Evaluation of extraocular muscles in patients with thyroid associated ophthalmopathy using apparent diffusion coefficient measured by magnetic resonance imaging before and after radiation therapy

Abstract

Background

Thyroid-associated ophthalmopathy (TAO) is an autoimmune orbital disease characterized by edema of extraocular muscles (EOMs).

Purpose

To characterize the inflammation of EOMs in patients with TAO before and after radiation therapy using apparent diffusion coefficient (ADC) and to analyze the correlation between ADC and clinical activity of TAO.

Material and Methods

The ADCs of superior rectus (SR), inferior rectus (IR), medial rectus (MR), and lateral rectus (LR) muscles were measured in 52 eyes of 26 patients with TAO before and three months after orbital radiation therapy. In addition, 38 eyes of 20 healthy volunteers were included. The clinical activity score (CAS) was evaluated. The ADC maps were reconstructed and measured on the coronal diffusion-weighted imaging (DWI) sequence and calculated in mm²/s.

Results

The mean ADCs of EOMs before treatment were 1.42 ± 0.23 in SR, 1.37 ± 0.23 in IR, 1.41 ± 0.21 in MR, and 1.28 ± 0.25 in LR. The mean ADCs after treatment were 1.27 ± 0.18, 1.22 ± 0.26, 1.30 ± 0.22, and 1.15 ± 0.21, respectively. The ADCs were significantly decreased after treatment (all P < 0.001). The ADCs of patients with TAO were significantly higher than those of controls. There was a statistically significant correlation between the mean ADCs and the CAS in each patient with TAO both before and after treatment (before: r = 0.520; P < 0.001; after: r = 0.625; P < 0.001).

Conclusion

The ADC values of EOMs can be exploited as a quantitative indicator to evaluate the clinical activity and monitor the therapeutic responses of patients with TAO.

Keywords

Thyroid-associated ophthalmopathy radiation therapy extraocular muscle diffusion-weighted imaging apparent diffusion coefficient

Introduction

Thyroid-associated ophthalmopathy (TAO) is an autoimmune orbital disease characterized by inflammation and edema of periorbital connective tissues, which results in the enlargement of extraocular muscles (EOMs) and fat in the orbit. Currently, intravenous injection of a high dose of methylprednisolone (iv-MP) represents the first-line therapeutic regime for TAO. Encouragingly, retrobulbar radiotherapy has been proven to be a promising therapeutic strategy, particularly for patients with poor tolerance or response to glucocorticoids. Its mechanism mainly depends on the non-specific anti-inflammatory effect of radiotherapy to suppress lymphocyte infiltration and inhibit fibroblast proliferation and mucopolysaccharide secretion. Retrobulbar radiotherapy has been reported to be a safe and effective treatment for progressive TAO (1 –5). The clinical activity score (CAS) has been widely used to grade the activity of TAO, which is based on the clinical evaluation of the anterior visible part of the orbit. The higher score is indicative of the more active disease. CAS is often supplemented with magnetic resonance imaging (MRI) to assess the involvement of orbital structures, such as EOMs, lacrimal glands, and orbit fat (6). MRI with diffusion-weighted imaging (DWI) has been demonstrated to be an important imaging tool for the diagnosis of tumors and inflammatory and vascular diseases, as well as for the evaluation of tumor response to therapy. Numerous studies focusing on DWI techniques have revealed the availability of apparent diffusion coefficient (ADC) evaluation in the diagnosis of orbital lymphoma, pseudotumour, and endophthalmitis (7 –9). A 2-ADC threshold model can categorize orbital masses as benign, malignant, or indeterminate with >90% confidence (10). The ADC values of medial and lateral rectus muscles in patients with TAO were higher than those of volunteers, serving as an indicator in the diagnosis of TAO. It is also reported that the ADC of lacrimal glands in patients with TAO is significantly higher than that of controls and is also positively correlated with CAS (11,12). The normalized ADC value of EOMs in patients with TAO is considered a valuable MRI tool for diagnosing active TAO and evaluating the treatment response to iv-MP therapy (13 –15).

Although the changes of inflammation and swelling of EOMs before and after treatment have been reported, the changes of each EOM involved in patients with TAO receiving radiation therapy remain unknown. The aim of the present study was to quantitatively assess the involvement of each EOM in patients with TAO before and after radiation therapy by evaluating the ADC values in DWI images, as well as to correlate ADCs with clinical severity before and after treatment. To the best of our knowledge, we were the first to report the application of DWI ADC in the detection of involvement of EOMs in patients with TAO receiving orbital radiotherapy.

Material and Methods

Patients

The study was approved by the Ethics Committee and complied with the tenets of the Declaration of Helsinki for clinical research. In the present study, 52 eyes of 26 patients with TAO (14 men, 12 women; mean age = 51.62 ± 12.48 years) and 38 eyes of 20 healthy volunteers (7 men, 13 women; mean age = 33.94 ± 12.26 years) were included. These patients presented to the Department of Ophthalmology from December 2016 to December 2018. The diagnosis of TAO was based on the EUGOGO consensus (2). Active TAO was defined as follows: (a) CAS of ≥3/7; or (b) CAS of < 3/7, but with the increased signal intensity of EOMs in the T2-weighted (T2W) STIR of the orbital MRI. None of the patients had visual loss due to optic nerve compression at the orbital apex caused by enlarged EOMs. Among them, 20 patients with active TAO were diagnosed by criterion (a) and 6 were diagnosed by criterion (b).

Clinical assessment

The clinical activity of each eye in all patients with TAO was evaluated using the CAS recommended by the European Group on Graves’ Orbitopathy. The CAS (maximum score of 7 points) consists of seven items: spontaneous retrobulbar pain; pain on attempted upward or downward gaze; redness of conjunctiva; redness of eyelids; inflammation of caruncle and/or plica; swelling of eyelids; conjunctival edema (2).

MRI technique

MRI was performed on a 3.0-T MRI system (Philips Ingenia; Philips, Best, Netherlands) with a head coil. The routine orbital MRI protocols included the following: axial T1-weighted (T1W) turbo spin-echo (TSE): slick thickness = 3 mm, repetition time/echo time (TR/TE) = 497.7/8.0 ms, turbo factor (TF) = 3, voxel size (VS) = 0.55 × 0.69 × 3 mm, number of sample acquisition (NA) = 2, matrix = 220 × 210 × 15 pixels, and field of view (FOV) = 120 × 150 × 49 mm; coronal T2W turbo spin-echo spectral pre-saturation with inversion recovery (SPIR) sequences: slice thickness = 3 mm, TR/TE = 3000.0/80.0 ms, TF = 17, VS = 0.5 × 0.65 ×3 mm, NA = 1.6, matrix = 240 × 226 × 15 pixels, and FOV =120 × 150 × 49 mm; coronal T2W DRIVE: slice thickness = 3.5 mm, TR/TE = 3000.0/90.0 ms, TF = 15, VS = 0.5 × 0.61 × 3.5 mm, NA = 1.6, matrix = 240 ×242 × 20 pixels, and FOV = 120 × 160 × 77 mm; coronal DWI: TR/TE = 4055.8/71.4 mm, FOV = 220 ×183 × 63 mm, matrix size = 124 × 91 × 16 pixels, NA = 4, slice thickness = 3 mm, and b-values = 0 and 1000 s/mm². The ADC maps were automatically reconstructed by a commercially available software and calculated in ×10^–3 mm²/s. The type of DW sequence used in this study was TSE DW sequence, a non-EPI DWI sequence. The ADCs of EOMs were measured by two radiologists who were blinded to the clinical history. The observers manually drew regions of interest (ROIs) from the thickest part of the muscle in selected coronal planes. ROIs were drawn using the ellipse tool as the cross-section of EOMs was oval. T1W images helped to identify and locate the area of each muscle on the DWI map (Fig. 1). Each EOM was measured three times by each observer independently and the average value of ADCs was calculated. Disagreement between observers was resolved by consensus. The differences in ADC values among groups were compared.

Fig. 1.

(a, b) ADC images of one same patient before and after radiation therapy. (c) Contrast T1W image that shows the enlargement and high signal activity in extraocular muscles, which helps to identify and locate the area of each muscle on the DWI map. (d) ROIs placed on each muscle to measure the ADC value. ADC, apparent diffusion coefficient; DWI, diffusion-weighted imaging; ROI, region of interest; T1W, T1-weighted.

Radiation therapy

All patients underwent retro-orbital irradiation with a 6MV linear accelerator using the Intensity Modulated Radiation Therapy (IMRT) technique. The clinical target volume (CTV) encompassed EOMs and retro-orbital fatty spaces. The organs at risk (OAR) included the lens, globes, optic nerves, and lacrimal glands. A prescription dose of 20 Gy was given to each patient in 10 fractions within 2–3 weeks using IMRT with non-coplanar irradiation fields. The planned dose distribution is shown in Fig. 2. After three months, these patients were followed up using MRI.

Fig. 2.

The planned dose distributions of IMRT for patients with TAO: (a) axial, (b) coronal). The red lines surrounding the orbital contents represent the 2000 cGy isodose. The dark blue line represents the 200 cGy isodose. The lens under the lowest radiation dose was excluded to avoid secondary cataract. IMRT, Intensity Modulated Radiation Therapy; TAO, thyroid-associated ophthalmopathy.

Statistical analysis

All statistical analyses were performed using SPSS Statistics 23 software (IBM, Armonk, NY, USA). ADC values were depicted as mean ± standard deviation (SD). Shapiro–Wilk test was conducted to test the normality of the numerical variables in the present study. Paired t test was used to compare the ADC and CAS values before and after treatment. Independent sample t test was used to compare the ADC values of patients with TAO and healthy controls. The correlation between the ADCs and CAS of patients with TAO was analyzed using Pearson’s rank correlation coefficient. A value of P < 0.05 was considered statistically significant.

Results

CASs

The mean CAS was 3.38 ± 1.53 before treatment and 1.77 ± 1.42 after treatment. The mean CAS was significantly decreased after treatment (P < 0.01) (Fig. 3).

Fig. 3.

A 52-year-old woman who did not respond to 4.5g of iv-MP therapy before being enrolled into the present study. (a, b) These images show a significant improvement in clinical activity before and after IMRT. IMRT, Intensity Modulated Radiation Therapy; iv-MP, methylprednisolone.

ADCs

The mean ADCs of EOMs in patients with TAO before treatment were 1.42 ± 0.23 in SR, 1.37 ± 0.23 in IR, 1.41 ± 0.21 in MR, and 1.28 ± 0.25 in LR, and that of EOMs in patients with TAO after treatment were 1.27 ± 0.18, 1.22 ± 0.26, 1.30 ± 0.22, and 1.15 ± 0.21, respectively. The mean ADCs of EOMs in healthy controls were 1.08 ± 0.19 in SR, 1.03 ± 0.15 in IR, 1.05 ± 0.17 in MR, and 0.97 ± 0.13 in LR. There was a significant drop in the ADC values of EOMs three months after radiation therapy (all P < 0.001). In addition, the ADCs of patients with TAO were significantly higher than those of the controls (Table 1, Fig. 4).

Table 1.

The mean ADC values (×10⁻³mm²/s) of all EOMs in patients with TAO before and after radiation therapy and in healthy controls.

ADC (×10^–3mm²/s)	Before treatment	After treatment	Controls	P value
ADC (×10^–3mm²/s)	Before treatment	After treatment	Controls	Before vs. after treatment	Before treatment vs. controls	After treatment vs. controls
SR	1.42 ± 0.23	1.27 ± 0.18	1.08 ± 0.19	<0.001	<0.001	<0.001
IR	1.37 ± 0.23	1.22 ± 0.26	1.03 ± 0.15	<0.001	<0.001	<0.001
MR	1.41 ± 0.21	1.30 ± 0.22	1.05 ± 0.17	<0.001	<0.001	<0.001
LR	1.28 ± 0.25	1.15 ± 0.21	0.97 ± 0.13	<0.001	<0.001	<0.001

Values are given as mean ± SD.

ADC, apparent diffusion coefficient; EOM, extraocular muscle; IR, inferior rectus; LR, lateral rectus; MR, medial rectus; SR, superior rectus; TAO, thyroid-associated ophthalmopathy.

Fig. 4.

The ADC of each EOM in patients with TAO was significantly decreased after radiation treatment. The ADCs of the TAO group were significant higher those of the control group. ADC, apparent diffusion coefficient; EOM, extraocular muscle; TAO, thyroid-associated ophthalmopathy.

Correlation between ADCs and CASs

There was a statistically significant correlation between the mean ADCs of all four muscles measured and CASs in patients with TAO both before and after treatment (before: r = 0.520, P < 0.001; after: r = 0.625, P < 0.001) (Fig. 5).

Fig. 5.

The correlation between CAS and ADC before and after treatment. The CAS had a significantly positive correlation with the mean ADCs of the four EOMs both before (r = 0.520, P < 0.001) and after (r = 0.625, P < 0.001) radiation treatment. ADC, apparent diffusion coefficient; CAS, clinical activity score; EOM, extraocular muscle.

Discussion

In this retrospective study, we analyzed the DWI ADC of EOMs in patients with TAO before and after radiation therapy and found a significant decrease in ADC values after treatment. The ADCs of patients with TAO were significantly higher than those of healthy controls. Additionally, there was a statistically significant correlation between the mean ADC and CAS in each patient with TAO both before and after treatment. These results suggested that ADC can be a quantitative indicator for the assessment of clinical activity and treatment response in patients with TAO.

Despite the wide application in the clinic, CAS examination is subjective and lacks quantitative criteria. CAS is often supported by MRI to examine the deep orbital tissue inflammation, and the combination of MRI and CAS shows a favorable evaluation effect in patients with TAO (16). In the present study, since the diagnosis of active TAO was based on the elevated signal of EOMs in the contrast-enhanced orbital MRI, some patients included in this study had low CASs. However, the ADCs of these patients were significantly higher than those of healthy controls and did show a decrease after treatment, which also proved the limitation of CAS assessment.

The quantitative evaluation with DWI ADC correlates well with the well-established MRI measure of activity in detecting active TAO and monitoring treatment response (15). A significant positive correlation between ADC and CAS has been found in 60 non-EPI-DWI scans, 368 extraocular muscles of patients with TAO, indicating that non-EPI-DWI is particularly useful in guiding clinical decision-making (17). The novel use of non-EPI-DWI for the monitoring of methylprednisolone treatment response has been reported in patients with TAO (18). Non-EPI DWI has the advantages of high-resolution images and reducing air–bone interface artifact distortion (19), which potentially allow greater clarity of orbital images and more reliable measurement of ADC values (17). Consistently, this study used non-EPI-DWI technique for orbital imaging to avoid image deformation since EOMs are relatively tiny structures in human body imaging.

The present study is the first to reveal the ADC values of EOMs in patients with TAO before and after radiation therapy. This study demonstrated that the ADC values of EOMs before radiotherapy were similar to those reported before (14). The mean ADCs of all measured muscles in patients with TAO after treatment were significantly lower than those before treatment. ADCs are affected by various factors, such as edema, fibrosis and infiltration of inflammatory cells, and decomposition of glycosamino glycan (GAG) (13). Radiation therapy induces lymphocyte apoptosis and fibroblast differentiation, which in turn breaks the inflammatory cycle and reduces GAG deposition and adipocyte production. The combination of these factors leads to the decrease of ADC values. Therefore, ADC measurement before and after radiation therapy contributes to quantitatively evaluating the therapeutic efficacy of individual muscle inflammation.

In the present study, ADCs exhibited a statistically significant positive correlation with the clinical activity of patients with TAO both before and after treatment. Similarly, a previous study has elucidated that higher ADC is associated with higher CAS (15). Therefore, swelling can reflect the inflammation of each EOM in patients with TAO both before and after treatment. Measuring the diffusion coefficient of EOMs can be an effective method to evaluate the inflammation of EOMs. Furthermore, the present study revealed that some patients with TAO had poor responses to radiation therapy and the inflammation of some muscles persisted, with ADCs remaining at a high level after treatment. After treatment, CAS remained unchanged in two cases (Cases 1 and 2) and CAS was increased in one case (Case 3), and all of them had increased ADCs in at least two EOMs. The detailed ADCs of each EOM in these three cases before and after treatment are shown in Table 2.

Table 2.

The ADC values (×10⁻³mm²/s) of all EOMs in cases with poor response to radiation therapy.

Case no.	Before treatment									After treatment
	CAS	Right eye				Left eye				CAS	Right eye				Left eye
	CAS	SR	IR	MR	LR	SR	IR	MR	LR	CAS	SR	IR	MR	LR	SR	IR	MR	LR
Case 1	3	1.254	1.220	1.068	1.364	1.519	1.206	1.251	1.201	3	1.394	1.245	1.471	1.531	1.326	1.085	1.417	1.241
Case 2	2	1.291	1.386	1.201	1.243	1.387	1.276	1.402	1.179	2	1.186	1.378	1.168	1.141	1.298	1.271	1.468	1.239
Case 3	2	1.269	1.419	1.411	1.127	1.307	1.790	1.418	1.277	3	1.239	1.339	1.213	1.330	1.478	1.394	1.264	0.890

ADC, apparent diffusion coefficient; CAS, clinical activity score; EOM, extraocular muscle; IR, inferior rectus; LR, lateral rectus; MR, medial rectus; SR, superior rectus; TAO, thyroid-associated ophthalmopathy.

The present study has some limitations. First, due to the limited number of patients insensitive to methylprednisolone, only 26 patients were enrolled in the present study. Second, the follow-up period in the present study was three months after treatment, and consequently, the long-term efficacy of radiation therapy on TAO could not be evaluated. Third, the present study did not include any other signal indexes such as semi-quantitative signal intensity ratios in STIR sequence. Moreover, the health volunteers were noticeably younger than these patients with TAO. Hence, the results between groups may be interfered by the impact of age. The lack of inter-observer agreement is also a limitation of the study. Further methods of evaluation and observational cohort studies should be included to improve the validity of our results.

In conclusion, EOM inflammation in patients with TAO was improved after orbital radiation therapy, and ADC was positively correlated with the clinical activity of patients with TAO both before and after treatment. The ADC values of EOMs can be exploited as a quantitative indicator to evaluate the clinical activity and therapeutic responses of patients with TAO.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China (81930024, 81761168037, 81770974, 81800695, 82071003, 82000879, 81570883, 81600766, 31701046, 31600971, and 31500714), the National Key R&D Program of China (2018YFC1106100, 2018YFC1106101), the Shanghai Sailing Program (18YF1412300), the Research Grant of the Shanghai Science and Technology Committee (20DZ2270800, 17DZ2260100, 19410761100, and 19DZ2331400), the Clinical Research Plan of SHDC (SHDC2020CR3051B), the Collaborative Research Project of Translational Medicine Collaborative Innovation Center, Shanghai JiaoTong University School of Medicine (TM201718), the Shanghai Municipal Education Commission–Gaofeng Clinical Medicine Grant Support (20152228), the Shanghai JiaoTong University Translational Medicine Crossed Research Grant. ZH2018ZDA12, ZH2018QNA07), the Sample Database Project of Shanghai Ninth People–s Hospital (YBKB201901), and the Joint Innovation Team for Young Physicians of Shanghai Ninth People's Hospital (QC 202002), and the Science and Technology Commission of Fengxian District, Shanghai (FK20191229).

ORCID iD

Zhou Huifang

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