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Hertel Exophthalmometry and Computed Tomography for the Evaluation of Exophthalmos in Patients with Thyroid-Associated Ophthalmopathy

Objective: To compare the values of exophthalmos measured by computed tomography (CT) and Hertel exophthalmometry (HE) in patients with thy-roid-associated ophthalmopathy (TAO). Material and Methods: One hun-dred and seventy eyes were examined in 85 patients with TAO. Each patient underwent a complete ophthalmic examination, Hertel exophthalmometry, and CT of the orbits through a 16-slice CT scanner (Bright Speed, General Electric), measuring the extraocular muscles, the total muscle thickness sum (MTS), and proptosis. The patients were divided into two groups—with activity and without TAO activity, the activity being assessed by means of the Clinical Activity Score (CAS) and the severity—according to the EUGOGO classification. Results: TAO activity was detected in 45 patients (90 eyes, 53%) with MTS of 23.54 ± 5.73 mm, IOP of 19.78 ± 4.49 mm Hg, Hertel exophthalmos of 23.08 ± 4.19 mm and measured by CT—23.32 ± 4.33 mm. Forty patients (80 eyes, 47%) were without TAO activity, with MTS of 19.28 ± 4.03, IOP of 16.6 ± 4.51 mm Hg, Hertel exophthalmos of 20.03 ± 3.84 mm and measured by CT—19.84 ± 4.47 mm. A correlation was detected between exophthalmos and: MTS, IOP, the activity and severity of TАО. High con-gruence was established between the two methods of measuring exophthal-mos—CT and HE (Pearson correlation, r = 0.690, p = 0.000). Conclusion: Our results showed a high degree of consistency between Hertel exophthalmometry and multidetector CT for the evaluation of exophthalmos in patients with TAO. Exophthalmos is an important clinical feature and its measurement and monitoring over time assess the clinical course and outcome of treatment.


Introduction
Thyroid-associated ophthalmopathy is the most common extrathyroidal manifestation of Graves' disease and the hyperthyroidism related to it. In rare cases, it is observed in patients with Hashimoto's thyroiditis, hypothyroidism or euthyroidism [1]. TAO is a chronic autoimmune process against orbital antigens, in which lymphocytic infiltration, fibroblast proliferation and adipogenesis develop, along with the accumulation of glucosaminoglycans in the tissues of the orbit and an increase in their volume, with typical fusiform thickening of the extraocular muscles and the eyeball being pushed forward as a sign of spontaneous decompression. The pathological process goes through two consecutive phases-an active inflammatory phase, which lasts from 6 months to 5 years, and an inactive fibrotic phase. The use of the Clinical Activity Score (CAS) allows for an assessment of the disease activity [2]. The clinical manifestations of TAO include eyelid retraction, exophthalmos, edema and hyperemia of the eyelids and conjunctiva, pain in the orbits, as well as eye movement pain and low vision.
A classic method of clinical evaluation of eye protrusion is Hertel exophthalmometry. Different types of exophthalmometers exist and there is some subjectivity in reading the values. In some patients with severe eyelid edema, ptosis, strabismus, and poor cooperation, it is difficult to measure the Hertel exophthalmos. Another method of determining proptosis, in which the possible measurement errors are considerably fewer and which provides an objective estimate, is the computed tomography of the orbits. CT scans are widely available and demonstrate high repeatability and reproducibility.
The purpose of the present study was to compare multidetector computed tomography and Hertel exophthalmometry in order to evaluate proptosis in patients with thyroid-associated ophthalmopathy.

Material and Methods
This prospective study included 85 patients with TAO (170 orbits), examined at the University Eye Clinic in the period 2012-2019. The diagnosis of TAO was established on the basis of clinical features, CT-changes and clinical laboratory tests in patients with a history of thyroid disease. As exclusion criteria were viewed patients with thyroid disease without TAO, the presence of another inflammatory or space-occupying process or traumas leading to exophthalmos; excessive myopia or orbital decompression performed prior to the study. A detailed medical history was taken in all patients and a complete ophthalmologic examination and consultation with an endocrinologist were performed. All patients underwent Hertel exophthalmometry, CT of orbits, a Goldmann eye pres-  at the time of the study, TSH, T3, T4, anti-TG, anti-TRO, TRAb levels were ex-amined. The disease activity was determined using the Clinical Activity Score (Mourits, 1989), based on the presence of the classic symptoms of inflammation: pain (2 points), hyperemia (2 points), edema (4 points), dysfunction (2 points). A score of 3 or more points defined the status as active, and a score of 2 or less than 2-as inactive [2]. The EUGOGO classification was used to evaluate the severity of TAO, dividing patients into 3 categories: 1) severe, sight-threatening; 2) moderate to severe; 3) mild degree [3] ( Table 1).
The same mirror Hertel exophthalmometer (Oculus) was used in all patients, and the study was performed by one examiner. The test complied with the following rules: the exophthalmometer was positioned in such a way that the concave sections of the two frames touched the outer rims of the orbits at the lowest point. During the examination, the patient looked straight ahead and fixed the opposing eye of the examiner, and the visual axis of his/her other eye was blocked by the physician's thumb, the examinee and examiner's eyes being aligned in one plane. The examiner detected the exophthalmos with one eye only: the right eye-to evaluate the exophthalmos of the patient's left eye and vice versa. Which division of the scale the corneal apex corresponded to for each eye was reported, as well as the distance at which the test was performed along the divisions of the rail (base).
Multidetector orbital computed tomography (MDCT) was performed using a 16-slice CT (Bright Speed, GE) according to standard orbital examination protocols for adult patients. All CT examinations were carried out without the use of intravenous contrast. In the axial slices, the thickness of the horizontal muscles (medial rectus muscle (MRM) and lateral rectus muscle (LRM) was measured in millimetres, and in the coronary sections-the thickness of the inferior rectus muscle (IRM) and superior muscular complex (SMC) including superior rectus muscle and superior oblique muscle were measured. All muscles were examined on different scans, taking into account their largest size. The muscle thickness sum (total muscle thickness) of each eye was measured in millimetres (MTS = MRM + LRM + SMC + IRM). The proptosis of each eye was examined in axial sections along the perpendicular distance between the anterior pole of the eye and the interzygomatic line ( Figure 1).
The statistical analysis was carried out using the SPSS program, version 23. A descriptive analysis was employed to describe the indices, presented by an arithmetic average and standard deviation. The Kolmogorov-Smirnov test was used to determine the type of quantitative trait distribution, the Independent Samples T-test to compare the values between two groups, and the One-Way ANOVA to compare the values between multiple groups. A value of p < 0.05 was considered significant (with a 95% confidence interval). Pearson's correlation coefficient was used to estimate a linear association. The Bland-Altman graph was used to evaluate the persistent and systematic deviation between the exophthalmos measuring methods.  2) Moderate to severe GO Patients without sight-threatening GO whose eye disease has sufficient impact on daily life to justify the risks of immunosuppression (if active) or surgical intervention (if inactive). Patients with moderate to severe GO usually have any one or more of the following: lid retraction >2 mm, moderate or severe soft tissue involvement, exophthalmos >3 mm above normal for race and gender, inconstant or constant diplopia.

3) Mild GO
Patients whose features of GO have only a minor impact on daily life insufficient to justify immunosuppressive or surgical treatment. They usually only have one or more of the following: minor lid retraction (<2 mm), mild soft tissue involvement, exophthalmos < 3 mm above normal for race and gender, transient or no diplopia, corneal exposure responsive to lubricants. All patients included in the study were Caucasian and had signed an informed consent to participate in the study.

Results
The Disease activity was detected in 45 patients (53%), while 40 (47%) showed none. The distribution of patients according to severity classification is presented in Table 3. Table 3 shows the values of exophthalmos measured by HE and CT in patients according to the activity and severity of the disease.
We found statistically significantly higher values of exophthalmos, measured by both methods, in patients with disease activity rather than in patients without activity (Independent Samples T-test, p < 0.001), as well as higher values in patients with severe and moderate severity of TAO (ANOVA, LSD, p < 0.05).
Descriptive statistics on the thickness of extraocular muscles and the muscle thickness sum (total muscle thickness) are presented in Table 4. We  We established a high degree of consistency between the two methods of examining exophthalmos in patients with TAO (Pearson correlation, r = 0.690, p = 0.000; for the right eye r = 0.730, p = 0.000; for the left eye r = 0.655, p = 0.000). Figure 4 shows the Bland-Altman graph demonstrating the consistency of the two methods.

Discussion
Exophthalmos is one of the most common objective symptoms in patients with TAO. We established higher values of exophthalmos in men with ophthalmopathy than in women, like in most literature reports. Doric et al. measured mean exophthalmos in males 23.16 ± 3.61 mm, and in females-21.42 ± 3.51 mm, and Li, in a study of Chinese TAO patients, also found higher mean values of proptosis in males (19.94 ± 3.45) compared to those in women (18.58 ± 3.31) [4] [5].
In her research Strianese detected a higher number of TAO activity points in exophthalmic eyes (3 to 6, average 4.1 points) than non-exophthalmic eyes (2 to 4, 2.8 points average) [6]. In patients with TAO activity, we found higher mean values of exophthalmos compared to patients without disease activity by both methods, which is explained by the swelling and the increase in soft tissue volume of the orbit during an active inflammatory process. The appearance of exophthalmos as an expression of spontaneous decompression in the increased volume of the soft tissues of the orbit is important for both the expansion of the orbital fat and the thickening of the extraocular muscles. Nishida et al. established that increased adipose tissue volume is of greater significance for the development of exophthalmos than enlarged extraocular muscles [7]. Fang discovered that both factors-the increase in orbital fat and the thickening of extraocular muscles play a role in both the protrusion of the eyeball, and the severity and prognosis of the disease [8]. In our study we established a correlation between greater muscle thickness sum and exophthalmos measured by both HE and CT, the patients with disease activity showing greater muscle thickness sum and greater exophthalmos. A classic method for clinical assessment of the eye protrusion is Hertel exophthalmometry. There are different types of exophthalmometers and there is a certain amount of subjectivity in the reading of the values, which necessitates the correct placement of the device and compliance with all rules when performing the exophthalmometry. Vardizer et al. compared the measurements from 8 different exophthalmometers and found that the design of the devices themselves affects the accuracy of measurement [9]. The authors also considered other factors for correct interpretation of the results, such as a change in the position of the patient's head during the measurement, a change in the direction of sight, incorrect placement of the concave sections of the two frames of the device to the outer rims of the orbits. When monitoring the exophthalmos in a patient with TAO, it is advisable that the measurements are taken by the same physician. Lam et al. studied the differences in the exophthalmometry values of patients with TAO obtained by one and two researchers, and found that there was no significant difference between the results of the same researcher and there is such a difference in the values obtained by different researchers examining the same patient [10]. Another method of estimating proptosis, in which the potential errors in reading values are significantly fewer, is the computed tomography study of the orbits. It determines, on axial scans, the perpendicular distance of the anterior pole of the eye from the interzygomatic line. We established a high Open Journal of Ophthalmology degree of consistency between Hertel exophthalmometry and multidetector CT when measuring the exophthalmos. Doric et al. also compared the two methods and established a high correlation between the protrusion of the bulb, measured by MDCT and HE, both for the right eye (r = 0.760; p = 0.000; CI 95%) and the left eye (r = 0.799; p = 0.000; CI 95%) [4]. Ampudia et al. tested 118 orbits of 59 patients with TAO and reported higher levels of exophthalmos measured by Hertel exophthalmometry than by CT, but also found a good correlation between the two methods (r = 0.72 for the right eye and r = 0.65 for left eye, p < 0.000) [11]. Hauck established slightly lower values of protrusion measured by CT compared to HE and determined an average value of the difference 0.03 mm [12]. Like Hauck, we measured an absolute value of the difference between the two methods equal to 0.032 mm, but with insignificantly higher CT measurements, and reported a high degree of consistency between the two methods for evaluating exophthalmos. Park et al. compared HE and CT, indicating 3 different methods for CT measuring of the exophthalmos [13] ( Figure 5). The first method measures the distance of the cornea to the line joining the two lateral orbital bones on an axial CT slice. The second method measures the exophthalmos of each eye individually along the line that connects the tip of the cornea with the line connecting the lateral and medial orbital rims of each individual orbit on an axial CT slice. The third method uses a sagittal CT slice and takes into account the protrusion along the distance of the cornea from the line that connects the upper and lower orbital rims of each orbit. In all three methods the authors established a high correlation with Hertel exophthalmometry (coefficient of Pearson r = 0.727 in method 1, r = 0.712 in method 2, and r = 0.623 in method 3).

Conclusion
Exophthalmos is an important clinical feature in patients with TAO, and its measurement and monitoring over time provide an assessment of the clinical course and outcome of the treatment. Hertel exophthalmometry is the most commonly used method of measuring the protrusion of the eyeball, but shows a different reproducibility of results between different researchers. Computed tomography examination of proptosis is easy and should always be used to evaluate orbital CT changes in thyroid-associated ophthalmopathy.