showed reciprocal changes to the surgical superior rectus muscles.
The EOMs are extremely adaptive to changes induced by recession and tenotomy surgery, responding with modulations in fiber remodeling and myosin expression. These adaptive responses could be manipulated to improve surgical success rates.
PMCID: PMC3061502  PMID: 20538996
Structural abnormalities of extraocular muscles (EOMs) or their pulleys are associated with some forms of human strabismus. This experiment was conducted to investigate whether such abnormalities are associated with artificial or naturally occurring strabismus in monkeys.
Binocular alignment and grating visual acuities were determined in 10 monkeys representing various species using search coil recording and direct observations. Four animals were orthotropic, two had naturally occurring “A”-pattern esotropia, two had concomitant and one had “V”-pattern esotropia artificially induced by alternating or unilateral occlusion in infancy, and one had “A”-pattern exotropia artificially induced by prism wear. After euthanasia, 16 orbits were examined by high-resolution magnetic resonance imaging (MRI) in the quasicoronal plane. Paths and sizes of horizontal rectus EOMs were analyzed quantitatively in a standardized coordinate system. Whole orbits were then serially sectioned en bloc in the quasicoronal plane, stained for connective tissue, and compared with MRI. Nerve and EOM features were analyzed quantitatively.
Quantitative analysis of MRI revealed no significant differences in horizontal rectus EOM sizes or paths among orthotropic or naturally or artificially strabismic monkeys. Histologic examination demonstrated no differences in EOM size, structure, or innervation among the three groups, and no differences in connective tissues in the pulley system. The accessory lateral rectus (ALR) EOM was present in all specimens, but was small, inconsistently located, and sparsely innervated. Characteristics of the ALR did not correlate with strabismus.
Major structural abnormalities of horizontal rectus EOMs and associated pulleys are unrelated to natural or artificial horizontal strabismus in the monkeys studied. The ALR is unlikely to contribute to horizontal strabismus in primates. However, these findings do not exclude a possible role of pulley abnormalities in disorders such as cyclovertical strabismus.
PMCID: PMC1975407  PMID: 17525187
American journal of ophthalmology  2010;150(6):925-931.e2.
To determine by magnetic resonance imaging (MRI) the prevalence and anatomy of anomalous EOM bands.
Prospective, observational case series.
High resolution, multi-positional, surface coil orbital MRI was performed using T1 or T2 fast spin echo weighting with target fixation control under a prospective protocol in normal adult subjects and a diverse group of strabismic patients between 1996 and 2009. Images demonstrating anomalous EOM bands were analyzed digitally to evaluate their sizes and paths, correlating findings with complete ophthalmic and motility examinations.
Among 118 orthotropic and 453 strabismic subjects, one (0.8%) orthotropic and 11 (2.4%) strabismic subjects exhibited unilateral or bilateral orbital bands having MRI signal characteristics identical to EOM. Most bands occurred without other EOM dysplasia and coursed in the retrobulbar space between rectus EOMs such as medial (MR) to lateral rectus (LR), or superior (SR) to inferior rectus (IR), or from one EOM to the globe. In two cases, horizontal bands from MR to LR immediately posterior to the globe apparently limited supraduction by collision with the optic nerve. All bands were too deep to be approached via conventional strabismus surgical approaches.
About 2% of humans exhibit on MRI deep orbital bands consistent with supernumerary EOMs. While band anatomy is non-oculorotary, some bands may cause restrictive strabismus.
PMCID: PMC2991531  PMID: 20801423
Background: Structural details of vertebrate extraocular muscles (EOMs) have shown an anatomically and functionally distinct laminar organization into an outer orbital (OL) and an inner global layer (GL). Since hyperthyroidism alters tissue oxidative metabolism through mitochondrial enzymes, it is expected that structural/mitochondrial changes may be seen in hyperthyroid EOMs. We investigated the alterations in the laminar organization and mitochondrial changes in hyperthyroid mouse EOMs. Methods: Hyperthyroidism was induced in C57BL/6 mice and fresh rectus muscles were obtained to identify functional mitochondria using MitoTracker® Green and confocal microscopy; frozen sections from rectus muscles were stained with anti-rabbit Troponin T (selectively present in the OL) to demonstrate changes in the OL and GL of the EOMs. Ultrastructural features of EOMs were studied using transmission electron microscopy (TEM). Results: Of all four rectus EOMs studied, the maximum change was seen in the inferior rectus muscle (IR) followed by medial rectus (MR). Myofiber cross-sectional area measurements and Troponin T staining in the control IR EOMs demonstrated a smaller OL (113.2 ± 3.66 μm2) and higher density staining with Troponin T (90%) and a larger GL (411 ± 13.84 μm2) with low intensity staining (10%), while hyperthyroidism resulted in an increased OL (205.9 ± 5.3 μm2) and decreased GL (271.7 ± 7.5 μm2) p = 0.001. Confocal microscopy demonstrated an intense staining especially in the outer rims in the hyperthyroid IR which was confirmed by TEM showing structural alterations in the mitochondria and a subsarcolemmal migration. Conclusions: The outer, thinner, OL of the mouse EOM contains smaller diameter myofibers and fewer mitochondria while the inner, larger GL contains larger diameter myofibers and larger density of mitochondria. Hyperthyroidism results in a significant alteration in the laminar organization and mitochondrial alterations of mouse EOMs.
PMCID: PMC3015165  PMID: 21212842
hyperthyroid mice; orbital layer; global layer; extraocular muscles; inferior rectus; Troponin T; mitochondria
Botulinum toxin A (Botox) is commonly used for strabismus treatment. Although other muscles atrophy after intramuscular injection with Botox, extraocular muscles (EOMs) do not. A continuous process of myonuclear addition in normal uninjured adult myofibers in rabbit EOMs was studied. In this study, the effect of Botox-induced muscle paralysis on myofiber remodeling in adult EOMs was examined.
The superior rectus muscles of adult rabbits were each injected with 5 units of Botox. The contralateral muscle received injections of saline only. Bromodeoxyuridine (BrdU) was administered for various periods after Botox treatment, followed by various BrdU-free periods. Myonuclear addition, the number of BrdU-positive satellite cells, and the number of MyoD-positive satellite cells were quantified, as were alterations in expression of immature myosins.
Intramuscular injection of Botox resulted in a significant increase in both the number of BrdU-positive myonuclei and satellite cells. MyoD expression in both satellite cells and myonuclei was significantly increased after Botox injection in EOMs. In Botox-treated EOMs, an increased number of myofibers positive for the neonatal myosin heavy chain (MyHC) isoform was detected in the orbital layer.
Botox-induced EOM paralysis resulted in a significant short-term increase in satellite cell activation and myo-nuclear addition in single myofibers in adult rabbit EOMs compared with control muscles. The appearance of MyoD-positive myonuclei suggests that protein synthesis becomes upregulated after Botox injection, and this, in turn, may help explain the minimal effects on myofiber size in EOMs after Botox injection. Understanding the effect of Botox on satellite cell activation and myonuclear addition in existing myofibers may suggest new ways to maximize the clinical effectiveness of Botox in patients with strabismus.
PMCID: PMC1847582  PMID: 16249488
Current eye research  2012;37(9):761-769.
The abducens (CN6) and oculomotor (CN3) nerves (nn) enter target extraocular muscles (EOMs) via their global surfaces; the trochlear (CN4) nerve enters the superior oblique (SO) muscle on its orbital surface. Motor nn are classically described as entering the EOMs in their middle thirds. We investigated EOM innervation that does not follow the classic pattern.
Intact, whole orbits of two humans and one each monkey, cow, and rabbit were paraffin embedded, serially sectioned in coronal plane, and prepared with Masson’s trichrome and by choline acetyltransferase (ChAT) immunohistochemistry. Nerves innervating EOMs were traced from the orbital apex toward the scleral insertion, and some were reconstructed in three dimensions.
Classical motor nn positive for ChAT entered rectus and SO EOMs and coursed anteriorly, without usually exhibiting recurrent branches. In every orbit, nonclassical (NC) nn entered each EOM well posterior to classical motor nn. These NC nn entered and arborized in the posterior EOMs, mainly within the orbital layer (OL), but often traveled into the global layer or entered an adjacent EOM. Other NC nn originated in the orbital apex and entered each EOM through its orbital surface, ultimately anastomosing with classical motor nn. Mixed sensory and motor nn interconnected EOM spindles.
EOMs exhibit a previously undescribed pattern of NC innervation originating in the proximal orbit that partially joins branches of the classical motor nn. This NC innervation appears preferential for the OL, and may have mixed supplemental motor and/or proprioceptive functions, perhaps depending upon species. The origin of the NC innervation is currently unknown.
PMCID: PMC3608520  PMID: 22559851
cranial nerve; eye movement; extra-ocular muscle; spindle
The British Journal of Ophthalmology  2004;88(11):1380-1386.
Aim: To evaluate the efficacy of periocular triamcinolone acetonide for the treatment of thyroid associated ophthalmopathy (TAO), and the presence of ocular or systemic adverse effects.
Methods: A multicentre prospective pilot study was performed on patients diagnosed with Graves’ ophthalmopathy less than 6 months before entry to the study. Patients were admitted to the study and were randomised into two groups: treatment and control. The treatment group received four doses of 20 mg of triamcinolone acetate 40 mg/ml in a peribulbar injection to the inferolateral orbital quadrant. Both groups were evaluated by measuring the area of binocular vision without diplopia on a Goldmann perimeter and the size of the extraocular muscles on computed tomography (CT) scans. Ophthalmological and systemic examinations were done to rule out ocular and systemic adverse effects. Follow up was 6 months for both groups.
Results: 50 patients were eligible for the study. 41 patients completed the study. There was an increase in the area of binocular vision without diplopia in the treatment group (Σ initial: mean 231.1 (SD 99.9) and final absolute change, mean 107.1 (SD 129.0)) compared to the control group (Σ initial: mean 350.7 (SD 86.5) and final absolute change, mean −4.5 (SD 67.6)). The sizes of the extraocular muscles were reduced in the treatment group (mean (inferior rectus initial values): 1.3 (0.7), final percentage change: −13.2 (25.7), medial rectus initial values: 1.2 (0.6), final percentage change: −8.2 (20.7), superior rectus-levator palpebrae initial values: 1.2 (0.6), final percentage change: −9.5 (29.1), lateral rectus initial values: 1.0 (0.4), final percentage change: −11.5 (20.6)) compared to the control group (inferior rectus initial values: 0.9 (0.3), final percentage change: −4.0 (21.5), medial rectus initial values: 0.9 (0.3), final percentage change: 0.6 (22.4), superior rectus-levator palpebrae initial values: 0.9 (0.3), final percentage change: 12.5 (37.5), lateral rectus initial values: 0.9 (0.4), final percentage change: −0.5 (31.6)). Both measurements (degree of diplopia and muscle thickness) were statistically significant between groups (initial − final). No systemic or ocular adverse effects were found.
Conclusions: Triamcinolone administered as a periocular injection is effective in reducing diplopia and the sizes of extraocular muscles in TAO ophthalmopathy of recent onset. This form of treatment is not associated with systemic or ocular side effects.
PMCID: PMC1772392  PMID: 15489477
thyroid associated ophthalmopathy; periocular injections; triamcinolone
To document the cyclovertical ocular motor mechanism used for vertical fusion in healthy subjects, and to explore whether vertical vergence training in healthy individuals can produce objectively confirmed vertical deviations that change with head tilt, revealing a basic mechanism that can produce a pattern of misalignment in an otherwise normal ocular motor system that is similar to superior oblique muscle paresis (SOP).
Seven subjects with normal orthoptic examinations were adapted to vertical image disparities using our tilting haploscopic eye-tracking apparatus presenting concentric circle targets without torsional cues. Static eye positions were recorded with head straight and when tilted 45 degrees to the left and right, during both binocular and monocular viewing.
Vertical fusional vergence was accompanied by a cycloversion, with the downward-moving eye intorting and the upward-moving eye extorting, implicating primary involvement of the oblique extraocular muscles. After adaptation to the slowly increasing vertical target separation, all subjects developed a temporary vertical deviation in the straight ahead position that increased with head tilt to one side and decreased with head tilt to the other side.
These results not only show that head-tilt–dependent changes in vertical deviation are not necessarily pathognomonic for SOP, but also, and more importantly, suggest mechanisms that can mimic SOP and suggest a possible role for vertical vergence training in reducing deviations and thus the amount of head tilt required for fusion. Ultimately, vertical vergence training may provide an adjunct or alternative to extraocular muscle surgery in selected cases.
Vertical vergence training in healthy individuals can produce an objective vertical deviation that changes with different head tilt positions, revealing a basic mechanism that can produce head tilt findings similar to those in superior oblique paresis in an otherwise normal ocular motor system.
PMCID: PMC3645368  PMID: 23572100
vertical vergence adaptation; superior oblique paresis; Bielschowsky head tilt test; basic cyclovertical deviation; video-oculography

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