Monitoring and Predicting Treatment Response of Extraocular Muscles in Grave's Orbitopathy by 99mTc-DTPA SPECT/CT

Objective: To investigate single-photon emission computed tomography/computed tomography (SPECT/CT) for assessing inflammation in the extraocular muscles (EOMs) and predicting the therapeutic efficacy of periocular glucocorticoid therapy (PGT) for Grave's ophthalmopathy (GO).Materials and Methods: A total of 412 eyes from 206 patients with GO referred for 99mTc-DTPA orbital SPECT/CT were enrolled. Fourteen age- and gender-matched healthy controls (28 eyes) were included. The thickness and uptake ratio (UR) of four EOMs were derived from SPECT/CT. Eighty-six eyes from patients with GO patients received PGT. Changes in SPECT/CT parameters were evaluated between the pre- and post-treatment.Results: 195 eyes and 217 eyes were classified as active and inactive stages by clinical activity score (CAS). Values of the thickness and UR of each EOM, Tmax, and Umax were all significantly higher in the active GO than in the inactive GO and controls (p < 0.01). Among the 86 eyes (48 GO patients) included in the efficacy analysis, 56 eyes and 30 eyes were classified as responders and non-responders. Values of thicknesses and UR of each EOM, the maximum thickness (Tmax), and the maximum UR (Umax) all dropped following PGT in the responders (p < 0.01). Logistic regression analysis identified the Umax as an independent predictor for the responders (p < 0.01). Moreover, the Umax demonstrated incremental predictive value over clinical characters and CAS, as evidenced by the improved area under the curve (0.85 vs. 0.78) and global chi-square (34.12 vs. 18.1).Conclusion:99mTc-DTPA SPECT/CT has the potential to assess inflammatory activity by detecting the involvement of EOMs in GO. Pre-treatment UR provides independent and incremental values for the prediction of PGT treatment response.

Quantitative evaluation of activity of thyroid-associated Ophthalmopathy using short-tau inversion recovery (STIR) sequence

Objective Quantitatively staging TAO using MRI remains limited. Our study aims to identify the cut-off signal intensity value for staging TAO using STIR sequence scan. Methods Between June 2018 and July 2020, a number of 51 patients with TAO (102 eyes) and 19 volunteer controls (38 eyes) were recruited. The clinical and biochemical parameters were measured in each patient. Disease activity was diagnosed based on the Clinical Activity Score (CAS). The signal intensities of extraocular muscles were scanned using short-tau inversion recovery (STIR) sequences from MRI. Results Compared to the inactive TAO patients and the controls, the signal intensity ratios (SIRs) of the superior rectus, inferior rectus, medial rectus, lateral rectus on STIR images were significantly increased in the active TAO patients. After adjustment for age and smokers, the SIRs of four extraocular muscles showed strong associations with CAS. By receiver operator characteristic (ROC) curve analysis, all four muscle SIRs demonstrated good efficiency for predicting disease activity [area under curve (AUC) 0.75–0.83, all P < 0.01]. The identified cut-off SIR values were further validated in a new group of TAO patients (30 eyes) enrolled between September 2020 and January 2021. The cut-off SIR value of > 2.9 in the inferior rectus showed optimal diagnostic value for staging the active TAO. Conclusions the signal intensity of extraocular muscles on STIR sequence was a good predictor for TAO activity. A cut-off SIR value of > 2.9 in the inferior rectus could be applied to evaluate the active stage of TAO.

Molecular basis of impaired muscle function in a mouse model of congenital myopathy due to compound heterozygous RYR1 mutations

Congenital myopathies (CM) are a group of early-onset, genetically diverse muscle disorders of variable severity with characteristic muscle biopsy findings. Mutations in RYR1, the gene encoding the RYR1, are the most common genetic cause, responsible for ∼30% of all human CM. They are linked to the pharmacogenetic disorder malignant hyperthermia susceptibility and to various disease phenotypes, including central core disease (which is primarily dominantly inherited), multiminicore disease (which is predominantly recessively inherited), some forms of centronuclear myopathy and congenital fiber-type disproportion (which can be either dominantly or recessively inherited), and King–Denborough syndrome (a CM characterized by skeletal abnormalities, dysmorphic features, and malignant hyperthermia susceptibility). The recessive forms of RYR1-linked CM are more severe, affecting children at birth and, in addition to profound muscle weakness, may also affect facial and extraocular muscles and cause skeletal deformities and feeding difficulties. To study the mechanism leading to the profound muscle weakness characterized by recessive RYR1-CM, we created transgenic mice knocked in for the compound heterozygous RYR1 p.Q1970fsX16+p.A4329D mutations (double knock-in mouse, or DKI) identified in a severely affected child. The in vivo and ex vivo physiological functions of fast twitch, slow twitch, and extraocular muscles were severely impaired in DKI mice; in addition, the mutations were accompanied by a &gt;50% decrease in RYR1 protein in all muscles examined, as well as changes in the expression of many proteins important for muscle function and chromatin structure. Muscle ultrastructure was disorganized, with fewer CRU and mitochondria and presence of cores. MyHC-EO, the superfast and ocular-muscle−specific myosin heavy isoform, was almost undetectable in EOMs from DKI mutant mice. Thus, the DKI mouse model faithfully recapitulates the human disease and could be exploited for preclinical studies aimed at developing therapeutic strategies to treat neuromuscular disorders linked to recessive RYR1 mutations.

Surgical Treatment and Muscle Protein Analysis of V-pattern Exotropia in Craniosynostosis

Purpose: The purpose of this study was to compare the differences of V-pattern exotropia in craniosynostosis and normal children.Methods: 39 children were included in this study, 19 craniosynostosis and 20 children in control group. They underwent comprehensive ocular examinations and received strabismus surgery. The extraocular muscle samples were analysed.Results: Compared with the control group, craniosynostosis group had larger deviation in primary and up gaze, larger V pattern, and more severe inferior oblique overaction. For 20-40, and 50-60 prism diopter exotropia, the lateral recession in the craniosynostosis group was larger than that in the control group, 7.13±0.44 mm vs 6.71±0.47 mm, 8.90±0.21 mm vs 7.75±0.46 mm (p=0.025, 0.000). The anterior transposition of craniosynostosis group was more anterior than that of control group, posterior 1.03±1.24 vs 2.68±0.94 mm (p=0.000). Compared with the control group, the extraocular muscle abnormality in craniosynostosis was significant, 32% vs 5% (p=0.031). There were 40 proteins in craniosynostosis group, which were different from those in control group.Conclusions: A larger V pattern and larger deviation is common in craniosynostosis children. For the same PD of deviation, it usually needs more recession in craniosynostosis because of the thinner and weaker extraocular muscles.

Neuro-ophthalmology: Extraocular Muscles and Cranial Nerves III, IV, and VI

Conjugate eye movement requires voluntary and reflexive input to the final common pathway (cranial nerves III, IV, and VI and their respective muscles). This chapter briefly repeats information about the pertinent anatomy of the extraocular muscles and cranial nerves III, IV, and VI but focuses on related clinical syndromes or diseases. Supranuclear input to these structures and dysfunction are discussed in other chapters. Six muscles move each eye globe: 4 recti (superior, inferior, medial, and lateral) and 2 oblique (superior and inferior) muscles.

The orbit and its contents

The function of the orbit is to protect and accommodate the globe in order to maximise its function. The bony orbits are paired four-sided conical cavities within the skull each comprising seven bones – ranging from the paper thin ethmoid and lacrimal plate medially to the buttress thick zygoma laterally. The conical shape consists of an apex posteriorly and a base anteriorly forming the outer margin. The medial wall and floor begin to blend towards the apex forming a posteromedial bulge as the orbit takes on a three-walled pyramidal structure. The walls are lined by periosteum (periorbita), which is continuous with the periosteal layer of the dura mater at the apex, the orbital septa and the fascial sheaths of the extraocular muscles. There are five principal openings of the orbit – three principal foramina located at the apex that transmit the neurovascular supply of the orbit and two lesser foramina located on the medial wall.