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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Focus on audiologic impairment in eosinophilic granulomatosis with polyangiitis.

OBJECTIVES/HYPOTHESIS: To evaluate the clinical features of audiologic impairment and its relationship with the nasal, vestibular, and rheumatologic profile in a cohort of patients with eosinophilic granulomatosis with polyangiitis (EGPA), formerly named Churg-Strauss syndrome. STUDY DESIGN: Prospective cross-sectional study. METHODS: Thirty-nine patients with EGPA, considered controlled according to the Birmingham Vasculitis Activity Score and the Vasculitis Damage Index, underwent a complete audiologic evalutaion with otomicroscopy, impedance audiometry, speech audiometry, and auditory brainstem responses; rhinologic evaluation was made by means of fiberoptic endoscopy and nasal cytology; the clinical evaluation was completed with analysis of the facial function and, in patients with referred vertigo, with videonystagmography (VNG). Data were compared to the rheumatologic profile (eosinophil count, antineutrophil cytoplasmic antibodies status). RESULTS: Thirty-four of 39 patients fulfilled the inclusion criteria. Of those, 18 (52, 8%) were affected by variable degrees of hearing loss (sensorineural hearing loss [SNHL]) in four cases (11, 8%), mixed sensorineural and conductive hearing loss in two (5, 9%), presbycusis in six (17, 6%), and otitis media with effusion (OME) in six (17, 6%). Vestibular impairment was represented by benign paroxysmal positional vertigo and unspecific dizziness in three (8, 8%) and four cases (11, 8%), respectively, all with normal VNG. Ear involvement was statistically related to the EGPA vasculitic pattern and independent from the nasal impairment, cytology, and duration of nasal symptoms. No facial palsy was registered. CONCLUSION: In our experience, the largest in the existing literature, the otological involvement in EGPA is common and may occur variably as SNHL or OME. Otological involvement occurs early in the course of the disease process, but is nonspecific in making the diagnosis of EGPA. Its recognition is therefore fundamental. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2792-2797, 2016.

Assessment of Vestibulo-oculomotor Reflex in Ménière's Disease: Defining an Instrumental Profile.

OBJECTIVES: To analyze and compare, in two groups of patients affected by definite Ménière's disease (MD) but treated differently, the Video Head Impulse Test findings especially by putting them in relationship with canal paresis, hearing loss, and duration of the disease. STUDY DESIGN: Retrospective chart review. PATIENTS: Seventy patients affected by unilateral definite MD (16 in Group 1 and 54 in Group 2) observed between March 2014 and May 2015 in a tertiary referral center were retrospectively studied and then divided into two groups: Group 1 was previously treated with intratympanic gentamicin, whereas Group 2 underwent only a conservative therapy. Instrumental tests included audiometry, caloric test, and Video Head Impulse Test. All the findings were statistically analyzed; significance was set at p = 0.005. INTERVENTION: Diagnostic. MAIN OUTCOMES MEASURES: If MD is treated conservatively the high-frequency vestibulo-oculomotor reflex gain determined with Video Head Impulse Test is normal; it is pathological if MD is treated with gentamicin. RESULTS: High-frequency vestibulo-oculomotor reflex gain showed a statistically significant reduction in Group 1; at the same time, it showed no correlation in both groups with hearing loss, duration of disease or canal paresis. CONCLUSION: High-frequency vestibulo-oculomotor reflex is naturally preserved even in late stage MD if the patient has been treated conservatively; the dissociation between Caloric Test and Video Head Impulse Test findings could be considered an instrumental hallmark of MD. Gentamicin significantly reduces high-frequency vestibulo-oculomotor reflex gain: this reduction can be taken into account when determining the effectiveness of an ablative treatment.

MicroRNA-34c-5p is related to recurrence in laryngeal squamous cell carcinoma.

OBJECTIVES/HYPOTHESIS: Altered microRNA expression has been found in many cancer types, including laryngeal squamous cell carcinoma (LSCC). We investigated the association of LSCC-related miR-34c-5p with disease-free survival and overall survival. STUDY DESIGN: Retrospective cohort study. METHODS: Expression levels of miR-34c-5p were detected in 90 LSCC formalin-fixed paraffin-embedded tissues by reverse-transcription quantitative polymerase chain reaction. Overall survival and disease-free survival were evaluated using the Kaplan-Meier method, and multivariate analysis was performed using Cox proportional hazard analysis. RESULTS: A downregulation of miR-34c-5p expression significantly correlated with worse disease-free and overall survival. In the multivariate analysis, low miR-34c-5p expression was associated with an increased risk of recurrence. CONCLUSIONS: A downregulation of miR-34c-5p in LSCC is independently associated with unfavorable disease-free survival, suggesting that miR-34c-5p might be a promising marker for evaluating the risk of recurrences. LEVEL OF EVIDENCE: NA.

Multiportal Combined Transorbital Transnasal Endoscopic Approach for the Management of Selected Skull Base Lesions: Preliminary Experience.

BACKGROUND: Skull base lesions are challenging to treat and may be managed using several approaches each with its own advantages and limitations. In selected cases, a modular, combined, multiportal approach could overcome the limits of a single approach and respond well to the needs of the patient. METHODS: We report a preclinical study on 5 cadaveric specimens and 4 preliminary clinical experiences with the combined multiportal transnasal transorbital endoscopic approach for the management of selected complex skull base pathologies. The technical feasibility and safety of this combined approach were evaluated in the preclinical study. The applicability in vivo of such an approach, together with early and late complications, specific morbidity, and hospitalization time were analyzed in the preliminary clinical experiences. RESULTS: The transnasal endoscopic extended approach combined with the transorbital endoscopic approach offered greater visualization and tissue handling than a single approach alone could. The multiportal combined transorbital transnasal endoscopic approach was used effectively in vivo to resect 1 case of malignant schwannoma arising from the second branch of the trigeminal nerve and 3 cases of spheno-orbital meningioma without significant complications and with minimal morbidity for the patients. CONCLUSIONS: The multiportal combined transorbital transnasal endoscopic approach is a safe and effective procedure for management of selected complex skull base lesions that is able to capitalize on the advantages and overcome the limitations of each single approach. This combined approach offers a multiperspective view of the spaces and allows for a more synergized procedure, especially when dealing with multicompartmental lesions.