miR-199a Downregulation as a Driver of the NOX4/HIF-1α/VEGF-A Pathway in Thyroid and Orbital Adipose Tissues from Graves' Patients.

Graves' disease (GD) is an autoimmune thyroiditis often associated with Graves' orbitopathy (GO). GD thyroid and GO orbital fat share high oxidative stress (OS) and hypervascularization. We investigated the metabolic pathways leading to OS and angiogenesis, aiming to further decipher the link between local and systemic GD manifestations. Plasma and thyroid samples were obtained from patients operated on for multinodular goiters (controls) or GD. Orbital fats were from GO or control patients. The NADPH-oxidase-4 (NOX4)/HIF-1α/VEGF-A signaling pathway was investigated by Western blotting and immunostaining. miR-199a family expression was evaluated following quantitative real-time PCR and/or in situ hybridization. In GD thyroids and GO orbital fats, NOX4 was upregulated and correlated with HIF-1α stabilization and VEGF-A overexpression. The biotin assay identified NOX4, HIF-1α and VEGF-A as direct targets of miR-199a-5p in cultured thyrocytes. Interestingly, GD thyroids, GD plasmas and GO orbital fats showed a downregulation of miR-199a-3p/-5p. Our results also highlighted an activation of STAT-3 signaling in GD thyroids and GO orbital fats, a transcription factor known to negatively regulate miR-199a expression. We identified NOX4/HIF-1α/VEGF-A as critical actors in GD and GO. STAT-3-dependent regulation of miR-199a is proposed as a common driver leading to these events in GD thyroids and GO orbital fats.

Selenium and the course of mild Graves' orbitopathy.

BACKGROUND: Oxygen free radicals and cytokines play a pathogenic role in Graves' orbitopathy. METHODS: We carried out a randomized, double-blind, placebo-controlled trial to determine the effect of selenium (an antioxidant agent) or pentoxifylline (an antiinflammatory agent) in 159 patients with mild Graves' orbitopathy. The patients were given selenium (100 µg twice daily), pentoxifylline (600 mg twice daily), or placebo (twice daily) orally for 6 months and were then followed for 6 months after treatment was withdrawn. Primary outcomes at 6 months were evaluated by means of an overall ophthalmic assessment, conducted by an ophthalmologist who was unaware of the treatment assignments, and a Graves' orbitopathy-specific quality-of-life questionnaire, completed by the patient. Secondary outcomes were evaluated with the use of a Clinical Activity Score and a diplopia score. RESULTS: At the 6-month evaluation, treatment with selenium, but not with pentoxifylline, was associated with an improved quality of life (P<0.001) and less eye involvement (P=0.01) and slowed the progression of Graves' orbitopathy (P=0.01), as compared with placebo. The Clinical Activity Score decreased in all groups, but the change was significantly greater in the selenium-treated patients. Exploratory evaluations at 12 months confirmed the results seen at 6 months. Two patients assigned to placebo and one assigned to pentoxifylline required immunosuppressive therapy for deterioration in their condition. No adverse events were evident with selenium, whereas pentoxifylline was associated with frequent gastrointestinal problems. CONCLUSIONS: Selenium administration significantly improved quality of life, reduced ocular involvement, and slowed progression of the disease in patients with mild Graves' orbitopathy. (Funded by the University of Pisa and the Italian Ministry for Education, University and Research; EUGOGO Netherlands Trial Register number, NTR524.).

Presentation of Graves' orbitopathy within European Group On Graves' Orbitopathy (EUGOGO) centres from 2012 to 2019 (PREGO III).

BACKGROUND: Graves' orbitopathy (GO) is subject to epidemiological and care-related changes. Aim of the survey was to identify trends in presentation of GO to the European Group On Graves' Orbitopathy (EUGOGO) tertiary referral centres and initial management over time. METHODS: Prospective observational multicentre study. All new referrals with diagnosis of GO within September-December 2019 were included. Clinical and demographic characteristics, referral timelines and initial therapeutic decisions were recorded. Data were compared with a similar EUGOGO survey performed in 2012. RESULTS: Besides age (mean age: 50.5±13 years vs 47.7±14 years; p 0.007), demographic characteristics of 432 patients studied in 2019 were similar to those in 2012. In 2019, there was a decrease of severe cases (9.8% vs 14.9; p<0.001), but no significant change in proportion of active cases (41.3% vs 36.6%; p 0.217). After first diagnosis of GO, median referral time to an EUGOGO tertiary centre was shorter (2 (0-350) vs 6 (0-552) months; p<0.001) in 2019. At the time of first visit, more patients were already on antithyroid medications (80.2% vs 45.0%; p<0.001) or selenium (22.3% vs 3.0%; p<0.001). In 2019, the initial management plans for GO were similar to 2012, except for lid surgery (2.4% vs 13.9%; p<0.001) and prescription of selenium (28.5% vs 21.0%; p 0.027). CONCLUSION: GO patients are referred to tertiary EUGOGO centres in a less severe stage of the disease than before. We speculate that this might be linked to a broader awareness of the disease and faster and adequate delivered treatment.

Orbital metastasis from thyroid cancer: a case report and review of the literature.

BACKGROUND: Differentiated thyroid cancer (DTC) is generally associated with an excellent prognosis. However up to 20% of DTC patients have disease events during subsequent follow-up; rarely patients present an aggressive disease with distant metastases (DM), mainly in the lung and bone. Metastases at unusual sites may also occur, generally in patients with disseminated disease. Orbital localization is rare and only few cases have been described so far. CASE DESCRIPTION: A 36 years-old man, treated with chemo and radiotherapy during childhood for non-Hodgkin lymphoma, was referred for suspicious lymph node (LN) and multiple lung metastases. Total thyroidectomy and latero-cervical (LC) lymphadenectomy were performed: papillary thyroid cancer (PTC), 25 mm, 11/17 LN metastases; pT2N1bM1. Post-treatment total body scan with I-131 showed LN and lung uptake. Eighteen months from diagnosis he presented progressive diplopia, proptosis and right exophthalmos due to an 18 mm orbital metastasis. Hence, due to I-131 refractoriness for structural disease progression despite I-131 therapy, he started therapy with Lenvatinib for 6 months, with initial partial response followed by disease progression, and then with Cabozantinib, which he stopped after 6 months for adverse events and disease progression after therapy reduction. Currently, the patient is receiving Lenvatinib, rechallenge therapy, with disease stabilization and biochemical response. Molecular analysis, performed on both primary and relapsed tumor didn't show any significant pathogenic alteration. CONCLUSIONS: This case of DTC with an unusual metastasis in the orbit, may suggest that patient's exposure to chemo- and radiotherapy during pediatric age might have played a role in the subsequent development of this unusually aggressive tumor, reinforcing the recommendation of long-term and intensive follow-up of these patients.

Downregulation of Caveolin-1 and Upregulation of Deiodinase 3, Associated with Hypoxia-Inducible Factor-1α Increase, Are Involved in the Oxidative Stress of Graves' Orbital Adipocytes.

Background: Even though the clinical features of Graves' orbitopathy (GO) are well known, its exact pathogenesis remains controversial. The imbalance of redox homeostasis in the connective tissue could play a crucial role leading to an inflammatory state and edema of soft orbital tissues, thus contributing to orbital hypoxia and increase in hypoxia-inducible factor (HIF)-1α. This oxidative stress appears to target the orbital cells such as fibroblasts and also adipocytes. This study aims to explore which pathways can lead to the aforementioned oxidative stress in GO adipose cells and therefore offers new plausible therapeutic targets. Methods: Orbital fat samples were obtained from patients with GO (Western blot [WB]: n = 8, immunohistochemistry [IHC]: n = 8) and from control patients (WB: n = 5, IHC: n = 3-5). They were processed for WB analysis and IHC of the antioxidants (catalase, superoxide dismutase 1) and for HIF-1α. The expression of caveolin-1 (Cav-1) and deiodinase 3 (DIO3), known to be regulated by HIF-1α, was also analyzed by WB and IHC, as well as the targets of Cav-1: glucose transporter type 4 (Glut-4), NADPH oxidase (NOX)-2, and endothelial nitric oxide synthase (eNOS). Triiodothyronine (T3) expression was also analyzed by IHC. Results: In GO adipocytes, the expression of catalase was reduced, whereas that of HIF-1α was strongly increased. A decreased local T3 supply was associated with DIO3 upregulation. The low expression of Cav-1 in GO adipocytes was associated not only with low expression of Glut-4 but also with an increased expression of NOX-2 and active eNOS phosphorylated on serine 1177. Conclusions: Cav-1 and DIO3, both sensitive to hypoxia and to the increase of HIF-1α, play a pivotal role in the oxidative stress in GO adipocytes. DIO3 regulates the cellular supply of T3, which is essential for the cell homeostasis. Cav-1 determines the cellular glucose supply through Glut-4 and regulates the activity of NOX-2 generating superoxide anions and that of eNOS generating nitric oxide (NO).

Traumatic neuroma of the infraorbital nerve subsequent to inferomedial orbital decompression for Graves' orbitopathy.

PURPOSE: To present and discuss the occurrence of a traumatic neuroma subsequent to inferomedial orbital decompression surgery in Graves' orbitopathy. METHODS: Case report. RESULTS: Approximately 1 month after surgery, a patient who underwent bilateral rehabilitative inferomedial orbital decompression developed a mass with clinical and radiologic characteristics compatible with a traumatic neuroma of the left infraorbital nerve. The lesion, which was thought to be the result of unnoticed nerve trauma at the time of surgical dissection of the infraorbital canal, remained stable in shape and other imaging characteristics during the 39-month follow-up period. Symptoms of trigeminal neuralgia could be only partially controlled with medical therapy (oral pregabalin 75 mg 3 times daily). CONCLUSIONS: The second branch of the trigeminal nerve may be damaged in the course of orbital floor removal decompression for Graves' orbitopathy. This may potentially induce the formation of traumatic or amputation neuromas. Such lesions should be included in the potential complications of decompressions when counseling patients about to undergo this type of surgery, as they are difficult to treat and may cause persistent and disabling pain.

Small versus coronal incision orbital decompression in Graves' orbitopathy.

Ideally the planning of decompression surgery should be adequate to the severity of the orbitopathy, its possible "lipogenic" or "myopathic" variants, the patient's specific orbital osteology and possible previous surgeries. Due to surgeon's experience and local traditions, however, a standardized rather than a tailored approach is often offered to the patient. An inferior fornix incision can be used for infero medial bony decompression and/or for removing fat from the medial and lateral inferior orbital quadrants. Through the same route a lateral osteotomy can also be performed although an upper skin crease incision offers a wider access to the lateral orbital wall. As an alternative the swinging eyelid technique, offering an adequate access to the bony orbit and to the orbital fat compartments is a versatile technique that can virtually be used as a standard approach for the greatest majority of patients needing decompression surgery. Orbital decompression by coronal incision is an invasive technique and for this not to be used as a standard approach to orbital decompression. Nevertheless, it is not to be abandoned as it can be an additional tool in surgeons' hands when dealing with patients who can better benefit out of a particular, tailored rather than a standardised approach. Many are the circumstances in which this may happen. Major complications associated with the coronal approach have been mainly described in small series, where only a few patients per year were operated. In this respect it is therefore unavoidable to emphasize that each technique has its own learning curve and it may be difficult to differentiate the effects of each technique from the experience of the surgeon.

Detection of Antibiotic-Resistance by MALDI-TOF Mass Spectrometry: An Expanding Area.

Several MALDI-TOF MS-based methods have been proposed for rapid detection of antimicrobial resistance. The most widely studied methods include assessment of ß-lactamase activity by visualizing the hydrolysis of the ß-lactam ring, detection of biomarkers responsible for or correlated with drug-resistance/non-susceptibility, and the comparison of proteomic profiles of bacteria incubated with or without antimicrobial drugs. Antimicrobial-resistance to a number of antibiotics belonging to different classes has been successfully tested by MALDI-TOF MS in a variety of clinically relevant bacterial species including members of Enterobacteriaceae family, non-fermenting Gram-negative bacteria, Gram-positive cocci, anaerobic bacteria and mycobacteria, opening this field to further clinically important developments. Early detection of drug-resistance by MALDI-TOF MS can be particularly helpful for clinicians to streamline the antibiotic therapy for a better outcome of patients with systemic infection, in all cases where a prompt and effective antibiotic treatment is essential to preserve organ function and/or patient survival.

Somatostatin receptor scintigraphy for optic nerve sheath meningiomas.

OBJECTIVE: To investigate the value of somatostatin receptor scintigraphy (SSRS) in the diagnosis of optic nerve sheath meningiomas (ONSMs). DESIGN: Prospective, comparative case series. PARTICIPANTS: SSRS was used to investigate 68 orbits in 61 patients diagnosed with an orbital tumor. METHODS: Patients were injected intravenously with 200 MBq of indium-111 ((111)In)-octreotide. SSRS with single photon emission computed tomography (SPECT) was performed 24 hours after injection. MAIN OUTCOME MEASURES: The (111)In-octreotide uptake in orbital lesions was determined by semiquantitative uptake-ratio analysis (lesion/brain) on attenuation-corrected transverse SPECT slices. RESULTS: All orbital meningiomas, including 14 ONSMs and 12 spheno-orbital meningiomas, showed high median (111)In-octreotide uptake ratios of 7.2 (range, 4.6-15.4) and 16.3 (range, 4.6-15.4), respectively. In 7 patients with a diagnosis of ONSM, the SSRS uptake ratio was significantly decreased 2.7 (1-6.8) after treatment with 54 Gy of radiotherapy. Median uptake ratios of other tumors were vascular anomalies/vascular tumors, 1.2 (range, 0.5-3.3); non-Hodgkin lymphomas, 2.9 (range, 0.9-4.2); optic nerve gliomas, 1.5 (range, 0.2-3.3); and idiopathic orbital inflammation, 1.6 (range, 1.4-1.9). By using a threshold uptake ratio of 5.9, the sensitivity of SSRS with (111)In-octreotide for ONSM was 100%, with a specificity of 97.2%. CONCLUSIONS: SSRS is a useful additional tool in diagnosing ONSM and has 100% sensitivity and 97% specificity at a threshold uptake ratio of 5.9.

Small versus coronal incision orbital decompression in Graves' orbitopathy.

Ideally the planning of decompression surgery should be adequate to the severity of the orbitopathy, its possible "lipogenic" or "myopathic" variants, the patient's specific orbital osteology and possible previous surgeries. Due to surgeon's experience and local traditions, however, a standardized rather than a tailored approach is often offered to the patient. An inferior fornix and/or upper skin crease incision can be used for infero medial and/or lateral, bony and/or fat decompression. As an alternative the swinging eyelid technique, offering an adequate access to the bony orbit and to the orbital fat compartments is a versatile technique that can virtually be used as a standard approach for the greatest majority of patients needing decompression surgery. Orbital decompression by coronal incision is an invasive technique and for this not to be used as a standard approach to orbital decompression. Nevertheless, it is not to be abandoned as it can be an additional tool in surgeons' hands when dealing with patients who can better benefit out of a particular, tailored rather than a standardised approach. Many are the circumstances in which this may happen. Major complications associated with the coronal approach have been mainly described in small series, where only a few patients per year were operated. In this respect it is therefore unavoidable to emphasize that each technique has its own learning curve and it may be difficult to differentiate the effects of each technique from the experience of the surgeon.

A new and validated CT-based method for the calculation of orbital soft tissue volumes.

PURPOSE: There is no consensus as how to calculate orbital soft tissue volume based on CT or MRI scans. The authors sought to validate their technique and to assess the intraobserver and interobserver variability of their calculations of bony orbital volume (OV), orbital fat volume (FV), and extraocular muscle volume (MV) on CT scans of humans. METHODS: The authors calculated these volumes with the use of a manual segmentation technique on CT scans with commercially available software. Two observers (one of them masked) calculated the orbital soft tissue volumes in a CT scan of a phantom constructed of dry skull, butter, and chicken muscle. These calculations were compared with previously taken standard volume measurements of these materials. Repetitive calculations on one CT scan by the same observer were compared. Soft tissue volumes taken from 10 orbital CT scans were calculated by two observers and compared. From the data acquired, intraobserver and interobserver variability was calculated. RESULTS: Outcomes of these calculations using this software approximated the volumes of the phantom measured with standardized techniques. Accuracy of the phantom calculations between the two observers varied from +0.7% to -0.7% for FV and between -1.5% and -2.2% for MV. Mean differences between the repeated calculations were smaller than 5%. The intraclass correlation coefficient varied from 0.961 to 0.999. CONCLUSIONS: Calculating orbital soft tissue volume using a manual segmentation technique for CT scans is a reliable and accurate tool.

The influence of previous orbital irradiation on the outcome of rehabilitative decompression surgery in graves orbitopathy.

PURPOSE: To investigate whether orbital irradiation influences the outcome of decompression surgery in Graves orbitopathy. DESIGN: Retrospective, comparative case series. METHODS: The medical records of all the patients with Graves orbitopathy treated with a three-wall orbital decompression through a coronal approach at our institution between January 1, 1990 and December 31, 2000 were reviewed. Only patients who underwent bilateral surgery for aesthetic rehabilitation, without preoperative diplopia, and who, in the active phase of the disease, had received orbital radiotherapy alone (20 Grays (Gy) in 10 daily fractions of two Gy over a period of two weeks; group R), systemic glucocorticoids alone (daily administration for more than three months independently from the dosage; group G), or both radiotherapy and glucocorticoids (group RG) were selected. Groups were compared for demographics, smoking habits, preoperative characteristics, and surgical outcome (mean reduction of exophthalmos, reduction of lid retraction, persistence of periorbital swelling requiring cosmetic eyelid surgery, onset of diplopia within 20 degrees of the central position of gaze, and variations in the peripheral field of diplopia). RESULTS: Sixty-one of 376 patients were selected for this study. There were no differences between group R (n=29), group G (n=15), and group RG (n=17) with respect to demographics or predecompression characteristics, whereas the number of smokers was significantly greater in group RG (P=.019). We could not find differences in surgical outcome by comparing the three groups. CONCLUSIONS: The total radiation dose, fraction size, and irradiated volume commonly used to treat active Graves orbitopathy do not adversely interfere with the outcome of rehabilitative decompression surgery.

Is sleeping position related to asymmetry in bilateral Graves' ophthalmopathy?

BACKGROUND: In agreement with the systemic nature of Graves' disease, Graves' ophthalmopathy (GO) presents as a symmetric bilateral eye disease in the vast majority of patients. However, asymmetric involvement of both eyes is frequently observed. We hypothesized that sleeping position might be involved in asymmetric GO; when, for example, the preferred sleeping position is on the right side, retrobulbar pressure might be somewhat higher in the right than in the left orbit, resulting in more severe eye changes in the right eye. METHODS: A prospective study in 75 consecutive untreated patients with GO, in whom eye changes and sleeping position were assessed independent of each other. Criteria for asymmetric eye changes were differences between both eyes in the presence of retrobulbar pain or of > or =1 grade in soft tissue involvement, and/or of > or =2 mm in exophthalmos, and/or > or =8 degrees in elevation. Preferred sleeping position was determined by questionnaire. RESULTS: All patients had bilateral GO. Eye changes were symmetrical in 50 patients, and asymmetrical in 25 patients based on differences in proptosis and elevation. Sleeping position did not differ between symmetric and asymmetric GO. Preferred sleeping position was on the left side in 23%; on the right side in 31%; and on the back, on the belly, or unknown in 46%. In patients with asymmetric GO, the most affected ("worst") eye was not related to preferred sleeping position on the right or left side. CONCLUSION: Slight asymmetry of eye changes between both eyes in patients with bilateral GO is not related to preferred sleeping position on either the right or left side.

Correction of lid retraction and exophthalmos.

Exophthalmos and eyelid retraction are typical symptoms of many orbital or systemic diseases, Graves' orbitopathy being the commonest. Independently from the cause, both may increase evaporation with drying of the ocular surfaces resulting in pain, tearing, and photophobia. The structural integrity of the cornea may also be damaged with possible compromise of the visual function. Acute onset of exophthalmos and/or eyelid retraction deserves maximum attention. In order to avoid corneal decompensation and waiting for a more definitive treatment, eye lubricants, moisture chambers, swimming goggles, temporary tarsorrhaphies or blepharorrhaphies represent the measures of choice. Exophthalmos depending on neoplastic, vascular, infectious, inflammatory or malformative causes is, in the majority of cases, amenable of medical or surgical causative treatment while, for endocrine exophthalmos the commonest treatment is surgical and symptomatic and consists of orbital bone decompressions. Eyelid retraction due to active inflammatory processes can be treated medically while for persistent eyelid retraction the treatment is surgical and based on lengthening of the anterior, and/or posterior, and/or mid-eyelid lamellae. Exophthalmos and eyelid retraction due to Graves' orbitopathy, their influence on ocular surface disorders and the treatment of these conditions will be specifically analysed in this chapter.

Reactivation of Graves' orbitopathy after rehabilitative orbital decompression.

OBJECTIVE: To present and discuss three cases of apparent reactivation of Graves' orbitopathy (GO) after orbital decompression and to evaluate the incidence of this phenomenon. DESIGN: Observational case series and retrospective follow-up study. PARTICIPANTS: A few weeks after surgery 2 patients with GO (patients 1 and 2), treated at our institution with rehabilitative bony orbital decompression during the static phase of the disease showed clinical and radiologic evidence of reactivated orbitopathy. After this observation, a sample of 249 patients who had consecutively undergone the same treatment for the same reason before the second of the 2 observed patients was selected for this study. METHODS: The records of the selected patients were retrospectively reviewed searching for cases presenting with clinical and radiologic evidence of GO reactivated as a consequence of any type of bony orbital decompression. Patients treated with perioperative systemic glucocorticoids or who had concurrent periorbital diseases, injuries, or surgeries, or who had immunocompromised conditions or a follow-up of < or =2 months, were excluded. MAIN OUTCOME MEASURES: Incidence of reactivation. Clinical history, clinical and radiologic characteristics, treatment modalities, and time course of the reactivation in patients presenting with this phenomenon. RESULTS: Decompression surgery took place between 1994 and 2000. Eleven patients were excluded for having been treated with perioperative glucocorticoids. Only 1 patient (patient 3) presented with reactivation. The incidence of the phenomenon that we regard as reactivation of GO after rehabilitative bony orbital decompression was therefore 1.3% (3/239). In all 3 patients, the reactivation took place a few weeks after surgery, after an early normal convalescence period and could be controlled with systemic immunosuppression or orbital radiotherapy. None of the patients we report developed further episodes of reactivation during the follow-up period (mean, 7.5 years). CONCLUSIONS: Based on its clinical characteristics, we suggest naming our observation delayed decompression-related reactivation and we propose using its acronym DDRR when referring to it. Although DDRR appears to be a rare event, it is important for physicians and patients to be aware of its possible occurrence with rehabilitative decompression surgery.

Determinants of liver damage associated with intravenous methylprednisolone pulse therapy in Graves' ophthalmopathy.

BACKGROUND: Intravenous methylprednisolone pulses (IVMP) are more efficacious and better tolerated than oral prednisone in Graves' ophthalmopathy (GO) patients. However, acute and severe liver damage has been reported in sporadic cases during IVMP, resulting in fatal acute liver failure in four patients so far. The mechanism causing the liver damage is incompletely understood. DESIGN: We performed a prospective observational study in 13 patients with dysthyroid optic neuropathy (group A) and in 14 patients with moderately severe GO (group B) who were treated with high-dose (group A) or low-dose (group B) IVMP; cumulative steroid doses were 8.45 g in group A and 4.5 g in group B, and follow-up time was 24 weeks. MAIN OUTCOME: Slight increases in serum aminotransferases (in alanine aminotransferase [ALAT] more than in aspartate aminotransferase [ASAT]) were observed, in seven patients exceeding the upper normal limit of 40 U/L. These changes were more prominent in group A than in group B as was also evident from a decrease in ASAT/ALAT ratio in group A but not in group B. Changes in serum aminotransferases occurred especially in the first 6 weeks of IVMP, becoming smaller thereafter with the decrease in steroid dosage. Pretreatment liver steatosis or diabetes were not related to liver damage, but preexistent viral hepatitis was. CONCLUSION: IVMP in GO patients causes dose-dependent liver damage by a direct toxic effect of glucocorticoids on hepatocytes. Nevertheless, IVMP seems to be pretty safe if cumulative doses exceeding 8 g are avoided and liver function is checked before and at regular intervals during pulse therapy.

Clinical features of dysthyroid optic neuropathy: a European Group on Graves' Orbitopathy (EUGOGO) survey.

BACKGROUND: This study was performed to determine clinical features of dysthyroid optic neuropathy (DON) across Europe. METHODS: Forty seven patients with DON presented to seven European centres during one year. Local protocols for thyroid status, ophthalmic examination and further investigation were used. Each eye was classified as having definite, equivocal, or no DON. RESULTS: Graves' hyperthyroidism occurred in the majority; 20% had received radioiodine. Of 94 eyes, 55 had definite and 17 equivocal DON. Median Clinical Activity Score was 4/7 but 25% scored 3 or less, indicating severe inflammation was not essential. Best corrected visual acuity was 6/9 (Snellen) or worse in 75% of DON eyes. Colour vision was reduced in 33 eyes, of which all but one had DON. Half of the DON eyes had normal optic disc appearance. In DON eyes proptosis was > 21 mm (significant) in 66% and visual fields abnormal in 71%. Orbital imaging showed apical muscle crowding in 88% of DON patients. Optic nerve stretch and fat prolapse were infrequently reported. CONCLUSION: Patients with DON may not have severe proptosis and orbital inflammation. Optic disc swelling, impaired colour vision and radiological evidence of apical optic nerve compression are the most useful clinical features in this series.

Early versus late orbital decompression in Graves' orbitopathy: a retrospective study in 125 patients.

PURPOSE: To determine if early rehabilitative orbital decompression in Graves' orbitopathy (GO) leads to a more effective postoperative outcome than the same intervention performed at a later, more likely, fibrotic stage. DESIGN: Retrospective comparative case series. PARTICIPANTS: The medical records of all GO patients treated with a 3-wall orbital decompression at our institution between 1990 and 2000 were reviewed retrospectively. Only patients operated bilaterally for aesthetic rehabilitation, without preoperative diplopia, were included. They were divided into group 1 (duration of GO < 4 years) and group 2 (duration > or = 4 years). METHODS AND MAIN OUTCOME MEASURES: The 2 groups were compared for demographics, smoking habits, preoperative characteristics (immunosuppressive treatments, Hertel values, score in NOSPECS [no signs or symptoms, only signs, soft tissue involvement with symptoms and signs, proptosis, extraocular muscle involvement, corneal involvement, sight involvement] class 2, degree of extraocular muscle enlargement), and surgical outcome (mean reduction of exophthalmos, symmetry of exophthalmos reduction, reduction in upper and lower lid retraction, any persistent periorbital swelling requiring cosmetic eyelid surgery, postdecompression diplopia). RESULTS: The medical records of 125 of 376 patients were selected for this study. There were no differences between group 1 (n = 70) mean GO duration (2.2+/-0.8 years) and group 2 (n = 55) mean GO duration (9.0+/-5.4 years) with respect to demographics, smoking habits, and preoperative characteristics except for the degree of extraocular muscle enlargement, which was significantly greater in group 1 (P = 0.039). There was no difference in surgical outcomes between the 2 groups, with the exception of postdecompression diplopia, which was significantly more frequent in group 1 than in group 2 (29% vs. 13%, P = 0.033). CONCLUSIONS: In GO, early rehabilitative orbital decompression does not improve surgical outcome and is associated with a higher risk of postdecompression diplopia.

The 2016 European Thyroid Association/European Group on Graves' Orbitopathy Guidelines for the Management of Graves' Orbitopathy.

Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease, though severe forms are rare. Management of GO is often suboptimal, largely because available treatments do not target pathogenic mechanisms of the disease. Treatment should rely on a thorough assessment of the activity and severity of GO and its impact on the patient's quality of life. Local measures (artificial tears, ointments and dark glasses) and control of risk factors for progression (smoking and thyroid dysfunction) are recommended for all patients. In mild GO, a watchful strategy is usually sufficient, but a 6-month course of selenium supplementation is effective in improving mild manifestations and preventing progression to more severe forms. High-dose glucocorticoids (GCs), preferably via the intravenous route, are the first line of treatment for moderate-to-severe and active GO. The optimal cumulative dose appears to be 4.5-5 g of methylprednisolone, but higher doses (up to 8 g) can be used for more severe forms. Shared decision-making is recommended for selecting second-line treatments, including a second course of intravenous GCs, oral GCs combined with orbital radiotherapy or cyclosporine, rituximab or watchful waiting. Rehabilitative treatment (orbital decompression surgery, squint surgery or eyelid surgery) is needed in the majority of patients when GO has been conservatively managed and inactivated by immunosuppressive treatment.

The removal of the deep lateral wall in orbital decompression: its contribution to exophthalmos reduction and influence on consecutive diplopia.

PURPOSE: To evaluate the contribution of maximal removal of the deep lateral wall of the orbit to exophthalmos reduction in Graves' orbitopathy and its influence on the onset of consecutive diplopia. DESIGN: Case-control study. METHODS: The medical records of two cohorts of patients affected by Graves' orbitopathy with exophthalmos > or = 23 mm, without preoperative diplopia, were retrieved at random from the pool of patients decompressed for rehabilitative reasons at our institution (01/1990 to 12/2003), and retrospectively reviewed. They had been treated with an extended (cases, group 1, n = 15) or conservative (controls, group 2, n = 15) 3-wall orbital decompression performed through a coronal approach. The deep portion of the lateral wall had been removed in the extended decompression group while preserved in the conservative decompression group. Demographics, preoperative characteristics, and surgical outcome were compared. The difference in mean exophthalmos reduction between groups 1 and 2 was considered to be the contribution of the deep lateral wall to reduction of exophthalmos. RESULTS: Groups 1 and 2 were drawn from a pool of 37 and 335 patients, respectively. Demographics and preoperative characteristics of the two groups were not significantly different. The mean contribution of the deep lateral wall to exophthalmos reduction was 2.3 mm. The onset of consecutive diplopia was not significantly different between the two groups (case n = 2/15, controls n = 5/15; P = .203). Diplopia resolved spontaneously in all the patients of group 1, while all the patients of group 2 required surgery. CONCLUSIONS: Removal of the deep lateral orbital wall as part of a coronal-approach, 3-wall decompression, enhances the degree of exophthalmos reduction without increasing the risk of consecutive diplopia.