Imaging of the medial rectus muscle predicts the development of optic neuropathy in thyroid ocular diseases

Radiological features in patients with DON have been a major subject of research. Changes such as an enlargement of the V. ophthalmica superior, an anterior displacement of the lacrimal gland or the presence of an intracranial fat prolapse were examined17,18,19. The most thoroughly studied radiological parameter supporting the diagnosis of DON is the increase in extraocular muscle size, which ultimately leads to apical crowding and DON.

In the underlying study, we were able to confirm an increase in muscle volume, especially the medial rectus muscle, as the strongest predictor for the development of DON in patients with TED. Although the dimensions of the bony orbits differed significantly between the groups studied, there was no predisposing difference for the development of DON in patients with TED prior to disease-related bony orbital changes.

In other studies, apical crowding was assessed on a categorical scale or by ratioing the diameters of the horizontal or vertical extraocular muscles to the diameter of the bony orbit20.21. Other authors calculated the ratio of soft to adipose tissue around the apex area to form a volumetric apical crowding index16.

To our knowledge, the underlying study is the only one that includes both measurements of the individual muscle volume and the bony orbit. In addition, our collective of DON patients appears to be the largest analyzed to date. Finally, previously published research ignored the unaffected orbits of patients with DON, which were analyzed as a separate subgroup in our study, since relevant anatomical differences prior to disease manifestation in the orbits of patients with and without DON cannot be ruled out.

Because the medial orbital wall is much thinner than the lateral orbital wall and the air-filled ethmoidal sinuses offer less resistance, the medial wall is more prone to bone remodeling. This thesis is supported by the fact that the change in medial orbital angle correlates with an increase in muscle volume, particularly the medial rectus muscle, as shown in the TED + DON group. Our findings on muscle volume are consistent with previously published research13:15showing that the volume or thickness of the medial rectus muscle is the most significant predictor for the development of DON, most likely due to its close anatomical relationship to the optic nerve in the optic canal15. At some point during the process of muscle enlargement, the compensatory mechanisms of the orbit (mainly extension into the ethmoid sinuses) seemed to exceed their limits, leading to a critical increase in pressure in the orbit and eventual damage to the optic nerve.

Subjects in the TED + DON group showed a significantly increased medial orbital angle compared to the TED group. The angles of both groups were also significantly increased compared to the control group. This is consistent with other studies12:13. However, adding a medial orbital angle change to our multivariate analysis did not improve diagnostic accuracy. This suggests that the increased deflection of the medial wall serves as a surrogate parameter for the increase in muscle volume. Interestingly, this result is in contrast to previous studies14:15, in which there was no significant difference in medial orbital wall curvature between these groups. Reasons for this could be the use of subjective evaluation methods to assess the curvature of the medial orbital wall15the higher number of subjects in our DON group or the extent of muscle enlargement they inherited.

Previous findings describing an increase in the lateral wall angle in patients with DON could not be replicated in our study. While subjects assigned to the TED + DON group had a greater sidewall angle than subjects in the TED group, the difference was not significant (p= 0.6). Reasons for this could be the larger sample size of our study, the different patient ethnicity, group composition or an even greater deflection of the medial wall, which leads to a reduction in pressure on the lateral wall. The fact that remodeling of the lateral orbital wall occurs later in the disease process may also explain this finding.

Unaffected (among others) orbits of DON patients did not differ significantly from orbits of the TED group with regard to the dimension of the bony orbits. Despite the small sample size and the assumption that both orbits developed more or less equally, these data may indicate that there are no characteristic bony differences, or that they are too minute to measure, leading to the development of DON- Patients before the thickening would affect the muscles.

In addition to bony orbital changes, the bulging of the eyeball is another effect of the increased intraorbital volume. Proptosis was remarkably higher in DON patients and correlated well with muscle volume (Table 1). The scatterplot (Fig. 5) of medial rectus volume (MRV) and medial angle change (MAC) of DON and TED + DON patients shows that a sharp delineation between these two groups is not possible and that some cases (red and yellow Points ) develop atypically. Thus, based on the measured values ​​obtained, these two groups cannot be easily distinguished from the unaffected or affected population and illustrate the difficulty of DON diagnosis based on anatomical-radiological data. Therefore, alternative approaches such as radiomics or diffusion tensor imaging could offer interesting approaches and are currently being investigated. However, at present, clinical ophthalmological examination is indispensable and increases sensitivity and specificity22.

Our data confirm the heterogeneity of the disease with several existing subtypes23. While most subjects with DON show a significant increase in muscle volume, a subgroup shows little or no increase. On the other hand, our data show a trend towards discriminating both groups (TED and TED + DON) and in our opinion it may be advisable to treat patients with known TED and a medial rectus volume greater than 0.9 cm3 should be monitored more closely regardless of bony orbital dimensions, as this was the lowest value in our population associated with the development of DON (Fig. 5, lower horizontal line). The heterogeneity of TED was also recognized by Uddin et al. emphasizes that TED is heterogeneous in its underlying pathogenesis, clinical manifestations, and response to medical and surgical treatment modalities24. In their manuscript, they criticized that several previous categorizations of the clinical presentation of TED were dichotomous and underrepresented the heterogeneity of the disease. Consequently, Uddin et al. proposed a new classification system that divides TED into six different classes based on the phenotypic characteristics (clinical and radiological) and their response to different treatments.

Not only has heterogeneity been reported for clinical and radiological findings in EO, but also different imaging modalities including MRI and PET (alone or in combination with MRI or CT) have been used to examine different morphological and functional parameters. In a recently published work, Weber et al. reported that PET-MRI is suitable for assessing EO inflammation and is a good discriminator of severe vs. mild to moderate EO25. A variety of other parameters have been analyzed in numerous other studies in EO. These were mainly morphological parameters such as volume or width of fat or muscle26 or the optic nerve27Herniation of the lacrimal gland28Contrast uptake and T2 hyperintensity (as surrogate parameters for inflammation)29.30quantitative MRI and T1 mapping of the eye muscles31:32, just to name a few. Therefore, imaging plays a significant role in the study of TED. Siakallis et al. rightly point out that a consensus on the use of the various imaging methods in the course of the disease has not yet been reached33.

Because it is unusual to routinely perform CT or MRI of the orbit prior to the onset of TED, no definitive statement can be made on risk factors related to muscle and bony orbital size that exacerbate progression from TED-only to TED+DON this retrospective study. Therefore, a follow-up study to accurately assess muscle volume changes in our TED patients could be of interest to identify new parameters (e.g., an increase in medial rectus volume over a period of time) that are better suited for risk stratification around TED to advance to TED + DON.

It should be noted that the gender ratio in our study differs from other publications. In our population, the proportion of men in the DON group was significantly lower than in comparable studies13,16,20. It might be worth noting that including patients with mild and inactive disease in the TED group (compared to moderate-to-severe and vision-threatening cases) can be a confounding factor. Since our center primarily treats patients with a more severe course of the disease, for whom computed tomography is justified, the measured values ​​are not necessarily comparable with those of the entire TED population. DON is in most cases a clinical diagnosis based on abnormalities in assessment of visual acuity, color vision/saturation, perimetry, fundoscopy, and/or pupillary light response/relative afferent pupillary defect assessment in patients with TED. While not mandatory, radiological imaging is intended to aid in diagnosis in borderline cases or to help identify patients at increased risk of developing DON.

In summary, the underlying study demonstrates the complexity of DON and the inherent problem of identifying patients with TED to develop DON. From our experience, volumetric measurements of the medial rectus muscle appear to offer the best sensitivity and specificity for the development of DON and patients with medial rectus volume greater than 0.9 cm3 should be closely monitored.

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