Grave's Orbitopathy Research Articles

Unveiling Modern Strategies for Diagnosing and Treating Grave Orbitopathy

Graves' Orbitopathy (GO), also known as thyroid eye disease or thyroid-associated orbitopathy is characterized by inflammation, ocular muscle hypertrophy, adipogenesis, and oedema (due to glycosaminoglycan accumulation). This condition leads to remodeling, tissue expansion, and/or fibrosis within the fibroadipose tissue or extraocular muscles of the orbit. GO manifests as an extrathyroidal aspect of autoimmune thyroid diseases in both Grave's disease (GD) and Hashimoto's thyroiditis.
 The pathophysiological foundation of GO entails the infiltration of B cells, T cells, and CD34+ fibroblasts in the orbit. B cells generate IGF (insulin-like growth factor), wherein IGF and TRab (Thyroid-Receptor antibodies) stimulate the IGF receptor complex and thyrotropin receptor (respectively) on the surface of CD34+ cells which triggers orbital tissue expansion, orbital protrusion, optic nerve compression, and eyeball displacement, resulting in exophthalmos.
 GO progress through an active phase (characterized by inflammation with visible manifestations), followed by a plateau phase (stabilization of GO manifestations), and a gradual resolution of distinctive residual signs and symptoms (inactive phase). This entire process spans between 18-24 months in untreated patients, where disease manifestations significantly depend on the phase during which the disease is identified.
 GO therapy is intended to shorten the active phase and supress its residual eye manifestations during the inactive phase. In general, GO therapy is categorized into general and disease severity-specific approaches.
 GO therapy often falls short of providing satisfactory results, prompting need of surgery to address lingering clinical manifestations. This review presents the latest insights into the pathogenesis and treatment of GO for better management and outcomes.

Normal diameter of the optic nerve using magnetic resonance imaging: A retrospective Nigerian study.

The variations in the diameter of the optic nerve (ON) are important clinically in the diagnosis of conditions associated with the ON such as raised intracranial pressure, meningioma, optic neuritis, and Grave's orbitopathy. This study determined the normal diameters of the ON in adult Nigerians seen in a Hospital in Delta State. Axial T1-weighted brain magnetic resonance imaging images of 150 patients (75 males and 75 females) aged ≥20 years were retrieved from the hospital's radiological database and retrospectively used to evaluate the diameter of the ON on axial and coronal sections. The data were analyzed and summarized using descriptive statistics. The mean diameters were compared based on gender, side, and age groups and correlated with age using inferential statistics. The significance level was considered at 5%. The diameter of the ON measured 0.45 ± 0.07 cm on the coronal section, besides 0.50 ± 0.07 cm, and 0.46 ± 0.06 cm at 0.3 cm and 0.8 cm from the posterior pole of the globe, respectively, on the axial slices. The diameters were significantly larger in males than in females (P < 0.05) and were symmetrical. However, they lacked significant association with age (P > 0.05). The three diameters measured had a significant positive correlation with each other (P < 0.05). The study provides a normal range of ON diameter in the study center to aid in the diagnosis of raised intracranial pressure and pathologies involving the nerve and its sheath.

Gender Differences in Quality-of-Life Outcome in Patients Undergoing Endoscopic Endonasal Skull Base Surgery.

Background Prior studies showed that female patients with chronic rhinosinusitis (CRS) suffer a worse disease-specific quality of life (QoL). Goal The aim of this study is to investigate gender differences in sinonasal QoL outcomes in patients requiring endoscopic endonasal skull base surgeries (EESBS). Methods Cross-sectional analysis of patients presenting to our clinic from August 2020 to December 2022 with skull base tumors, spontaneous cerebrospinal fluid (CSF) rhinorrhea, or Grave's orbitopathy (for orbital decompression) was performed. Baseline and postsurgical QoL were measured using the 22-item Sinonasal Outcome Test (SNOT-22). Patients' demographics and comorbidities were reviewed. Patients with concomitant CRS were excluded. Results Eighty-six patients were included (54 with skull base tumors, 17 Grave's orbitopathy, and 15 spontaneous CSF rhinorrhea). The mean age of the patients was 52 years (range: 12.4-81.5 years), and 51.6% of the patients were females. There was no age difference between female and male patients. Smoking history, asthma, and allergic rhinitis were also similar between the two groups. Female patients had a significantly higher incidence of depression (58.3 vs. 32.4%, p = 0.018) and migraine (50.0 vs. 21.6%, p = 0.007). Female patients had a significantly worse overall SNOT-22 scores at baseline (33.6 vs. 18.2, p = 0.001), at the 3-month follow-up (29.7 vs. 15.5, p = 0.002), and at the 6-month follow-up (33.5 vs. 14.9, p = 0.005). This worse QoL was seen mainly in the ear/facial, sleep, and psychological domains. Linear regression of the SNOT-22 scores and its subdomains adjusting for comorbidities showed that migraine was found to be the most significant determinant of gender differences in the QoL. Conclusion Female patients who undergo EESBS show higher overall SNOT-22 scores secondary to higher incidence of migraine.

Importance of HLA in Grave's orbitopathy development in Caucasian population

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Monitoring and Predicting Treatment Response of Extraocular Muscles in Grave's Orbitopathy by 99mTc-DTPA SPECT/CT.

Objective: To investigate single-photon emission computed tomography/computed tomography (SPECT/CT) for assessing inflammation in the extraocular muscles (EOMs) and predicting the therapeutic efficacy of periocular glucocorticoid therapy (PGT) for Grave's ophthalmopathy (GO).Materials and Methods: A total of 412 eyes from 206 patients with GO referred for 99mTc-DTPA orbital SPECT/CT were enrolled. Fourteen age- and gender-matched healthy controls (28 eyes) were included. The thickness and uptake ratio (UR) of four EOMs were derived from SPECT/CT. Eighty-six eyes from patients with GO patients received PGT. Changes in SPECT/CT parameters were evaluated between the pre- and post-treatment.Results: 195 eyes and 217 eyes were classified as active and inactive stages by clinical activity score (CAS). Values of the thickness and UR of each EOM, Tmax, and Umax were all significantly higher in the active GO than in the inactive GO and controls (p < 0.01). Among the 86 eyes (48 GO patients) included in the efficacy analysis, 56 eyes and 30 eyes were classified as responders and non-responders. Values of thicknesses and UR of each EOM, the maximum thickness (Tmax), and the maximum UR (Umax) all dropped following PGT in the responders (p < 0.01). Logistic regression analysis identified the Umax as an independent predictor for the responders (p < 0.01). Moreover, the Umax demonstrated incremental predictive value over clinical characters and CAS, as evidenced by the improved area under the curve (0.85 vs. 0.78) and global chi-square (34.12 vs. 18.1).Conclusion: 99mTc-DTPA SPECT/CT has the potential to assess inflammatory activity by detecting the involvement of EOMs in GO. Pre-treatment UR provides independent and incremental values for the prediction of PGT treatment response.

Grave's orbitopathy - Metastatic breast cancer presenting as orbitopathy, not previously recorded in the endocrine literature

Grave's orbitopathy - Metastatic breast cancer presenting as orbitopathy, not previously recorded in the endocrine literature

Treatment of moderate to severe orbitopathy: Current modalities and perspectives

Graves’ orbitopathy (GO) is the primary cause of exophthalmos in adults. It appears in 30 to 50% of patients with Graves’ disease. About 5% are moderate-to-severe cases that might be see-threatening or lead to long term disabling sequelae. Recommendations have been established in 2016 by the European thyroid association (ETA) and the European group on Grave's orbitopathy (EUGOGO), suggesting a wide use of corticosteroids in moderate to severe forms. However, disappointing results have been reported in 20 to 30% of cases. Improved understanding of pathophysiological mechanisms has allowed the use of non-specific immunomodulatory agents, currently under evaluation, and which place in the therapeutic strategy remains to be determined. Very recently, new promising therapeutic advances have emerged with the identification of new therapeutic targets, such as the TSH receptor and IGF-1 receptor complex.

Orbital wall decompression in the management of Graves' orbitopathy: a systematic review with meta-analysis.

To systematically review outcomes of orbital bony wall decompression for Grave's orbitopathy according to the surgical approach. A systematic search for studies published in "Ovid MEDLINE", "Web of Science" and "Embase" of patients with surgical treatment of Grave's orbitopathy was performed. The overall postoperative change in Hertel exophthalmometry was calculated by random-effect meta-analysis model with 95% confidence interval (CI). A total of 33 studies, including 1686 patients and 2946 procedures, were included. The weighted mean Hertel value overall reduction was - 4.56 mm (95% CI - 5.05 to - 4.07 mm). According to surgical techniques the reduction was - 4.36 mm (95% CI - 5.22 to - 3.50) for infero-medial technique, - 4.88 mm (- 5.68 to - 4.08) for medial-lateral technique, - 4.32 mm (- 4.80to - 3.84) for lateral technique, - 5.45 mm (- 6.16 to - 4.74) for three-wall technique and - 3.47 mm (- 5.81 to - 1.12) for medial technique. The overall rate of new-onset of primary gaze diplopia was reported in 23 studies. The included procedures were 653 and results were heterogeneous (heterogeneity: Q = 78.8 df = 22, I2 = 72.09%, p<0.01). The pooled proportion (95% CI) rate of new-onset of primary gaze diplopia was 12% (7-16). Our metanalysis highlights that orbital bony wall decompression represents an effective surgical procedure. The three wall approach was associated with the best results in terms of exophthalmos reduction. Data suggest that an exclusive lateral approach may help to avoid the new-onset of primary gaze diplopia during the postoperative period.

Prostaglandin F2α and EP2 agonists, and a ROCK inhibitor modulate the formation of 3D organoids of Grave's orbitopathy related human orbital fibroblasts

3D organoid cultures were used to elucidate the periocular effects of several anti-glaucoma drugs including a prostaglandin F2α analogue (bimatoprost acid; BIM-A), EP2 agonist (omidenepag; OMD) or a Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor (ripasudil; Rip) on Grave's orbitopathy (GO) related orbital fatty tissue. 3D organoids were prepared from GO related human orbital fibroblasts (GHOFs) obtained from patients with GO. The effects of either 100 nM BIM-A, 100 nM OMD or 10 μM Rip on the 3D GHOFs organoids were examined with respect to organoid size, physical properties by a micro-squeezer, and the mRNA expression of extracellular matrix (ECM) proteins including collagen (COL) 1, COL 4, COL 6, and fibronectin (FN), ECM regulatory genes including lysyl oxidase (LOX), Connective Tissue Growth Factor (CTGF) and inflammatory cytokines including interleukin-1β (IL1β) and interleukin-6 (IL6). The size of the 3D GHOFs organoids decreased substantially in the presence of BIM-A, but also increased substantially in the presence of the others (OMD or Rip). The physical stiffness of the 3D GHOFs organoids was significantly decreased by Rip. BIM-A caused significantly the down-regulation of three ECM genes, Col 1, Col 6 and Fn, and two ECM regulatory genes and the up-regulation of IL6. In the presence of OMD, two ECM genes, Col 1 and Fn, and LOX were significantly down-regulated but IL1β and IL6 were significantly up-regulated. In the case of Rip, Col 1, FN and CTGF were significant down-regulated. Our present findings indicate that anti-glaucoma drugs modulate the structures and physical properties 3D GHOFs organoids in different manners by modifying the gene expressions of ECM, ECM regulatory factors and inflammatory cytokines. The results indicate that the benefits and demerits of anti-glaucoma medications need to be scrutinized carefully, in cases of patients with GO.

Pterional Orbit Decompression in Grave Disease with Dysthyroid Optic Neuropathy

The choice of surgical technique in sight-threatening Grave's orbitopathy remains controversial. Available data are mostly derived from mixed cohorts with multiple surgical indications and techniques. The authors assessed predictors for visual outcome after standardized pterional orbital decompression for dysthyroid optic neuropathy (DON). Retrospective analysis of 62 pterional orbital decompressions performed on 40 patients with DON. Visual acuity improved by an average of 3.8 lines in eyes with preoperative visual impairment (95% confidence interval [CI]: 1.8 - 5.8 lines, p < 0.001) and remained stable in eyes without prior visual impairment (95% CI -1.3 - 1 lines, p = 0.81). Proptosis was reduced by an average of 3.1 mm (95% CI 1.8 - 4.3 mm, p < 0.001). Higher degrees of proptosis were predictive of worse visual outcomes (p = 0.017). New-onset diplopia developed in two patients, while previous diplopia resolved after surgery in six patients. This cohort is the largest series of pterional orbit decompressions, and the first to focus exclusively on dysthyroid neuropathy. Complication rates were low. Decompression surgery was highly effective at restoring and maintaining visual acuity in patients with dysthyroid optic neuropathy.

Use of the Multidisciplinary Specialised Case Conference at the Freiburg Orbital Centre

The treatment of tumors increasingly takes place in specialised interdisciplinary centres. Therapeutic decisions are usually made at case conferences. Ophthalmologists, oromaximillofacial surgeons, ENT physicians, neurosurgeons, as well as pediatricians, radiotherapists and radiologists are all involved in the treatment of orbital diseases. The aim of this article is to present the concept of a multidisciplinary case conference for orbital diseases and to analyse case numbers, indications, and the influence on the patient's therapy. We analysed an anonymized data set of patients who presented in the case conference of the University Hospital Freiburg from 2008 to 2018 with regard to clinical diagnosis, histological diagnoses, number of surgical interventions, and number of interdisciplinary therapy decisions. From 2008 to 2018, 545 patients were presented in a weekly conference. Of these, 453 were available for anonymous evaluation. The median age was 56 years (quartiles 41; 69). The most frequent indication was an orbital tumour of unclear malignancy (n = 52; 11%). Further indications included Grave's orbitopathy (n = 39; 9%), orbital pseudotumour (n = 36; 8%), cranial nerve palsy (n = 22; 5%), and orbital lymphoma (n = 22; 5%). The most frequent histological diagnoses were B-cell lymphoma (n = 10; 2%), venous malformation (cavernoma, n = 8; 2%), marginal zone lymphoma (n = 8; 2%), and squamous cell carcinoma (n = 6; 1%). An interdisciplinary therapeutic approach was defined for 174 patients. A high demand for the interdisciplinary case conference was demonstrated. The high rate of primary or secondary interdisciplinary decisions indicates the value of such a conference. Hence, the patient is spared multiple examinations in the individual specialist areas and quick and effective therapy decisions can be achieved.

Endoscopic orbital fat decompression for the management of proptosis in Grave's orbitopathy using a laryngeal skimmer blade.

Intraoperative handling and manipulation of orbital fat remains a challenge to orbital surgeons. We present a case series of endoscopic orbital fat decompression with medial orbital wall decompression for proptosis management in Grave's orbitopathy, describing a technique for fat excision using a laryngeal skimmer blade, reporting clinical and surgical outcomes, and complications. All patients who underwent endoscopic orbital fat decompression, with medial orbital wall decompression, for proptosis management in Grave's orbitopathy between 2011 and 2018, under the care of a single surgeon, were included in this retrospective interventional case series. Nineteen patients were included in this study. Using a laryngeal skimmer blade, orbital fat was excised endoscopically at the time of medial orbital wall decompression. The mean volume of orbital fat excised was 1.45 ± 0.63 ml and the mean reduction in proptosis was 4.5 ± 1.02 mm. There were no intraoperative complications. In this study, we describe our experience of using a laryngeal skimmer blade as a method of excising orbital fat for orbital decompression in patients with proptosis secondary to Grave's orbitopathy.

Grave's orbitopathy: clinical, paraclinical and therapeutic features

Grave's orbitopathy: clinical, paraclinical and therapeutic features

Grave's Orbitopathy -Setting up an Orbital MDT and the Role of the Maxillofacial Surgeon

Background: Grave's Orbitopathy (GO) presents major clinical and therapeutic challenges. Clinically significant GO develops in 50% of patients with Grave's, with 3-5% being severe. The management pathway is based on the guidelines from the European Group on Grave's Orbitopathy (EUGOGO). In our unit, patients undergo multidisciplinary management with input from Endocrinology, Ophthalmology, Orthoptics, Radiology, ENT and in symptomatic cases Oral and Maxillofacial surgery, when orbital decompression is indicated.

Treatment of corticosteroid resistant Grave's orbitopathy with tocilizumab

Treatment of corticosteroid resistant Grave's orbitopathy with tocilizumab

MRI evaluation of extraocular muscles in patients with Grave's orbitopathy

MRI evaluation of extraocular muscles in patients with Grave's orbitopathy

Clinicoradiologic Relationships in Case of Grave's Orbitopathy

Purpose. To evaluate the relationship of clinical and radiologic findings in improving of diagnostics and amendment of the outcome.Material and methods. 52 patients (104 orbial cavities) in the age of 18–61 years were examined. Patients with the clinical symptoms of Grave’s orbitopathy were examined using ophthalmological evaluation and MSCT-visualization of orbial cavities.Results. The most significant MSCT-parameters for the determination of severity are: prolapse of orbital fat (р = 0.0009), protrusion of eye bulb (р = 0.001), apical inspissations (р = 0.019), density of RBCmin (р = 0.004), size of external terminal membrane (р = 0.001), size of LRM (р = 0.002), size of MRM (р = 0.006), length of optic nerve (р = 0.0001), diameter of optic nerve in 1 cm from the macula (р = 0.01), width of lacrimal gland (р = 0.0002).Conclusions. There is significant relationship between clinical and radiologic (MSCT) features. It lets develop the protocolof examination for diagnostics and treatment of Grave’s orbitopathy.

Prevalence of Open-angle Glaucoma, Glaucoma Suspect, and Ocular Hypertension in Thyroid-related Immune Orbitopathy

To determine the prevalence of open-angle glaucoma (OAG), glaucoma suspects (GS), and ocular hypertension (OHT) in patients with thyroid-related immune orbitopathy (TRIO) and compare it with a control group. In this cross-sectional analytic study, 233 eyes of 117 patients with TRIO (case group) and 240 eyes of 120 normal age and sex-matched individuals (control group) underwent complete ocular examinations. Grave orbitopathy (GO) was diagnosed by clinical examinations with the help of an endocrinologist and para clinic tests. Controls were selected among apparently healthy individuals with no history of previous orbitopathy or thyroid diseases. Prevalence of OAG and OHT was 2.5% and 8.5% in the case group, respectively. In contrast, OAG was detected in only 2 eyes (0.8%) of the control group and there were no instances of GS or OHT in the control group. Although the prevalence of OAG and GS were higher in cases than controls, this difference was not statistically significant. However, OHT was more common in cases (P<0.01). Ten eyes in the case group (4.3%) developed compressive optic neuropathy (CON); high intraocular pressure was detected in 5 of them (2.1%). All cases of OAG and GS in the case group were classified as stage 3 or higher of No symptoms or signs, Only signs no symptoms, Soft tissue, Proptosis, Extraocular muscle, Cornea, Sight loss. Active GO was only more prevalent in patients with OHT (P<0.001). The prevalence of OHT was higher in cases with GO than age and sex-matched controls. Ophthalmologic examinations including intraocular pressure measurement (and if needed automated visual fields) should be regularly performed in patients with GO particularly in higher stages and those with active disease.

Glissement du muscle droit supérieur dans l’orbitopathie dysthyroïdienne

Superior rectus slippage after its surgical recession is characterized by short-term progressive overcorrection. Similarities with inferior rectus slippage are pronounced, especially a history of Grave's orbitopathy and the use of an adjustable suture. In the present clinical case, upper eyelid retraction and a history of upper eyelid elevator muscle surgery might be specific risk factors, due to the close anatomical links between the superior rectus and the upper eyelid elevator.

Die Behandlung der Oberlidretraktion bei endokriner Orbitopathie durch die Rücklagerung des Levatorkomplexes

The chronic stage in Grave's orbitopathy is characterised by fibrotic changes within the orbital soft tissues, especially the extraocular muscles. Retraction of the eyelids is a common clinical feature of this phenomenon. To solve this problem several techniques for lengthening the upper eyelid have been described with variable rates of success. In this report we describe our modified Harvey's technique for the correction of upper eyelid retraction which includes a complete recession of the Muller's muscle/levator complex from the tarsal plate without the interposition of a spacer. Finally only the skin and the superficial orbicularis muscle are sutured. We also report about our results with this procedure. 8 patients (1 male, 7 female) with lid retraction in Grave's ophthalmopathy were recorded who had undergone the modified lengthening technique by an external approach between 2001 and 2004. Four patients underwent a bilateral procedure and 1 patient showed a significant under-correction, necessitating reoperation. So a total of 13 procedures were included in this follow-up study. Beside the common ophthalmological examination, special interest was put in the difference of the two eyelid apertures in primary position pre- and postoperatively. Within a follow-up period of at least 3 months we recorded an averaged lengthening of the upper eyelid of 3.1 mm. The difference of the two eyelid apertures in primary position improved from 2.2 mm preoperatively to 1.0 mm postoperatively. Only 1 patient needed reoperation because of a significant under-correction. There were no late over-corrections observed. The modified Harvey's technique to lengthen the upper eyelid is a safe and effective method to reduce upper eyelid retraction in Grave's disease. An eventually required orbital decompression or extraocular muscle surgery has to be done before the lid surgery.