Magnetic resonance imaging determination of extraocular eye muscle volume in patients with thyroid-associated ophthalmopathy and proptosis

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1 ACTA OPHTHALMOLOGICA SCANDINAVICA 26 Magnetic resonance imaging determination of extraocular eye muscle volume in patients with thyroid-associated ophthalmopathy and proptosis Jan Kvetny, 1 Katriina Bøcker Puhakka 2 and Lisbeth Røhl 3 1 Department of Endocrinology, Esbjerg County Hospital, Esbjerg, Denmark 2 Department of Radiology, Esbjerg County Hospital, Esbjerg, Denmark 3 Department of Radiology, AarhusSygehus, AarhusUniversity Hospital, Aarhus, Denmark ABSTRACT. Purpose: Recent studies concerning the association between extraocular muscle (EOM) enlargement in thyroid-associated ophthalmopathy (TAO) and immunological and clinical activity have not been conclusive, probably due to a lack of uniform imaging methods (ultrasonography, computer tomography [CT] or magnetic resonance imaging [MRI]) and difficulties in the determination of EOM volume. The aim of the present study was to examine the significance of EOM enlargement as established by MRI-based volume determination, with reference to proptosis and the presence of autoantibodies, clinical activity and the duration of active disease. Methods: We determined EOM volume using MRI in 15 patients concomitantly with the determination of TSH, thyroid hormones, thyrotropin receptor antibodies (TRab) thyroid peroxidase antibodies (TPOab) and clinical activity score (CAS) at entry. We also established the duration until cessation of clinically active TAO. Results: All 15 patients had bilateral EOM enlargement, but swelling of orbital fatty tissue was absent. Significant correlations between thickness of musculi rectales and proptosis, values of TRab, CAS, and duration of activity were observed. Conclusion: Our results support the hypothesis of a role of thyrotropin receptor antibodies in the pathogenesis of TAO and suggest that only EOM enlargement is responsible for proptosis in TAO. Key words: thyroid-associated ophthalmopathy magnetic resonance imaging proptosis thyrotropin receptor antibodies Acta Ophthalmol. Scand. 26: 84: Copyright # Acta Ophthalmol Scand 26. doi: /j x Introduction Thyroid-associated ophthalmopathy (TAO) is viewed as an autoimmune disease characterized by lymphocyte infiltration of the retrobulbar tissues. The infiltrating lymphocytes produce cytokines, which stimulate glycosaminglycan production by the orbital fibroblasts present in the extraocular eye muscles and orbital fat, leading to oedema and swelling, and resulting in proptosis and diplopia (Bahn 22). The introduction of computed tomography (CT) and magnetic resonance imaging (MRI) for the examination of extraocular muscle (EOM) enlargement in patients with TAO (Forbes et al. 1986; Hiromatsu et al. 1992) has raised suggestions that there may not be a simple association between EOM enlargement and proptosis in these patients (Villadolid et al. 1995). These observations indicate that the proptosis present in severe TAO may not always be caused by EOM enlargement, and therefore that orbital fat swelling may also induce proptosis in active TAO. Clinical studies in which thyroid-stimulating antibodies were shown to be closely related to proptosis (Gerding et al. 2a) have been contrasted by recent studies in which no association between autoimmunity and EOM size determined by ultrasonography was observed (Zimmermann- Belsing et al. 22). The aim of the present study was to examine the significance of EOM enlargement as established by MRIbased volume determination with reference to the presence of autoantibodies and the duration of active disease in patients with TAO and proptosis >21 mm. 419

2 ACTAOPHTHALMOLOGICA SCANDINAVICA 26 Materials and Methods Patients The study was part of a quality assessment study (which did not require approval by the local ethical committee) including consecutive patients with TAO and proptosis (defined as proptosis >21 mm) referred to the Department of Endocrinology, Esbjerg County Hospital between January 2 and December 23. One patient had been followed from She underwent surgical decompression in 2, but was again referred in 2 showing signs of relapse with a clinical activity score (CAS) >1. The study included patients with clinical signs of TAO and proptosis >21 mm (No signs soft tissue involvement proptosis extra ocular involvement corneal involvement (NOSPEC) >3). Patients with mild oph-thalmopathy and proptosis <21 mm and patients with eye symptoms considered by the endocrinologist and ophthalmologist not to represent TAO were excluded. For practical reasons the onset of TAO was defined as the debut of eye symptoms as described by the patient. No patients had had TAO for longer than 2 weeks before referral. All patients were managed so that euthyroidism was achieved as quickly as possible. The patients were treated with tiamazole 4 mg daily until euthyroid, at which point thyroxin was added (1 15 mg daily). Assessment of orbital disease This was performed serially by examination and measurements of various individual clinical parameters. The severity of the disease was assessed using the NOSPEC classification (Werner 1977). The degree of proptosis was measured with a Hertel exophthalmometer. The activity of the eye disease was assessed by registration of the classic signs of inflammation: orbital pain; redness of the conjunctiva or eyelids; swelling of the caruncle or eyelids or chemosis, and impaired function. This assessment served as a basis for determination of the CAS (Mourits et al. 1997). Patients were initially assessed by the Department of Ophthalmology in collaboration with an endocrinologist (JK) every month during high activity (CAS > 1) and then every 4 months by the same experienced endocrinologist. The criteria for initiating medical (steroid) treatment for the eye disease were as follows: presence of optic nerve compression; progressive deterioration of eye disease over time; presence of severe inflammatory signs; and troublesome symptoms in patients with no evidence of optic nerve compression but with symptoms that failed to respond to simple measures (artificial tears, elevation of bed head) or to correction of thyroid dysfunction. The end-points for establishing the duration of active TAO were defined as CAS ¼ and no alteration of NOSPEC score during 3 months. Assessment of thyroid status At the initial visit, we documented patients smoking habits (currently smoking [<1 cigarettes daily, 1 2 cigarettes daily, >2 cigarettes daily] or no smoking within the last 3 months) and family history of thyroid disease. At each visit patients were assessed clinically with regard to thyroid status and blood was withdrawn for total T 3, total T 4, thyroxine binding capacity (TBC), thyrotropin (TSH), thyrotropin receptor antibody (TRab) and thyroid peroxidase antibody (TPOab) assessment. Serum hormone determinations Commercially available methods were used for the determinations of thyroid hormone binding capacity of serum proteins (TBC) (Abbott Diagnostic MEIA and FPIA; AXSYM, Abbott Park, Illinois, USA), serum T 4 (Imx Abbott, Abbott Park, Illinois, USA), serum T 3 (Imx Abbott), and serum TSH (IRMA; CIC, Gif sur Yvette, France). FT 4 I was determined as total T 4 TBC. The determination of TPOab was performed by the Statens Serum Institut, Copenhagen. TPOab was measured by radioimmunoassay (RIA) (DYNOtest Ò antitpo; BRAHMS Diagnostica, Berlin, Germany). Values <6 U/ml are considered negative and expressed as U/ml and values >3 U/ml are given as 3 U/ml. The determination of TRab was performed by MediLab, Copenhagen (TRAK-assay; BRAHMS Diagnostica). Values <1 U/are considered normal. Radiological examinations and measurements The examination of the EOMs was partly based upon a previously described method (Tian et al. 2). The EOMs were scanned by MRI in all patients within 2 months of their admission to the endocrinological clinic. MRI was obtained with a 1. Tesla unit (Impact Expert; Siemens, Malvern, Pennsylvania, USA) using a coronal T1-weighted turbo spinecho sequence (slice thickness 4. mm, spacing.4 mm). One patient was examined with a STIR-sequence with the same slice parameters. Volumes of orbital fatty tissue (OFT) and five of the EOMs were measured (MR ¼ medial rectus, LR ¼ lateral rectus, SR ¼ superior rectus, IR ¼ inferior rectus, SO ¼ superior oblique). The measurements were taken with a planimetric technique using a commercially available software package (ALICE TM ; Hayden Image Processing Solutions, Boulder, Colorado, USA). The muscle volumes were measured independently by two radiologists (KBP, LR) who were blinded to the patients clinical data. ALICE TM has an autosegmentation tool that finds the best guess edge of an object (based on local image intensity gradients) and draws a region of interest (ROI) around the object (Fig. 1). The ROI was modified by the radiologist to exclude non-anatomical structures that were sometimes accidentally included in the ROI. The mean interobserver variability of the muscle volumes determined by the coefficient of variance in a subset of the images was 14.8%. Therefore, the results of one of the radiologists (KBP) were used in the calculations. Statistical analyses Students t-test was used for comparison of normally distributed parameters. The Spearman correlation coefficient was used to evaluate the correlation of the variables. A value of p <.5 was considered statistically significant. All data processing was performed with StatSoft software (StatSoft, Inc., Tulsa, Oklahoma, USA). 42

3 ACTA OPHTHALMOLOGICA SCANDINAVICA 26 Results LR IR SR Extraocular muscle enlargement was observed in all patients (15 women, aged 44 9 years) (Table 1) and all patients were hyperthyroid at admittance, with TSH ¼.1.5 mu/l (reference range: mu/l); FT 4 I ¼ arbitrary units (a.u.) (reference range: 6 13 a.u.); T 3 ¼ nmol/l (reference range: nmol/l). A family history of thyroiddiseasewasreportedineight patients. Twelve were smokers (1 2 cigarettes per day), nine patients had O evident restriction of eye muscle motility, and it became necessary to initiate prednisolone treatment in nine patients and sandostatin treatment in three. Surgical decompression was performed in one patient. All patients had MR enlargement on the right (dxt) and/or left (sin) side (Table 1) and, as we found a statistically significant correlation (p <.1) between the total EOM volume and MR, we have chosen to examine volume of MR dxt or sin using the muscle with the largest volume when comparing EOM enlargement with the various Table 1. Volumes of extraocular muscles and orbital fatty tissue in 15 patients, in means SDs. EOM/OFT Volume (ml) p (Student s t-test) Mean SD SO MR Fig. 1. T1-weighted coronal MRI scan of the orbits of a TAO patient. Regions-of-interest around the right extraocular muscles are shown. The optical nerve (O) is located in the centre of the orbit. The dotted line demonstrates the outer margins of the orbital fat. MR ¼ medial rectus; SR ¼ superior rectus; IR ¼ inferior rectus; LR ¼ lateral rectus; SO ¼ superior oblique. Reference values MR dxt <.1 MR sin <.1 LR dxt <.1 LR sin <.1 SR dxt <.1 SR sin <.1 IR dxt <.1 IR sin <.1 SO dxt <.1 SO sin <.1 OFT dxt <. OFT sin <. * Tian et al. 2. EOM ¼ extraocular muscle; MR ¼ medial rectus; LR ¼ lateral rectus; SR ¼ superior rectus; IR ¼ inferior rectus; SO ¼ superior oblique; OFT ¼ orbital fatty tissue. parameters. There were no patients with EOM enlargement on only one side, corresponding to the fact that all patients had bilateral proptosis by Hertel measurement. There was a significant correlation between EOM volume and proptosis in mm (Fig. 2), values of TRab (Fig. 3), CAS (Fig. 4) and duration of activity in the 12 patients in which the CAS score had ceased <1 (Fig. 5). In contrast, we did not observe a correlation between EOM volume and TPOab or values of thyroid hormones and TSH at the time of admittance. Orbital fat volume did not correlate with any of the above parameters and was significantly diminished in most patients (Table 1). Discussion The major finding in the present study of patients with proptosis >21 mm was that the proptosis was caused solely by EOM enlargement and not by extraorbital fatty tissue swelling. In newly diagnosed severe TAO, the EOM enlargement correlated with TRab values, CAS and proptosis. Furthermore, the duration of activity correlated with the initial EOM enlargement. This observation suggests that EOM enlargement is associated with proptosis and with TRab. Our results correspond with those of previous reports (Hiromatsu et al. 1992; Nishikawa et al. 1993) in which eye muscle volume showed significantly positive correlations with severity of eye disease, duration of eye symptoms and thyrotropin receptor antibodies. Extraocular muscle enlargement was observed in most patients, although these studies also included patients with eye symptoms of up to 4 years duration. In contrast to the view that EOM enlargement causes proptosis is a report that EOM enlargement by MRI determination was present in a number of patients with untreated Graves disease but without TAO (Villadolid et al. 1995). However, the NOSPEC score, or, rather, the degree of proptosis, was not reported. Moreover, as suggested by the authors, EOM volume and proptosis in Japanese people may be essentially different from those in other ethnic groups. Our observation of a correlation between EOM enlargement and TRab and clinical activity in patients with proptosis may correspond to the 421

4 ACTAOPHTHALMOLOGICA SCANDINAVICA proptosis dxt mm findings of a number of previous studies which established a significant correlation between TBII or TSI titres and the clinical activity of Graves ophthalmopathy (Gerding et al. 2a; Bahn 23). A significant correlation between signal intensity by MRI of EOM and OFT, suggesting possible similar pathological processes in these tissues in TAO, has been reported (Hiromatsu et al. 1992). In the present study, we Fig. 2. Correlation between the volume of the medial rectus (MR) (ml) and proptosis (mm) in 15 patients with newly diagnosed TAO (proptosis > 21 mm, CAS > 1); r ¼.72592, p <.1. TRab U/I observed a diminished volume of OFT. The explanation might be that volume determination and signal intensity measure different entities and our observation of diminished OFT is probably caused by the fact that the muscle swelling compressed the OFT. A recent study by Szucs-Farkas et al. (25) concluded that connective tissue in certain orbital compartments correlated well with cumulative smoking, whereas EOMs were not influenced by smoking. Almost all the patients in the present study were smokers and we were unable to detect a possible statistically significant difference in proptosis, EOM enlargement or OFT volume, probably due to the small number of non-smokers. Of more interest is the contrast to observations in ultrasonographic studies, which reported a lack of association between EOM enlargement and TRab values. A recent study by Zimmermann-Belsing et al. (22), in which a B-scan ultrasonographic assessment of the four horizontal rectus muscle thicknesses was made, reported that muscle thickness did not correlate with thyroid autoimmune activity (TRab and TPOab). Gerding et al. (2b) reported that ultrasound reactivity did not correlate with the CAS. An explanation might be that the patient group comprised a number of patients with longstanding and perhaps not clinically active TAO. However, it appears that there is no agreement between results obtained with ultrasonography and those obtained with MRI. It is noteworthy that in none of the patients with proptosis >21 mm was the proptosis caused by orbital fat swelling, but rather by EOM enlargement. This observation contrasts with the findings of a previous study, in which it was demonstrated that OFT involvement was related to the degree of exophthalmus (Nishida et al. 22). One explanation might be that it is not possible to compare the studies as the clinical status of the thyroid eye disease (NOSPEC score and CAS) was not reported. In conclusion, our results indicate EOM enlargement to be the principal cause of proptosis and support the hypothesis of a pathogenetic role of TSH receptor antibodies in the pathogenesis of TAO. They also stress the significance of MRI-based volume determination of EOM Fig. 3. Correlation between the volume of the medial rectus (MR) (ml) and the value of thyrotropin receptor antibodies (TRab) in 15 patients with newly diagnosed TAO (proptosis > 21 mm, CAS > 1); r ¼.54235, p ¼.37. Acknowledgements The Department of Ophthalmology, Hospital of Ribe County is appreciated for its help in examining the patients in this study. 422

5 ACTA OPHTHALMOLOGICA SCANDINAVICA 26 clinical activity score a.u. Duration months Fig. 4. Correlation between the volume of the medial rectus (MR) (ml) and CAS in 15 patients with newly diagnosed TAO (proptosis > 21 mm, CAS > 1); r ¼.55685, p ¼ Fig. 5. Correlation between the volume of the medial rectus (MR) (ml) and duration (months) until cessation of clinical activity (CAS ¼ ) in 12 patients with severe TAO (proptosis > 21 mm, CAS > 1 at debut). In one patient the total observation period included a period before surgical decompression and a subsequent period with continuing clinical activity; r ¼.8671, p ¼.1. HiromatsuY,KojimaK,IshisakaN,TanakaK, Sato M, Nonaka K, Nishimura H & Nishida H (1992): Role of magnetic resonance imaging in thyroid-associated ophthalmopathy: its predictive value for therapeutic outcome of immunosuppressive therapy. Thyroid 2: Mourits MP, Prummel MF, Wiersinga WM & Koornmeef L (1997): Clinical activity score as a guide in the management of patients with Graves ophthalmopathy. Clin Endocrinol 47: Nishida Y, Tian S, Isberg B, Hayashi O, Tallstedt L & Lennerstrand G (22): Significance of orbital fatty tissue for exophthalmos in thyroid-associated ophthalmopathy. Graefes Arch Clin Exp Ophthalmol 24: Nishikawa M, Yoshimura M, Toyoda N et al. (1993): Correlation of orbital muscle changes evaluated by magnetic resonance imaging and thyroid-stimulating antibody in patients with Graves ophthalmopathy. Acta Endocrinol 129: Szucs-Farkas Z, Toth J, Kollar J et al. (25): Volume changes in intra- and extraorbital compartments in patients with Graves ophthalmopathy: effect of smoking. Thyroid 15: Tian S, Nishida Y, Isberg B & Lennerstrand G (2): MRI measurements of normal extraocular muscles and other orbital structures. Graefes Arch Clin Exp Ophthalmol 238: Villadolid MC, Yokohama N, Izumi M et al. (1995): Untreated Graves disease patients without clinical ophthalmopathy demonstrate a high frequency of extraocular muscle (EOM) enlargement by magnetic resonance. J Clin Endocrinol Metab 8: Werner SC (1977): Modification of the classification of the eye changes of Graves disease. Am J Ophthalmol 83: Zimmermann-Belsing T, Feldt-Rasmussen U & Fledelius HC (22): Ultrasound measurement of the horizontal external eye muscles in patients with thyroid disease. Is orbital involvement associated with thyroid autoantibodies? Eur J Ophthalmol 12: References Bahn RS (22): Thyrotropin receptor expression in orbital adipose/connective tissues from patients with thyroid-associated ophthalmopathy. Thyroid 12: Bahn RS (23): Pathophysiology of Graves ophthalmopathy: the cycle of disease. J Clin Endocrinol Metab 88: Forbes G, Gorman CA, Brennam MD, Gehring DG, Ilstrup D & Earnest F (1986): Ophthalmopathy of Graves disease: computerized volume measurements of the orbital fat and muscle. Am J Neuroradiol 7: Gerding MN, Meer JWC, Broeninkn M, Bakker J, Wiersinga OWM & Prummel MF (2a): Association of thyrotropin receptor antibodies with the clinical features of Graves ophthalmopathy. Clin Endocrinol 52: Gerding MN, Prummel MF & Wiersinga WM (2b): Assessment of disease activity in Graves ophthalmopathy by orbital ultrasonography and clinical parameters. Clin Endocrinol 52: Received on May 2th, 25. Accepted on October 2nd, 25. Correspondence: Jan Kvetny MD, DMedSc Chief Physician Department of Endocrinology Hospital of Stoerstroem County DK-47 Næstved Denmark Tel: þ ext Fax: þ jan@kvetny.dk 423