Normal Extraocular Muscles Research Articles

Continuous remodeling of adult extraocular muscles as an explanation for selective craniofacial vulnerability in oculopharyngeal muscular dystrophy.

Oculopharyngeal muscular mystrophy (OPMD) is an inherited disorder caused by mutations of the polyadenylate binding protein nuclear 1 (PABPN1) gene. While a pathogenic hypothesis has been formulated that links the genetic and molecular abnormalities to cellular abnormalities, there is no proven explanation for the targeting of the craniofacial muscles. We propose a hypothesis that bridges this gap. It is based on the phenomenon of continuous remodeling of normal adult extraocular muscles (EOMs). Unlike the EOMs, the myonuclei of other skeletal muscles are postmitotic in the adult unless the muscles are injured. Continuous myofiber remodeling most likely requires upregulation of genes involved in cell cycling, and in protein degradation and synthesis. PABPN1 is a nuclear protein that performs the essential function of controlling polyadenylation of mRNA and the fidelity of protein synthesis. In OPMD, the ongoing production of mutant PABPN1 in muscles undergoing continuous remodeling could result in a failure of accurate production of mRNA required for the maintenance of the myocytes. Over many years, this would lead to cumulative myonuclear loss and finally to myofiber loss. This hypothesis offers an explanation for the selective involvement of extraocular muscles affected in OPMD and the onset of symptoms in adulthood.

Comprehensive evaluation of the extraocular muscle critical period by expression profiling in the dark-reared rat and monocularly deprived monkey.

To address the consequences of visual deprivation paradigms in rat (dark rearing) and monkey (monocular deprivation) on extraocular muscle (EOM) development using genome-wide expression profiling. Serial analysis of gene expression (SAGE) was used to determine alterations in the EOM transcriptome induced by dark rearing of rats from birth to postnatal day 45. Data were compared with previously published normal EOM SAGE library. DNA microarray similarly assessed changes in gene expression patterns of EOMs of monkeys reared from birth to 4 months of age with monocular deprivation. Dark rearing produced changes in expression of 280 transcripts in rat EOM. Of these, 71 were known genes representing functional categories that included energy metabolism/mitochondrial-related (21%), protein synthesis and modification (14%), lipid metabolism (13%), and muscle-related (6%) transcripts. Together, the predominant pattern reflected an energetic shift toward fatty acid beta-oxidation and integrated alterations in both myofibers and supportive tissues. The response of monkey rectus muscles to monocular deprivation was considerably less severe. The visual deprivation paradigms used in this study mimic alterations that are associated with the common disorders of strabismus, congenital cataract, and amblyopia. These data show that postnatal EOM maturation is broadly susceptible to changes in activity patterns that are a consequence of visuomotor maldevelopment. The data extend the concept of an EOM-critical period and establish that activity patterns in developing eye movement systems play vital determinant roles in the novel EOM phenotype.

Constitutive properties, not molecular adaptations, mediate extraocular muscle sparing in dystrophic mdx mice.

Extraocular muscle (EOM) is spared in Duchenne muscular dystrophy. Here, we tested putative EOM sparing mechanisms predicted from existing dystrophinopathy models. Data show that mdx mouse EOM contains dystrophin-glycoprotein complex (DGC)-competent and DGC-deficient myofibers distributed in a fiber type-specific pattern. Up-regulation of a dystrophin homologue, utrophin, mediates selective DGC retention. Counter to the DGC mechanical hypothesis, an intact DGC is not a precondition for EOM sarcolemmal integrity, and active adaptation at the level of calcium homeostasis is not mechanistic in protection. A partial, fiber type-specific retention of antiischemic nitric oxide to vascular smooth muscle signaling is not a factor in EOM sparing, because mice deficient in dystrophin and alpha-syntrophin, which localizes neuronal nitric oxide synthase to the sarcolemma, have normal EOMs. Moreover, an alternative transmembrane protein, alpha7beta1 integrin, does not appear to substitute for the DGC in EOM. Finally, genomewide expression profiling showed that EOM does not actively adapt to dystrophinopathy but identified candidate genes for the constitutive protection of mdx EOM. Taken together, data emphasize the conditional nature of dystrophinopathy and the potential importance of nonmechanical DGC roles and support the hypothesis that broad, constitutive structural cell signaling, and/or biochemical differences between EOM and other skeletal muscles are determinants of differential disease responsiveness.

Normal Magnetic Resonance Contrast Enhancement of Extraocular Muscles: A Quantitative Analysis

The purpose was to evaluate quantitatively the magnetic resonance contrast enhancement of normal extraocular muscles and the use of temporal muscles as a reference of enhancement. Eighty extraocular and 20 temporal muscles were taken into analysis. Before contrast administration, mean intensity of extraocular muscles was found to be higher than that of temporal muscles (p < 0.000). With contrast agent, all extraocular muscles were enhanced more (111% enhancement) than the temporal muscles (45% enhancement, p < 0.000). Lateral recti had the lowest signal intensity, both in pre- and postcontrast images (p < 0.005). Normal extraocular muscles showed prominent enhancement on contrast-enhanced T₁-weighted images. Temporal muscles were also enhanced in all subjects, urging the observers to compare the enhancement of extraocular muscles not with the latter.

Management of the trochlea of the superior oblique muscle in the repair of orbital roof trauma

Purpose: This study evaluated whether reattachment of the trochlea is necessary to assure normal postoperative extraocular muscle movements after orbital roof exploration and trochlea detachment.Patients and Methods: This was a retrospective review of 889 operative records of one surgeon practicing at a level I trauma center between January 1, 1992 and December 31, 1998. Three hundred twenty-four of these cases were trauma related, 97 of which involved the upper facial third or upper midface. From this group, 15 patients required orbital roof exploration with trochlea detachment. Age, gender, cause of injury, form of craniofacial injury, method of repair, materials used, date of first notation of intact extraocular movement, and date of last follow-up were recorded and analyzed.Results: From among the 15 patients requiring orbital roof exploration and repair, 14 (93%) were male, with a mean age of 34.7 ± 15.2 years. Eight (53%) were involved in motor vehicle accidents, 3 (20%) in motorcycle accidents, and 4 (27%) in high-energy impacts. Most (95%) had injuries that included the frontal sinus, the naso-orbital-ethmoid region (60%), and the orbital rims (60%). After bitemporal flap reflection, careful subperiosteal dissection, supraorbital and supratrochlear nerve repositioning, and trochlea detachment, simple reapproximation of the orbital soft tissues to the reconstructed orbit resulted in satisfactory extraocular muscle movements in all cases.Conclusions: When careful subperiosteal dissection is used, simple reapproximation of the soft tissues adjacent to the reconstructed orbital roof, without reattachment of the trochlea, is all that was necessary to assure satisfactory extraocular muscle movements postoperatively.

Management of the trochlea of the superior oblique muscle in the repair of orbital roof trauma

<h2>Abstract</h2> <b>Purpose:</b> This study evaluated whether reattachment of the trochlea is necessary to assure normal postoperative extraocular muscle movements after orbital roof exploration and trochlea detachment. <b>Patients and Methods:</b> This was a retrospective review of 889 operative records of one surgeon practicing at a level I trauma center between January 1, 1992 and December 31, 1998. Three hundred twenty-four of these cases were trauma related, 97 of which involved the upper facial third or upper midface. From this group, 15 patients required orbital roof exploration with trochlea detachment. Age, gender, cause of injury, form of craniofacial injury, method of repair, materials used, date of first notation of intact extraocular movement, and date of last follow-up were recorded and analyzed. <b>Results:</b> From among the 15 patients requiring orbital roof exploration and repair, 14 (93%) were male, with a mean age of 34.7 ± 15.2 years. Eight (53%) were involved in motor vehicle accidents, 3 (20%) in motorcycle accidents, and 4 (27%) in high-energy impacts. Most (95%) had injuries that included the frontal sinus, the naso-orbital-ethmoid region (60%), and the orbital rims (60%). After bitemporal flap reflection, careful subperiosteal dissection, supraorbital and supratrochlear nerve repositioning, and trochlea detachment, simple reapproximation of the orbital soft tissues to the reconstructed orbit resulted in satisfactory extraocular muscle movements in all cases. <b>Conclusions:</b> When careful subperiosteal dissection is used, simple reapproximation of the soft tissues adjacent to the reconstructed orbital roof, without reattachment of the trochlea, is all that was necessary to assure satisfactory extraocular muscle movements postoperatively. © 2000 American Association of Maxillofacial Surgeons

Enhancement pattern of normal extraocular muscles in dynamic contrast-enhanced MR imaging with fat suppression.

To evaluate the internal structure of normal extraocular muscles on fat-suppressed dynamic contrast-enhanced MR imaging. Ten subjects were examined using fat-suppressed dynamic contrast-enhanced MR imaging. We evaluated the enhancement pattern (C-shaped or ring-like) of extraocular muscles and quantified the maximum ratios of enhancement (Rmax) and maximum ratios of signal increase (Vmax). We also quantified Rmax and Vmax in the central and peripheral portions of medial rectus muscles. In the early phase of dynamic contrast-enhanced MR imaging, a C-shaped or ring-like pattern was observed in 100% of inferior rectus, 95% of medial rectus, 55% of superior rectus, 20% of lateral rectus, and 15% of superior oblique muscles. Overall mean Rmax and Vmax values showed statistically significant differences to the temporal muscles. For the peripheral portion of medial rectus muscles, mean Rmax and Vmax values were greater than for the central portion. Using fat-suppressed dynamic contrast-enhanced MR imaging, the C-shape or ring-like internal structure of the extraocular muscles could be visualized, and were considered to reflect their structure of orbital and global layers. Potential usefulness of the fat-suppressed dynamic contrast-enhanced MR imaging for detecting pathological status is suggested.

Normative measurements of orbital structures using CT.

The purposes of this study were to establish criteria for the diameters of normal extraocular muscles, to determine the normal position of the globe as revealed by CT, and to investigate the effects of age and sex on these structures. Diameters of extraocular muscles, distance from the interzygomatic line to the posterior margin of the globe, width of the optic nerve-sheath complex, and length of the interzygomatic line were calculated for 200 normal orbits of 100 patients on axial and direct coronal CT images. Effects of age and sex on muscle diameters and globe position were analyzed. Normal ranges for the diameters (mean +/- 2SDs) of extraocular muscles were medial rectus, 3.3-5.0 mm; lateral rectus, 1.7-4.8 mm; inferior rectus, 3.2-6.5 mm; and superior group, 3.2-6.1 mm. The normal position of the globe was 9.4 mm behind the interzygomatic line (range, 5.9-12.8 mm). The mean diameters of the extraocular muscles and the length of the interzygomatic line in male patients were significantly larger than in female patients (p < .001). Statistically significant correlation was found between age and the diameters of the inferior and lateral rectus muscles (r = .32, p = .013; and r = .23, p = .048, respectively). Our results may be important in interpreting CT scans of the orbit because, to our knowledge, no reliable normative data exist regarding these orbital structures.

Heterotopic muscle pulleys or oblique muscle dysfunction?

Introduction: The description of connective tissue sleeves that function as pulleys for the rectus extraocular muscles (EOMs) suggests that abnormalities of EOM pulley position might provide a mechanical basis for some forms of incomitant strabismus. Pulleys determine the paths and thus the pulling directions of EOMs. Methods: High-resolution magnetic resonance images spanning the orbits were obtained in primary position, upgaze, and downgaze for each subject. Paths of the EOMs were measured with reference to the orbital center and permitted inference of pulley locations. Results: Data from 18 orbits of orthotropic subjects defined means and SDs of normal EOM pulley coordinates. Eight patients, aged 17 to 60 years, had heterotopic EOM pulleys, defined as displaced at least 2 SDs from normal. We found one to eight heterotopic pulleys (considering both orbits) in each of four patients who had been diagnosed with marked superior oblique (SO) overaction and mild to marked inferior oblique (IO) underaction. Each patient had superior mislocation of at least one lateral rectus pulley by 1.8 to 4.9 mm. Three patients diagnosed with mild to moderate IO overaction and mild to moderate SO underaction in only one orbit had one to three heterotopic EOM pulleys. Each of those patients had at least one lateral rectus pulley inferiorly dislocated by 1.9 to 4.9 mm. The final patient, who was diagnosed with mild IO underaction and normal SO function bilaterally, had bilateral superior mislocation of the medial rectus pulleys by greater than 2 mm. Computer simulations using the Orbit program (Eidactics, San Francisco) incorporating individually measured pulley positions reproduced the clinical patterns of incomitant strabismus in all cases without postulating abnormalities of oblique muscle innervation or contractility. Conclusion: Heterotopic EOM pulleys can cause patterns of incomitant strabismus that have been attributed to oblique muscle dysfunction. Even isolated mislocations of less than 2 mm, coupled with smaller mislocations of the other pulleys, can produce the clinical appearance of bilateral oblique dysfunction. Pulley heterotopy should be considered in the differential diagnosis of incomitant strabismus and oblique dysfunction.

High-resolution magnetic resonance imaging of the normal extraocular musculature.

Magnetic resonance imaging (MRI) of the extraocular muscles has attracted growing interest for the evaluation of complex motility disorders. However, little information is available on the high-resolution MRI anatomy of the normal extraocular muscles and their connective tissue system. The study describes the imaging anatomy of the recti and oblique muscles and the levator palpebrae superioris muscle. MRI of the orbit at 1 tesla was performed in four normal volunteers using a surface coil. Many anatomical details such as Zinn's tendinous annulus, the trochlea, the superior oblique tendon, the intermuscular septa, the check ligaments, Lockwood's ligament and the common sheath between the superior rectus muscle and the levator muscle were visualised. A striking imaging feature was the curved path of both the recti muscles and the levator palpebrae muscle. The inferior oblique muscle also showed a marked curvature in the region of Lockwood's ligament. High-resolution MRI is capable of demonstrating the anatomy of the extraocular musculature and parts of its connective tissue system. The curved path of the extraocular muscles can be explained by the configuration of the orbital connective tissue system which couples each extraocular muscle with the adjacent orbital wall. We discuss the clinical implications of our findings and review previous radiological studies regarding the functional anatomy of the extraocular muscles.

Orbital pathology in thyroid-associated ophthalmopathy

Thyroid-associated ophthalmopathy (TAO) is a disfiguring disease. The clinical symptoms are the consequence of inflammation in the orbital tissues in response to as yet unknown antigens, causing swelling of the extraocular muscles, edema and fibrosis, and subsequently eye movement impairment, exophthalmos and sometimes compression of the optic nerve. Analysis of orbits from 40 patients with Graves' ophthalmopathy showed an increased volume of both the extraocular muscles and the orbital adipose/connective tissue in 48%, increased muscle volume with normal adipose/connective tissue in 20% and normal muscles with increased adipose/connective tissue in 28%. The other orbits were normal (4%).Knowledge of the overall anatomy and the distribution of immunocompetent cells may help to shed light on the pathophysiology of TAO. In normal orbital tissues B-lymphocytes were scarce, but T-lymphocytes were numerous in normal extraocular muscles, orbital connective tissue septa and in the loose connective tissue surroun...

Extreme Eyelid Swelling as an Unusual Presentation of Dysthyroid Orbitopathy

We describe seven cases of dysthyroid orbitopathy initially seen as severe periocular lid swelling. Imaging techniques typically demonstrate normal extraocular muscles, although moderate muscle enlargement may occur. Patients do not respond to steroids, radiation therapy, antihistamines, or diuretics. We believe this clinical picture represents a unique population of dysthyroid orbitopathy patients who are best managed by long-term observation followed by cosmetic surgery.

Pentoxifylline inhibits the proliferation and glycosaminoglycan synthesis of cultured fibroblasts derived from patients with Graves' ophthalmopathy and pretibial myxoedema.

Excessive amounts of glycosaminoglycans accumulate in the extraocular muscles of patients with Graves' ophthalmopathy and in the affected skin of patients with pretibial myxoedema. It is widely accepted that fibroblasts are the sources of glycosaminoglycan synthesis. Pentoxifylline, an analogue of the methylxanthine theobromine, inhibits the proliferation and certain biosynthetic activities of fibroblasts derived from normal human skin and from skin of patients with some fibrotic disorders. Our objective was to determine whether pentoxifylline has similar effects on fibroblasts derived from patients with Graves' ophthalmopathy and pretibial myxoedema and could serve as a candidate for the treatment of these manifestations. Fibroblasts from the extraocular muscles of two patients with Graves' ophthalmopathy and normal extraocular muscles of two subjects with strabismus, as well as the affected skin of two patients with pretibial myxoedema were cultured in vitro in the presence and absence of pentoxifylline to assay its effect on the proliferation of fibroblasts and their production of glycosaminoglycans. In subconfluent fibroblast cultures, pentoxifylline treatment caused a dose-dependent inhibition of serum-driven fibroblast proliferation. In confluent fibroblast cultures both in the presence and absence of serum, exposure to pentoxifylline similarly resulted in a dose-dependent inhibition of glycosaminoglycan synthesis for all these different kinds of fibroblasts. These findings may form the rationale for a clinical trial using pentoxifylline for the treatment of Graves' ophthalmopathy and pretibial myxoedema.

Diameter of Normal Extraocular Recti Muscles With Echography

To establish the range of diameters of normal extraocular muscles, we used standardized A-scan echography to measure the superior recti/levator complex, medial, lateral, and inferior recti muscles in 38 subjects with healthy orbital tissues. The relationships of age, gender, height, and weight to axial length of the globe were considered. These factors and extraocular muscle diameters were not consistently associated. Our normative data were compared with previously reported studies of extraocular muscle diameter performed with standardized A-scan and contact B-scan echography and computed tomographic scanning.

Cloning and Sequencing of a Novel 64-kDa Autoantigen Recognized by Patients with Autoimmune Thyroid Disease*

Screening 10(6) plaque-forming units from a lambda gt11 human thyroid cDNA library with a pool of 10 sera from patients with Hashimoto's thyroiditis resulted in the isolation of a clone, D1, of 292 basepairs with an open reading frame of 97 amino acids which did not share significant similarity with any known protein. Rescreening the library using D1 as a probe led to the full-length cDNA being cloned and sequenced which has the potential to encode a 572-amino acid polypeptide. This would correspond to a 63-kDa nonglycosylated protein which is probably membrane bound. The recombinant fusion protein from the original D1 clone was recognized in dot blot or Western blot assays by 4 of 19 patients with Hashimoto's thyroiditis, 3 of 9 patients with Graves' disease, and 1 of 6 patients with idiopathic myxedema; all other sera (12), including that from normal subjects, were negative. Clone affinity-purified autoantibodies bound to a protein of 64 kDa in a Western blot of human thyroid tissue. Using D1 as a probe in a Northern blot revealed 3.9-kilobase (kb) transcripts in poly(A)+ RNA from normal human thyroid and extraocular muscle, but not skeletal muscle. The dog equivalent of D1 cDNA was isolated by screening 10(6) plaque-forming units from a dog thyroid cDNA library using clone D1. A fragment of dog cDNA was, in turn, used as a probe in a Northern blot of dog poly(A)+ RNAs from thyroid, brain, lung, heart, liver, kidney, spleen, and stomach; a faint signal at 3.9 kb was observed in all tissues except the thyroid, which displayed a strong transcript of 2.6 kb. It is concluded that the D1 cDNA clone encodes an autoantigen shared by the thyroid and eye muscle. Its possible relevance to autoimmune ophthalmopathy is discussed.

Potential antigen-presenting cells in normal extraocular muscles demonstrated with double immunoenzyme staining

Antigen-presenting cells are of crucial importance for the initiation and regulation of regional immune responses. In a previous study, indirect morphological evidence that morphologically normal human orbital tissues contain HLA-DR-positive macrophages, which may represent antigen-presenting cells, has ben obtained. In the present study, these cells were characterized in detail using double immunoenzyme staining techniques with monoclonal antibodies directed against several well-characterized monocyte/macrophage markers and against HLA-DR gene products. The orbital muscular tissues appear to contain numerous HLA-DR, monocyte/macrophage marker double-stained cells, which are considered to be potential antigen-presenting cells. The cells are widely distributed in the connective tissue of all the orbital muscular tissues studied and consist of several subsets with different phenotypes. Furthermore, site-specific differences were shown between recti muscles and the levator/Müller's muscles with respect to the distribution of HLA-DR and one monocyte/macrophage marker (OKM5). Many of the orbital antigen-presenting cells appear to be of the dendritic type and are considered to be of major importance in regulating local orbital immunity.

Morphometric Comparison between Human and Rat Abducens and Oculomotor Nerves

A morphologic and morphometric comparison between normal human and rat extraocular muscle nerves was performed using a computer-assisted method to obtain scatter diagrams of relative sheath thickness (g ratio = quotient axon diameter/fiber diameter). Human and rat extraocular muscle nerves (nervus abducens and ramus medialis n. oculomotorii) were excised immediately before the nerve branching at the entering point into the muscle. There was no difference in the absolute number of myelinated fibers between the oculomotor and abducens nerves in both species. The distribution of myelinated fibers was classified according to their g ratios into a two-stage density cluster analysis. Two main populations of nerve fibers for human oculomotor and rat oculomotor and abducens nerves and three main populations for human abducens nerve were differentiated morphometrically and mathematically, differing in their relative sheath thicknesses. There are distinct differences between scatter diagrams of human and rat extraocular muscle nerves, in correlation with the basically different oculomotor functions of these two species. The morphometric differences between human and rat extraocular muscle nerves suggest a difference in the myelination process and the presence of functionally different nerve fibers, strongly indicated by the populations and subpopulations of myelinating nerve fibers peculiar to extraocular muscle. The existence of more than two different types of myelinated fibers in the human nerves implies that the traditional classification based on fiber caliber must be reviewed and a comparison of different classes of nerve and muscle fibers should be performed.

Long-term follow-up and recent observations on 305 cases of orbital decompression for dysthyroid orbitopathy.

Dysthyroid exophthalmopathy (orbitopathy) results from an enlargement of extraglobal orbital structures, producing ocular proptosis, optic nerve compression, and corneal exposure. Treatment with corticosteroids and radiation may be beneficial; refractory cases require surgical decompression of the orbit. Transantral orbital decompression was described by Walsh and Ogura and has been performed in over 350 patients at this institution. A review of 305 patients with long-term follow-up was performed. Visual acuity improved or was maintained at preoperative levels in over 95% of the patients, with ocular recession ranging from 1 to 12 mm (average: 4 mm). Postoperative ocular balance of relative exophthalmos was to within 1 mm in 76% of the patients and to within 2 mm in approximately 90% of the patients. Normal postoperative extraocular muscle balance was present in 99 patients. Immediate postoperative diplopia was noted in 206 patients. Long-term follow-up revealed that in 137 of these patients, diplopia resolved or responded to conservative management. Extraocular muscle surgery was required for correction in 69 patients. Twenty-seven patients had postoperative complications. These included 16 patients with hypesthesia of the infraorbital nerve, 5 patients with sinusitis, 3 patients who had incomplete decompression, 2 patients with oral antral fistulae, and 1 patient who had CSF rhinorrhea. Five patients, despite surgery, radiation, and steroid therapy progressed to blindness. We conclude that this procedure is effective and carries few complications. Orbital imaging, using computed tomography or magnetic resonance sequence with reconstructive capabilities, permits early diagnosis and treatment of dysthyroid compression optic neuropathy.

Intermitochondrial junctions in the extraocular muscle of the rat.

Intermitochondrial junctions with a spacing of 17-21 nm were observed in the superior rectus muscle of a rat. Periodic rounded densities are aligned midway between the apposed outer mitochondrial membranes at some of these junctions. Such densities have a diameter of about 8-10 nm and a center-to-center spacing of about 26-30 nm. These junctions occur in cases where one mitochondrial profile is enclosed within another or where two profiles are interlocked so that their combined overall form has a smoothly contoured profile. Intermitochondrial junctions seem not to have been previously described in muscle, but have been reported in other kinds of tissues. In agreement with those previous reports, the presently observed intermitochondrial junctions usually involve mitochondria that display atypical features indicative of tissue abnormality or stress. Such junctions were never observed in normal extraocular muscle.

Chronic Progressive External Ophthalmoplegia

Chronic progressive external ophthalmoplegia (CPEO) was first described by Albrecht von Graefe in 1868 and it is appropriate that his photograph graces the cover of this new book. Dr von Graefe looks strangely unhappy in the photograph, as if he had anticipated how little important information would be added about this group of diseases in the 111 years since his description. Despite hundreds of publications, we do not know what really causes CPEO or how to cure it. Dr Bastiaensen's book is the only publication that I know of dedicated to the subject of CPEO. It begins with a chapter on the anatomy, physiology, chemistry, and pharmacology of the normal extraocular muscle. The second chapter details the history of the entity from 1868 until the publication by Kiloh and Nevin in 1951 that suggested that CPEO was primarily myopathic in nature. The concept of an ocular myopathy is expanded in