PURPOSE: Given the subjective nature of clinical activity score (CAS) and variability between observers, this study evaluated the inter-observer variability of soft tissue signs (STS) in the CAS using periocular photographs and compared the diagnostic performance of photographic CAS (P-CAS) with clinical assessment for detecting active thyroid eye disease (TED). METHODS: This retrospective cohort study included 754 TED patients who underwent periocular photography at Seoul National University Bundang Hospital between 2006 and 2021. Five oculoplastic specialists independently evaluated five STS of CAS using periocular photographs. Inter-observer agreement and concordance between photographically (P-STS) and clinically (C-STS) assessed STS, assessment consistency, were analyzed using Kappa statistics. Diagnostic accuracy of P-CAS was evaluated via receiver operating characteristic (ROC) curves with additional analysis incorporating demographic variables such as sex, age, and smoking dose. RESULTS: Assessment consistency was moderately good for redness of eyelid and conjunctiva (Kappa = 0.418, 0.499). The diagnostic performance of P-CAS (area under the curve, AUC = 0.774) was lower than that of clinical CAS (C-CAS) (AUC = 0.818, p = 0.007), However, it significantly improved when demographic factors were added (AUC = 0.851). CONCLUSION: Periocular photography provides a reproducible and clinically valuable adjunct for assessing TED activity. The redness-related items showed higher agreement than swelling-related ones, and integrating demographic variables enhances diagnostic performance. This approach may contribute to standardizing TED assessment and serve as a foundation for future automated or image-based evaluation tools.

The aim of this study is to characterize the microRNA (miRNA) expression signatures in patients with thyroid eye disease (TED) and identify miRNA biomarkers of disease activity. Total RNA was isolated from the sera of patients with TED (n = 10) and healthy controls (HCs, n = 5) using the miRNeasy Serum/Plasma Kit. The NanoString assay was used for the comprehensive analysis of 798 miRNA expression profiles. Analysis of specific miRNA signatures, mRNA target pathway analysis, and network analysis were performed. Patients with TED were divided into two groups according to disease activity: active and inactive TED groups. Differentially expressed circulating miRNAs were identified and tested using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) tests in the validation cohort. Among the 798 miRNAs analyzed, 173 differentially downregulated miRNAs were identified in TED patients compared to those in the HCs. Ten circulating miRNAs were differentially expressed between the active and inactive TED groups and regarded as candidate biomarkers for TED activity (one upregulated miRNA: miR-29c-3p; nine downregulated miRNAs: miR-4286, miR-941, miR-571, miR-129-2-3p, miR-484, miR-192-5p, miR-502-3p, miR-597-5p, and miR-296-3p). In the validation cohort, miR-484 and miR-192-5p showed significantly lower expression in the active TED group than in the inactive TED group. In conclusion, the expression levels of miR-484 and miR-192-5p differed significantly between the active and inactive TED groups, suggesting that these miRNAs could serve as circulating biomarkers of TED activity, however, these findings need to be validated in further studies.

PURPOSE: To investigate the association between the bony nasolacrimal duct (NLD) size and outcomes of nasolacrimal silicone intubation for incomplete primary acquired nasolacrimal duct obstruction (PANDO). METHODS: Patients who underwent silicone intubation for incomplete PANDO and had undergone facial computed tomography (CT) were included. Surgical success was judged by both epiphora improvement and normalized tear meniscus height (TMH; < 300 μm) on anterior segment optical coherence tomography at 3 months after tube removal. The area, major axis diameter, and minor axis diameter of the elliptic bony NLD sections were measured in 1.0 mm-thick axial CT images. These bony NLD sizes were analyzed for associations with surgical success and TMH normalization. RESULTS: Eighty-one eyes of 48 patients were investigated. The smallest area and the smallest minor axis diameter were significantly larger in the success group (49 eyes), compared with those in the failure group (median smallest minor axis diameter: 4.7 mm vs. 3.8 mm, P = 0.008, Mann-Whitney U test). There was also a tendency for the TMH normalization rate to significantly increase as the smallest area and the smallest minor axis diameter increased (P = 0.028 and 0.037, respectively, Fisher's 2 × 4 tests). Under multivariable logistic regression analysis using generalized estimating equation, a larger smallest minor axis diameter was associated with success of the nasolacrimal silicone intubation (odds ratio: 2.481, 95% confidence interval: 1.143-5.384). CONCLUSION: Surgical success of the nasolacrimal silicone intubation in incomplete PANDO is associated with a larger smallest minor axis diameter of the bony NLD. This finding will help understand the pathophysiology of surgical failure after nasolacrimal silicone intubation.

Although the clinical activity score (CAS) is a validated scoring system for identifying disease activity of thyroid-associated orbitopathy (TAO), it may produce differing results depending on the evaluator, and an experienced ophthalmologist is required for accurate evaluation. In this study, we developed a machine learning (ML)-assisted system to mimic an expert's CAS assessment using digital facial images and evaluated its accuracy for predicting the CAS and diagnosing active TAO (CAS ≥ 3). An ML-assisted system was designed to assess five CAS components related to inflammatory signs (redness of the eyelids, redness of the conjunctiva, swelling of the eyelids, inflammation of the caruncle and/or plica, and conjunctival edema) in patients' facial images and to predict the CAS by considering two components of subjective symptoms (spontaneous retrobulbar pain and pain on gaze). To train and test the system, 3,060 cropped images from 1020 digital facial images of TAO patients were used. The reference CAS for each image was scored by three ophthalmologists, each with > 15 years of clinical experience. We repeated the experiments for 30 randomly split training and test sets at a ratio of 8:2. The sensitivity and specificity of the ML-assisted system for diagnosing active TAO were 72.7% and 83.2% in the test set constructed from the entire dataset. For the test set constructed from the dataset with consistent results for the three ophthalmologists, the sensitivity and specificity for diagnosing active TAO were 88.1% and 86.9%. In the test sets from the entire dataset and from the dataset with consistent results, 40.0% and 49.9% of the predicted CAS values were the same as the reference CAS, respectively. The system predicted the CAS within 1 point of the reference CAS in 84.6% and 89.0% of cases when tested using the entire dataset and in the dataset with consistent results, respectively. An ML-assisted system estimated the clinical activity of TAO and detect inflammatory active TAO with reasonable accuracy. The accuracy could be improved further by obtaining more data. This ML-assisted system can help evaluate the disease activity consistently as well as accurately and enable the early diagnosis and timely treatment of active TAO.

PURPOSE: Given the subjective nature of clinical activity score (CAS) and variability between observers, this study evaluated the inter-observer variability of soft tissue signs (STS) in the CAS using periocular photographs and compared the diagnostic performance of photographic CAS (P-CAS) with clinical assessment for detecting active thyroid eye disease (TED). METHODS: This retrospective cohort study included 754 TED patients who underwent periocular photography at Seoul National University Bundang Hospital between 2006 and 2021. Five oculoplastic specialists independently evaluated five STS of CAS using periocular photographs. Inter-observer agreement and concordance between photographically (P-STS) and clinically (C-STS) assessed STS, assessment consistency, were analyzed using Kappa statistics. Diagnostic accuracy of P-CAS was evaluated via receiver operating characteristic (ROC) curves with additional analysis incorporating demographic variables such as sex, age, and smoking dose. RESULTS: Assessment consistency was moderately good for redness of eyelid and conjunctiva (Kappa = 0.418, 0.499). The diagnostic performance of P-CAS (area under the curve, AUC = 0.774) was lower than that of clinical CAS (C-CAS) (AUC = 0.818, p = 0.007), However, it significantly improved when demographic factors were added (AUC = 0.851). CONCLUSION: Periocular photography provides a reproducible and clinically valuable adjunct for assessing TED activity. The redness-related items showed higher agreement than swelling-related ones, and integrating demographic variables enhances diagnostic performance. This approach may contribute to standardizing TED assessment and serve as a foundation for future automated or image-based evaluation tools.

The aim of this study is to characterize the microRNA (miRNA) expression signatures in patients with thyroid eye disease (TED) and identify miRNA biomarkers of disease activity. Total RNA was isolated from the sera of patients with TED (n = 10) and healthy controls (HCs, n = 5) using the miRNeasy Serum/Plasma Kit. The NanoString assay was used for the comprehensive analysis of 798 miRNA expression profiles. Analysis of specific miRNA signatures, mRNA target pathway analysis, and network analysis were performed. Patients with TED were divided into two groups according to disease activity: active and inactive TED groups. Differentially expressed circulating miRNAs were identified and tested using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) tests in the validation cohort. Among the 798 miRNAs analyzed, 173 differentially downregulated miRNAs were identified in TED patients compared to those in the HCs. Ten circulating miRNAs were differentially expressed between the active and inactive TED groups and regarded as candidate biomarkers for TED activity (one upregulated miRNA: miR-29c-3p; nine downregulated miRNAs: miR-4286, miR-941, miR-571, miR-129-2-3p, miR-484, miR-192-5p, miR-502-3p, miR-597-5p, and miR-296-3p). In the validation cohort, miR-484 and miR-192-5p showed significantly lower expression in the active TED group than in the inactive TED group. In conclusion, the expression levels of miR-484 and miR-192-5p differed significantly between the active and inactive TED groups, suggesting that these miRNAs could serve as circulating biomarkers of TED activity, however, these findings need to be validated in further studies.

PURPOSE: To investigate the association between the bony nasolacrimal duct (NLD) size and outcomes of nasolacrimal silicone intubation for incomplete primary acquired nasolacrimal duct obstruction (PANDO). METHODS: Patients who underwent silicone intubation for incomplete PANDO and had undergone facial computed tomography (CT) were included. Surgical success was judged by both epiphora improvement and normalized tear meniscus height (TMH; < 300 μm) on anterior segment optical coherence tomography at 3 months after tube removal. The area, major axis diameter, and minor axis diameter of the elliptic bony NLD sections were measured in 1.0 mm-thick axial CT images. These bony NLD sizes were analyzed for associations with surgical success and TMH normalization. RESULTS: Eighty-one eyes of 48 patients were investigated. The smallest area and the smallest minor axis diameter were significantly larger in the success group (49 eyes), compared with those in the failure group (median smallest minor axis diameter: 4.7 mm vs. 3.8 mm, P = 0.008, Mann-Whitney U test). There was also a tendency for the TMH normalization rate to significantly increase as the smallest area and the smallest minor axis diameter increased (P = 0.028 and 0.037, respectively, Fisher's 2 × 4 tests). Under multivariable logistic regression analysis using generalized estimating equation, a larger smallest minor axis diameter was associated with success of the nasolacrimal silicone intubation (odds ratio: 2.481, 95% confidence interval: 1.143-5.384). CONCLUSION: Surgical success of the nasolacrimal silicone intubation in incomplete PANDO is associated with a larger smallest minor axis diameter of the bony NLD. This finding will help understand the pathophysiology of surgical failure after nasolacrimal silicone intubation.

Although the clinical activity score (CAS) is a validated scoring system for identifying disease activity of thyroid-associated orbitopathy (TAO), it may produce differing results depending on the evaluator, and an experienced ophthalmologist is required for accurate evaluation. In this study, we developed a machine learning (ML)-assisted system to mimic an expert's CAS assessment using digital facial images and evaluated its accuracy for predicting the CAS and diagnosing active TAO (CAS ≥ 3). An ML-assisted system was designed to assess five CAS components related to inflammatory signs (redness of the eyelids, redness of the conjunctiva, swelling of the eyelids, inflammation of the caruncle and/or plica, and conjunctival edema) in patients' facial images and to predict the CAS by considering two components of subjective symptoms (spontaneous retrobulbar pain and pain on gaze). To train and test the system, 3,060 cropped images from 1020 digital facial images of TAO patients were used. The reference CAS for each image was scored by three ophthalmologists, each with > 15 years of clinical experience. We repeated the experiments for 30 randomly split training and test sets at a ratio of 8:2. The sensitivity and specificity of the ML-assisted system for diagnosing active TAO were 72.7% and 83.2% in the test set constructed from the entire dataset. For the test set constructed from the dataset with consistent results for the three ophthalmologists, the sensitivity and specificity for diagnosing active TAO were 88.1% and 86.9%. In the test sets from the entire dataset and from the dataset with consistent results, 40.0% and 49.9% of the predicted CAS values were the same as the reference CAS, respectively. The system predicted the CAS within 1 point of the reference CAS in 84.6% and 89.0% of cases when tested using the entire dataset and in the dataset with consistent results, respectively. An ML-assisted system estimated the clinical activity of TAO and detect inflammatory active TAO with reasonable accuracy. The accuracy could be improved further by obtaining more data. This ML-assisted system can help evaluate the disease activity consistently as well as accurately and enable the early diagnosis and timely treatment of active TAO.

PURPOSE: To quantitatively analyze morphological and functional alterations of the meibomian glands in eyes with marginal entropion and their changes after surgery. METHODS: Sixty eyes of 52 patients with marginal entropion and underwent meibography and interferometer were included. One-hundred and seventeen age- and sex-matched eyes with minimal to mild meibomian gland dysfunction (MGD) were recruited as control eyes. Meibomian gland loss (MGL) and lipid layer thickness (LLT) were compared between eyes with marginal entropion and control eyes. Subgroup analysis was performed according to the extent of entropion. MGL and average LLT at 1 and 5 months after surgery were compared with those of 20 eyes with marginal entropion followed without surgery. RESULTS: In eyes with marginal entropion, MGL was higher (27.7% vs. 12.8%, P = 0.014), and average LLT was thinner (64 nm vs. 86 nm, P = 0.005) than those in control eyes. MGL was higher in eyes with more extensive entropion (> 2/3 eyelid width) than in eyes with less extensive entropion (≤ 1/3 eyelid width) (40.5% vs. 13.2%, P = 0.001). Average LLT increased after surgery (97 nm at 1 month, P = 0.003; 75 nm at 5 months, P = 0.319), and thicker than that of eyes followed without surgery (97 nm vs. 66 nm, P = 0.046). MGLs after surgery remained unchanged from the preoperative MGL (all P > 0.7). CONCLUSION: Marginal entropion is associated with morphological and functional alterations of the meibomian glands. Functional improvement after entropion repair suggests that marginal entropion could cause or exacerbate MGD. Further studies are required to establish the role of entropion repair in managing MGD.

PURPOSE: The Clinical Activity Score (CAS) is widely used to assess thyroid eye disease (TED) activity but can vary based on the evaluator's expertise. We developed and externally validated Glandy CAS, a machine learning (ML)-assisted system for detecting active TED (CAS ≥3) using digital facial images. This clinical trial aimed to gain approval from the Korea Ministry of Food and Drug Safety (KMFDS) for this Software as a Medical Device (SaMD). METHODS: This is a clinical trial based on the retrospective cohort. Glandy CAS analysed 756 photos of patients with TED, classifying them as having active or inactive TED. Its diagnostic performance was compared with that of three general ophthalmologists (less than 5 years of experience), using the F1 score. The reference CAS was determined by an oculoplastic specialist. RESULTS: Active TED was detected in 207 of 756 patients. Glandy CAS achieved a sensitivity of 87.9%, specificity of 95.8% and an F1 score of 0.88. In comparison, general ophthalmologists had a sensitivity of 60.4%, specificity of 83.0% and an F1 score of 0.57. Glandy CAS predicted CAS within 1 point of the reference score in 82.3% of cases, with a mean absolute error of 0.83. CONCLUSIONS: Glandy CAS, an ML-assisted system for detecting active TED using facial images, showed high accuracy and outperformed general ophthalmologists. This system can consistently and accurately assess disease activity, facilitating early detection and timely treatment of active TED. Based on this clinical trial, the SaMD received KMFDS approval (Product Licence No., 24-93).

Objective: To develop and evaluate a deep learning (DL)-assisted system for proptosis measurement using facial photographs in thyroid eye disease (TED). Design: A retrospective cohort study. Participants: This study included 1108 patients with TED from Severance Hospital (SH) and 171 from Seoul National University Bundang Hospital (SNUBH). Methods: The DL-assisted system was trained using 1610 facial images paired with Hertel exophthalmometry measurements from SH and externally validated using 511 SNUBH images. The system employs a dual-stream ResNet-18 neural network, utilizing both red-green-blue images and depth maps generated by the ZoeDepth algorithm. Main Outcome Measures: Accuracy was assessed using mean absolute error (MAE), Pearson correlation coefficient, intraclass correlation coefficient (ICC), and area under the curve of the receiver operating characteristic curve. Results: The DL-assisted system achieved an MAE of 1.27 mm for the SH dataset and 1.24 mm for the SNUBH dataset. Pearson correlation coefficients were 0.82 and 0.77, respectively, with ICCs indicating strong reliability (0.80 for SH and 0.73 for SNUBH). The receiver operating characteristic curve analysis showed area under the curves of 0.91 for SH and 0.88 for SNUBH in detecting proptosis. The system detected significant proptosis changes (≥ 2 mm) with 74.6% accuracy. Conclusions: The DL-assisted system offers an accurate, accessible method for exophthalmometry in patients with TED using facial photographs. This tool presents a promising alternative to traditional exophthalmometry, potentially improving access to reliable proptosis measurement in both clinical and nonspecialist settings. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.