Extraocular Muscle Volumetry for Assessment of Thyroid Eye Disease

In this study we evaluate the diagnostic accuracy of extraocular muscle volumetry in detecting thyroid eye disease and to compare the results with simple measurements of maximal medial rectus (MR) diameter.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Extraocular Muscle Volumetry for Assessment of Thyroid Eye Disease Georgios Bontzos, MD, PhD, Efrosini Papadaki, MD, PhD, Michael Mazonakis, PhD, Thomas G. Maris, PhD, Nikolaos G. Tsakalis, MD, Eleni E. Drakonaki, MD, PhD, Efstathios T. Detorakis, MD, PhD Background: In this study we evaluate the diagnostic accuracy of extraocular muscle volumetry in detecting thyroid eye disease and to compare the results with simple measurements of maximal medial rectus (MR) diameter. Methods: Cross-sectional study that included 47 eyes of 47 patients with thyroid eye disease and 47 healthy controls. Patients underwent slitlamp examination and imaging consisting of computed tomography scans. Image segmentation and volume measurements were performed by 2 independent researchers. Intraobserver and interobserver reliability testing was also conducted. Results: Total extraocular muscle volume was 7.31 ± 1.88 cm3 and medial volume was 2.38 ± 0.73 cm3 in the study group. In this group, the maximum measured diameter of the MR was 6.67 ± 0.35 mm. MR volume was statistically associated with maximum MR diameter (r = 9.78; P , 0.001). Both MR volume and maximum MR diameter measurements showed good predictive efficacy as shown using receiver operator characteristic curve analysis. Conclusions: Complications of thyroid eye disease are often sight threatening, and timely diagnosis is crucial for the management of the entity and its sequelae. The results of Departments of Ophthalmology (GB, NGT, ETD), and Radiology (EP), University Hospital of Heraklion, Heraklion, Greece; Department of Medical Physics (MM, TGM), University of Crete, Heraklion, Greece; and Independent Imaging Services (EED), Heraklion, Crete, Greece. The authors report no conflicts of interest. All authors have approved the final version of the manuscript. Conception and design: G. Bontzos, E. Papadaki, E. E. Drakonaki, and E. T. Detorakis. Data collection: G. Bontzos, T. G. Maris, M. Mazonakis, and N. G. Tsakalis. Analysis and interpretation: G. Bontzos, N. G. Tsakalis, M. Mazonakis, E. Papadaki, and E. E. Detorakis. Overall responsibility: G. Bontzos, E. Papadaki, M. Mazonakis, T. G. Maris, N. G. Tsakalis, E. E. Drakonaki, and E, T, Detorakis. Statement of Ethics: The Human Ethics Committees at the University Hospital of Heraklion, Greece, approved the study. All research adhered to the tenets of the Declaration of Helsinki. All participants provided informed consent. Address correspondence to Georgios Bontzos, MD, PhD, Department of Ophthalmology, ‟Korgialenio-Benakio” General Hospital, 11526 Athanasaki 1, Athens, Greece; E-mail: [e-mail] e274 this study imply that simple measurements of maximum MR diameter are sensitive enough to establish diagnosis. Journal of Neuro-Ophthalmology 2022;42:e274–e280 doi: 10.1097/WNO.0000000000001339 © 2021 by North American Neuro-Ophthalmology Society T hyroid eye disease (TED) is an autoimmune disorder of the orbit and periorbital tissues most frequently associated with Graves disease (1), and less commonly in Hashimoto thyroiditis (2) or in patients with euthyroid (3). TED primarily involves inflammatory changes and subsequent enlargement of orbital tissues such as orbital fat, extraocular muscle (EOM), and the lacrimal gland (4,5). The pathophysiology of the disease is based on a complex interplay among inflammatory cells, genetics, and environmental factors. Histopathological studies reveal extensive deposition of hyaluronan between the muscle fibers, inflammatory infiltration, and overexpression of cytokines (6). Fibroblasts are also abundant in affected tissues and are strongly implicated in TED pathogenesis (7). Clinical manifestations of TED include exophthalmos, eyelid retraction, lateral flare, strabismus, and optic neuropathy. Such signs are mostly attributed to the enlargement of orbital soft tissues. Soft tissues confined within the orbital walls may become congested leading to a vicious circle of increased inflammation (8). Vision-threatening sequelae include increased intraocular pressure and mechanical compression of the optic nerve at the orbital apex (8). Early detection and treatment before visual loss is paramount for optimal visual outcome (9). Therefore, a precise and objective assessment of the inflammatory activity is essential for the correct diagnosis and management of patients with TED. Currently, computed tomography (CT) imaging is the modality of choice for evaluation of TED (10). Generalized enlargement of EOMs is readily observed on CT imaging, which reveals a characteristic fusiform pattern with sharp Bontzos et al: J Neuro-Ophthalmol 2022; 42: e274-e280 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution borders. Lucent zones of hyaluronate develop within the muscles. The belly of the muscle appears enlarged, whereas the tendinous insertion is often spared. Changes most frequently involve the inferior rectus followed by medial, superior, and lateral recti (11). In early CT studies, an increase of EOMs and orbital fat volume was correlated with the observed proptosis (12). Ever since, several studies have examined the relationship between quantitative volume of orbital tissues and clinical features in patients with TED (13–15). The most common approach to evaluate EOM enlargement is to measure the maximum cross-sectional area of the muscles on a standard, axial or coronal, CT slice (16). This technique is relatively easy to perform with a short learning curve (16). However, estimation of the EOM volume would provide more information than cross-sectional measurements because it uses data from a wide section of the muscles (17). Nevertheless, current volume measurement techniques are time-consuming, a fact that prevents their routine clinical practice. The aim of this study is to evaluate the clinical applicability of EOM volumetry in detecting TED in patients with Graves disease and to compare the accuracy of the results with standard 2D cross-sectional measurements of the recti muscles in CT data sets. The imaging protocol consisted of CT scans using the standard orbital protocol using a 16-detector row CT system (Somatom Sensation 16; Siemens, Erlangen, Germany). The reconstructed slice width was always 0.625 mm, and the mean pixel dimensions were 0.301 · 0.301 mm. Patient’s head was positioned parallel to the Frankfurt plane. Patients were asked to look at a fixation point that corresponded to primary gaze position. Image assessment and segmentation were performed independently by 2 experienced researchers (G.B. and N.T.) to test interobserver reliability. A soft tissue window was set to discriminate between orbital fat and EOM. Soft tissue thresholds were set at 2200 to 230 hounsfield units (HU) for fat and 230 to +100 HU for the EOM (13). DICOM images were analyzed using the open-source image processing software 3D Slicer v.4.6.0 for image segmentation by applying manual 3D volume rendering (Fig. 1). The orbit boundaries were manually delineated in axial slices, and the window was set at 2200 to +100 HU. The posterior boundary of the orbit was defined as the crossing line between the medial and lateral walls of the cavity around the optic foramen. The volume (V) of the segmented orbital cavity (Fig. 1) was calculated by Equation 1: METHODS where T is the section thickness, ai is the area of orbital cavity in section i that is manually selected, and m is the total number of slices containing the region of interest. Computation of EOM volume was conducted accordingly using the soft tissue threshold. Total EOM volume was calculated as a sum of the medial, lateral, inferior, and superior rectus. The levator palpebrae and the superior rectus were assessed together (superior rectus complex) because it was difficult to separate them in the image data sets. The medial rectus (MR) volume was also calculated and analyzed separately by the above equation after manual selection of its boundaries in every slice. For the MR, we also evaluated its maximal diameter horizontally, using axial scans as described before (16,20). For this analysis, we manually placed the Ruler tool in 3D Slicer over the largest transverse diameter of the MR (Fig. 2). This is a prospective cross-sectional study that included patients from 2 centers: the University Hospital of Heraklion, Greece, and the ‟Korgialenio-Benakio” Red Cross Hospital, Athens, Greece. The study was approved by local ethics committee and adhered to the tenets of the Declaration of Helsinki. The purpose of this study was explained to all participants, who gave signed written consent. For this study, 47 adult patients, clinically diagnosed with TED, underwent CT imaging as part of their regular clinical care. Diagnosis of TED was based on the Bartley criteria (18), and the inflammatory activity was assessed using the seven-point Clinical Activity Score (CAS) formulation (19). The orbit with a higher CAS score for each patient was used in this study. In addition, the presence of optic neuropathy was reported in the study group (Table 1). In addition, 47 right eyes of 47 patients without known orbital pathology were analyzed. Patients who had received immunosuppressive treatment with steroids or orbital radiotherapy or with a previous history of surgical decompression or any other orbital surgery were excluded. Patients were clinically evaluated with standard slitlamp examination and dilated fundus examination. They underwent Hertel exophthalmometry and kinetic applanation tonometry, and ocular motility was examined for any signs of diplopia or strabismus. Disease duration from the onset of the ophthalmic symptoms was also reported. Bontzos et al: J Neuro-Ophthalmol 2022; 42: e274-e280 V¼ m X ðTai Þ (1) i Statistical Analysis Statistical analysis was performed using SPSS (IBM SPSS Statistics for Windows, version 22.0). Descriptive statistics are presented as mean ± SD. All P values relate to 2-sided tests with a significance level of a = 0.05. Differences between mean volumes and maximum MR diameter between groups were tested using the analysis of variance and Student t test. To compare the measured values, the Pearson correlation coefficient was used to identify significant correlations between MR volume, MR diameter, and other clinical parameters. To test the proportion of agreement among measurements, we tested intraobserver and interobserver agreement as follows: e275 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Demographics of the study population N (%) or Mean ± SD TED Age, yrs Female sex (%) Optic neuropathy CAS 46 ± 16.34 32 (68) 2 (4) 2.79 ± 1.66 Control Group 42 ± 18.53 30 (64) — — The intraobserver reliability of CT measurements was calculated by comparing 2 separate measurements performed by one observer 1 month apart to minimize recall bias. The interobserver reliability of CT measurements was calculated by comparing volume measurements of 2 separate observers, using the same methodology. The intraclass correlation coefficient (ICC) (2-way mixed model) was computed to estimate the interrater and intrarater reliability. An ICC value of .0.7 in absolute single measures was considered to be an acceptable agreement. Receiver operator characteristic curve (ROC) and area under the curve (AUC) were calculated to assess predictive value MR volume and maximum MR diameter in patients with TED. RESULTS In this analysis, we included 47 eyes of 47 patients with TED and 47 eyes of healthy controls. Clinical measurements are summed up in Table 2. The total orbital volume in the study group was 26.83 ± 0.59 cm 3 and 25.32 ± 0.66 cm3 in the control group (P = 0.455). Total EOM FIG. 1. Left panels: manual delineation of the extraocular muscles and optic nerve, in a patient with thyroid eye disease from a computed tomography scan using 3D Slicer. Right panel: Segmentation and illustration of the 3D model. e276 Bontzos et al: J Neuro-Ophthalmol 2022; 42: e274-e280 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Measurement of the maximal medial rectus (MR) diameter on a computed tomography data set of a patient with thyroid eye disease using the ‟Ruler” tool in 3D Slicer (A) and placing its limits over the largest observed transverse diameter of the MR (B). volume was 7.31 ± 1.88 cm3 and MR volume was 2.38 ± 0.73 cm3 in the TED group; both values differed significantly from the control group (P , 0.001). The maximum measured diameter of the MR was 6.67 ± 0.35 mm in the TED group and 4.91 ± 0.29 mm in the control group (P , 0.001). An illustration of the measured parameters is shown in Figure 3. MR volume was statistically associated with maximum MR diameter (r = 9.78; P , 0.001) while no significant correlation was found between MR volume and total orbital volume or CAS score or Hertel measurements (Table 3). The intraobserver reliability values for EOM volume measurements were 0.921 while the interobserver reliability was measured 0.894. The ICC was excellent for both intraobserver (ICC = 0.975; P , 0.001) and interobserver (ICC = 0.902; P , 0.001) measurements, respectively. Both MR volume and maximum MR diameter measurements showed good predictive efficacy as shown in the ROC curve (Fig. 4) with AUC = 0.881 for MR volume and AUC = 0.892 for MR diameter. CONCLUSIONS TED is an inflammatory disorder of the orbit, and the increased size of EOM and fatty tissue edema are the hallmarks of the disease. As many as half of the patients diagnosed with Graves disease develop ophthalmic symptoms within a year of diagnosis or even decades following it (21). Early identification of the disease is crucial in treatment of the inflammatory process at the active stages of the disease (8) and related complications (9). In this study, we used a quantitative assessment of the orbital structures to determine the optimal imaging technique for estimation of TED. Because volume measurements would provide more comprehensive information compared with the measured cross-sectional thickness (22), we hypothesized that the EOM volume evaluation would be a more sensitive marker for disease identification. For this reason, we compared the total EOM volume as well as the MR volume and maximum diameter in patients with TED and in an age-matched healthy control group. The MR was selected for further analysis over the lateral rectus because the latter’s diameter in patients with TED is commonly found (23) to lie within a normal value range. TABLE 2. Clinical characteristics of the study population Mean ± SD TED Hertel exophthalmometry Orbital volume, cm3 Total EOM volume, cm3 Maximum MR diameter, mm MR volume, cm3 Maximum IR diameter, mm IR volume, cm3 Maximum LR diameter, mm LR volume, cm3 21.46 26.83 7.31 6.67 2.38 7.15 2.56 4.74 1.56 ± ± ± ± ± ± ± ± ± Control Group 2.62 0.59 1.88 0.35 0.73 0.71 0.52 0.54 0.41 15.53 25.32 4.87 4.91 1.49 5.04 1.71 4.58 1.32 ± ± ± ± ± ± ± ± ± 2.87 0.66 0.74 0.29 0.61 0.66 0.46 0.31 0.54 P* ,0.001 0.455 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 0.08 0.02 *Independent samples t test. EOM, extraocular muscles; IR, inferior rectus; LR, lateral rectus; MR, medial rectus; TED, thyroid eye disease. Bontzos et al: J Neuro-Ophthalmol 2022; 42: e274-e280 e277 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 3. Box plots of the measured parameters obtained from computed tomography (CT) imaging. The extraocular muscle (EOM) volume, maximal medial rectus (MR) diameter, and MR volume differed significantly in thyroid eye disease (TED) group. Based on our analysis, we found that there was no significant difference between standard MR muscle diameter measurements as compared to MR volume measurements for TED identification. The intraobserver and interobserver analysis further support the robustness of our results. In addition, the ROC analysis comparing the diagnostic ability of MR diameter to MR volume found no significant difference in the AUC. To the best of our knowledge, this is the first study to systematically compare the 2 methods for TED diagnosis. Similar to our results, in a previous report (24), it was shown that the maximum cross-sectional EOM area, rather than EOM volume, is a reliable marker to monitor progression in patients with TED. Although CT has proven a useful tool for diagnostic and follow-up in patients with TED (5,25), MRI has also been evaluated in TED investigation (26). More specifically, previous studies, using MRI, have evaluated the presence of abnormal signal in EOM by quantification of T2relaxation times. Differentiation of normal population from patients with TED (26) as well as a correlation between T2-relaxation time and CAS has been described recently (27). TABLE 3. Correlation coefficients (r) between medial rectus (MR) volume and measured variables in the study cohort R* MR diameter Orbital volume Hertel exophthalmometry CAS Total EOM volume *Pearson correlation coefficient. e278 0.978 0.176 0.371 0.088 0.579 (P (P (P (P (P , 0.001) = 0.466) = 0.098) = 0.237) = 0.159) FIG. 4. Receiver operator characteristic curve (ROC) for medial rectus (MR) volume and maximum MR diameter measurements. Both parameters display significant predictive efficacy with area under the curve (AUC) = 0.881 for MR volume and AUC = 0.892 for MR diameter. Bontzos et al: J Neuro-Ophthalmol 2022; 42: e274-e280 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Initially, most patients with TED present with mild ocular findings, which can either be asymptomatic or cause ocular discomfort and diplopia (28). The mainstay of treatment in these cases would comprise topical lubrication with artificial tears or prism correction to restore binocular vision. Nevertheless, even in its milder expressions, TED can significantly affect the patients’ quality of life (29). Early diagnosis of TED is paramount in the management of sightthreatening complications (30,31). Although there is no single clinical sign that is pathognomonic of TED, imaging of the orbital components is essential for the timely identification of severe complications, such as compressive optic neuropathy, an entity that will require high doses of intravenous corticosteroids or even urgent orbital decompression if there is little or no response to medical treatment (30). It should be noted here that although muscles are commonly involved in TED, in a minority of cases, EOM enlargement is heralded by conjunctival redness or edema overlying the insertion of an EOM (32). In these cases, the clinical assessment of muscle measurements using CT imaging is limited because clinical examination alone would allow the prompt diagnosis of the affected patients (32). Previous research has attempted to investigate alternative methods for early identification of TED manifestations. Using electrophysiology, it was found that optic neuropathy could be applied to detect small functional changes before visual diminution (33). Moreover, ocular surface seems to be involved early during the course of the disease, and changes can be quantified using appropriate tests (34). For this study, we choose to use CT imaging because it is the most commonly used modality in the evaluation of patients with TED (10). To minimize bias, we evaluated the intraobserver and interobserver reliability of our measurements. The fixation point used during CT scans corresponded to primary gaze position. This is important because the maximal belly diameter is affected by gaze direction and differential between muscle contraction and relaxation. Limitations of the presented work include the crosssectional design of this study that did not allow the monitoring of disease progression. The wide spectrum of the disease should also be considered as patients can present with soft tissues volume changes ranging from pure muscle to pure fat involvement (35). Furthermore, manual delineation of the EOMs is challenging because the exact starting and ending points of the muscle tendon are not always easy to determine. Thus, the number of slices outlining the muscle may differ in each patient, affecting the computed volume. Precise measurements of muscle diameter rely on identification of its maximum width within the given data set. However, the maximum width could be ‟hidden” in between available slices. Moreover, anatomical changes due to muscle contraction and the error inherent to the partial volume effects might compromise the measured values. In conclusion, we compared the accuracy of MR maximum diameter and MR volume measurements to Bontzos et al: J Neuro-Ophthalmol 2022; 42: e274-e280 predict TED. 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