Purpose: Severity of Graves’ orbitopathy (GO) shows wide individual differences. For optimal treatment, it is important to be able to predict the natural course of the disease as accurate as possible to counteract with anti-inflammatory and surgical treatment. Therefore, we aimed to further elucidate the impact of sex, age and smoking on GO.Methods: We collected the clinical and demographic data of all patients of our tertiary referral center from January 2008 till December 2018 and analyzed it with descriptive statistics. Only patients with a complete data set were included in the further analysis. Odds ratio’s for moderate-to-severe and sight-threatening GO in relation to age, sex and smoking were calculated by means of multivariate logistic regression models.Results: We evaluated the data of 4260 patient with GO and complete data sets. Most of these were women (83%). There were no significant differences between male and female patients regarding smoking habits and thyroid treatment. Men were significantly older at initial manifestation of TED (51.8 vs. 49.9y, p<0.01) and showed significant more often severe stages (61% vs. 53%, p<0.0001). Therefore, they needed significantly more intense treatment with steroids, irradiation, orbital decompression and muscle surgery. In multivariate logistic regression analyses age (OR 0.97, 95% CI:0.97-0.98, p<0.0001), male sex (OR 1.64, 95% CI:1.38-1.9, p<0.0001), smoking (OR 1.19, 95% CI:1.04-1.36, p=0.01), Grave’s disease (OR 1.55, 95% CI:1.26-1.90, p<0.0001) and history of radioiodine treatment (RAI) (OR 2.44, 95% CI:2.10-2.86, p<0.0001) showed an significant association with severe stages of GO.Discussion: Our retrospective analysis showed once more that women are more often afflicted by GO. In contrast, men seem to be more severely afflicted and in need of anti-inflammatory and surgical treatments. This might be due to a different approach to the health system and resilience to GO specific symptoms, as well as previously described worse thyroid control. Estrogen mediated effects might also play a role as in other autoimmune diseases and should be subject of further trials. Besides the biological sex, smoking could again be confirmed as serious risk factor for severe GO. Of note, RAI was associated with more severe stages of GO, which should be subject to further investigation.

The inflammatory eye disease Graves’ orbitopathy (GO) is the main complication of autoimmune Graves’ disease. In previous studies we have shown that hypoxia plays an important role for progression of GO. Hypoxia can maintain inflammation by attracting inflammatory cells such as macrophages (MQ). Herein, we investigated the interaction of MQ and orbital fibroblasts (OF) in context of inflammation and hypoxia. We detected elevated levels of the hypoxia marker HIF-1α, the MQ marker CD68, and inflammatory cytokines TNFα, CCL2, CCL5, and CCL20 in GO biopsies. Hypoxia stimulated GO tissues to release TNFα, CCL2, and CCL20 as measured by multiplex enzyme-linked immunosorbent assay (ELISA). Further, TNFα and hypoxia stimulated the expression of HIF-1α, CCL2, CCL5, and CCL20 in OF derived from GO tissues. Immunofluorescence confirmed that TNFα-positive MQ were present in the GO tissues. Thus, interaction of M1-MQ with OF under hypoxia also induced HIF-1α, CCL2, and CCL20 in OF. Inflammatory inhibitors etanercept or dexamethasone prevented the induction of HIF-1α and release of CCL2 and CCL20. Moreover, co-culture of M1-MQ/OF under hypoxia enhanced adipogenic differentiation and adiponectin secretion. Dexamethasone and HIF-1α inhibitor PX-478 reduced this effect. Our findings indicate that GO fat tissues are characterized by an inflammatory and hypoxic milieu where TNFα-positive MQ are present. Hypoxia and interaction of M1-MQ with OF led to enhanced secretion of chemokines, elevated hypoxic signaling, and adipogenesis. In consequence, M1-MQ/OF interaction results in constant inflammation and tissue remodeling. A combination of anti-inflammatory treatment and HIF-1α reduction could be an effective treatment option.

Orbital decompression surgery is performed in patients with Graves’ orbitopathy to treat dysthyroid optical neuropathy (DON) and reduce disfiguring proptosis. The intended proptosis reduction can deviate from the postoperative result and changes of motility with consecutive diplopia can occur. We performed a retrospective study to identify anatomical factors in computed tomography (CT), which influence the surgical effect and postoperative ocular motility and diplopia. Pre- and postoperative CT-scans of 125 eyes of 68 patients, who mainly underwent a balanced orbital decompression for disfiguring proptosis (≥18mm Hertel Index), have been analyzed. Proptosis, ductions, misalignment and diplopia were assessed before and after surgery. Medial and lateral orbital wall length, conus angle, depth of ethmoidal sinus, orbital surface, length of medial and orbital defect, depth of tissue prolapse and horizontal muscle diameters were analyzed in CT scans before and after surgery. With linear regression and multivariate analyses these parameters have been correlated with postoperative proptosis, abduction deficit, deviation and binocular single vision (BSV). Proptosis could be reduced by 5.3±2mm. Patients with 5mm reduction (13% vs. 56%, p = 0.02). Multiple linear regression showed a significant correlation between tissue prolapse and depth of the ethmoidal sinus as well as age (p<0.001, r = 0.71). Proptosis reduction could not be predicted by tissue prolapse, defect length or depth of ethmoidal sinus. The abduction deficit correlated significantly with tissue prolapse and orbital surface area (p<0.001, r = 0.37) but not with the horizontal muscle diameter. We were able to show that orbital morphology influences the outcome of balanced orbital decompression surgery in terms of proptosis reduction and motility. However, the rather low coefficients of correlation show that the surgical outcome cannot be predicted with simple CT measurements, although risk factors for postoperative abduction deficit could be found. Therefore, preoperative planning should consider especially the orbital surface area and depth of ethmoidal sinus. Patients should be informed about the higher risk of diplopia with higher proptosis reduction.

Purpose: Currently, therapeutic management of patients with Graves’ orbitopathy (GO) relies on clinical assessments and MRI. However, monitoring of inflammation remains difficult since external inflammatory signs do not necessarily represent the orbital disease activity. Therefore, we aimed to evaluate the diagnostic value of ¹⁸F-FDG-PET/MRI to assess the inflammation of GO patients. Methods: Enrolled patients with new onset of GO underwent ophthalmological examinations to evaluate the activity (CAS) and severity of GO (NOSPECS), as well as an ¹⁸F-FDG-PET/MRI (Siemens Biograph mMR) with dual time point imaging (immediately post-injection and 60 min p.i.). A subset of PET parameters including maximum standardized uptake value (SUVmax), metabolic target volume (MTV), and total lesion glycolysis (TLG) were obtained separately per eye and per extraocular eye muscle (EOM). EOM thickness was measured on the co-registered MRI. Results: Of 14 enrolled patients, three showed mild, seven moderate-to-severe, and four sight-threatening GO. Patients with severe GO showed statistically significant higher TLG than patients with mild GO (p = 0.02) and higher MTV than patients with mild (p = 0.03) and moderate (p = 0.04) GO. Correlation between NOSPECS on one hand and MTV and TLG on the other was significant (R² = 0.49–0.61). Conclusion: TLG and MTV derived from FDG-PET appear to be good discriminators for severe vs. mild-to-moderate GO and show a significant correlation with NOSPECS. As expected, PET parameters of individual eye muscles were not correlated with associated eye motility, since fibrosis, and not inflammation, is mainly responsible for restricted motility. In conclusion, ¹⁸F-FDG-PET/MRI can be used for assessment of GO inflammation.

Background: Although most patients with visual impairment due to corneal diseases can be treated successfully with surgery, some require visual rehabilitation to restore reading ability. To evaluate the best LVAs especially in terms of reading speed and characterize this specific patient group we performed a prospective, randomized cross-over trial. Methods: All 34 patients underwent a detailed examination (slit-lamp, funduscopy, SD-OCT, ETDRS) as screening. Only patients with corneal diseases without other ocular diseases were included. Reading-speed was assessed with International-Reading-Speed-Texts (IReST) consecutively with five different LVAs (low vision aids) during one day in a randomized cross-over design. Corneal haze was quantified with corneal densitometry (Pentacam). Results: Patients were either visually impaired (n = 28), severely impaired (n = 4) or legally blind (n = 2). Patients read significantly faster with LVAs (p < 0.0001). Fastest reading speed could be achieved with video magnifier (CCTV). Optical magnifier and portable-electronic magnifier enabled significantly lower reading speeds (p < 0.01). In a subgroup of patients (VA < 3/60,n = 6) black background enabled patients to read significantly faster compared to white background (p = 0.03). Conclusion: Patients with low magnification requirement can be treated successfully with optical LVAs and portable-electronic magnifiers. More severely afflicted patients need a CCTV. Black background enables fastest reading-speeds, probably due to less blinding. Visual impairment can be estimated with corneal densitometry. Our trial confirms the capability of LVAs to successfully restore the reading ability in patients with corneal diseases, which is a crucial part of visual rehabilitation. Trial registration: This trial was registered at the German Clinical Trials Register as DRKS00010887 at 09.08.2016.

Purpose: Graves’ orbitopathy (GO) is an autoimmune disorder leading to inflammation, adipogenesis, and fibrosis. The severity of GO can vary widely among individuals, making it challenging to predict the natural course of the disease accurately, which is important for tailoring the treatment approach to the individual patient. The aim of this study was to compare the clinical characteristics, course, treatment, and prognosis of GO patients under 50 years with older patients. Methods: We reviewed the medical records of a random sample of 1000 patients in our GO database Essen (GODE) comprising 4260 patients at our tertiary referral center. Patients were divided into two groups: Group 1 (≤50 years) and Group 2 (>50 years). Only patients with a complete data set were included in the further statistical analysis. Results: The results showed that younger patients (n = 484) presented significantly more often with mild GO (53% vs. 33%, p < 0.0001), while older patients (n = 448) were more likely to experience moderate-to-severe disease (44% vs. 64%, p < 0.0001). Older patients showed more severe strabismus, motility, and clinical activity scores (5.9 vs. 2.3 PD/310° vs. 330° both p < 0.0001, CAS: 2.1 vs. 1.7, p = 0.001). Proptosis and occurrence of dysthyroid optic neuropathy (DON) showed no significant difference between groups (both 3%). Multiple logistic regression revealed that the need for a second step of eye muscle surgery was most strongly associated with prior decompression (OR = 0.12, 95% CI: 0.1–0.2, p < 0.0001) followed by orbital irradiation and age. The model showed good fitness regarding the area under the curve (AUC = 0.83). Discussion: In conclusion, younger GO patients present with milder clinical features such as a lower rate of restrictive motility disorders and less pronounced inflammatory signs. Therefore, older patients tend to need more steroids, irradiation, and lid and eye muscle surgery. Still, the risk of DON and the necessity of secondary eye muscle surgery are not or only slightly associated with age, respectively.