Cavernous Sinus Dural Arteriovenous Fistula in a Patient with Thyroid-Associated Ophthalmopathy: Complete Resolution after Medical Treatment

Thyroid-associated ophthalmopathy (TAO) is a well-known and frequent epiphenomenon of a hyperthyroid autoimmune disease that can present with proptosis, strabismus, and diplopia. Ophthalmopathy can occur in the absence of overt Graves’ disease, even in euthyroid patients. Cavernous sinus dural fistulas (CS-DAVF) are abnormal communications between the cavernous sinus (CS) and dural branches from internal carotid or external carotid arteries. They can often present with ocular symptoms that can mimic a thyroid-associated ophthalmopathy. CS-DAVF are usually successfully treated with an endovascular embolization that can be pursued both through a transvenous or transarterial approach. TAO and CS-DAVF can coexist especially when the ocular symptoms are unilateral. In those cases, an endovascular embolization is usually curative, but sometimes the procedure can fail. Our hypothesis is that some cases of CS-DAVF may be of secondary nature (i.e., caused by compression of the venous outlet by the hypertrophic ocular muscles); therefore, treating the ocular disease with medical therapy may solve the vascular problem as well. We present a case of a CS-DAVF in a patient with TAO successfully treated with sole medical therapy after the failure of a first-line endovascular treatment.

Therapeutic IGF-I receptor inhibition alters fibrocyte immune phenotype in thyroid-associated ophthalmopathy

Thyroid-associated ophthalmopathy (TAO) represents a disfiguring and potentially blinding autoimmune component of Graves’ disease. It appears to be driven, at least in part, by autoantibodies targeting the thyrotropin receptor (TSHR)/insulin-like growth factor I receptor (IGF-IR) complex. Actions mediated through either TSHR or IGF-IR are dependent on IGF-IR activity. CD34+ fibrocytes, monocyte lineage cells, reside uniquely in the TAO orbit, where they masquerade as CD34+ orbital fibroblasts. Fibrocytes present antigens to T cells through their display of the major histocompatibility complex class II (MHC II) while providing costimulation through B7 proteins (CD80, CD86, and programmed death-ligand 1 [PD-L1]). Here, we demonstrate that teprotumumab, an anti-IGF-IR inhibitor, attenuates constitutive expression and induction by the thyroid-stimulating hormone of MHC II and these B7 members in CD34+ fibrocytes. These actions are mediated through reduction of respective gene transcriptional activity. Other IGF-IR inhibitors (1H7 and linsitinib) and knocking down IGF-IR gene expression had similar effects. Interrogation of circulating fibrocytes collected from patients with TAO, prior to and following teprotumumab treatment in vivo during a phase 2 clinical trial, demonstrated reductions in cell-surface MHC II and B7 proteins similar to those found following IGF-IR inhibitor treatment in vitro. Teprotumumab therapy reduces levels of interferon-γ and IL-17A expression in circulating CD4+ T cells, effects that may be indirect and mediated through actions of the drug on fibrocytes. Teprotumumab was approved by the US Food and Drug Administration for TAO. Our current findings identify potential mechanisms through which teprotumumab might be eliciting its clinical response systemically in patients with TAO, potentially by restoring immune tolerance.

Altered Static and Dynamic Interhemispheric Resting-State Functional Connectivity in Patients With Thyroid-Associated Ophthalmopathy

Purpose: Thyroid-associated ophthalmopathy (TAO) is a debilitating and sight-threatening autoimmune disease that severely impairs patients’ quality of life. Besides the most common ophthalmic manifestations, the emotional and psychiatric disturbances are also usually observed in clinical settings. This study was to investigate the interhemispheric functional connectivity alterations in TAO patients using resting-state functional magnetic resonance imaging (rs-fMRI).Methods: Twenty-eight TAO patients and 22 healthy controls (HCs) underwent rs-fMRI scans. Static and dynamic voxel-mirrored homotopic connectivity (VMHC) values were calculated and compared between the two groups. A linear support vector machine (SVM) classifier was used to examine the performance of static and dynamic VMHC differences in distinguishing TAOs from HCs.Results: Compared with HCs, TAOs showed decreased static VMHC in lingual gyrus (LG)/calcarine (CAL), middle occipital gyrus, postcentral gyrus, superior parietal lobule, inferior parietal lobule, and precuneus. Meanwhile, TAOs demonstrated increased dynamic VMHC in orbitofrontal cortex (OFC). In TAOs, static VMHC in LG/CAL was positively correlated with visual acuity (r = 0.412, P = 0.036), whilst dynamic VMHC in OFC was positively correlated with Hamilton Anxiety Rating Scale (HARS) score (r = 0.397, P = 0.044) and Hamilton Depression Rating Scale (HDRS) score (r = 0.401, P = 0.042). The SVM model showed good performance in distinguishing TAOs from HCs (area under the curve, 0.971; average accuracy, 94%).Conclusion: TAO patients had altered static and dynamic VMHC in the occipital, parietal, and orbitofrontal areas, which could serve as neuroimaging prediction markers of TAO.

Analysis of Macular Blood Flow Alterations In Thyroid Associated Ophthalmopathy

Purpose: To evaluate the alterations in macular superficial retinal vessels density and relation with visual acuity in thyroid associated ophthalmopathy (TAO) patients with different severity levels.Method: This cross-sectional observational study included 70 TAO patients and 70 healthy controls. Only the data from the right eyes were analyzed. TAO patients were divided into 7 subgroups according to the NOSPECS score grading from 0 to 6 with 10 cases in each subgroup. Foveal avascular zone (FAZ), vascular density (VD) and perfusion density (PD) of macular 1mm diameter and 6mm diameter areas were measured by optical coherence tomography angiography (OCTA). Results: In TAO patients, significant increases were found in macular and foveal vascular densities (FVD) and perfusion densities (FPD) while significant decrease was found in FAZ area when comparing with control group (p<0.05). Spearman correlation analysis and multiple linear regression analysis showed that TAO severity grade was negatively correlated with FVD (β=-1.150, p=0.032), FPD (β=-0.024, p=0.042), MVD (β=-0.583, p=0.020) and MPD (β=-0.011, p=0.010). Clinical activity score (CAS) score showed positive correlation with FVD(β=0.794, p=0.035) and FPD(β=0.017, p=0.041). FVD(β=-0.009, p=0.033), MVD(β=-0.034, p<0.001), FPD(β=-0.416, p=0.039) and MPD(β=-2.428, p<0.001) all showed negative correlation with best corrected visual acuity (BCVA).Conclusion: Superficial macular blood flow in TAO patients showed an overall increase comparing with healthy controls and a decrease as TAO disease severity worsen. Superficial macular blood flow density was negatively correlated with BCVA.

Correlation Between Extent of Lacrimal Gland Prolapse and Clinical Features of Thyroid- Associated Ophthalmopathy: A Retrospective Observational Study

Background: Studies on the factors related to lacrimal gland prolapse (LGP) in patients with thyroid-associated ophthalmopathy (TAO) are limited. This study aimed to assess the ability of abnormal location of the lacrimal gland on magnetic resonance images to predict disease activity in patients with TAO.Methods: Thirty-six patients (72 orbits) with inactive TAO (43 orbits, Clinical Activity Score [CAS] <3) or active TAO (29 orbits, CAS ≥3) were investigated retrospectively. All patients underwent ophthalmic evaluation and orbital magnetic resonance imaging. The severity of LGP and proptosis and the extraocular muscle (EOM) volume were measured. LGP and related factors were assessed by correlational and linear regression analyses. The value of LGP for discriminating the activity of TAO was evaluated by receiver-operating characteristic curve analysis.Results: The mean LGP was significantly higher in the active TAO group than in the inactive TAO group (P<0.001). There were significant positive correlations between LGP severity and the CAS (r=0.51, P<0.001), proptosis (r=0.72, P<0.001), and EOM volume (superior rectus [r=0.49, P<0.001], inferior rectus [r=0.47, P<0.001], lateral rectus [r=0.59, P<0.001], medial rectus [r=0.62, P<0.001], superior oblique [r=0.48, P<0.001], and all EOMs [r=0.59, P<0.001]). Receiver-operating characteristic curve analysis revealed an LGP of 13.65 mm (area under the curve, 0.824; sensitivity, 79.3%; specificity, 81.4%) to be the cut-off value that differentiated active and inactive TAO.Conclusions: LGP measurements obtained from orbital magnetic resonance images were positively correlated with CAS, proptosis and EOM volum. The extent of LGP appears to be a good indicator of disease activity in patients with TAO.

Altered peripapillary vessel density and nerve fiber layer thickness in thyroid-associated ophthalmopathy using optical coherence tomography angiography

Objective To measure the peripapillary vessel density (VD) and retinal nerve fiber layer thickness (RNFLT) in thyroid-associated ophthalmopathy (TAO) and dysthyroid optic neuropathy (DON) patients using optical coherence tomography angiography (OCTA), and determine their prognostic relevance. Methods Forty-three TAO patients with or without DON (82 eyes in total) and 26 healthy subjects (52 eyes) were enrolled. All participants underwent ophthalmology and endocrinology tests. The peripapillary VD in retinal peripapillary capillary layer and RNFLT were analyzed using OCTA images. Multiple linear regression analysis was used to assess the relationship between peripapillary VD /RNFLT and the relevant factors. Results The total peripapillary VD and RNFLT were significantly lower in the DON patients compared to the other groups (P < 0.001, 95% confidence intervals), and each quadrant of VD and RNFLT showed similar results except temporal RNFLT. No significant difference was seen between the RNFLT and VD of active non-DON (ANDON), inactive non-DON (NDON) patients and normal control (NC) group. Multivariable linear regression model showed that high IOP is an independent risk factor for lower peripapillary VD and RNFLT (β = −0.465, P < 0.001 and β = −0.343, P = 0.002 respectively). Conclusion OCTA parameters are suitable indicators for diagnosing DON. TAO patients with high IOP should be considered at high risk of retinal vessel and nerve fiber layer deterioration. In addition, patients with TAO should be advised to quit smoking since it could affect peripapillary VD and RNFLT.

Epigenetics effect on pathogenesis of thyroid-associated ophthalmopathy

Thyroid-associated ophthalmopathy (TAO) is an autoimmune disease. Recent studies have found the aberrant epigenetics in TAO, including DNA methylation, non-coding RNAs, and histone modification. Many genes have an aberrant level of methylation in TAO. For example, higher levels are found in CD14, MBP, ANGLE1, LYAR and lower levels in DRD4 and BOLL. Non-coding RNAs are involved in the immune response (miR-146a, miR-155, miR-96, miR-183), fibrosis regulation (miR-146a, miR-21, miR-29), adipogenesis (miR-27) and are thought to play roles in TAO. MicroRNA is also related to the clinical activity score (miR-Let7d-5p) and may be a predictor of glucocorticoid therapy (miR-224-5p). The quantities of H4 in TAO are increased compared with euthyroid control subjects, and the role of histone modifications in Graves’ disease may lead to better understanding of its role in TAO. More studies are needed to explain the role of epigenetics in TAO and provide potential therapeutic strategies.