Individual Extraocular Muscles Research Articles

TWIST1, a gene associated with Saethre-Chotzen syndrome, regulates extraocular muscle organization in mouse

Heterozygous loss of function mutations in TWIST1 cause Saethre-Chotzen syndrome, which is characterized by craniosynostosis, facial asymmetry, ptosis, strabismus, and distinctive ear appearance. Individuals with syndromic craniosynostosis have high rates of strabismus and ptosis, but the underlying pathology is unknown. Some individuals with syndromic craniosynostosis have been noted to have absence of individual extraocular muscles or abnormal insertions of the extraocular muscles on the globe. Using conditional knock-out alleles for Twist1 in cranial mesenchyme, we test the hypothesis that Twist1 is required for extraocular muscle organization and position, attachment to the globe, and/or innervation by the cranial nerves. We examined the extraocular muscles in conditional Twist1 knock-out animals using Twist2-cre and Pdgfrb-cre drivers. Both are expressed in cranial mesoderm and neural crest. Conditional inactivation of Twist1 using these drivers leads to disorganized extraocular muscles that cannot be reliably identified as specific muscles. Tendons do not form normally at the insertion and origin of these dysplastic muscles. Knock-out of Twist1 expression in tendon precursors, using scleraxis-cre, however, does not alter EOM organization. Furthermore, developing motor neurons, which do not express Twist1, display abnormal axonal trajectories in the orbit in the presence of dysplastic extraocular muscles. Strabismus in individuals with TWIST1 mutations may therefore be caused by abnormalities in extraocular muscle development and secondary abnormalities in innervation and tendon formation.

Structural Functional Associations of the Orbit in Thyroid Eye Disease: Kalman Filters to Track Extraocular Rectal Muscles.

Pathologies of the optic nerve and orbit impact millions of Americans and quantitative assessment of the orbital structures on 3-D imaging would provide objective markers to enhance diagnostic accuracy, improve timely intervention and eventually preserve visual function. Recent studies have shown that the multi-atlas methodology is suitable for identifying orbital structures, but challenges arise in the identification of the individual extraocular rectus muscles that control eye movement. This is increasingly problematic in diseased eyes, where these muscles often appear to fuse at the back of the orbit (at the resolution of clinical computed tomography imaging) due to inflammation or crowding. We propose the use of Kalman filters to track the muscles in three-dimensions to refine multi-atlas segmentation and resolve ambiguity due to imaging resolution, noise, and artifacts. The purpose of our study is to investigate a method of automatically generating orbital metrics from CT imaging and demonstrate the utility of the approach by correlating structural metrics of the eye orbit with clinical data and visual function measures in subjects with thyroid eye disease. The pilot study demonstrates that automatically calculated orbital metrics are strongly correlated with several clinical characteristics. Moreover, the superior, inferior, medial and lateral rectus muscles obtained using Kalman filters are each correlated with different categories of functional deficit. These findings serve as foundation for further investigation in the use of CT imaging in the study, analysis and diagnosis of ocular diseases, specifically thyroid eye disease.

Muscle compartmentalization: twice the muscles, three times the actions

Relevance: Recent research shows that most individual extraocular muscles (EOMs) consist of two compartments innervated by separate nerve branches, creating mechanically-independent sets of fibers that act at different sites along the scleral insertions. The compartmental structure of EOMs should be considered in the diagnosis and treatment of strabismus. Cyclovertical actions of horizontal rectus EOMs should be suspected in paralytic or complex strabismus, as they may explain otherwise paradoxical clinical findings.

Understanding the Extraocular Muscles and Oculomotor, Trochlear, and Abducens Nerves Through a Simulation in Physical Examination Training: An Innovative Approach*

The purpose of this study was to investigate the effect of an innovative exhibitory eye model simulation in a physical examination laboratory format on explaining Listing's Law concerning the individual extraocular muscle action and the rationale for cranial nerve testing. Participants were 71 volunteers in the third quarter of a chiropractic training program. The study involved a specially designed eyeball model used to explain the movements of individual extraocular muscles based on Listing's law and their cranial innervations in conjunction with the physical examination. Pre- and post-written tests were used to assess participants' understanding of the subjects taught. The test results were compared with those of nonparticipants who also took the same pre- and posttests. An independent samples t-test of the posttest showed a significant difference between the groups. The study group students achieved higher scores than their counterparts in the control group. Using an innovative approach to explain Listing's law and rationale for cranial nerve tests can improve physical examination skill and help produce more effective written test results.

Unusual presentations of cavernous carotid aneurysms: Further evidence for topographic organization of the oculomotor nerve

Two patients with carotid cavernous aneurysms presented with uncommon patterns of third nerve involvement, one with an isolated elevation deficit without ptosis and the other with a depression deficit with possible pupillary involvement. These patterns are best explained by topographic organization of third nerve fibers within the cavernous sinus (prior to its anatomic bifurcation) that subserve individual extraocular muscles.

A case of relapsing flitting bilateral idiopathic orbital inflammation

Idiopathic orbital inflammation (IOI) is defined as a benign non-infective clinical syndrome characterized by features of non-specific inflammation of the orbit without identifiable local or systemic causes. This can be called orbital myositis if the inflammation is predominantly in the orbital muscles. It is a diagnosis of exclusion based on clinical, radiological, and if necessary, histological findings. The most commons symptoms are swelling, ptosis, proptosis and painful eye movements. To our knowledge, this patient is the first with IOI to demonstrate relapsing flitting bilateral involvement of several individual extra-ocular muscles.

A simplified approach to teaching medical students ocular movements and the rationale in testing the oculomotor, trochlear, and abducent nerves

The actions of the individual extraocular muscles are best explained to medical students in a lecture format by showing the relationship of each muscle to the axes of the globe and the walls of the bony orbit. The lateral and medial rectus muscles cross only the vertical axis, and consequently, cause only abduction and adduction, respectively. These muscles can be tested simply by asking the patient to abduct or adduct. Inability to do so indicates that the muscles and/or their innervation have been compromised. In contrast, the superior and inferior oblique and rectus muscles cross all three axes (vertical, horizontal, and anteroposterior) of the globe. Therefore, concentric contraction of each of these muscles results in three movements; abduction or adduction, elevation or depression, and intorsion or extorsion. These muscles must be tested with a sequence of two movements. Gaze can be either elevated or depressed by both an oblique and a rectus muscle. If abduction or adduction occurs first, one muscle of the pair becomes incapable of causing elevation or depression of the pupil. The rationale for abducting or adducting first is that either the oblique or rectus muscle of the pair will no longer cross the horizontal axis and will then be unable to effect the desired movement. Inability to elevate or depress gaze from the abducted or adducted position shows which muscle, the oblique or rectus, and/or its innervation has been compromised.

Be the apple of my eye: demonstrating the actions of the extraocular muscles.

Understanding the actions of the extraocular muscles, especially within the context of clinical testing of eye movements, often poses a challenge for beginning anatomy students. A simple demonstration of these muscle actions can greatly clarify the mechanical concepts in question. Required supplies include an apple (other select fruit will suffice), dissecting needle, several rubber bands, and several push pins. The stem of the apple represents the pupil, the dissecting needle serves as the axis of rotation of the eye, and the rubber bands (held in place with the push pins) represent the individual extraocular muscles. Pulling each rubber band causes the apple to turn about the dissecting needle in each of the three axes of rotation, allowing the user to test and visualize the muscle actions. This teaching tool is affordable and easy‐to‐master, thus allowing students to repeat the lesson at their leisure.

Comparison of Saccade-Associated Neuronal Activity in the Primate Central Mesencephalic and Paramedian Pontine Reticular Formations

The oculomotor system must convert signals representing the target of an intended eye movement into appropriate input to drive the individual extraocular muscles. Neural models propose that this transformation may involve either a decomposition of the intended eye displacement signal into horizontal and vertical components or an implicit process whereby component signals do not predominate until the level of the motor neurons. Thus decomposition models predict that premotor neurons should primarily encode component signals while implicit models predict encoding of off-cardinal optimal directions by premotor neurons. The central mesencephalic reticular formation (cMRF) and paramedian pontine reticular formation (PPRF) are two brain stem regions that likely participate in the development of motor activity since both structures are anatomically connected to nuclei that encode movement goal (superior colliculus) and generate horizontal eye movements (abducens nucleus). We compared cMRF and PPRF neurons and found they had similar relationships to saccade dynamics, latencies, and movement fields. Typically, the direction preference of these premotor neurons was horizontal, suggesting they were related to saccade components. To confirm this supposition, we studied the neurons during a series of oblique saccades that caused "component stretching" and thus allowed the vectorial (overall) saccade velocity to be dissociated from horizontal component velocity. The majority of cMRF and PPRF neurons encoded component velocity across all saccades, supporting decomposition models that suggest horizontal and vertical signals are generated before the level of the motoneurons. However, we also found novel vectorial eye velocity encoding neurons that may have important implications for saccade control.

Zonal organization of the vestibulo-cerebellum in the control of horizontal extraocular muscles using pseudorabies virus: I. flocculus/ventral paraflocculus

Much literature has studied the relationship between the organization of neurons in the flocculus/ventral paraflocculus and vestibulo-ocular reflex pathways. Although activation of a flocculus central zone produces ipsilateral horizontal eye movement, anatomical tracing evidence in rats suggests that there may not be a simple one-to-one correspondence between flocculus/ventral paraflocculus zones and control of single extraocular muscles or coplanar pairs of antagonistic extraocular muscles. This study used the retrograde transynaptic transport of pseudorabies virus to identify the topographical organization of Purkinje cells in the flocculus/ventral paraflocculus that control the lateral rectus (LR) and medial rectus (MR) muscles in rats. A survival time of 80 h and 84 h was necessary to observe consistent transynaptically labeled cells in the flocculus/ventral paraflocculus following injections of pseudorabies virus into the MR and LR, respectively. The organization of Purkinje cells in the dorsal flocculus and ventral paraflocculus abided by the traditional boundaries, whereas the labeling pattern in the ventral flocculus showed a more complex, interdigitated arrangement. In agreement with prior studies, transynaptically labeled neurons were also observed in specific vestibular nuclear regions within the medial and superior vestibular nuclei and dorsal Y group. The distribution of labeled neurons in ipsilateral and contralateral vestibular nuclei was associated with features of ipsilateral and contralateral retrograde labeling of Purkinje cells in flocculus/ventral paraflocculus. Importantly, this study provides the first evidence of vestibulo-cerebellar zones controlling individual extraocular muscles and also overlapping distribution of neurons in flocculo-vestibular zones that influence the LR and MR motoneuron pools. This suggests that some of these neurons may be responsible for controlling both muscles.

Radiotherapy in the management of Graves' ophthalmopathy.

To report the results of radiotherapy for patients with failure, adverse reactions or relative contraindications to the use of steroids or immunosuppressants, by using newly developed quantitative indexes. Fourteen female and six male patients with Graves' ophthalmopathy were treated with radiotherapy between 1989 and 1996. Prior to radiotherapy, eight patients received treatment with prednisone, four received immunosuppressants and four received a combination of both. Four patients with contraindications to steroids were initially managed with radiotherapy. Most of the patients received a dose of 24-28 Gy in 2 Gy fractions. We used the newly developed motility limitation index to assess extraocular motility. Treatment was well tolerated. There have been no late complications. All 12 patients with soft tissue signs such as edema, irritation, tearing and pain were improved. Proptosis did not improve or improved only slightly, 3 mm at best. However, proptosis in all but two has been stabilized and has not deteriorated in the follow-up period. Most of the patients have experienced an improvement of eye-muscle motility. Extraocular muscles that work for elevation were impaired more severely than the other muscles and this tended to remain. Of the 16 patients using steroids before or when radiotherapy was initiated, 15 were tapered off and only one patient required additional steroids, thus sparing the majority from steroid adverse reactions. Radiotherapy was effective in preventing exacerbations of active inflammatory ophthalmopathy in patients with Graves' disease with minimal morbidity and thus eliminated the adverse reactions associated with protracted corticosteroid use. The newly developed motility limitation index was useful in detecting delicate changes in motility of individual extraocular muscles.

Muscles of a different 'color'

The rules that govern many aspects of skeletal muscle structure and function are very different for the extraocular muscle allotype. The myoblast lineages present in the extraocular muscle primordia are permissive for generation of an unusually wide range of fiber types. The balance that is struck between genetic specification and activity dependent factors in shaping fiber phenotype to suit the demands of complex visuomotor systems is not yet well defined. Because skeletal muscle has high energy demands, diversity in fiber types is needed to maximize efficiency; greater diversity in fiber composition then indicates a more diverse functional repertoire. Together, the characteristics of small motor unit size, precise dependence of muscle force upon motor neuron discharge rate, high contractile speed but low tension development, and contractile protein heterogeneity contribute toward the high precision and diversity that is required for eye movements. Finally, the structural and functional characteristics and plasticity of the individual extraocular muscle fiber types play an important role in determining their response to disease or manipulation. The lack of uniform responses across the muscle allotypes in disease, or in response to pharmaceutical or surgical interventions, requires that we obtain a better understanding of the fundamental differences that exist between muscle groups.

The value of the short tau inversion recovery sequence in magnetic resonance imaging of thyroid eye disease

22 patients with thyroid eye disease were examined with magnetic resonance imaging (MRI) and the results compared with 10 controls. Imaging was performed on a 1.0 T scanner using a head coil. All patients were examined using both T1W and short tau inversion recovery (STIR) sequences. The relative signal intensity (SI) of individual extraocular muscles were quantified by comparison with SI from the adjacent temporalis muscle to give a signal intensity ratio (SIR). The results were compared with clinical disease activity assessed by the Werner grading system. Visual evaluation of muscle size and calculated SIRs showed an increase when compared to normals in 15 of the 22 patients. This difference was significant in patients with high grade (4-6) clinical disease. The known histological changes in this disease suggest that this increase in signal is caused by oedema secondary to acute inflammation. STIR sequences suppress the retro-orbital fat and thus enhance these changes both in the muscles and in the fat itself. The MR findings suggest that the STIR sequence can be used to predict those patients that will respond to anti-inflammatory treatment.

Somatotopic Organization of the Axons Innervating the Superior Rectus Muscle in the Oculomotor Nerve of the Rat

It has long been known that the pupillomotor fibers have a localized course in the dorsomedial periphery through the subarachnoid portion of the oculomotor nerve. However we do not have detailed knowledge about the organization of the fibers innervating individual extraocular muscles. This subject is of clinical importance for locating the site of lesions in patients with partial oculomotor nerve palsies. In this study the peripheral course of the axons innervating the superior rectus muscle were studied in the subarachnoid portion of the oculomotor nerve of the rat by making multiple injections of horseradish peroxidase solution into the muscle and reacting the nerve with tetramethylbenzidine as a chromogen. Coronal sections of the nerve showed that the axons innervating the superior rectus muscle were localized in the dorsal part of the nerve. Within the precavernous portion these axons showed a wider distribution invading dorsomedial and dorsolateral parts of the nerve.

Spatial arrangement of the vestibular and the oculomotor system in the rat

The treatment of the spatial aspects of vestibular sensation, ocular movement near primary position, and their neural processing requires numerical information about the directions of maximal sensitivity of the semicircular canals (SCC), the direction of gaze at primary position, and the directions of eye rotation generated by each individual extraocular muscle (EOM). A good approximation of this information can be gained from stereotaxic measurements of the geometrical arrangement of the canals' bony structure, from measurements of the pupil's orientation, and from measurements of the directions of muscle pull as well as of the center of eye rotation. The results of measurements in pigmented rats are given as unit sensitivity vectors and unit action in head-fixed coordinate systems and compared with data from rabbit, cat, monkey, and human. The misalignment of ‘coplanar’ SCC with 2.5–15.6° is second only to humans, while the misalignment of the vectors of ‘antagonistic’ EOM with 27.2–39° is even more oblique than in humans and thereby even more so than in the other mammals. Misalignment of SCC and ‘corresponding’ EOM with 15.5–34.2° again is largest, followed by that in humans and then the other mammals. The rat may therefore be useful in studying those mechanisms by which the central nervous system deals with the obliqueness of systems that play such an important role in humans, too.

Extra‐ and intracellular HRP analysis or the organization of extraocular motoneurons and internuclear neurons in the guinea pig and rabbit

The distribution of extraocular motoneurons and abducens and oculomotor internuclear neurons was determined in guinea pigs by injecting horseradish peroxidase (HRP) into individual extraocular muscles, the abducens nucleus, the oculomotor nucleus, and the cerebellum. Motoneurons in the oculomotor nucleus innervated the ipsilateral inferior rectus, inferior oblique, medial rectus, and the contralateral superior rectus and levator palpebrae muscles. Most motoneurons of the trochlear nucleus projected to the contralateral superior oblique muscle although a small number innervated the ipsilateral superior oblique. The abducens and accessory abducens nuclei innervated the ipsilateral rectus and retractor bulbi muscles, respectively. The somata of abducens internuclear neurons formed a cap around the lateral and ventral aspects of the abducens nucleus. The axons of these internuclear neurons terminated in the medial rectus subdivision of the contralateral oculomotor nucleus. At least two classes of guinea pig oculomotor internuclear interneurons exist. One group, located primarily ventral to the oculomotor nucleus, innervated the abducens nucleus and surrounding regions. The second group, lying mainly in the dorsal midline area of the oculomotor nucleus, projected to the cerebellum. Intracellular staining with HRP demonstrated similar soma-dendritic organization for oculomotor and trochlear motoneurons of both guinea pigs and rabbits. Dendrites of oculomotor motoneurons radiated symmetrically from the soma to cover approximately one-third of the entire nucleus, and each motoneuron sent at least one dendrite into the central gray overlying the oculomotor nucleus. In both species, a small percentage of oculomotor motoneurons possessed axon collaterals that terminated both within and outside of the nucleus. The dendrites of trochlear motoneurons extended into the medial longitudinal fasciculus and the reticular formation lateral to the nucleus. Our data on the topography of motoneurons and internuclear neurons in the guinea pig and soma-dendritic organization of motoneurons in the guinea pig and rabbit show that these species share common organizational and morphological features. In addition, comparison of these data with those from other mammals reveals that dendritic complexity (number of dendrites per motoneuron) of extraocular motoneurons exhibits a systematic increase with animal size.

Distribution of motoneurones innervating extraocular muscles in the brain of the marmoset (Callithrix jacchus).

Extraocular muscle motoneurones were localised in the oculomotor nucleus (ON), trochlear nucleus (TN) and abducens nucleus (AN) in the marmoset brain using the horseradish peroxidase (HRP) retrograde labelling technique. HRP pellets injected into individual extraocular muscles revealed one or more groups of labelled neurones occupying discrete loci within these nuclei. Relatively little overlap of motoneurone pools was observed, except in the case of the inferior oblique and superior rectus muscles. Injections of HRP into the medial rectus muscle revealed three separate populations of labelled cells in the ipsilateral ON. Motoneurones innervating the inferior rectus muscle were mainly localised in the lateral somatic cell column of the ipsilateral ON. A second smaller grouping was observed in the medial longitudinal fasciculus. The inferior oblique muscle motoneurones were localised in the ipsilateral medial somatic cell column intermingled with motoneurones supplying the superior rectus muscle of the opposite eye. The superior oblique muscle motoneurones occupied the entire TN and the lateral rectus muscle motoneurones the AN. It was concluded that the organisation of nuclei and subnuclei responsible for controlling the extraocular muscles in the marmoset is broadly similar to that of other primates.

Peripheral and central oculomotor organization in the goldfish, Carassius auratus.

Peripheral and central oculomotor organization was studied in the goldfish. The sizes of the extraocular muscles were quantified by counting the fibers contained in a given muscle and by area measurements of the cross-sectional surfaces. All the muscles were of approximately similar size. Kinematics were determined by electrical stimulation of a given muscle. The macroscopic appearance and kinematics of the muscles had the characteristics of other lateral-eyed animals (e.g., rabbit). Locations of extraocular motor neurons were found by retrograde transport of horseradish peroxidase (HRP) following injections into individual extraocular muscles. The eye muscles were innervated by four ipsilateral (lateral rectus, medial rectus, inferior oblique, inferior rectus) and two contralateral (superior rectus, superior oblique) motor neuron pools. The oculomotor nucleus was found in the midbrain, at the level of the caudal zone of the inferior lobe of the hypothalamus. Inferior rectus motor neurons were located rostrally in the oculomotor nucleus, whereas medial rectus, superior rectus, and inferior oblique motor neurons were intermingled in its more caudal portions. All labelled cells were located dorsally and medially to the medial longitudinal fasciculus (MLF) in close proximity to either the floor of the ventricle or the midline region. Occasionally, motor neurons were interspersed within the fiber bundles of the MLF or the exiting fibers of the oculomotor nerve. The trochlear nucleus, containing superior oblique motor neurons, was found in the immediate lateral and caudal neighborhood of the oculomotor nucleus, where its rostral border overlapped with the caudal border of the latter. The abducens nucleus, containing lateral rectus motor neurons, was located in the posterior brainstem in the neighborhood of the vestibular nuclear complex. This nucleus was divided into a rostral and a caudal portion. The axons of ipsilaterally projecting motor neurons headed toward their respective nerve roots via the shortest possible route, as did the axons of superior rectus motor neurons, which crossed the midline without detour to enter the contralateral oculomotor nerve. In contrast, trochlear motor neuron axons arched around the dorsal aspect of the ventricle through the cerebellar commissure to reach the contralateral trochlear nerve. The morphology of individual motor neurons was visualized by intrasomatic injection of HRP. Cell somata had oblong shapes, and their large dendrites were oriented laterally and ventrally. The axons did not collateralize within the midbrain region or the oculomotor nerve as far as they could be traced.(ABSTRACT TRUNCATED AT 400 WORDS)

Innervation of monkey extraocular muscles: localization of sensory and motor neurons by retrograde transport of horseradish peroxidase.

AbstractNeurons that provide sensory and motor innervation of extraocular muscles in the monkey have been identified and localized by retrograde transport of horseradish peroxidase (HRP). Injections of HRP into individual extraocular muscles of rhesus or pig‐tail monkeys labeled pseudounipolar neurons that were localized within the ipsilateral semilunar ganglion. The distribution of labeled neurons within the ganglion was consistent with its somatotopic organization as the majority were found within the ophthalmic subdivision. Absence of labeled neurons within either the trigeminal mesencephalic or spinal nucleus was in agreement with previous findings in the cat (Porter and Spencer, '82). Intracranial transection of the ophthalmic nerve prior to muscle injection eliminated all labeling within the ganglion. These data indicate that the extraocular muscles can be selectively deafferented in order to examine the potential role(s) of proprioception in the neural control of eye movements.Injections of HRP into the extraocular muscles also resulted in the la beling of individual motoneuron populations. Each extraocular muscle was found to receive solely unilateral innervation, with contralateral representation of only the superior rectus and superior oblique. Within the oculomotor nucleus there was a moderate topographic segregation of individual motoneuron populations. Primate medial rectus and inferior rectus representations, while at variance with the classical descriptions (Warwick, '53), were consistent with those obtained in contemporary tracer studies (Büttner Ennever and Akert, '81; Spencer and Porter, '81). Superior rectus motoneurons were distributed along the medial aspect of the contralateral nucleus, with the predominant representation at caudal to midnuclear levels. Inferior oblique motoneurons filled the gap lateral to those of the superior rectus and ventral to medial rectus (dorsal subgroup) and inferior rectus representations at their respective levels. Following injections of the lateral rectus and superior oblique labeled motoneurons were found within the ipsilateral abducens nucleus and contralateral trochlear nucleus, respectively. Superior oblique motoneurons were strictly confined to the well‐defined neuronal borders of the trochlear nucleus. Those innervating the lateral rectus, in addition to lying within the abducens proper, extended ventrolaterally from the nucleus to form a discrete ventral abducens nucleus. Our data provide a complete description of the innervation pattern of primate extraocular muscles which is based upon contemporary tracer techniques. These findings include the first demonstration of the localization of monkey first‐order afferent neurons which subserve extraocular muscle proprioception.

Clinical significance of extraocular muscle volumes in Graves' ophthalmopathy: a quantitative computed tomography study.

• Orbital and extraocular muscle volumes were calculated from high-resolution computed tomographic scans in patients with Graves' ophthalmopathy. Total and individual extraocular muscle volumes were found to be increased, compared with controls. Only the medial and lateral muscle groups increased in volume proportional to the degree of ophthalmopathy.