First Use of a New Robotic Endoscope Guiding System in Endoscopic Orbital Decompression.

PURPOSE: Over the last years, robot-assisted surgery gained in importance in head and neck surgery. In our study, we used a new robotic endoscope guiding system in patients undergoing endoscopic balanced orbital decompression. The aim of the study is to evaluate the feasibility and benefit of a robotic arm in endoscopic orbital surgery. METHODS: The Medineering Robotic Endoscope Guiding System is a robotic arm designed for holding an endoscope during interventions. An endoscope equipped with a 4K camera was attached at the tip of the robotic arm and placed in the surgical field. The surgeon controlled the movements of the endoscope with foot pedal. Eight patients underwent balanced endoscopic orbital decompression showing typical symptoms of Graves' orbitopathy preoperatively. Balanced decompression was performed via a combined approach transnasally and laterally via a small skin incision. RESULTS: Attaching the endoscope to the robotic guiding system and placing it in the nasal cavity were relatively simple procedures. Setup time was less than 10 minutes. Tool motion and control using the foot pedal were comfortable and adequately precise. Movements of the attached endoscope inside the nose were feasible and allowed 2-hand surgery. The patients did not show any adverse events or complications. CONCLUSION: The Medineering Robotic Endoscope Guiding System seems to be a safe and effective support in endoscopic skull base surgery especially for orbital decompression, thus allowing 2-hand or even 4-hand settings. To the best of our knowledge, this is the first study describing the successful application of a robotic system in orbital surgery.

Fingolimod Improves the Outcome of Experimental Graves' Disease and Associated Orbitopathy by Modulating the Autoimmune Response to the Thyroid-Stimulating Hormone Receptor.

Graves' disease (GD) and Graves' orbitopathy are associated with stimulating thyrotropin receptor (TSHR) autoantibodies and autoreactive T cells. Recent in vitro studies suggested that sphingosine-1-phosphate (S1P) signaling is involved in the pathogenesis of orbitopathy. In this study, we explored the immune modulatory potential of S1P receptor antagonist fingolimod in a murine model for GD. Fingolimod was orally administered preventively during disease onset or therapeutically after disease onset. Administration of fingolimod during disease onset completely prevented the formation of TSHR-stimulating autoantibodies. Intervention after disease onset rarely reduced TSHR-stimulating autoantibodies and blocking autoantibodies were induced in some animals. Consequently, autoimmune hyperthyroidism characterized by elevated serum thyroxin levels, hyperplastic thyroid morphology accompanied by T cell infiltration, weight gain, enhanced body temperature, and tachycardia did not manifest preventively and showed milder manifestation in therapeutically treated animals. Importantly, examination of orbital tissue showed significant amelioration of orbitopathy manifestations through reduction of T cell infiltration, adipogenesis, and hyaluronan deposition. Autoimmune hyperthyroidism and orbitopathy were accompanied by changes in peripheral and splenic T cell proportions with high CD3+, CD4+, and CD8+ T cells. Activated T cells CD4+CD25+ were elevated whereas regulatory T cells CD4+Foxp3+ cells remained unchanged in spleens. Fingolimod decreased elevated T cell levels and increased CD4+CD25+Foxp3+ regulatory T cell populations. Analysis of total disease outcome revealed that treatment during disease onset protected animals against autoimmune hyperthyroidism and orbitopathy. Of note, therapeutic intervention after disease onset suppressed disease in half of the animals and in the other half disease remained at mild stages. The results of this study support a clinical trial to investigate the immunologic and clinical benefits of early treatment with S1P-based drugs in GD.

A comparative analysis of piezosurgery and oscillating saw for balanced orbital decompression.

Introduction: Different minimally invasive surgical approaches to the orbit allow individualized bone resection to reduce proptosis and decompress the optic nerve in patients with Graves' orbitopathy (GO). This study aims to compare piezosurgery to an oscillating saw used to resect bone from the lateral orbital wall. Methods: In a retrospective study, we analyzed balanced orbital decompressions performed on 174 patients (318 cases) with GO. An oscillating saw was used in 165 cases (saw group) and piezosurgery in 153 cases (piezo group). Peri- and postoperative complications, reduction of proptosis, new onset of diplopia and improvement of visual acuity in cases of pre-operative optic nerve compression were analyzed. Results: We observed no significant differences in the surgical outcome between the two groups. Proptosis reduction was 4.6 mm in the saw group (p < 0.01) and 5.3 mm in the piezo group (p < 0.01). Intraoperative handling of the piezosurgery device was judged superior to the oscillating saw, due to soft tissue conservation and favourable cutting properties. Duration of the surgery did not differ between the groups. No serious adverse events were recorded in both groups. Conclusion: The application of piezosurgery in orbital decompression is more suitable than an oscillation saw due to superior cutting properties such as less damage to surrounding soft tissue or a thinner cutting grove.

[Corrective Surgery of Severe Esotropia after Decompression in Patients with Graves' Orbitopathy - Comparison of Tendon Elongation and Recession of the Medial Rectus Muscle]. / Korrektur horizontaler Schielwinkel nach Dekompressionsoperation bei Patienten mit endokriner Orbitopathie ­ Vergleich von Sehnenverlängerung und einfacher Rücklagerung des M. rectus medialis.

BACKGROUND: Patients with Graves' orbitopathy (GO) often show severe esotropia after decompression surgery, especially in cases with severe enlargement of muscles before decompression. In severely afflicted patients, simple recessions of the medial rectus muscle are not sufficient. In these patients, tendon elongation with bovine pericardium (Tutopatch®) is an alternative for simultaneous resection of the lateral rectus muscle. We retrospectively analysed our clinical data of patients who underwent corrective surgery of the medial rectus following three-wall decompression surgery. METHODS: Patients who underwent classical uni- or bilateral medial recession (MR, BMR; n = 87) or bilateral medial recessions combined with tendon elongation with a graft at one or both muscles (n = 60), were analysed for surgical success (≤ 10 Δ esotropia, central 20° field of binocular single vision), dose effect (° per mm recession/elongation distance) and postoperative ductions. Clinical data directly after surgery and 3 and 12 months later were evaluated in a retrospective manner. RESULTS: All patients showed lower dose effects compared to medial recessions without prior decompression: Unilateral recession 1.2 ± 0.4°/mm, bilateral 1.0 ± 0.3°/mm, unilateral tendon elongation with contralateral simple recession 0.92 ± 0.3°/mm and bilateral tendon elongation 0.87 ± 0.3°/mm. Because of a preoperatively overestimated dose effect, some patients showed undercorrections after surgery. Under consideration of the actual dose effect, surgical success could often be achieved in these severely afflicted GO patients: After simple recessions in 90% and after tendon elongations in 70% of patients. CONCLUSIONS: In patients following three-wall decompression, higher dosages have to be used for medial recessions and recessions with tendon elongation than with patients without prior decompression. Simple recessions are therefore only to be recommended up to 15° esotropia. In more severe cases up to 25°, tendon elongation can be used.

The influence of orbital decompression on objective nasal function in patients with graves' orbitopathy.

PURPOSE: To determine the influence of anatomical changes after orbital decompression to nasal function. METHODS: We examined postoperative nasal function after orbital decompression in patients with GO in a prospective study. 25 patients were enrolled between 2014 and 2016. Sense of smell (Sniffin' Test) and nasal airflow (anterior rhinomanometry) were tested pre- and 6 weeks postoperatively. In addition, postoperative incidence of sinus infections, persistent pressure pain, and infraorbital hypoesthesia were assessed by means of a questionnaire. RESULTS: The olfactory performance showed a significant increase (p < 0.05) after surgery, while the nasal airflow significantly decreased (p < 0.05). Acute sinus infection occurred in three, infraorbital sensibility disorders in eight cases within the first 6 weeks after surgery. No persistent pain was recorded. CONCLUSION: We demonstrate that decompression of the medial orbital wall leads to a decrease in nasal airflow, whereof patients should be informed before the procedure. This is most likely due to a medialization of the medial turbinate and the prolapse of orbital content into the nasal cavity. The increase of the olfactory performance is, in our opinion, more likely due to variation within the standard deviation than to anatomical changes.

Graves' orbitopathy occurs sex-independently in an autoimmune hyperthyroid mouse model.

Graves' orbitopathy (GO) is the most common extra thyroidal complication of Graves' disease (GD) and occurs predominantly in women but more severe in men. The reason for this effect of gender on GO is unknown. Herein we studied the manifestation of GO in both sexes of an induced mouse model in absence of additional risk factors present in patients like advanced age, genetic variabilities or smoking. Male and female mice were immunized with human TSHR A-subunit encoding plasmid. Both sexes comparably developed autoimmune hyperthyroidism characterized by TSHR stimulating autoantibodies, elevated T4 values, hyperplastic thyroids and hearts. Autoimmune mice developed inflammatory eye symptoms and proptosis, although males earlier than females. Serial in vivo 1H/19F-magnetic resonance imaging revealed elevated inflammatory infiltration, increased fat volume and glycosaminoglycan deposition in orbits of both sexes but most significantly in female mice. Histologically, infiltration of T-cells, extension of brown fat and overall collagen deposition were characteristics of GO in male mice. In contrast, female mice developed predominately macrophage infiltration in muscle and connective tissue, and muscle hypertrophy. Apart from sex-dependent variabilities in pathogenesis, disease classification revealed minor sex-differences in incidence and total outcome. In conclusion, sex does not predispose for autoimmune hyperthyroidism and associated GO.

Noninflammatory Diffuse Follicular Hypertrophy/Hyperplasia of Graves Disease: Morphometric Evaluation in an Experimental Mouse Model.

OBJECTIVES: Experimental models of Graves hyperthyroid disease accompanied by Graves orbitopathy (GO) can be efficiently induced in susceptible inbred strains of mice by immunization by electroporation of heterologous human TSH receptor (TSHR) A-subunit plasmid. The interrelated pathological findings in the thyroid glands of Graves disease (GD) that explain the core changes classically include diffuse follicular hyperplasia and multifocal mild lymphocytic infiltrate. However, the relative contributions of different thyroid tissue components (colloid, follicular cells, and stroma) have not been previously evaluated. In this study, we characterize the thyroid gland of an experimental mouse model of autoimmune GD. Our objective was to define the relative contribution of the different thyroid tissue components to the pathology of glands in the experimental model. METHODS: Mice were immunized with human TSHR A-subunit plasmid. Antibodies induced to human TSHR were pathogenic in vivo due to their cross-reactivity to mouse TSHR. RESULTS: Autoimmune thyroid disease in the model was characterized by histopathology of hyperplastic glands with large follicular cells. Further examination of thyroid glands of immunized animals revealed a significantly increased follicular area and follicle/stroma ratio, morphometrically correlated with a noninflammatory follicular hyperplasia/hypertrophy. The increased follicle/stroma ratio was the most relevant morphometrically variable summarizing the pathological changes for screening purposes. CONCLUSION: GD thyroid glands are enlarged and characterized by a noninflammatory diffuse follicular cell hyperplasia/hypertrophy and a significant increase in the follicles with an increased follicle/stroma ratio. Overall, this mouse model is a faithful model of an early hyperthyroid status of GD (diffuse glandular involvement and follicular expansion).

Functional diagnostics for thyrotropin hormone receptor autoantibodies: bioassays prevail over binding assays.

Autoantibodies to the thyrotropin hormone receptor (TSH-R) are directly responsible for the hyperthyroidism in Graves' disease and mediate orbital manifestations in Graves' orbitopathy (otherwise known as thyroid eye disease). These autoantibodies are heterogeneous in their function and collectively referred to as TRAbs. Measurement of TRAbs is clinically important for diagnosis of a variety of conditions and different commercial assays with high sensitivity and specificity are available for diagnostic purposes. This review provides overwhelming evidence that the TRAbs detected in binding assays by mainly the automated electrochemical luminescence immunoassays (ECLIA) do not distinguish TRAbs that stimulate the TSH-R (called TSIs or TSAbs) and TRAbs that just inhibit the binding of TSH without stimulating the TSH-R (called TBAbs). However, TSAbs and TBAbs have divergent pathogenic roles, and depending which fraction predominates cause different clinical symptoms and engender different therapeutic regimen. Therefore, diagnostic distinction of TSAbs and TBAbs is of paramount clinical importance. To date, only bioassays such as the Mc4 TSH-R bioassay (ThyretainTM, Quidel) and the Bridge assay (Immulite 2000, Siemens) can measure TSAbs, with only the former being able to distinguish between TSAbs and TBAbs. On this note, it is strongly recommended to only use the term TSI or TSAb when reporting the results of bioassays, whereas the results of automated TRAb binding assays should be reported as TRAbs (of undetermined functional significance). This review aims to present a technical and analytical account of leading commercial diagnostic methods of anti-TSH-R antibodies, a metaanalysis of their clinical performance and a perspective for the use of cell based TSH-R bioassays in the clinical diagnostics of Graves' disease.

Stromal versus tumoral inflammation differentially contribute to metastasis and poor survival in laryngeal squamous cell carcinoma.

In solid tumors the biology and clinical course are strongly influenced by the interaction of tumor cells and infiltrating stromal host cells. The aim of this study was to assess the relative importance of stromal vs. tumoral inflammation for metastasis and survival in patients with laryngeal squamous cell carcinoma (LSCC). In 110 patients with tissues from histologically proven LSCC the expression of CD45, CD11b, CD3, MMP-9 and COX-2 was semiquantitatively analyzed in stromal regions and tumor nests. CD45, CD11b, CD3 and MMP-9 positive cells were more abundant in stroma whereas COX-2 was predominantly expressed in epithelial tumor nests. High expression of stromal CD45 and CD11b on immune cells in tumor regions correlated with COX-2 expression on tumor cells. High levels of CD45 in stroma as well as CD11b and COX-2 in tumor nests were associated with increased metastasis. In contrast, high frequencies of CD3 cells in the tumor core area were associated with reduced metastasis. Overall survival was reduced in patients with high stromal CD45, high tumoral CD11b and high tumoral COX-2 expression. This is the first study which separately analyzes peritumoral stroma and tumor core area in laryngeal squamous cell carcinoma in terms of CD45, CD11b, CD3, MMP-9 and COX-2 expression. Our results indicate that stroma and tumor islands need to be considered as two separate compartments in the inflammatory tumor microenvironment. Inflammatory stromal leukocytes, abundant myeloid cells in tumor regions and high expression of COX-2 on tumor cells are linked to metastatic disease and poor overall survival.

CD31 and VEGF are prognostic biomarkers in early-stage, but not in late-stage, laryngeal squamous cell carcinoma.

BACKGROUND: Patients suffering from squamous cell carcinoma of the larynx (LSCC) with lymphatic metastasis have a relatively poor prognosis and often require radical therapeutic management. The mechanisms which drive metastasis to the lymph nodes are largely unknown but may be promoted by a pro-angiogenic tumor microenvironment. In this study, we examined whether the number of microvessels and the expression level of vascular endothelial growth factor (VEGF) in the primary tumor are correlated with the degree of lymph node metastasis (N-stage), tumor staging (T) and survival time in LSCC patients. METHODS: Tissue-Microarrays of 97 LSCC patients were analyzed using immunohistochemistry. The expression of VEGF was scored as intensity of staining (low vs high) and the number of CD31-positive vessels (median

Tendon Elongation with Bovine Pericardium in Patients with Severe Esotropia after Decompression in Graves' Orbitopathy-efficacy and Long-term Stability.

BACKGROUND/AIMS: We performed a retrospective analysis to examine clinical results, establish a dose-effect coefficient and analyze the long-term efficacy of tendon elongation with bovine pericardium (Tutopatch®) for surgical correction of severe esotropia, occurring after three-wall orbital decompression for dysthyroid optic neuropathy in patients with Graves' orbitopathy (GO). METHODS: Tendon elongation of the medial rectus muscle (MR) was performed in our institution using an interponate of bovine pericardium in 60 patients (27 underwent unilateral and 33 bilateral surgery). Success-rate (total horizontal deviation of 10 prism-diopters (PD) or less and evidence of binocular single vision with or without prism glasses) and horizontal motility were examined 3 months, 1 and >4 years after surgery. A dose-effect coefficient for deviation reduction (PD) per recession distance (mm) was established. RESULTS: Horizontal deviations between 28-80Δ were corrected. Diplopia in primary-gaze disappeared in 65% of the patients after 3 months and in 83% after one year (including 12 patients who underwent subsequent surgery after 3-month follow-up). Patients with deviations ≤40Δ after unilateral and ≤50Δ after bilateral tendon elongation showed higher primary success-rates after 3 months (78% and 72%). Vertical deviations (≤10Δ) were corrected by the procedure in 28% without need of recession of the inferior rectus (IR). Only 3 patients showed overcorrection after one year. One of these underwent revision surgery, in which the interponate was no longer discernible from surrounding fibrotic scar tissue. At >4-year follow-up (4.3-15years) effects were stable and 95% of patients showed fusion in primary gaze. Median dose-effect coefficient was lower after tendon elongation (1.8Δ/mm) compared to conventional medial rectus recession in patients with GO. Horizontal motility was slightly decreased, but much more symmetric around primary gaze. CONCLUSION: Tendon elongation with a bovine pericardium implant is a safe surgical method, suitable to correct severe esotropia after decompression surgery. A lower dose-effect has to be taken into account. Patients with esotropia ≥42Δ should not be treated with unilateral, but bilateral tendon elongation, to avoid undercorrections. In patients with deviations ≥52Δ it has to be further investigated if the application of even higher elongation distances is viable or if another approach-the recession of more than one rectus muscle has to be performed simultaneously to handle the severe restriction. Generally, a step-by-step approach is advisable, since small vertical deviations could also be corrected in a third of patients with the procedure and the dose-effect was more variable as in medial recessions without tendon elongation.

Multimodal assessment of orbital immune cell infiltration and tissue remodeling during development of graves disease by 1 H19 F MRI.

PURPOSE: To evaluate key molecular and cellular features of Graves orbitopathy (GO) by simultaneous monitoring of alterations in morphology, inflammatory patterns, and tissue remodeling. METHODS: To this end, we utilized a murine model of GO induced by immunization with a human thyroid-stimulating hormone receptor A-subunit plasmid. Altogether, 52 mice were used: 27 GOs and 25 controls (Ctrl) immunized with ß-galactasidose plasmid. From these, 17 GO and 12 Ctrl mice were subjected to multimodal MRI at 9.4T, whereas 23 mice only underwent histology. Beyond anatomical hydrogen-1 (1 H) MRI, we employed transverse relaxation time (T2 ) mapping for visualization of edema, chemical exchange saturation transfer (CEST) for detection of hyaluronan, and fluorine-19 (19 F) MRI for tracking of in situ-labeled immune cells after intravenous injection of perfluorcarbons (PFCs). RESULTS: 1 H/19 F MRI demonstrated substantial infiltration of PFC-loaded immune cells in peri and retro-orbital regions of GO mice, whereas healthy Ctrls showed only minor 19 F signals. In parallel, T2 mapping indicated onset of edema in periorbital tissue and adjacent ocular glands (P = 0.038/0.017), which were associated with enhanced orbital CEST signals in GO mice (P = 0.031). Concomitantly, a moderate expansion of retrobulbar fat (P = 0.029) was apparent; however, no signs for extraocular myopathy were detectable. 19 F MRI-based visualization of orbital inflammation exhibited the highest significance level to discriminate between GO and Ctrl mice (P = 0.006) and showed the best correlation with the clinical score (P = 0.0007). CONCLUSION: The present approach permits the comprehensive characterization of orbital tissue and holds the potential for accurate GO diagnosis in the clinical setting. Magn Reson Med 80:711-718, 2018. © 2018 International Society for Magnetic Resonance in Medicine.

[Endoscopic Browlift via Endotine Forehead Device in Patients with Facial Palsy]. / Das endoskopische Browlift mittels Endotine Forehead Device bei Fazialisparese.

Objective Forehead and brows form a critical aesthetic and functional subunit of the face. Chronical pPeripheral paralysis of the facial nerve or its frontal branch may cause brow ptosis and eyelid deformities with a limited field of vision and loss of facial symmetry. Techniques, especially endoscopic methods have evolved significantly. Endotine Forehead Device, an adsorbable device, is a promising tool for brow suspension. Material and Methods 9 patients underwent brow and forehead lift surgery via Endotine Forehead Device. Intraoperative handling, complications, and the surgical outcome were assessed. To analyze postoperative symmetry FACEgram software was used. Follow-up was about 3,6 months after surgery. As a patient oriented outcome parameter the Glasgow Benefit Inventory Questionnaire was assessed about 10 months after surgery. Results Using the Endotine Forehead Device via an endoscopic approach was helpful to recreate a symmetrical upper third of the face. Few adverse effects could be observed:. One relapse was detected, one patient complained about the palpability of the device. Patients stated an improved quality of life after surgery, overall benefit in quality of life was +29,2 (SD 13,6). Conclusions Endotine Forehead Device is a successful minimally invasive tool for endoscopic brow and forehead lift surgery in patients with facial paralysis.

[Extracranial schwannomas of the Head and Neck: Clinical -approach based on 20 cases]. / Extrakranielle Schwannome im Kopf-Hals-Bereich: Klinische Implikationen anhand von 20 Fällen.

Background Schwannomas are rare benign tumors originating from the perineural cells forming the myelin layer in the peripheral nervous system (PNS). While well established therapeutic concepts exist for intracranial schwannomas, there is a lack of consistent clinical standards for extracranial schwannomas. Method This retrospective study describes the clinical pathway of 20 patients with histologically proven extracranial schwannomas of the head and neck. The diagnostic and therapeutic strategies for schwannomas are discussed with special emphasis on localization and functional outcome. Results Extracranial schwannomas of the head and neck region mostly originated from the facial nerve (n = 4), vagal nerve (n = 4) or sympathetic chain (n = 3). Most common symptoms were swelling (n = 12) and pain (n = 3). Preoperative imaging included MRI (n = 13), ultrasound (n = 12) and CT (n = 3). Surgical intervention was performed in 18 cases (n = 14 complete extirpation, n = 3 partial extirpation, n = 1 unknown). Regarding completely extirpated schwannomas of motor nerves (n = 10) severing the nerve of origin was more often required in patients with a preexisting functional deficit (3 out of 4 = 75 %) than in patients without preexisting deficits (2 out of 6 = 33 %). Conclusion Representing rare tumors of the head and neck region mostly originating from the facial nerve, sympathetic chain or caudal cranial nerves extracranial schwannomas require a systematic diagnostic and therapeutic approach. Postoperative functional deficits after complete extirpation must especially be anticipated in patients with a preexisting functional deficit.

Evaluation of the application of rhino-septal splints in endoscopic transsphenoidal skull base surgery.

The endoscopic transnasal route for the surgical removal of tumors in the sellar region is frequently associated with nasal complications such as synechiae or impaired nasal breathing. In this study, we investigated the impact of septal splints on avoiding surgery-related co-morbidities. 49 patients in whom endoscopic transnasal, transsphenoidal surgery for sellar tumors was performed between 2012 and 2014 were studied. In 30 of these, nasal septal splints were applied at the end of surgery to both sides of the septum and left in situ for 10 days (group 1), 19 patients received no splints (group 2). A standardized postsurgical follow-up investigation with endoscopic nasal examination, rhinomanometry and olfactory testing was performed on average 2 months postoperatively. Patients' subjective nose-related discomfort at follow-up was assessed descriptively using a set of standardized self-rating statements on nasal problems. Synechias occurred less likely with nasal septal splints (n = 15; 50 %) than without (n = 16; 84.2 %). Moreover, multiple synechiae were predominantly observed in the group without septal splints (n = 10 vs. n = 2). Rhinomanometry showed improved flow-V150-inspiration scores when splints were used (with significant differences between groups for the left nostril: p = 0.039 and p = 0.022, resp.). In accordance, impaired nasal breathing after surgery was reported more frequently by 76.9 % of patients without splints, but only 56 % of patients with splints. Our results provide support for the application of nasal septal splints when operating endoscopically on tumors in the sellar region to reduce postoperative synechias and to improve nasal breathing.