Functional outcomes and complications in refractory dysthyroid optic neuropathy management: Experience with 3 different surgical protocols.

INTRODUCTION: Dysthyroid optic neuropathy (DON) is the most severe complication of Graves' orbitopathy (GO) and its management may require decompression surgery. Clear recommendations do not exist about which surgery should be performed and how extended the decompression should be. In this paper we present our experience regarding the management of DON via 3 different surgical protocols: a modified extended orbital apex decompression, a 2 walls decompression (inferior and lateral) and a 3 walls decompression (inferior, lateral and medial) and evaluate the functional outcomes. METHODS: Retrospective evaluation of subjects affected by DON not responding to medical therapy has been performed. All patients were submitted to pre- and post-operative ophthalmologic evaluations and orbital and sinuses CT scan in order to evaluate functional and surgical outcomes. RESULTS: 27 patients were enrolled in the study. Surgical procedures were performed on 42 orbits. A statistically significant post-operative improvement was recorded in visual acuity, proptosis, color vision and fundus oculi evaluation for all groups. No patient developed major or minor complications after surgery. CONCLUSIONS: Extended endonasal approach and 3 walls decompression have been proved effective in the management of DON. The choice between them is done according to degree of proptosis, general status and eye-surface damages.

Vesicular monoamine transporters expression in pheochromocytomas and paragangliomas according to scintigraphy and positron emission tomography behavior.

BACKGROUND: The expression of vesicular catecholamine transporters (VMAT1 and 2) in pheochromocytomas (PHEOs) and paragangliomas (PGLs) and the possible relationships with [18F]FDOPA PET/CT and [123I]MIBG scintigraphy uptake are unknown. Our purpose was to investigate possible correlations of either VMAT1 and VMAT2 expression with the functional imaging in patients with PHEOs and PGLs. METHODS: An observational 3-year time study was performed by enrolling 31 consecutive patients with PHEO (N.=17) or PGL (N.=14). They underwent the same diagnostic work-up; moreover, [123I]MIBG SPECT/CT (N.=20) and [18F]FDOPA PET/CT (N.=14) were performed in a subset of patients. After surgery, routine histology and semiquantitative analysis of VMAT1/VMAT2 immunoreactivity were carried out in all cases. RESULTS: VMAT1 immunoreactivity was found in all tumors, but two PHEOs. VMAT1 immunoreactivity was higher in PGLs than in PHEOs, though at not significant extent. Elevated VMAT2 immunoreactivity score was present in all but two negative tumors. Normal [123I]-MIBG uptake was independent from VMAT1/2 immunoreactivity. Patients undergoing [18F]FDOPA PET/CT showed a high score level of both VMATs and were detected by the technique in all cases. CONCLUSIONS: VMAT1 and VMAT2 are highly expressed in most tumors, though VMAT1 immunoreactivity is apparently prevalent in PGLs as compared to PHEOs. Presence and expression of VMAT1 and VMAT2 are not limiting factors for MIBG uptake. The status of VMAT expression might help to understand why the more frequently used radiotracers do not always have the expected diagnostic performance. Finally, the present study points out the importance of developing new radiotracers with higher sensitivity, specificity and accuracy consequently reducing healthcare costs.

Graves' orbitopathy: a multidisciplinary approach.

Orbitopathy is the main extra thyroidal manifestation of Graves' disease. It is a very challenging condition, which requires a cooperation between many specialists (endocrinologists, ophthalmologists, radiologists, radiotherapeutic, orbital surgeons) for an optimal clinical management. An accurate diagnostic assessment is required, in order to plan an adequate treatment of Graves' orbitopathy. Medical therapy, radiotherapy or surgery may be necessary to control the disease. In this review, the authors analyze the various therapeutic strategies, as well the more recent therapies based on pharmacologic immunomodulation.

Focus on the Involvement of the Nose and Paranasal Sinuses in Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome): Nasal Cytology Reveals Infiltration of Eosinophils as a Very Common Feature.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a necrotizing vasculitis that predominantly affects small- to medium-sized vessels. It is characterized by a wide spectrum of extrapulmonary symptoms, including sinonasal and paranasal sinus abnormalities. These are the most common features of this disease, constituting diagnostic criteria for EGPA. However, the actual clinical features, cellular mechanisms and impact on patients' quality of life (QoL) are still a matter of study. METHODS: Thirty-nine EGPA patients underwent multidimensional rhinological evaluations, including rhinofibroscopy, nasal cytology, and QoL questionnaires. This was coupled with respiratory and rheumatological assessments. RESULTS: Twenty-eight patients were diagnosed with chronic rhinosinusitis (CRS). Of these, 18 had nasal polyposis (NP). Chronic rhinitis was diagnosed in 10 patients. Of these, 3 had allergic rhinitis (AR) and seven had non-AR (NAR). Overall, only 1 patient (2.6%) was normal. Nasal cytology showed that hypereosinophilia was present in 17/28 patients with CRS, 4/7 patients with NAR and all patients with AR. SNOT-22 and SF-36 showed a severe impact of nasal symptoms on QoL. No differences in asthma control or rheumatological patterns for EGPA were observed among patients with or without NP. CONCLUSIONS: Even when the rheumatological assessment scored EGPA "under control" according to the Birmingham Vasculitis Activity Score and Vasculitis Damage Index, sinonasal diseases and related nasal inflammatory processes were not controlled. Therefore, there is a need for clinical monitoring and targeted treatment to control the inflammatory processes and improve the QoL of EGPA patients.

Frey Syndrome, First Bite Syndrome, great auricular nerve morbidity, and quality of life following parotidectomy.

PURPOSE: Parotidectomy may be burdened by numerous complications that may worsen subjects' quality of life (QoL). These include paresis or paralysis of the facial nerve, face profile asymmetry, keloids, salivary fistula, Frey Syndrome (FS), First Bite Syndrome (FBS), and hypo-anaesthesia of the skin. This study is an effort to assess the incidence of complications following parotidectomy and their impact on subjects' QoL. METHODS: Subjects undergoing parotidectomy for benign neoplasms from 2012 to 2015 were selected and invited to attend our outpatient clinic. After a brief anamnesis, the medical examiners tested their tactile perception and performed the Minor test for FS. Depending on the complications showed, subjects were asked to complete from 1 to 4 questionnaires about their QoL. RESULTS: 76 subjects completed the medical examination. The most frequent complication was the hypo-anaesthesia of the skin (71%). 21 subjects (28%) were positive to the Minor test, while 8 subjects (11%) reported FBS-compatible symptoms. Two subjects (3%) showed a facial nerve paralysis. Free abdominal fat graft was used in 16 subjects (21%) and it was associated with a lower incidence of FS. Surgery of the deep lobe of the parotid was associated with FBS. CONCLUSIONS: FBS appears to have a greater influence on subjects' QoL than FS and hypo-anaesthesia of the skin. Moreover, this work confirms that surgery of the deep lobe of the parotid is a risk factor for developing FBS and the free abdominal fat graft is a reliable technique to prevent FS.

Endoscopic-assisted transoral-transpharyngeal approach to parapharyngeal space and infratemporal fossa: focus on feasibility and lessons learned.

The parapharyngeal space (PPS) is a challenging anatomical region, rich in vascular and nervous vital structures. Surgery is considered the treatment of choice for the majority of PPS lesions. Herein, we present a retrospective evaluation on ten patients with various types of lesions of the parapharyngeal and infratemporal fossa (ITF) regions operated on via an endoscopic-assisted transoral-transpharyngeal approach (EATTA), focusing on feasibility and safety. A retrospective evaluation of patients treated by means of EATTA to PPS and/or ITF lesions was carried out. The clinical records of patients who were operated on with EATTA for PPS and/or ITF lesions between March 2009 and October 2015 at two referral centres were reviewed and the intra-operative and post-operative complications were analysed. Ten patients who underwent EATTA on the PPS and ITF were included in this series. The procedure was performed in six patients for tumour removal, in three patients for diagnostic purposes and in one patient for pain control. No major complications occurred. No conversion to external approach was required. We observed only two minor complications which were promptly solved. No dysphagia or other problems during the food intake were observed in our series. One day after surgery all patients, except one, referred a value of VAS minor than 4. To date, no evidence of disease recurrence has been assessed in all six oncological cases. Although preliminary, our experience seems to demonstrate the feasibility and safety of EATTA when properly planned and performed.

Transorbital endoscopic assisted resection of a superior orbital fissure cavernous haemangioma: a technical case report.

OBJECTIVES: Superior orbital fissure and orbital apex lesions are challenging to manage, regardless of the approach chosen, due to the potential morbidity. The objectives of this study are to describe an innovative, minimally invasive surgical approach addressing this critical area and to discuss its indications and outcomes. SUBJECT: A young patient presented with visual disturbances (reduction of color discrimination, central scotoma) and mild exophthalmos owing to the presence of a right orbital apex cavernous haemangioma with superior orbital fissure invasion. METHODS: The lesion was removed via a minimally invasive, neuronavigated, transorbital superior eyelid endoscopic-assisted approach. MAIN OUTCOME MEASURES: Technical feasibility and safety, early and late complications, length of hospitalization time and follow-up data were collected and analyzed. RESULTS: The lesion was radically resected minimizing the surgical morbidity and hospitalization time for the patient and with encouraging functional and cosmetic outcomes. No recurrences were observed 1 year after surgery. CONCLUSIONS: The endoscopic-assisted transorbital approach should be considered a safe and effective option that can be applied in the treatment of lesions affecting such complex anatomical regions, as it offers excellent visualization of the surgical field, acceptable sequelae and reduced morbidity in relation to the traditional transcranial/transfacial approaches. Further studies and larger case series are needed in order to validate the reproducibility and range of applications of this surgical technique.

Quantitative study on endoscopic endonasal approach to the posterior sino-orbito-cranial interface: implications and clinical considerations.

The posterior sino-orbito-cranial interface is a critical area in the skull base since it represents a gateway to deeper vital regions. Quantification of the surgical freedom for any given point/area is an objective method for comparing in a reproducible way different surgical approaches. Three freshly injected cadaver heads (six sides) were dissected under the magnetic navigation control system. The surgical freedom (SF) and the angle of attack of fixed target points were determined from the ipsilateral nasal fossa, from the contralateral nasal fossa (after posterior septectomy), and after an anteromedial maxillotomy (according to the Denker procedure). The mean pre-operative SF value resulted to be 403.07 ± 102.73 mm(2) for the ipsilateral nostril, increasing by 126.97 % for the binostril approach, by 118.45 % for the monolateral nostril approach after anteromedial maxillotomy, and by 310.48 % for the binostril approach after bilateral anteromedial maxillotomy. Laterally extended lesions require an anteromedial maxillotomy, while more medially located lesions can be managed by means of a posterior septectomy. When addressing the posterior sino-orbito-cranial interface, the transnasal binostril approach and anteromedial maxillotomy both increase the SF. The choice between them depends on exact position, relationship and clinical behaviour of the lesion to treat.

Endoscopic endonasal anatomy of superior orbital fissure and orbital apex regions: critical considerations for clinical applications.

The superior orbital fissure is a critical three-dimensional space connecting the middle cranial fossa and the orbit. From an endoscopic viewpoint, only the medial aspect has a clinical significance. It presents a critical relationship with the lateral sellar compartment, the pterygopalatine fossa and the middle cranial fossa. The connective tissue layers and neural and vascular structures of this region are described. The role of Muller's muscle is confirmed, and the utility of the maxillary and optic strut is outlined. Muller's muscle extends for the whole length of the inferior orbital fissure, passes over the maxillary strut and enters the superior orbital fissure, representing a critical surgical landmark. Dividing the tendon between the medial and inferior rectus muscle allows the identification of the main trunk of the oculomotor nerve, and a little laterally, it is usually possible to visualize the first part of the ophthalmic artery. Based on a better knowledge of anatomy, we trust that this area could be readily addressed in clinical situations requiring an extended approach in proximity of the orbital apex.

Ectopic intraorbital lacrimal ductal cyst: a case report.

Lacrimal ductal cysts are uncommon lesions that can occur everywhere in and around the eye. Ectopic location is very rare and can be misleading in the differential diagnosis of orbital masses. In this article we present the case of a 61-year-old-man with a medial intraconal ductal cyst of his right orbit. The patient was successfully treated with surgical excision.

Horizontal semicircular canal benign paroxysmal positional vertigo: effectiveness of two different methods of treatment.

The aim of this study is to compare the results obtained using 2 methods of treatment for horizontal semicircular canal benign paroxysmal positional vertigo (HSC-BPPV): the barbecue maneuver + forced prolonged position (FPP) versus the Gufoni maneuver. In a randomized prospective clinical trial, we recruited 147 patients affected by HSC-BPPV. The primary outcome was the absence of vertigo and nystagmus upon application of the supine roll test during the follow-up examination. A statistical evaluation was performed in order to assess whether any parameters (e.g. age, duration of nystagmus and symptoms) could influence in any way the results obtained with the 2 methods of treatment. One hundred and three of the 147 patients affected by HSC-BPPV had the geotropic form and 44 had the apogeotropic type. We were able to transform 29 cases of HSC-BPPV from apogeotropic to geotropic. Finally, we obtained a group of 112 patients who were randomized either to the barbecue + FPP procedure (54 patients) or to the Gufoni maneuver (58 patients). The most evident result is the higher percentage of success (statistically significant) with the Gufoni maneuver at the first session of treatment (86 vs. 61%). The final control showed that 44 out of 54 (81%) patients treated with the barbecue maneuver + FPP were symptom free compared to 54 out of 58 (93%) treated with the Gufoni maneuver. Both the barbecue maneuver + FPP and the Gufoni maneuver are valid methods for treating HSC-BPPV (geotropic forms). However, our results also indicate that the Gufoni maneuver has a significant advantage: the success rate shown at the follow-up, although without statistical significance, is undoubtedly higher (93 vs. 81%). This result, together with the fact that it is very easy to perform and that patient compliance is better, make the Gufoni maneuver the method of choice in HSC-BPPV treatment.

The challenge of orbital decompression in a patient with multiple autoimmune diseases and graves' orbitopathy: a case report and review of literature.

The association between multiple autoimmune diseases can make management of the ocular proptosis very difficult and challenging for the orbit surgeon. We report an interesting case of a patient affected by Stiff person syndrome, type-1 diabetes and Graves' disease with Graves' orbitopathy, who underwent orbital decompression. Anaesthesiologic problems, as well as factors affecting the post-operative result, are discussed in detail; pertinent literature review was performed and discussed.

Temporalis myofascial flap in maxillary reconstruction: anatomical study and clinical application.

The authors describe indications and advantages of temporalis myofascial flap in the reconstruction of surgical defects after partial maxillectomies. This flap is thin and reliable and can be used as an alternative to free flap tissue transfer in the reconstruction of partial defects of the upper maxilla. The surgical steps to raise the flap are simple, but the dissection must be careful to avoid damages to the fronto-temporal branches of the facial nerve on the outer surface, and to the feeding vessels on the inner surface of the temporal muscle. In the present series no major surgical complications were observed. No injuries to the facial nerve branches were reported. Neither total nor partial flap losses were experienced. Post-operative aesthetic and functional results were satisfying. Temporalis muscle flap can be considered as a first-line reconstructive option for limited resection of the upper maxilla with sparing of the orbital floor and of the anterior alveolar crest.

Management of severely bleeding ethmoidal arteries.

OBJECTIVES: Ethmoidal arteries (EAs) can be responsible for severe bleeding. Clinical features of EA bleeding are rather extensive because it can occur within the nasal cavity or in orbital spaces. Furthermore, surgical management of EA bleeding is challenging. STUDY DESIGN: Retrospective evaluation. METHOD OF STUDY: Five clinical patients with severe bleeding from EAs and/or epistaxis refractory to sphenopalatine artery closure were included in this work. Careful anatomic dissection of the orbitoethmoidal region was performed in 3 fresh injected heads. RESULTS: Ethmoidal artery management is not uniform because it depends on the rapidity and severity of the bleeding and the chambers within which it happens. Trauma-related bleeding usually requires a lateral canthotomy, whereas in intraoperative bleeding, efforts should be made to directly coagulate the bleeding vessel, even within the orbital fat. Spontaneous epistaxis refractory to sphenopalatine artery closure is to be addressed externally, preferably under endoscopic vision. CONCLUSIONS: Ethmoidal artery management differs according to the clinical situation. Elective surgery is advisable for spontaneous epistaxis, whereas emergency treatment, ranging from intraorbital coagulation of the bleeding vessel to lateral canthotomy (when the patient is in a sight-threatening condition), is necessary when the bleeding occurs within orbital spaces. A treatment management algorithm is useful in cases of severe and refractory EA bleeding.

Predicting the Outcome after Acute Unilateral Vestibulopathy: Analysis of Vestibulo-ocular Reflex Gain and Catch-up Saccades.

Objectives (1) To describe the relationships among the main instrumental features characterizing an acute unilateral vestibulopathy and (2) to clarify the role of the video head impulse test in predicting the development of chronic vestibular insufficiency. Study Design Case series with chart review. Setting Tertiary referral center. Subjects and Methods Sixty patients suffering from acute unilateral vestibulopathy were retrospectively analyzed: 30 who recovered spontaneously (group 1) and 30 who needed a vestibular rehabilitation program (group 2). The main outcome measures included Dizziness Handicap Inventory score, canal paresis, high-velocity vestibulo-oculomotor reflex gain, and catch-up saccade parameters. The tests were all performed between 4 and 8 weeks from the onset of symptoms. Results The high-velocity vestibulo-oculomotor reflex gain correlated with the Dizziness Handicap Inventory score ( P = .004), with the amplitude of covert and overt saccades ( P < .001), and with the prevalence of overt saccades ( P < .001). Patients in need for vestibular rehabilitation programs had a significantly lower gain ( P < .001) and a higher prevalence and amplitude of overt saccades ( P = .002 and P = .008, respectively). Conversely, we found no differences in terms of response to the caloric test ( P = .359). Conclusions Lower values of high-velocity vestibulo-oculomotor reflex gain and a high prevalence of overt saccades are related to a worse prognosis after acute unilateral vestibulopathy. This is of great interest to clinicians in identifying which patients are less likely to recover and more likely to need a vestibular rehabilitation program.

Endoscopic Transorbital Superior Eyelid Approach for the Management of Selected Spheno-orbital Meningiomas: Preliminary Experience.

BACKGROUND: Feasibility and safety of spheno-orbital meningioma resection by means of endoscopic-assisted transorbital route. OBJECTIVE: To evaluate the feasibility and outcomes of the transorbital endoscopic management of selected spheno-orbital meningiomas. As secondary aims, symptom improvement and tumor volume removed were evaluated. METHODS: Retrospective chart evaluation of patients with spheno-orbital meningiomas treated by means of endoscopic transorbital superior eyelid approach in 3 referral centers over the last 4 yr. RESULTS: Fourteen cases were included in this study. In 4 patients, the transorbital endoscopic approach was combined with an endonasal route. Mean age was 51 and male-to-female ratio was 1:6. In 8 patients (57.1%), an intraorbital involvement was observed, 3 of them (21.4%) showed significant intraconal disease. No patient presented significant cavernous sinus infiltration. Main presenting symptoms were proptosis, diplopia, and visual impairment in 14, 6, and 6 patients, respectively. Mean proptosis improvement was 2 mm (standard deviation 2.3). We observed no major postoperative complications. CONCLUSION: Our preliminary clinical experience seems to demonstrate that selected spheno-orbital meningiomas can be safely managed by means of an endoscopic transorbital route through a superior eyelid approach. Patients with orbital or cavernous sinus infiltration are at highest risk of persistence.

Association of T and B Cells Infiltrating Orbital Tissues With Clinical Features of Graves Orbitopathy.

Importance: Graves orbitopathy (GO) responds to immunosuppressive treatments when clinically active but poorly when inactive. In other autoimmune diseases, response has been ascribed to a reduction in lymphocytes infiltrating the target organ. It is not known whether active vs inactive GO differs in this regard, which would help in understanding the link between GO immunologic features and clinical behavior. Objective: To investigate the association between orbital lymphocytic infiltrate and GO clinical features. Design, Setting, and Participants: A cohort study aimed at assessing the extent and immunohistochemical phenotype of orbital lymphocytes and associating it with the ophthalmologic features of GO, especially its clinical activity score (CAS), was conducted at a tertiary referral center. Twenty consecutive patients with GO who underwent orbital decompression were included. The study was conducted from January 1 to May 31, 2017. Exposures: Orbital tissue histology and immunohistochemistry testing as well as ophthalmologic evaluation. Main Outcomes and Measures: Association between CAS and orbital lymphocytes, analyzed as total number of lymphocytes and main lymphoid subsets. Results: The patient population included 8 men and 12 women, all of white race, with a mean (SD) age of 46 (13) years. With an established cutoff value of 300 lymphoid cells per tissue sample, lymphocytes above this value were found in orbital tissues of 9 of 20 patients (45%), often organized into distinct foci. The lymphocytes comprised a mixture of T (CD3-positive) and B (CD20-positive) cells, suggesting a mature, polyclonal autoimmune response. In a simple linear regression model, the total number of lymphocytes, as well as the number of CD3- and CD20-positive subsets, correlated with CAS (R = 0.63; 95% CI, 0.27-0.84; P = .003; R = 0.59; 95% CI, 0.20-0.82; P = .006; and R = 0.65; 95% CI, 0.30-0.85; P = .002, respectively). In a multiple linear regression model, lymphocytes maintained their effect on CAS when adjusted for 2 additional variables that were correlated with CAS-smoking and GO duration-highlighting even more the important role of orbital lymphocytes in affecting CAS (total number: R = 0.58; 95% CI, 0.18-0.82; P = .01; CD3-positive: R = 0.58; 95% CI, 0.17-0.82; P = .01; and CD20-positive: R = 0.59; 95% CI, 0.19-0.83; P = .01). Conclusions and Relevance: This study shows a correlation between T and B lymphocytes infiltrating orbital tissues and the activity of GO, possibly enhancing our understanding of the association between GO immunologic features and clinical expression.

Anaplastic thyroid carcinoma: from clinicopathology to genetics and advanced therapies.

Anaplastic thyroid carcinoma (ATC) is a rare malignancy, accounting for 1-2% of all thyroid cancers. Although rare, ATC accounts for the majority of deaths from thyroid carcinoma. ATC often originates in a pre-existing thyroid cancer lesion, as suggested by the simultaneous presence of areas of differentiated or poorly differentiated thyroid carcinoma. ATC is characterized by the accumulation of several oncogenic alterations, and studies have shown that an increased number of oncogenic alterations equates to an increased level of dedifferentiation and aggressiveness. The clinical management of ATC requires a multidisciplinary approach; according to recent American Thyroid Association guidelines, surgery, radiotherapy and/or chemotherapy should be considered. In addition to conventional therapies, novel molecular targeted therapies are the most promising emerging treatment modalities. These drugs are often multiple receptor tyrosine kinase inhibitors, several of which have been tested in clinical trials with encouraging results so far. Accordingly, clinical trials are ongoing to evaluate the safety, efficacy and effectiveness of these new agents. This Review describes the updated clinical and pathological features of ATC and provides insight into the molecular biology of this disease. The most recent literature regarding conventional, newly available and future therapies for ATC is also discussed.

Natural history of graves' orbitopathy after treatment.

Intravenous glucocorticoids are used for Graves' orbitopathy, alone or associated with/followed by additional treatments (orbital radiotherapy, orbital decompression, palpebral or eye surgery). However, the relation between associated/additional treatments and other variables with Graves' orbitopathy outcome following intravenous glucocorticoids is not clear. Thus, the present study was conducted to investigate retrospectively the impact of associated/additional treatments and other variables on Graves' orbitopathy outcome after intravenous glucocorticoids. We evaluated 226 untreated Graves' orbitopathy patients. Following first observation, patients were given intravenous glucocorticoids and re-examined after a median of 46.5 months. The end-points were the relation between Graves' orbitopathy outcome, outcome of NOSPECS score and of the single Graves' orbitopathy features with several variables, including associated/additional treatments. All Graves' orbitopathy features improved significantly after treatment. Overall, Graves' orbitopathy improved in ~60 % of patients (responders), whereas it was stable or worsened in ~40 % of patients (non-responders). Time between first and last observation and clinical activity score at first observation correlated significantly with Graves' orbitopathy outcome. The outcomes of NOSPECS, eyelid aperture, clinical activity score and diplopia correlated with time between the first and last observation. The NOSPECS outcome correlated with gender. The outcomes of proptosis, eyelid aperture and visual acuity correlated with orbital decompression. The outcome of diplopia correlated with orbital radiotherapy. Taking into account the limitations of retrospective investigations, our findings confirm that time (i.e. the natural history of Graves' orbitopathy) is a key factor in determining the long-term outcome of Graves' orbitopathy, radiotherapy is effective for diplopia, and orbital decompression is followed by an amelioration of several Graves' orbitopathy features.

Antioxidant Actions of Selenium in Orbital Fibroblasts: A Basis for the Effects of Selenium in Graves' Orbitopathy.

BACKGROUND: A recent clinical trial has shown a beneficial effect of the antioxidant agent selenium in Graves' orbitopathy (GO). In order to shed light on the cellular mechanisms on which selenium may act, this study investigated its effects in cultured orbital fibroblasts. METHODS: Primary cultures of orbital fibroblasts from six GO patients and six control subjects were established. Cells were treated with H2O2 to induce oxidative stress, after pre-incubation with selenium-(methyl)selenocysteine (SeMCys). The following assays were performed: glutathione disulfide (GSSG), as a measure of oxidative stress, glutathione peroxidase (GPX) activity, cell proliferation, hyaluronic acid (HA), and pro-inflammatory cytokines. RESULTS: H2O2 induced an increase in cell GSSG and fibroblast proliferation, which were reduced by SeMCys. Incubation of H2O2-treated cells with SeMCys was followed by an increase in glutathione peroxidase activity, one of the antioxidant enzymes into which selenium is incorporated. At the concentrations used (5 µM), H2O2 did not significantly affect HA release, but it was reduced by SeMCys. H2O2 determined an increase in endogenous cytokines involved in the response to oxidative stress and GO pathogenesis, namely tumor necrosis factor alpha, interleukin 1 beta, and interferon gamma. The increases in tumor necrosis factor alpha and interferon gamma were blocked by SeMCys. While the effects of SeMCys on oxidative stress and cytokines were similar in GO and control fibroblasts, they were exclusive to GO fibroblasts in terms of inhibiting proliferation and HA secretion. CONCLUSIONS: Selenium, in the form of SeMCys, abolishes some of the effects of oxidative stress in orbital fibroblasts, namely increased proliferation and secretion of pro-inflammatory cytokines. SeMCys reduces HA release in GO fibroblasts in a manner that seems at least in part independent from H2O2-induced oxidative stress. Some effects of SeMCys are specific for GO fibroblasts. These findings reveal some cellular mechanisms by which selenium may act in patients with GO.