[Excisional surgery of orbital tumors]. / Exzisionale Chirurgie orbitaler Tumoren.

The indications for orbital tumor surgery are an incisional biopsy to confirm the diagnosis or in malignant operable tumors a complete excision or a debulking to avoid complications in large invasively infiltrating tumors. In the case of benign tumors, the indications for surgery depend mostly on the clinical symptoms and cosmetic esthetic disfigurement. In the present article the preoperative examinations as well as surgical access approaches to different orbital regions, endoscopic procedures and methods of intraoperative navigation are presented. Magnetic resonance imaging is the instrument of choice, whereby in many cases computed tomography (CT) adds further information. Depending on the indications, diffusion-weighted sequences, CT angiography and digital subtraction angiography (DSA, catheter angiography) are added to the preoperative diagnostics. For space-occupying lesions located anterior to the bulbar equator, an anterior orbitotomy can be performed transconjunctivally or transpalpebrally. A lateral orbitotomy is used to reach lateral, laterocranial, and lateroinferior orbital segments, whereas transcranial approaches are suitable for processes located far posterior and for those with retro-orbital intracranial extension as well as for processes in the optic foramen/superior orbital fissure. The indications for an endonasal access approach are processes medial to the bulb or optic nerve and up to the orbital apex. A transantral access can be chosen for caudal, mediolateral, and medioinferior space-occupying lesions. Modern orbital surgery is complemented by endoscopic procedures and intraoperative navigation. Orbital tumors belong to the interdisciplinary relevant diseases. Therefore, an optimal management takes place at specialized multidisciplinary centers.

Thyrotropin receptor antibodies and Graves' orbitopathy.

CONTEXT AND PURPOSE: The thyrotropin receptor (TSHR) is the key autoantigen in Graves' disease (GD) and associated orbitopathy (GO). Antibodies targeting the TSHR (TSHR-Ab) impact the pathogenesis and the course of GO. This review discusses the role and clinical relevance of TSHR-Ab in GO. METHODS: Review of the current and pertinent literature. RESULTS: GO is the most common extrathyroidal manifestation of GD and is caused by persistent, unregulated stimulation of TSHR-expressing orbital target cells (e.g. fibroblasts and pre-adipocytes). Serum TSHR-Ab and more specifically, the stimulatory Ab (TSAb) are observed in the vast majority of patients with GD and GO. TSHR-Ab are a sensitive serological parameter for the differential diagnosis of GO. TSHR-Ab can be detected either with conventional binding immunoassays that measure binding of Ab to the TSHR or with cell-based bioassays that provide information on their functional activity and potency. Knowledge of the biological activity and not simply the presence or absence of TSHR-Ab has relevant clinical implications e.g. predicting de-novo development or exacerbation of pre-existing GO. TSAb are specific biomarkers of GD/GO and responsible for many of its clinical manifestations. TSAb strongly correlate with the clinical activity and clinical severity of GO. Further, the magnitude of TSAb indicates the onset and acuity of sight-threatening GO (optic neuropathy). Baseline serum values of TSAb and especially dilution analysis of TSAb significantly differentiate between thyroidal GD only versus GD + GO. CONCLUSION: Measurement of functional TSHR-Ab, especially TSAb, is clinically relevant for the differential diagnosis and management of GO.

Charles Bonnet's syndrome: not only a condition of the elderly.

PURPOSE: To investigate whether the experience of visual hallucinations, namely Charles Bonnet's syndrome, in psychologically healthy people is a phenomenon solely of elderly, visually impaired people. METHODS: In a prospective controlled study, four groups of subjects (total 324) were formed: age ≤40 years, no visual impairment; age ≤40 years, visually impaired; age >40 years, no visual impairment; age >40 years, visually impaired. Visual impairment was defined as best-corrected visual acuity ≤0.3 (Snellen) in the better-seeing eye. Each group consisted of 81 subjects. Visual hallucinations were defined as complex visual perceptions. After ruling out psychiatric causes for visual hallucinations or medication related to the experience of visual hallucinations, affected subjects underwent a detailed interview about their visual hallucinations. RESULTS: The prevalence of visual hallucinations among young subjects with visual impairment was 4.9 %; among the elderly visually impaired subjects, it was 6.2 %. The difference was not statistically significant. No subject without visual impairment experienced visual hallucinations. CONCLUSIONS: Charles Bonnet's syndrome is not limited to elderly people suffering from visual impairment, though there tends to be a higher prevalence of visual hallucinations in this group.

Proteomics of Orbital Tissue in Thyroid-Associated Orbitopathy.

CONTEXT: A potentially altered protein expression profile in orbital tissue from patients with thyroid-associated orbitopathy (TAO) is suspected. OBJECTIVE: To detect for the first time changes in proteomic patterns of orbital connective tissue in TAO and compare these with control tissue using mass spectrometry. DESIGN: Proteomics cross-sectional, comparative study. SETTING: Two academic endocrine institutions. SAMPLES: A total of 64 orbital and peripheral adipose tissue samples were collected from 39 patients with TAO and 25 control subjects. METHODS: Samples were analyzed and identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry technology. MAIN OUTCOME MEASURES: Mean intensity values of all identified peptides per protein. RESULTS: Thirty-one proteins were identified, of which 16 differentiated between controls and patients with TAO. Different protein patterns between orbital and peripheral adipose tissue were observed. Compared to controls, 10 proteins were markedly up-regulated (≥ 2-fold) in the orbital tissue of untreated patients: beta IV spectrin (6.2-fold), GTP binding G protein 2 (5.6-fold), POTE ankyrin domain family member F (5.4-fold), xylulokinase (4.1-fold), kinesin family member 1A and lipocalin 1 (both 3.6-fold), semicarbazide-sensitive metalloproteinase amine oxidase 3 and polymerase I transcript release factor (both 3.4-fold), cell-cycle protein elongin A binding protein 1 (3.3-fold), annexin A2 and cavin (both 3-fold), protein pointing to cell proliferation histone H4 (2.8-fold), and ADAM metallopeptidase with thrombospondin type 1 motif 14 (2.7-fold). The highest protein up-regulations were noted in the orbital tissue of medically untreated patients. Steroid therapy markedly reduced up-regulation of these proteins, foremost in nonsmokers. CONCLUSIONS: Proteins involved in tissue inflammation, adipose tissue differentiation, lipid metabolism, and tissue remodeling were up-regulated in orbital tissue of untreated patients with TAO. Steroids decreased the expression of these proteins, whereas smoking attenuated such effect.

Prevalence and risk factors of retinal vein occlusion: the Gutenberg Health Study.

OBJECTIVE: To determine the age- and sex-specific prevalence and determinants of retinal vein occlusions (RVOs) in a large population-based German cohort. METHODS: The investigation included 15,010 participants (aged 35-74 years) from the Gutenberg Health Study. We determined the prevalence of RVO (central retinal vein occlusion [CRVO] and branch retinal vein occlusion [BRVO]) for the local population by assessing fundus photographs of 12 954 (86.3%; 49.8% women and 50.2% men) participants. Further, we analyzed the associations of RVO with cardiovascular, anthropometric, and ophthalmic parameters. RESULTS: The weighted prevalences of RVO, CRVO, and BRVO were 0.40%, 0.08%, and 0.32%, respectively. Men were 1.7 times more frequently affected by RVO than were women. Prevalence of RVO was 0.2% in participants aged 35-44 and 45-54 years, respectively, 0.48% in those aged 55-64 years, and 0.92% in those aged 65-74 years. Of persons with RVO, 91.5% had one or more cardiovascular risk factor or disease vs. 75.9% of persons without RVO. BRVO was associated with arterial hypertension (odds ratio 2.69, 95% confidence interval 1.27-5.70) and atrial fibrillation (3.37, 1.24-9.12) and CRVO with higher age (7.02, 1.63-30.19) and a family history of stroke (4.64, 1.18-18.25). Median visual acuity (base 10 logarithm of minimum angle of resolution) was 0.2 in persons with RVO vs. 0.05 in those without. CONCLUSION: The prevalence of RVO in this German population was 0.4%, and men were 1.7 times more frequently affected than women. CRVO was associated with higher age and a family history of stroke, and BRVO was associated with arterial hypertension and atrial fibrillation.

Thyroid-stimulating immunoglobulins indicate the onset of dysthyroid optic neuropathy.

PURPOSE: Recognition of dysthyroid optic neuropathy (DON) requires sensitive diagnostic tools. Clinical assessment may fail to reliably evaluate the acuteness of DON especially if signs for inflammation are missing. Aim of this cross-sectional study was to assess the relationship between thyroid-stimulating immunoglobulins (TSI) and onset of DON. METHODS: At a multidisciplinary orbital center, serum TSI levels were measured in 180 consecutive patients with thyroid eye disease (TED) and 302 healthy controls with a FDA-cleared cell-based bioassay using a chimeric TSH receptor and a CRE-dependent luciferase. RESULTS: Thirty of 180 (16.7 %) patients with TED had DON of recent onset or a past history of DON (post-DON). Optic disk swelling was present and visual-evoked potentials were pathologic in all eyes with DON of recent onset, but in one of 13 (7.7 %) with post-DON, only (p = 0.005). 19/20 (96 %) patients with DON of recent onset were TSI-positive. TSI was associated with DON of recent onset (OR: 20.96; 95 % CI 1.064-412.85, p = 0.045). All controls were TSI negative. TSI correlated with the clinical activity score (R = 0.70, p < 0.001) and higher TSI-levels were noted in active vs. inactive TED (485.1 ± 132.3 vs. 277.7 ± 143.7 %, cut-off < 140 %; p < 0.001). Six of seven (85.7 %) patients with inactive TED with recent onset DON versus one of four (25 %) with active post-DON were TSI-positive (p = 0.006). A discriminatory cut-point of 377 SRR % for TSI was determined based on a ROC analysis (sensitivity: 0.95, specificity: 0.8). CONCLUSIONS: Serum TSI levels identify patients with DON of recent onset requiring urgent therapy.

Thyroid-associated orbitopathy is linked to gastrointestinal autoimmunity.

Common autoimmune disorders tend to co-exist in the same subjects and cluster in families. The objective of this study was to determine the prevalence of autoimmune co-morbidity in patients with autoimmune thyroid disease (AITD) with and without thyroid-associated orbitopathy (TAO). This was a cross-sectional study conducted at an academic tertiary referral centre. Of 1310 patients with AITD [n = 777 or 59% with Graves' disease (GD) and n = 533, 41% with Hashimoto's thyroiditis (HT)] followed at a specialized joint thyroid-eye out-patient clinic, 176 (13·4%) had an adult type of the autoimmune polyglandular syndrome, 129 (9·8%) type 1 diabetes, 111 (8·5%) coeliac disease, 60 (4·6%) type A autoimmune gastritis, 57 (4·4%) vitiligo and 25 (1·9%) Addison's disease. Coeliac disease and autoimmune gastritis were associated positively with GD [odds ratio (OR) = 2·18; P = 0·002 and OR = 6·52; P < 0·001], whereas type 1 diabetes, Addison's disease, autoimmune primary hypogonadism, alopecia areata, rheumatoid arthritis and Sjögren's syndrome were 'protective' for GD and thus linked to HT, OR = 0·49 (P < 0·001), 0·06 (P < 0·001), 0·25 (P < 0·001), 0·50 (P = 0·090) and 0·32 (P = 0·003), respectively. Of 610 (46·6%) AITD patients with TAO, 584 (95·7%) and 26 (4·3%) had GD and HT, respectively (P < 0·001). TAO was most prevalent in GD patients with coeliac disease (94%, OR = 1·87, P < 0·001). Multivariate analysis showed high OR for coeliac disease and autoimmune gastritis (3·4 and 4·03, both P < 0·001) pertaining to the association with TAO while type 1 diabetes, Addison's disease and alopecia areata were protective for TAO. In patients with TAO, coeliac disease is the most prevalent co-morbid autoimmune condition and rates are increased compared to GD patients without TAO.

[Ophthalmological aspects of the Gutenberg Health Study (GHS): an interdisciplinary prospective population-based cohort study]. / Ophthalmologische Aspekte der Gutenberg Gesundheitsstudie: Eine interdisziplinäre prospektive populationsbasierte Kohortenstudie.

The Gutenberg Health Study (GHS) is a prospective, single center, population-based cohort study. It is an interdisciplinary project for investigation of ocular, cardiovascular, psychosomatic and immune diseases in the population of the City of Mainz and the district of Mainz-Bingen in central Germany. The main goals of the ophthalmological branch of GHS are determination of the prevalence and incidence of major ocular risk factors and diseases, exploring the genetic determinants and assessing complex interdisciplinary associations. The study cohort includes 15,010 participants aged between 35 and 74 years at the time of inclusion. After completing the baseline investigations the 5-year follow-up of the whole study cohort started in April 2012. The GHS is the most extensive data set of major ophthalmological conditions and risk factors in Germany and will help researchers in understanding complex medical associations.

[Vascular anomaly of the iris]. / Gefäßanomalie der Iris.

A 48-year-old man presented with a vascular anomaly of the iris in the left eye. Slit-lamp microscopy revealed dilated and tortuous vessels of the iris between 12 and 4 o'clock. Fluorescein angiography confirmed a diagnosis of arteriovenous (AV) malformation of the iris. The vessel originated at the iris base, passed to the pupillary margin and returned to the base. Such AV-malformations of the iris are very rare, benign vascular anomalies that have to be distinguished from other, potentially malignant pathologies of the iris (e. g. tortuous vessels in iris melanoma).

Clinical review: Intravenous glucocorticoids for Graves' orbitopathy: efficacy and morbidity.

CONTEXT: The administration of iv glucocorticoid pulses has been advocated as a treatment approach for patients with inflammatory and moderate to severe Graves' orbitopathy (GO). This review offers an update on this controversial regimen. EVIDENCE ACQUISITION: PubMed and the MeSH-Database were searched (with no temporal limit) for the following topics: management of active and severe GO; glucocorticoid therapy of GO; iv glucocorticoid administration; mechanism and pharmacokinetics of iv glucocorticoids; and adverse events, morbidity, and mortality of iv glucocorticoids. The articles were evaluated according to their setting and study design. EVIDENCE SYNTHESIS: All randomized and uncontrolled trials, consensus statement, systematic reviews, and meta-analyses dealing with the efficacy and morbidity of iv glucocorticoids in GO were identified. CONCLUSIONS: The current first-line treatment for active, moderate-to-severe GO is a 12-wk course of high-dose iv glucocorticoid pulses. The response rate of this regimen is approximately 80%. Intravenous glucocorticoids have a statistically significant advantage over oral treatment and cause significantly fewer adverse events. However, major side effects related to preexisting diseases, administered dose, and treatment schedule have been reported. The morbidity and mortality of iv glucocorticoid therapy are 6.5 and 0.6%, respectively. Thus, careful patient selection is warranted. Before iv glucocorticoid administration, patients should be screened for recent hepatitis, liver dysfunction, cardiovascular morbidity, severe hypertension, inadequately managed diabetes, and glaucoma. The cumulative dose should not exceed 8 g, and with the exception of sight-threatening GO the single doses preferably should not be administered on consecutive days. Monthly monitoring during subsequent treatment is warranted.

Dose of intravenous steroids and therapy outcome in Graves' orbitopathy.

BACKGROUND AND AIM: Several trials have proved the efficacy of intravenous (IV) steroids in Graves' orbitopathy (GO). However, the impact of administered dose and therapy schedule has not been assessed yet. SUBJECTS AND METHODS: Nine randomized and 14 non-randomized controlled trials of IV steroids in GO were evaluated according to the applied single and cumulative doses with respect to outcome, efficacy on clinically relevant issues and adverse events. RESULTS: High single (1 g per day) and cumulative (>6 g) doses of IV steroids are superior to lower single (0.5 g/d) and cumulative (<5 g) doses with respect to therapy response (84 vs 75%; p=0.034 and 83 vs 77%; ns, respectively), improvement of eye symptoms (87 vs 75%, p=0.052 and 85 vs 71%; ns, respectively) and disappearance of diplopia (32 vs 27%; ns and 48 vs 27%; p=0.08, respectively). Decrease of both clinical activity score (3 vs 2.5 points and 2.5 vs 3, ns) as well as proptosis (-1.4 vs -1.2 mm, ns and 1.5 vs 1.2, ns) are similar in both groups. However, high single and/or cumulative doses are accompanied with a 2-fold higher rate of adverse events (56 vs 28%; p<0.001 and 52 vs 33%; p=0.034, respectively). CONCLUSIONS: Tailoring the IV steroid dose to severity of GO can be concluded and implies that a prospective randomized trial comparing different doses of IV steroids in active/severe GO is keenly warranted.

A novel thyroid stimulating immunoglobulin bioassay is a functional indicator of activity and severity of Graves' orbitopathy.

CONTEXT: Immunoglobulins stimulating the TSH receptor (TSI) influence thyroid function and likely mediate extrathyroidal manifestations of Graves' disease (GD). OBJECTIVES: The aim of this study was to assess the clinical relevance of TSI in GD patients with or without Graves' orbitopathy (GO), to correlate the TSI levels with activity/severity of GO, and to compare the sensitivity/specificity of a novel TSI bioassay with TSH receptor (TSH-R) binding methods (TRAb). DESIGN: TSI were tested in two reporter cell lines designed to measure Igs binding the TSH-R and transmitting signals for cAMP/CREB/cAMP regulatory element complex-dependent activation of luciferase gene expression. Responsiveness to TSI of the novel chimeric (Mc4) TSH-R (amino acid residues 262-335 of human TSH-R replaced by rat LH-R) was compared with the wild-type (wt) TSH-R. RESULTS: All hyperthyroid GD/GO patients were TSI-positive. TSI were detected in 150 of 155 (97%, Mc4) and 148 of 155 (95%, wt) GO patients, in six of 45 (13%, Mc4) and 20 of 45 (44%, wt) mostly treated GD subjects, and in 0 of 40 (Mc4) and one of 40 (wt) controls. Serum TSI titers were 3- and 8-fold higher in GO vs. GD and control, respectively. All patients with diplopia and optic neuropathy and smokers were TSI-positive. TSI strongly correlated with GO activity (r = 0.87 and r = 0.7; both P < 0.001) and severity (r = 0.87 and r = 0.72; both P < 0.001) in the Mc4 and wt bioassays, respectively. Clinical sensitivity (97 vs. 77%; P < 0.001) and specificity (89 vs. 43%; P < 0.001) of the Mc4/TSI were greater than TRAb in GO. All 11 of 200 (5.5%) TSI-positive/TRAb-negative patients had GO, whereas all seven of 200 (3.5%) TSI-negative/TRAb-positive subjects had GD only. CONCLUSION: The novel Mc4/TSI is a functional indicator of GO activity and severity.

[Management of Graves' orbitopathy: evidence-based recommendations]. / Vorgehen bei endokriner Orbitopathie. Evidenzbasierte Empfehlungen.

Patients with Graves' orbitopathy (GO) suffer from disfiguring proptosis, orbital pain and diplopia. Compression of the optic nerve may cause functional restrictions to the point of loss of vision. Since suboptimal management of GO seems to be widespread, the European Group On Graves' Orbitopathy (EUGOGO) provided a consensus statement on the management of GO. According to EUGOGO, patients with GO should be referred to multidisciplinary specialist centers. All patients should be encouraged to quit smoking. Prompt treatment of thyroid dysfunction is mandatory in order to restore and maintain euthyroidism. The first-line treatment for optic neuropathy and/or corneal ulceration are intravenous glucocorticoids. If the response is poor after 1-2 weeks, orbital decompression surgery should follow. Intravenous glucocorticoids are also recommended in patients with moderate-to-severe and active GO. If GO is inactive, surgery should be considered. Local measures and an expectant strategy are sufficient in most patients with mild GO, but if quality of life is affected significantly, specific treatment may be justified. Thus, management of GO remains challenging and is best performed within a multidisciplinary orbital center.