Eye Muscle MRI in Myasthenia Gravis and Other Neuromuscular Disorders.

INTRODUCTION: MRI of extra-ocular muscles (EOM) in patients with myasthenia gravis (MG) could aid in diagnosis and provide insights in therapy-resistant ophthalmoplegia. We used quantitative MRI to study the EOM in MG, healthy and disease controls, including Graves' ophthalmopathy (GO), oculopharyngeal muscular dystrophy (OPMD) and chronic progressive external ophthalmoplegia (CPEO). METHODS: Twenty recently diagnosed MG (59±19yrs), nineteen chronic MG (51±16yrs), fourteen seronegative MG (57±9yrs) and sixteen healthy controls (54±13yrs) were included. Six CPEO (49±14yrs), OPMD (62±10yrs) and GO patients (44±12yrs) served as disease controls. We quantified muscle fat fraction (FF), T2water and volume. Eye ductions and gaze deviations were assessed by synoptophore and Hess-charting. RESULTS: Chronic, but not recent onset, MG patients showed volume increases (e.g. superior rectus and levator palpebrae [SR+LPS] 985±155 mm3 compared to 884±269 mm3 for healthy controls, p < 0.05). As expected, in CPEO volume was decreased (e.g. SR+LPS 602±193 mm3, p < 0.0001), and in GO volume was increased (e.g. SR+LPS 1419±457 mm3, p < 0.0001). FF was increased in chronic MG (e.g. medial rectus increased 0.017, p < 0.05). In CPEO and OPMD the FF was more severely increased. The severity of ophthalmoplegia did not correlate with EOM volume in MG, but did in CPEO and OPMD. No differences in T2water were found. INTERPRETATION: We observed small increases in EOM volume and FF in chronic MG compared to healthy controls. Surprisingly, we found no atrophy in MG, even in patients with long-term ophthalmoplegia. This implies that even long-term ophthalmoplegia in MG does not lead to secondary structural myopathic changes precluding functional recovery.

Augmented loop myopexy with concurrent intraocular lens implantation for myopic strabismus fixus.

Purpose: To evaluate safety profile and surgical outcomes of loop myopexy with concurrent intra-ocular lens implantation in cases of myopic strabismus fixus (MSF). Methods: A retrospective chart review of patients who underwent loop myopexy with concurrent small incision cataract surgery with intra-ocular lens implantation between January 2017 and July 2021 for MSF at a tertiary eye care centre was undertaken. A minimum of 6 months of follow-up after surgery was required for inclusion. The main outcome measures were improvement in alignment postoperatively, improvement in extra-ocular motility postoperatively, intraoperative and postoperative complications and post-operative visual acuity. Results: 12 eyes of 7 patients (male (6): female (1)) underwent modified loop myopexy at a mean age of 46.86 years (range 32-65 years). 5 patients underwent bilateral loop myopexy with intra-ocular lens implantation whereas 2 patients underwent unilateral loop with intra-ocular lens implantation. All eyes underwent additional medial rectus (MR) recession with lateral rectus (LR) plication. At the last follow-up, mean esotropia improved to 16 prism dioptres (PD) (Range: 10-20 PD) from 80 PD (Range:60-90PD), P = 0.016; and success (deviation ≤20PD) was achieved in 73% (95% CI 48 to 89%). Mean hypotropia at presentation was 10 PD (range 6-14 PD), which improved to 0 PD (range 0-9 PD), P = 0.063. Mean BCVA improved from 1.08 LogMar to 0.3 LogMar units. Conclusion: Loop myopexy combined with intra-ocular lens implantation is a safe and effective procedure in the management of patients who have Myopic Strabismus Fixus with visually significant cataract and improves both visual acuity and ocular alignment significantly.

The use of lyophilized bovine pericardium (Tutopatch®) in the management of third nerve palsy following prior conventional strabismus surgery - a case series.

To study the secondary management of strabismus due to third nerve palsy using bovine pericardium (Tutopatch®) when previous conventional surgical therapy had failed. Review of our clinic records of selected patients with third nerve palsy, in whom residual deviation had been managed using Tutopatch® after previous surgical correction. The squint angle was measured preoperatively, and at 1 day, 3 months, and if possible 6 months postoperatively. Nine patients were enrolled in this study. One patient had mainly residual vertical deviation and was corrected with tendon elongation of the contralateral superior rectus. Three patients were operated on with tendon elongation of the lateral rectus muscle with or without medial rectus muscle resection and/or advancement (Group 1). Lateral rectus splitting after tendon elongation in addition to the resection and/or advancement of the medial rectus was performed in five patients with complete third nerve palsy (Group 2). In Group 1, the preoperative median squint angle was -20° (range -17° to -25°), which improved postoperatively to -4.5° (range -12° to +3°). In Group 2, the preoperative horizontal and vertical median squint angles were -27° (range -20° to -40°) and 0.5° (range 0° and 20°), respectively. Postoperatively, they had improved to -12.5° (range-2° to -25°), and 1.5° (range 0° to 7°), respectively. Two patients of Group 2 were re-operated due to residual exotropia. No postoperative complications were observed in any patient. In this small series several complex re-do situations of patients with third nerve palsy were evaluated in which Tutopatch® markedly improved outcomes after an initially ineffective surgical management. For better evaluation of its usefulness a study with more patients is recommended.

Clinical and imaging clues to the diagnosis and follow-up of ptosis and ophthalmoparesis.

Ophthalmoparesis and ptosis can be caused by a wide range of rare or more prevalent diseases, several of which can be successfully treated. In this review, we provide clues to aid in the diagnosis of these diseases, based on the clinical symptoms, the involvement pattern and imaging features of extra-ocular muscles (EOM). Dysfunction of EOM including the levator palpebrae can be due to muscle weakness, anatomical restrictions or pathology affecting the innervation. A comprehensive literature review was performed to find clinical and imaging clues for the diagnosis and follow-up of ptosis and ophthalmoparesis. We used five patterns as a framework for differential diagnostic reasoning and for pattern recognition in symptomatology, EOM involvement and imaging results of individual patients. The five patterns were characterized by the presence of combination of ptosis, ophthalmoparesis, diplopia, pain, proptosis, nystagmus, extra-orbital symptoms, symmetry or fluctuations in symptoms. Each pattern was linked to anatomical locations and either hereditary or acquired diseases. Hereditary muscle diseases often lead to ophthalmoparesis without diplopia as a predominant feature, while in acquired eye muscle diseases ophthalmoparesis is often asymmetrical and can be accompanied by proptosis and pain. Fluctuation is a hallmark of an acquired synaptic disease like myasthenia gravis. Nystagmus is indicative of a central nervous system lesion. Second, specific EOM involvement patterns can also provide valuable diagnostic clues. In hereditary muscle diseases like chronic progressive external ophthalmoplegia (CPEO) and oculo-pharyngeal muscular dystrophy (OPMD) the superior rectus is often involved. In neuropathic disease, the pattern of involvement of the EOM can be linked to specific cranial nerves. In myasthenia gravis this pattern is variable within patients over time. Lastly, orbital imaging can aid in the diagnosis. Fat replacement of the EOM is commonly observed in hereditary myopathic diseases, such as CPEO. In contrast, inflammation and volume increases are often observed in acquired muscle diseases such as Graves' orbitopathy. In diseases with ophthalmoparesis and ptosis specific patterns of clinical symptoms, the EOM involvement pattern and orbital imaging provide valuable information for diagnosis and could prove valuable in the follow-up of disease progression and the understanding of disease pathophysiology.

Comparison of the Accuracy of Anterior Segment Optical Coherence Tomography and Ultrasound Biomicroscopy in Localizing Rectus Muscle Insertions.

PURPOSE: To compare the accuracy of anterior segment optical coherence tomography (AS-OCT) and ultrasound biomicroscopy (UBM) in localizing rectus muscle insertions. METHODS: The study was performed on 27 patients (39 rectus muscles) who required primary or secondary surgery. Using caliper function in the AS-OCT and UBM software, the distance from the insertion site to the anterior chamber angle was measured. The actual muscle insertion distance from limbus was considered as the measured distance plus 1 mm. The measurements by UBM and AS-OCT were compared with intraoperative measurements and with each other. RESULTS: AS-OCT and UBM were performed on 13 medial rectus, 24 lateral rectus, and 2 superior rectus muscles. Ninety two percent of UBM measurements (36 muscles) were within 1 mm, one was within 1-1.5 mm, and 2 were within 1.5-2 mm of surgery measurements. Eighty five percent of AS-OCT measurements (33 muscles) were within 1 mm, 5 were within 1-1.5 mm, and one was within 1.5-2 mm of surgery measurements. In all cases, the mean absolute error of the UBM (0.54 ± 0.44) and AS-OCT (0.51 ± 0.36) showed no significant difference (p = .76). CONCLUSION: AS-OCT and UBM can be used interchangeably to localize rectus muscle insertions and showed good agreement with intraoperative measurements.

The feasibility of quantitative MRI of extra-ocular muscles in myasthenia gravis and Graves' orbitopathy.

Although quantitative MRI can be instrumental in the diagnosis and assessment of disease progression in orbital diseases involving the extra-ocular muscles (EOM), acquisition can be challenging as EOM are small and prone to eye-motion artefacts. We explored the feasibility of assessing fat fractions (FF), muscle volumes and water T2 (T2water ) of EOM in healthy controls (HC), myasthenia gravis (MG) and Graves' orbitopathy (GO) patients. FF, EOM volumes and T2water values were determined in 12 HC (aged 22-65 years), 11 MG (aged 28-71 years) and six GO (aged 28-64 years) patients at 7 T using Dixon and multi-echo spin-echo sequences. The EOM were semi-automatically 3D-segmented by two independent observers. MANOVA and t-tests were used to assess differences in FF, T2water and volume of EOM between groups (P < .05). Bland-Altman limits of agreement (LoA) were used to assess the reproducibility of segmentations and Dixon scans. The scans were well tolerated by all subjects. The bias in FF between the repeated Dixon scans was -0.7% (LoA: ±2.1%) for the different observers; the bias in FF was -0.3% (LoA: ±2.8%) and 0.03 cm3 (LoA: ± 0.36 cm3 ) for volume. Mean FF of EOM in MG (14.1% ± 1.6%) was higher than in HC (10.4% ± 2.5%). Mean muscle volume was higher in both GO (1.2 ± 0.4 cm3 ) and MG (0.8 ± 0.2 cm3 ) compared with HC (0.6 ± 0.2 cm3 ). The average T2water for all EOM was 24.6 ± 4.0 ms for HC, 24.0 ± 4.7 ms for MG patients and 27.4 ± 4.2 ms for the GO patient. Quantitative MRI at 7 T is feasible for measuring FF and muscle volumes of EOM in HC, MG and GO patients. The measured T2water was on average comparable with skeletal muscle, although with higher variation between subjects. The increased FF in the EOM in MG patients suggests that EOM involvement in MG is accompanied by fat replacement. The unexpected EOM volume increase in MG may provide novel insights into underlying pathophysiological processes.

Double-bellied medial rectus muscle in a patient with Down syndrome and congenital esotropia.

A 13-year-old male with Down syndrome, pseudophakic secondary to congenital cataract presented with esotropia. During bilateral medial rectus recession, a unilateral two-bellied right medial rectus was identified and recessed successfully with complete resolution of the deviation. Clinicians facing a two-bellied medial rectus can consider continuing with their surgical plan.

Visual field and orbital computed tomography correlation in dysthyroid optic neuropathy due to thyroid eye disease.

Purpose: The pathogenesis of dysthyroid optic neuropathy (DON) in thyroid eye disease (TED) is thought to be compression of the apical optic nerve by hypertrophied extraocular muscles. We correlated worsening DON to the area occupied by extraocular muscles.Methods: Records of adults with TED DON evaluated from 1/1/2013 to 1/1/2018 were retrospectively reviewed. Each patient's visual field with the worst mean deviation (MD) was selected. Orbit CT scans were reviewed. Reformatted oblique coronal images were created perpendicular to the optic nerve. The cross-sectional area (CSA) of the orbit and each muscle group was measured and expressed as ratios of the CSA of the orbital apex. Univariate and multivariate analysis was performed for predictors of HVF MD.Results: 34 orbits with TED DON were analyzed. On orbital CT, the superior muscle complex occupied 15% of the apex (range 6-26%), inferior 18% (range 6-33%), lateral 10% (range 4-18%), medial 17% (range 8-27%), and all combined 61% (range 28-80%). Increasing total muscle area and superior complex area correlated with worsening MD. In multivariate linear regression, the superior muscle complex remained a significant predictor of MD (p = 0.01) over total muscle area (p = 0.25).Conclusions: Enlargement of extraocular muscles is common in TED, but DON occurs in only 6%. Our findings demonstrate that as DON worsens, as quantified by visual field MD, the superior muscle complex crowds the apex. This is consistent with the typical inferior visual field findings seen in TED DON. Hypertrophy of the superior rectus and levator palpabrae superioris complex may be predictive of worsening DON.

A rare case of orbital myositis.

The orbital myositis is a rare inflammatory disorder of extraocular muscles and is considered a subtype of nonspecific orbital inflammatory syndrome. It is usually a unilateral disease process with a limited course. We report a case of a 34-year-old man who was referred to the Radiology Department at Shifa International Hospital, Islamabad with 6 months history of severe pain, swelling, and redness in the left eye associated with blurring of vision and headache. Initially, the patient had contrast enhanced CT scan orbits which showed asymmetrically thickened, minimally enhancing left optic nerve having indistinct margins with thickened superior rectus and superior oblique muscles, indistinct superior ophthalmic vein, soft tissue nodularity in the medial intraconal space fat, and slight left exophthalmos. Differentials of orbital pseudo tumour and lymphoma were given. Further evaluation by post contrast MRI with orbits protocol was suggested which showed proptosis, the significant infiltrative disease in the superomedial aspect of left orbit involving the adjacent fat with thickening, enlargement, and heterogeneous enhancement of the superior rectus, medial rectus, and superior oblique muscles with relatively lesser degree involvement of their tendons. The infiltrative thickening also involved the optic nerve sheath and seen invading the optic nerve at the orbital apex. On basis of the imaging features and clinical picture, a diagnosis of orbital myositis with optic neuropathy was given. The patient was given corticosteroids and showed rapid symptomatic improvement.

Localization of Tfap2ß, Casq2, Penk, Zic1, and Zic3 Expression in the Developing Retina, Muscle, and Sclera of the Embryonic Mouse Eye.

Optic development involves sequential interactions between several different tissue types, including the overlying ectoderm, adjacent mesoderm, and neural crest mesenchyme and the neuroectoderm. In an ongoing expression screen, we identified that Tfap2ß, Casq2, Penk, Zic1, and Zic3 are expressed in unique cell types in and around the developing eye. Tfap2ß, Zic1, and Zic3 are transcription factors, Casq2 is a calcium binding protein and Penk is a neurotransmitter. Tfap2ß, Zic1, and Zic3 have reported roles in brain and craniofacial development, while Casq2 and Penk have unknown roles. These five genes are expressed in the major tissue types in the eye, including the muscles, nerves, cornea, and sclera. Penk expression is found in the sclera and perichondrium. At E12.5 and E15.5, the extra-ocular muscles express Casq2, the entire neural retina expresses Zic1, and Zic3 is expressed in the optic disk and lip of the optic cup. The expression of Tfap2ß expanded from corneal epithelium to the neural retina between E12.5 to E15.5. These genes are expressed in similar domains as Hedgehog (Gli1, and Ptch1) and the Wnt (Lef1) pathways. The expression patterns of these five genes warrant further study to determine their role in eye morphogenesis.

KIF21A Gene c.2860C>T Mutation in CFEOM1A: The First Report from Iran.

Congenital Fibrosis of the Extra Ocular Muscles1 (CFEOM1) is an autosomal dominant condition, caused by mutation in the KIF21A and TUBB3. It is characterized by congenital non-progressive restrictive ophthalmoplegia and ptosis. Mutational analysis of the known genes in such rare diseases by Sanger sequencing not only prevents wasting the time and expenses but also speeds diagnosis process, genetic counseling, and the possibility of prenatal diagnosis. Here, for the first time, association of pathogenic variant c.2860C>T in KIF21A gene in an Iranian family with positive history of CFEO-M1A was reported.

Congenital cranial dysinnervation disorders.

The European Neuromuscular Centre (ENMC) derived the term Congenital Cranial Dysinnervation Disorders in 2002 at an international workshop for a group of congenital neuromuscular diseases. CCDDs are congenital, non-progressive ophthalmoplegia with restriction of globe movement in one or more fields of gaze. This group of sporadic and familial strabismus syndromes was initially referred to as the 'congenital fibrosis syndromes' because it was assumed that the primary pathologic process starts in the muscles of eye motility. Over the last few decades, evidence has accumulated to support that the primary pathologic process of these disorders is neuropathic rather than myopathic. This is believed that for normal development of extra ocular muscles and for preservation of muscle fiber anatomy, normal intra-uterine development of the innervation to these muscles is essential. Congenital dysinnervation to these EOMs can lead to abnormal muscle structure depending upon the stage and the extent of such innervational defects. Over last few years new genes responsible for CCDD have been identified, permitting a better understanding of associated phenotypes, which can further lead to better classification of these disorders. Introduction of high-resolution MRI has led to detailed study of cranial nerves courses and muscles supplied by them. Thus, due to better understanding of pathophysiology and genetics of CCDDs, various treatment modalities can be developed to ensure good ocular alignment and better quality of life for patients suffering from the same.

Comparative morphology and development of extra-ocular muscles in the lamprey and gnathostomes reveal the ancestral state and developmental patterns of the vertebrate head.

The ancestral configuration of the vertebrate head has long been an intriguing topic in comparative morphology and evolutionary biology. One peculiar component of the vertebrate head is the presence of extra-ocular muscles (EOMs), the developmental mechanism and evolution of which remain to be determined. The head mesoderm of elasmobranchs undergoes local epithelialization into three head cavities, precursors of the EOMs. In contrast, in avians, these muscles appear to develop mainly from the mesenchymal head mesoderm. Importantly, in the basal vertebrate lamprey, the head mesoderm does not show overt head cavities or signs of segmental boundaries, and the development of the EOMs is not well described. Furthermore, the disposition of the lamprey EOMs differs from those the rest of vertebrates, in which the morphological pattern of EOMs is strongly conserved. To better understand the evolution and developmental origins of the vertebrate EOMs, we explored the development of the head mesoderm and EOMs of the lamprey in detail. We found that the disposition of lamprey EOM primordia differed from that in gnathostomes, even during the earliest period of development. We also found that three components of the paraxial head mesoderm could be distinguished genetically (premandibular mesoderm: Gsc+/TbxA-; mandibular mesoderm: Gsc-/TbxA-; hyoid mesoderm: Gsc-/TbxA+), indicating that the genetic mechanisms of EOMs are conserved in all vertebrates. We conclude that the tripartite developmental origin of the EOMs is likely to have been possessed by the latest common ancestor of the vertebrates. This ancestor's EOM developmental pattern was also suggested to have resembled more that of the lamprey, and the gnathostome EOMs' disposition is likely to have been established by a secondary modification that took place in the common ancestor of crown gnathostomes.

Inferior oblique muscle paresis as a sign of myasthenia gravis.

Myasthenia gravis may affect any of the six extra-ocular muscles, masquerading as any type of ocular motor pathology. The frequency of involvement of each muscle is not well established in the medical literature. This study was designed to determine whether a specific muscle or combination of muscles tends to be predominantly affected. This retrospective review included 30 patients with a clinical diagnosis of myasthenia gravis who had extra-ocular muscle involvement with diplopia at presentation. The diagnosis was confirmed by at least one of the following tests: Tensilon test, acetylcholine receptor antibodies, thymoma on chest CT scan, or suggestive electromyography. Frequency of involvement of each muscle in this cohort was inferior oblique 19 (63.3%), lateral rectus nine (30%), superior rectus four (13.3%), inferior rectus six (20%), medial rectus four (13.3%), and superior oblique three (10%). The inferior oblique was involved more often than any other muscle (p<0.01). Eighteen (60%) patients had ptosis, six (20%) of whom had bilateral ptosis. Diagnosing myasthenia gravis can be difficult, because the disease may mimic every pupil-sparing pattern of ocular misalignment. In addition diplopia caused by paresis of the inferior oblique muscle is rarely encountered (other than as a part of oculomotor nerve palsy). Hence, when a patient presents with vertical diplopia resulting from an isolated inferior oblique palsy, myasthenic etiology should be highly suspected.

Extra-ocular muscle cells from patients with Graves' ophthalmopathy secrete α (CXCL10) and ß (CCL2) chemokines under the influence of cytokines that are modulated by PPARγ.

To our knowledge, no study has evaluated the involvement of T helper (Th)1- and Th2-chemokines in extra-ocular muscle (EOM) myopathy in "patients with thyroid-associated ophthalmopathy" (TAO-p). We tested the effects of interferon (IFN)γ and tumor necrosis factor (TNF)α stimulation, and of increasing concentrations of peroxisome proliferator-activated receptor (PPAR)γ agonists (pioglitazone or rosiglitazone; 0.1 µM-20 µM), on Th1-chemokine [C-X-C motif ligand (CXCL)10] and Th2-chemokine [C-C motif ligand (CCL)2] secretion in primary EOM cultures from TAO-p vs. control myoblasts. Moreover, we evaluated serum CXCL10 and CCL2 in active TAO-p with prevalent EOM involvement (EOM-p) vs. those with prevalent orbital fat expansion (OF-p). Serum CXCL10 was higher in OF-p and EOM-p vs. controls, while serum CCL2 was not significantly different in controls, or in OF-p and EOM-p. We showed the expression of PPARγ in EOM cells. In primary EOM cultures from TAO-p: a) CXCL10 was undetectable in the supernatant, IFNγ dose-dependently induced it, whereas TNFα did not; b) EOM produced basally low amounts of CCL2, TNFα dose-dependently induced it, whereas IFNγ did not; c) the combination of TNFα and IFNγ had a significant synergistic effect on CXCL10 and CCL2 secretion; and d) PPARγ agonists have an inhibitory role on the modulation of CXCL10, while they stimulate CCL2 secretion. EOM participates in the self-perpetuation of inflammation by releasing both Th1 (CXCL10) and Th2 (CCL2) chemokines under the influence of cytokines, in TAO. PPARγ agonist activation plays an inhibitory role on CXCL10, but stimulates the release of CCL2.