Setting: The study was conducted at the University Hospital Thyroid-Eye Clinic.

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1 ORIGINAL ARTICLE Double Vision Is a Major Manifestation in Moderate to Severe Graves Orbitopathy, but It Correlates Negatively With Inflammatory Signs and Proptosis Peter Laurberg, Dalia C. Berman, Inge Bülow Pedersen, Stig Andersen, and Allan Carlé Departments of Endocrinology (P.L., I.B.P., A.C.), Ophthalmology (D.C.B.) and Geriatric Medicine (S.A.), Aalborg University Hospital, and Institute of Clinical Medicine (P.L., I.B.P., S.A.), Aalborg University, DK Aalborg Denmark; and Diagnostic Centre (A.C.), Silkeborg Hospital, DK-8600 Silkeborg, Denmark Context: Double vision (diplopia) is a major determinant of work disability in patients with Graves orbitopathy (GO), but is not part of the classification NOSPECS classification of GO. Objective: The objectives of the study were to quantitate diplopia in patients with moderate to severe GO and to study associations with other disease and patient variables. Design: This was a single-center prospective study of consecutive patients at the time of referral. Setting: The study was conducted at the University Hospital Thyroid-Eye Clinic. Patients: Patients included 216 patients diagnosed with moderate to severe and active GO. Main Outcome Measures: Binocular diplopia in field of gaze and monocular fields of motility were prospectively recorded on diagrams and measured by planimetry. Fields of diplopia were correlated to other disease and patient variables. Results: Six patients had only one functional eye and were excluded. Among the remaining 210 patients, diplopia was present in 75.2%. In patients with diplopia, this ranged from 5% to 100% (observed in 11.4% of patients) of binocular field of gaze. The field of diplopia correlated positively with eye motility restriction and with asymmetrical affection of orbits but negatively with signs of inflammationandproptosisthatoftenarethemainoutcomemeasuresinclinicalstudiesofgotherapy. Conclusion: Diplopia is very common in moderate to severe GO and a major cause for active therapy. In moderate to severe GO, the field of diplopia correlates negatively with some other indicators of disease activity, which may be explained by the physiological properties of binocular fusion. (J Clin Endocrinol Metab 100: , 2015) Graves disease (GD) is a common autoimmune disease that may have various clinical manifestations (1). An essential abnormality is autoimmunity against the TSH receptor (2). One of the organs that may be affected is the orbit, and signs of Graves orbitopathy (GO) are observed in 20% 30% of newly diagnosed patients with hyperthyroidism caused by Graves disease (3 5). Often GO is mild and self-limiting, as described in detail in the European Consensus Report on GO (6) and in recent reviews (1, 7). ISSN Print X ISSN Online Printed in U.S.A. Copyright 2015 by the Endocrine Society Received December 30, Accepted February 13, First Published Online February 19, 2015 About 5% of patients with GD develop moderate to severe GO, which for unknown reasons is mostly seen in GD patients aged older than 40 years (8). The characteristics and procedures to classify GO to be moderate to severe have been described (6, 9). A practical consequence of such classification is that patients may be candidates for specific immunosuppressive therapy, whereas patients with mild GO are not (1, 10). Moderate to severe GO hampers daily activities and decreases quality of life (11, Abbreviations: CT, computed tomography; GD, Graves disease; GO, Graves orbitopathy; TRAb, TSH receptor autoantibody jcem.endojournals.org J Clin Endocrinol Metab, May 2015, 100(5): doi: /jc

2 doi: /jc jcem.endojournals.org ), but the combination of GO manifestations may vary much between patients. In a recent German study by Ponto et al (12), the effects of individual GO manifestations and various other patient characteristics on work disability were investigated in detail. The main result was that diplopia alone predicted work disability in multivariate analyses, whereas there were no independent effects of other factors. Various systems have been developed to grade and describe GO in detail, the classical one being NOSPECS (13). NOSPECS describes eyelid abnormalities, signs of inflammation, proptosis, restriction of eye motility, corneal involvement, and loss of sight. NOSPECS does not mention diplopia; however, scoring of diplopia from patient history as being absent, inconstant (depending on gaze), intermittent, or constant is often performed as part of other scoring systems (1, 14, 15). Because diplopia interferes greatly with the daily living of patients, we studied in more detail diplopia in a prospective cohort of patients with moderate to severe GO. For this we quantified area of diplopia in binocular field of vision along with monocular motility restriction. Materials and Methods Graves orbitopathy patients studied The present study used data recorded at the inclusion in a cohort of 216 consecutive patients diagnosed with moderate to severe GO after being seen in the collaborate Thyroid-Eye Clinic of Aalborg University Hospital, Thus, the present study is based on objective registration of GO manifestations at inclusion, except for the duration of GO, which was based on the interview. The diagnosis of moderate to severe GO was made by ophthalmological and endocrinological specialists in collaboration, as described in the European Consensus Report (6). Patients diagnosed to have moderate to severe orbitopathy were considered for specific therapy using orbital radiation and medical immunosuppression, whereas patients with mild GO were not (1, 10). Throughout the study period, clinical details collected at the time of diagnosis were systematically and prospectively recorded in a registry by the same investigators using the same standardized procedures as reported in detail previously (8). The Thyroid- Eye Clinic of Aalborg University Hospital is the only clinic for such patients in the region of North Jutland, and all patients who developed moderate to severe GO and lived in this region were seen in the clinic. In addition, a group of patients from adjacent areas had been referred to the clinic. All patients were judged to have active GO at the time of referral. A subgroup of patients (n 35) had been treated with prednisolone by local physicians before they were seen in the Thyroid-Eye Clinic, but apart from this, no specific therapy (immune suppressive medication, orbital radiation, or surgery) had been given for the orbitopathy. All patients were Caucasians except for one, who was of Asian ancestry. Characterization of the orbitopathy Both an ophthalmology and an endocrinology specialist performed a systematic investigation to characterize the disease and to evaluate the possibility of other interfering diseases, and orbital computed tomography (CT) or magnetic resonance imaging scans were done. As described previously (8), our system of recording was in many details similar to other systems of classification (13 20) but somewhat simplified to be suitable for our daily clinical practice. In brief, sight threatening orbitopathy was registered in the case of recent progressive subjective loss of vision on at least one eye in relation to the development of GO and the finding of a visual acuity of 0.67 or less with no other cause being detected. Signs of orbital inflammation were recorded using a score of 0 (no signs); 1 (mild redness and swelling, having to look for it); 2 (moderate redness and swelling); 3 (considerable redness and swelling with chemosis); or 4 (severe chemosis, swelling, and redness). Eyelid abnormalities were measured by a ruler as millimeters of visible sclera below and above the central corneal limbus with the head and eye in neutral position and as millimeters of closure deficiency. Proptosis of each eye was recorded in millimeter using a Hertel exophthalmometer. Motility was recorded on a diagram for each eye by drawing on a simple circle split into quarters and the circumference of the circle representing expected motility in each direction. Normal eye motility in various directions varies between approximately 40 (up) and 60 (down), depending on the method used to measure (21, 22). As described in detail earlier (8), eye motility was investigated with the head of the patient in a fixed neutral position. If found normal, the entire field of motility for that eye was marked positive (0% reduction). A motility reduction was subsequently quantified from the diagram by point-counting planimetry (23) using a grid in which each crossing point represented 5% of the entire expected field of motility for that eye. Similarly, the patient s subjective fields of binocular single and double vision were recorded on a circular diagram split into quarters. With the head in a fixed neutral position, the patient was asked to follow a 1-cm object held in a 60-cm distance and to indicate whether single or double vision were experienced. The object was moved from neutral to maximal limit of sight in all directions, field of diplopia was recorded on the diagram, and quantification of the area of diplopia in percent of the entire field was performed by planimetry. An example of diplopia and motility recording is shown for the patient case presented. The method used was a simplification of previously described methods to perform scoring of fields of single and binocular vision (24 26). In a study by Sullivan et al (26), the field of binocular single vision in a group of healthy individuals was found to approximate a circle with a 60 radius to prime position. In GO, diplopia normally starts in far eccentric gaze (most often in the upper part of the field of gaze) and potentially progresses to involve primary position and more. We did not score according to position of field of diplopia, but double vision in GO would most often give considerable to severe functional disturbance when exceeding approximately 40% of the field. All recordings of motility and diplopia for the present study had been performed by the same investigator (P.L.). Subsequently a lateralization scoring was performed and recorded: 0, no lateralization (symmetrical involvement of the two orbits); 1, slight lateralization with some side difference but with moderate to severe orbitopathy on both sides; 2, pronounced lateralization with only mild GO on one side; and 3, strictly

3 2100 Laurberg et al Double Vision in Graves Orbitopathy J Clin Endocrinol Metab, May 2015, 100(5): unilateral involvement. Finally, we recorded which manifestation was the dominant cause for classifying the GO to be moderate to severe. For this we evaluated in sequence the following: 1, loss of vision; 2, diplopia in 40% of field or greater; 3, eye motility restriction in 40% of uniocular field of fixation or greater (worst eye); 4, Hertel measurement of 25 mm or greater (worst eye); and 5, combinations including severe inflammation. The manifestation with the lowest number was recorded as being dominant. Laboratory methods TSH receptor autoantibodies (TRAbs) were measured using competitive immunoassays from BRAHMS (now Thermo-Fischer). In the year 2000, the method changed to be more specific and sensitive (27). For the data analysis of the present study, TRAb values obtained using the old method were converted to approximate values given with the new method, as previously described (27). We used a TRAb detection limit of 1.0 IU/L (28). Statistical analyses of data We used IBM-SPSS (version 15.0) for the calculation and analysis of data. Type of statistical test is indicated where used. P.05 was considered statistically significant. A subgroup of patients (n 35) had been treated with prednisolone by local physicians before they were seen in the Thyroid-Eye Clinic. In all analyses, it was evaluated whether exclusion of these patients from the analyses had major influence on results. Data processing was approved by the Danish Data Protection Agency. Results Among the 216 patients, six had only one functional eye and they were excluded from the study. Characteristics of the remaining 210 patients are given in Table 1. The average age of the patients was higher than recorded for an unselected group of patients with Graves disease (29). This is in accordance with our previous finding that moderate to severe GO is relatively rare in young patients ( 40 y of age) with Graves disease (8). Diplopia We systematically evaluated various manifestations of the disease. In more than half of the patients, our main cause for the classification of the GO to be moderate to severe and thus to be evaluated for radiation and immu- Table 1. Characteristics of 210 Patients With Moderate to Severe GO and After Stratification According to Degree of Diplopia Diplopia Field None 5 50% 55 80% >85% P Value All Patients n Women/men, n 46/6 38/8 43/16 44/9.20 d 171/39 Age, y a 54 (48 64) 52 (48 61) 51 (44 60) 55 (47 64).16 c 53 (46 63) Weight, kg a 71 (58 80) 69 (64 88) 72 (62 82) 67 (58 77).34 c 70 (61 81) Hyper-/eu-/hypothyroid 42/6/4 42/2/2 51/3/5 47/5/1.49 d 182/16/12 GO duration, mo a 8 (5 15) 7 (5 11) 7 (4 9) 7 (4 12).44 c 7 (4 12) Hyper/hypo duration a 11 (5 18) 12 (7 23) 12 (5 36) 14 (8 24).54 c 12 (6 27) Radioiodine association, n, % 4 (7.7) 3 (6.5) 6 (10.2) 3 (5.7).82 d 16 (7.6) Current smoker, n, % 33 (63.5) 36 (78.3) 39 (66.1) 36 (67.9).42 d 144 (68.6) Smoker 10 cigarettes/d 25 (48.1) 28 (60.9) 29 (49.2) 24 (45.3).44 d 106 (50.5) Lateralization score (0 3), n 36/10/6/0 26/17/2/1 21/18/16/4 22/9/17/5.001 c 105/54/41/10 Visus reduction, n, % 8 (15.4) 7 (15.2) 5 (8.5) 3 (5.7).28 d 23 (11.0) Inflammation score (0 4), n 1/8/10/14/19 2/5/15/18/6 1/8/29/17/4 5/11/16/15/6.001 d 9/32/70/64/35 Sclera upper visibility, n, % 27 (51.9) 23 (50.0) 30 (50.8) 33 (62.3).56 d 113 (53.8) Sclera lower visibility, n, % 19 (36.5) 19 (41.3) 17 (28.8) 9 (17.0).04 d 64 (30.5) Closure deficiency n, % 17 (32.7) 17 (37.0) 21 (35.6) 10 (18.9).72 d 65 (31.0) Diplopia, % of field a 0 35 (20 45) 70 (60 75) 95 (90 100) 55 (5 85) Motility reduction n, % 39 (75.0) 44 (95.7) 59 (100) 53 (100).001 d 195 (92.9) Motility reduction, % of field a 35 (0 60) 30 (10 45) 45 (30 55) 55 (30 70).001 c 45 (20 60) Hertel, mm a 25 (22 28) 23 (22 26) 23 (20 24) 21 (20 24).001 c 23 (21 26) TRAb, IU/L a 15.5 ( ) 6.3 ( ) 6.0 ( ) 4.7 ( ).022 c 6.7 ( ) Radioiodine association indicates that orbitopathy developed within 6 months after radioiodine therapy for hyperthyroidism. Double vision percentage of field and motility reduction percentage of field medians were calculated from data in patients having such manifestations. Lateralization scores were as follows: 0, no lateralization; 1, slight lateralization; 2, pronounced lateralization; 3, one sided. For TRAb, 27 were referred before TRAb was available and they are not included, 64 were analyzed with the old method (40 positive), and 119 with the new method (111 positive). a Median (25% 75%). b Normal test. c Kruskal-Wallis. d Pearson 2 /Fisher. P for comparison of the four groups.

4 doi: /jc jcem.endojournals.org 2101 Table 2. Dominating Manifestation Leading to Classification of GO to Be Moderate to Severe Number, % 1. Impaired vision 23 (11.0) 2. Double vision 40% of field 116 (55.2) 3. Restricted eye movement 40% of field 26 (12.4) 4. Proptosis 25 mm 21 (10.0) 5. Combinations including severe inflammation 24 (11.4) All 210 (100.0) Manifestations are listed according to the sequence of evaluation. If impaired vision had developed, this would be to cause. If not, diplopia would be evaluated, and if 40% or greater of field, this would be the cause, etc. nosuppressive therapy was diplopia (Table 2). However, the sequence of doing such an evaluation of manifestations would considerably influence the figures given in Table 2, eg, a total of 118 patients (56.2% of all) had motility restriction corresponding to 40% or greater of field, 67 patients had proptosis with Hertel measurement of 25 mm or greater, and 99 had inflammation with chemosis (Table 1). The occurrence of various degrees of diplopia in the 210 patients is shown in Figure 1. Only one of four (52 of 210) had single binocular vision in the entire field of gaze. The remaining had diplopia ranging from 5% up to 100% of field, which was found in 24 of the patients (11.4%). Correlation with other variables We stratified patients according to the field of diplopia (Table 1) and also performed correlation analysis (Spearman) between the field of diplopia and other variables. Figure 1. Cumulative number of patients with diplopia according to percentage of binocular field of gaze affected in 210 consecutive patients with moderate to severe Graves orbitopathy. Fields of binocular single and double vision were recorded in all directions of gaze on a circular diagram, and field of diplopia was measured by point-counting planimetry using a grid in which each crossing represented 5% of the entire field of gaze. Diplopia correlated positively with eye motility reduction (worst eye), although the coefficient of correlation was quite low (Spearman s rho 0.26, P.001). As illustrated in Figure 2, the positive correlation was mainly caused by less diplopia in patients with no or a low degree of motility restriction ( 10%). Among the 23 patients with 75% or greater reduction of the monocular field of motility (worst eye), 11 had no diplopia, and 12 of the 44 patients with diplopia in 90% or greater of field of gaze had 30% or less reduction in uniocular field of motility. When patients with motility restriction 10% or less were excluded, the positive correlation between motility restriction and diplopia was no longer statistically significant (rho 0.13, P.09). In contrast, diplopia correlated negatively with the variables often recorded in therapeutic clinical trials: inflammation score (rho 0.25, P.001) and proptosis (millimeters, worst eye; rho 0.36, P.001). The pattern was very clear for proptosis (Figure 2), in which nearly 90% of patients with normal to borderline exophthalmometer readings of mm had diplopia in 40% or greater of field, whereas this was only about 25% of patients in the group with the most severe proptosis. Considering inflammation, the negative correlation was mostly driven by the subgroup with the most severe inflammation having the lowest frequency of severe diplopia (Figure 2). Lateralization of disease (asymmetrical involvement of the orbits) was positively associated with diplopia (rho 0.38, P.01) (Figure 2), whereas serum TRAb concentration correlated negatively with diplopia (rho 0.25, P.01) and also with asymmetry/lateralization (rho 0.30, P.01). There were no significant correlations between percentage field of diplopia and the patient s age or smoking habits, sex, body weight, type and duration of thyroid dysfunction, duration of orbitopathy, visual acuity, position of eyelids, eye closure deficiency, intraocular pressure readings, or previous radioiodine therapy. Findings were consistent after restriction of the analysis to the 175 patients who had not received prednisolone at the time of the investigation and in multivariate analysis (data not shown). Case with diplopia Figure 3 illustrates the type of patient who may present with diplopia in combination with asymmetrical eye motility restriction, exophthalmometer readings within the reference range, and virtual absence of signs of inflammation. The photo of the eyes illustrates absence of inflammatory signs, parallel eye axes in neutral position, and a slight retraction of right lower eyelid. The motility and

5 2102 Laurberg et al Double Vision in Graves Orbitopathy J Clin Endocrinol Metab, May 2015, 100(5): Figure 2. Percentage of patients having diplopia in 40% or greater of field of gaze according to various characteristics: motility restriction (worst eye) in percentage of expected motility. Exophthalmometer readings (Hertel) in millimeters [worst eye; upper reference in men was 21 mm and in women 19 mm (9); one patient was excluded for technical reasons]. Inflammation score, in which the score 0 was no signs of abnormal inflammation, and score 4 was severe chemosis, swelling, and redness. Asymmetry score, in which the score 0 was no side difference, score 1 was some difference but with moderate to severe GO in both orbits, 2 was considerable side difference with only mild GO in one orbit, and 3 was onesided orbitopathy. N in columns indicates the number of patients in the specific group. diplopia diagram below the photo shows diplopia at upgaze and gaze to the left (middle circle) and that diplopia was caused by a restriction of right eye motility up and to the left. Motility of the left eye was normal (right circle). The cause for the motility restriction of the right eye is seen on the CT scan (lower part of figure), in which there is a clear affection with thickening of the right inferior rectus muscle (arrow), leading to the restriction of up rotation, and also a less common affection of the lateral rectus muscle (arrow), leading to restriction of nasal rotation. Compare with the corresponding muscles in the nonaffected left orbit (arrows). Discussion Principal observations In a cohort of 210 consecutive patients with moderate to severe GO and binocular vision seen at a University Hospital Thyroid-Eye Clinic, diplopia was the most common cause for classifying GO to be moderate to severe and thus to be considered for specific therapy. Systematic recording of the fields of single and double binocular vision revealed that three of four patients suffered from diplopia, varying from 5% to 100% of the field of gaze. The field of diplopia correlated significantly and positively with the field of motility restriction as well as to asymmetry of the orbital involvement. Unexpectedly, diplopia correlated negatively and rather strongly with signs of orbital inflammation and with proptosis that often are the main outcome measures in clinical trials testing therapy of GO. Moreover, diplopia also correlated negatively with the serum concentration of TRAb. Comparison with other studies Our finding that diplopia is of major importance in patients with moderate to severe GO is in accordance with a number of studies. In a multicenter investigation of 152 patients with GO performed by the European Group on Graves Orbitopathy group of investigators (30), 49% of patients indicated that they had some degree of diplopia, and in various clinical studies, similar frequencies have been reported. In a recent German study (12), the authors investigated the public health relevance of GO in a group of 215 pa-

6 doi: /jc jcem.endojournals.org 2103 Figure 3. Case: 70-year-old woman with a second episode of Graves hyperthyroidism again being treated with methimazole now for 7 months. Therapy of hyperthyroidism has been uncomplicated. No previous eye problems. New complaint: inconstant diplopia developed over the last 3 months, now rather disturbing, especially when the patient tries to drive a car. Clinical eye examination shows normal visual acuity, no signs of inflammation, parallel eye axes in neutral, Hertel 18/14 mm, slight retraction of right lower eye lid, no eye closure deficiency. Serum TRAb is 5.3 IU/L. As illustrated in the motility and diplopia diagram (middle panel showing from left to right circles: field of motility right eye, field of diplopia, field of motility left eye), the patient has diplopia when looking up and to the left (arrow 1). The reason for the diplopia is a selective motility restriction of the right eye with restricted up and in rotation (arrow 2). The coronal CT scan of the orbits (lower panel) shows that the reason for the restricted up rotation is autoimmune affection of the right lower rectus muscle (arrow 3), and the restriction of nasal rotation is affection of the right lateral rectus muscle (arrow 4). Compare the two swollen muscles in the right orbit with the corresponding muscles in the left orbit (arrows 5 and 6). tients with clinically overt GO who had been employed at the time they developed the disease. Some degree of work disability had occurred in 21% of patients with no diplopia and 42% with inconstant and 74% with constant diplopia. In a multivariate analysis of predictors of the inability to work, the only independent predictor was diplopia. On the other hand, age, sex, clinical activity score (31), proptosis, optic neuropathy, thyroid function, and smoking had no independent effect on outcome. We are aware of no previous study that investigated the types of correlations observed in the present study. The reason for this is likely to be that no previous study quantitated field of diplopia in a large group of patients with moderate to severe GO. Measurement of diplopia Among the various systems developed to classify GO, the classical is NOSPECS (13, 17), which is a combination of grading of severity from no signs or symptoms to loss of sight, and a systematic description of the various clinical manifestations of GO. Whereas diplopia is not mentioned in NOSPECS, the E stands for extraocular muscle signs that are graded from absent to fixation of globes. The cause of diplopia in GO is restriction of eye motility in one or several directions that may affect one or both eyes, and the restriction of motility is caused by autoimmune affection of individual external eye muscles that may typically be seen swollen on a CT or magnetic resonance imaging scan of the orbits, as illustrated in Figure 3. Even if we found the correlation between field of motility restriction (worst eye) and field of diplopia to be highly significant (P.001), less than 10% of the variation in field of diplopia was explained by the variation in field of motility restriction. This corresponds to the clinical observation that even severe motility restriction may not always cause double vision, as also observed in the present cohort. Thus, in the individual patient, diplopia (binocular function) should be recorded separately from single-eye motility impairment. A commonly used GO classification records the patient s history of constant, inconstant, intermittent, or no double vision (1, 18). This is useful, as, for example, illustrated by the study of Ponto et al (12) but does not allow the same degree of detailed analysis as would a more quantitative recording. The simple motility and double vision diagram we used is illustrated by the case reported. We experienced such a diagram to be a useful tool to discuss the mechanisms and degree of disease with the individual patient. Several authors have described systems to quantitate diplopia in strabismus patients using a perimeter and various functional scores (24 26). A common principle has been to split the field of gaze into small parts and give each small field a score that depends on the importance for the patient s daily function. Thus, fields around neutral and also down-gaze would score higher, and the combined score would be a functional relevant score. A limitation of the present study is that our method was simpler and designed to be used in daily clinical practice. Thus, it was fast and required only simple equipment. The point-counting planimetry method we used for measurement of fields of diplopia and motility restriction is a standard method that compares favorably with other methods for measuring areas (23), and it has been applied in many areas of research. A general limitation in the study of eye motility in the active phase of GO is that patients may experience pain by eye movement, which may hamper precise recording of motility restriction and diplopia. Thus, inter- and intraobserver variation in recording would be dependent on the group of patients studied and the phase of the disease. All

7 2104 Laurberg et al Double Vision in Graves Orbitopathy J Clin Endocrinol Metab, May 2015, 100(5): measurements performed as part of the present study were performed by the same investigator, thereby eliminating interobserver variation. Imprecision would tend to diminish the associations observed in the present study Mechanism behind correlations Several mechanisms may have led to the combination of correlations between field of diplopia and the other disease characteristics studied. The exact cellular processes leading to the various manifestations of GO are only partly understood (1), and one possibility could be that the autoimmune affection of external eye muscles is substantially different from the affection of other orbital contents, such as fibrocytes and adipocytes (32, 33). To explain the correlations observed, this would necessitate that one type of abnormality would tend to be associated with less severity of the other type of abnormality. The dual mechanisms discussed above would be a very interesting cause for our results, but we find that another cause is more likely. This is the special coupling of innervation and function of external eye muscles that has been called Hering s law of equal innervation (34, 35). External eye muscles are activated in concert to focus the eyes on a specific target, and this coupling may explain why correlation between muscle restriction and diplopia is less strong than might be anticipated. Even profound restriction in all directions of eye movement may not lead to diplopia if both eyes are similarly affected. On the other hand, a modest restriction of a single muscle on one side may lead to severe diplopia if overactivation of the opposing set of muscles to compensate leads to deviation of the other eye. In the present study, we found positive correlations between signs of orbital inflammation, proptosis, and serum TRAb values that may all be seen as an expression of the overall autoimmune activity of the disease. On the other side, diplopia correlated positively with asymmetrical affection of orbits and both of these negatively with the above-mentioned autoimmune activity variables. We speculate, that a more severe autoimmune activity in GO would lead to a more general affection of orbits with less asymmetry and less diplopia. This would be parallel to severe rheumatoid arthritis, leading to affection of nearly all joints. On the other hand, less severe autoimmune activity in GO may lead to affection of only one or a few muscles in one orbit, with asymmetry and more diplopia. A parallel would be less severe rheumatoid arthritis with affection of only a few joints. More studies are needed to better understand disease mechanisms in GO and to see whether the findings of the present study have implications for the choice of therapy in patients with moderately severe orbitopathy. Conclusion Diplopia is the most common cause for classifying GO to be moderate to severe. It has been shown that diplopia in GO patients depicts inability to work (12) and that correction of diplopia considerably improves the quality of life (36). However, diplopia does not always develop in parallel with signs of inflammation and proptosis in GO. Detailed recording of eye muscle restriction and field of diplopia is advisable in individual patients with GO and also in controlled clinical studies of the disease. Acknowledgments Address all correspondence and requests for reprints to: Peter Laurberg, MD, Department of Endocrinology, Aalborg University Hospital, Sdr. Skovvej 15, DK-9000 Aalborg, Denmark. peter.laurberg@rn.dk. Disclosure Summary: The authors have nothing to declare. References 1. Bahn RS. Graves ophthalmopathy. N Engl J Med. 2010;362: Davies TF, Ando T, Lin RY, Tomer Y, Latif R. Thyrotropin receptor-associated diseases: from adenomata to Graves disease. J Clin Invest. 2005;115: Tanda ML, Piantanida E, Liparulo L, et al. Prevalence and natural history of Graves orbitopathy in a large series of patients with newly diagnosed Graves hyperthyroidism seen at a single center. J Clin Endocrinol Metab. 2013;98: Abraham-Nordling M, Bystrom K, Torring O, et al. Incidence of hyperthyroidism in Sweden. Eur J Endocrinol. 2011;165: Laurberg P, Nygaard B, Andersen S, et al. Association between TSHreceptor autoimmunity, hyperthyroidism, goitre, and orbitopathy in 208 patients included in the remission induction and sustenance in Graves disease study. J Thyroid Res. 2014;2014: Bartalena L, Baldeschi L, Dickinson A, et al. European Group on Graves Orbitopathy (EUGOGO). 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