Thyroid stimulating immunoglobulin concentration is associated with disease activity and predicts response to treatment with intravenous methylprednisolone in patients with Graves' orbitopathy.

Background: Thyroid stimulating immunoglobulins (TSI) play a central role in the pathogenesis of Graves' orbitopathy (GO), while soluble interleukin-2 receptor (sIL-2R) is a marker for T-cell activity. We investigated TSI and sIL-2R levels in relation to thyroid function, disease activity and severity and response to treatment with intravenous methylprednisolone (IVMP) in patients with GO. Methods: TSI (bridge-based TSI binding assay), sIL-2R, TSH and fT4 levels were measured in biobank serum samples from 111 GO patients (37 male, 74 female; mean age 49.2 years old) and 25 healthy controls (5 male, 20 female; mean age 39.8 years old). Clinical characteristics and response to treatment were retrospectively retrieved from patient files. Results: Higher sIL-2R levels were observed in GO patients compared to controls (p < 0.001). sIL-2R correlated with fT4 (r = 0.26), TSH (r = -0.40) and TSI (r = 0.21). TSI and sIL-2R concentrations were higher in patients with active compared to inactive GO (p < 0.001 and p < 0.05, respectively). Both TSI and sIL-2R correlated with total clinical activity score (CAS; r = 0.33 and r = 0.28, respectively) and with several individual CAS items. Cut-off levels for predicting active GO were 2.62 IU/L for TSI (AUC = 0.71, sensitivity 69%, specificity 69%) and 428 IU/mL for sIL-2R (AUC = 0.64, sensitivity 62%, specificity 62%). In multivariate testing higher TSI (p < 0.01), higher age (p < 0.001) and longer disease duration (p < 0.01) were associated with disease activity. TSI levels were higher in patients with a poor IVMP response (p = 0.048), while sIL-2R levels did not differ between responders and non-responders. TSI cut-off for predicting IVMP response was 19.4 IU/L (AUC = 0.69, sensitivity 50%, specificity 91%). In multivariate analysis TSI was the only independent predictor of response to IVMP (p < 0.05). Conclusions: High TSI levels are associated with active disease (cut-off 2.62 IU/L) and predict poor response to IVMP treatment (cut-off 19.4 IU/L) in GO. While sIL-2R correlates with disease activity, it is also related to thyroid function, making it less useful as an additional biomarker in GO.

Eye Muscle MRI in Myasthenia Gravis and Other Neuromuscular Disorders.

INTRODUCTION: MRI of extra-ocular muscles (EOM) in patients with myasthenia gravis (MG) could aid in diagnosis and provide insights in therapy-resistant ophthalmoplegia. We used quantitative MRI to study the EOM in MG, healthy and disease controls, including Graves' ophthalmopathy (GO), oculopharyngeal muscular dystrophy (OPMD) and chronic progressive external ophthalmoplegia (CPEO). METHODS: Twenty recently diagnosed MG (59±19yrs), nineteen chronic MG (51±16yrs), fourteen seronegative MG (57±9yrs) and sixteen healthy controls (54±13yrs) were included. Six CPEO (49±14yrs), OPMD (62±10yrs) and GO patients (44±12yrs) served as disease controls. We quantified muscle fat fraction (FF), T2water and volume. Eye ductions and gaze deviations were assessed by synoptophore and Hess-charting. RESULTS: Chronic, but not recent onset, MG patients showed volume increases (e.g. superior rectus and levator palpebrae [SR+LPS] 985±155 mm3 compared to 884±269 mm3 for healthy controls, p < 0.05). As expected, in CPEO volume was decreased (e.g. SR+LPS 602±193 mm3, p < 0.0001), and in GO volume was increased (e.g. SR+LPS 1419±457 mm3, p < 0.0001). FF was increased in chronic MG (e.g. medial rectus increased 0.017, p < 0.05). In CPEO and OPMD the FF was more severely increased. The severity of ophthalmoplegia did not correlate with EOM volume in MG, but did in CPEO and OPMD. No differences in T2water were found. INTERPRETATION: We observed small increases in EOM volume and FF in chronic MG compared to healthy controls. Surprisingly, we found no atrophy in MG, even in patients with long-term ophthalmoplegia. This implies that even long-term ophthalmoplegia in MG does not lead to secondary structural myopathic changes precluding functional recovery.

Globe-sparing surgical treatment for periocular malignancies with anterior orbital invasion: a consecutive case series.

PURPOSE: Orbital exenteration of periocular tumors complicated by orbital invasion is a heavy burden for patients and leads to disfiguring cosmesis and loss of vision. Here, we report our experience with globe-sparing surgery in a series of patients with periocular malignancies other than basal cell carcinoma (BCC), all exhibiting anterior orbital invasion. METHODS: In this consecutive case series, we examined medical records of all patients between 2000 and 2018 with periocular malignancies (other than BCC) invading the anterior orbit (without extraocular muscle or scleral invasion) treated by one orbital surgeon (DP). The main outcome measures included local recurrence, regional and distant metastasis, survival, and visual acuity. RESULTS: Nine patients were identified. Of the non-BCC cancers invading the orbit, squamous cell carcinoma (SCC) (44.4%) was the most prevalent type in our series. Excision included the removal of visibly distinguishable tumor and a free clinical margin of up to 5 mm with histological confirmation of radicality of the invasive tumor component. Reconstruction was achieved by a variety of oculoplastic reconstructive procedures. At a mean follow-up of 70 months (range 11-177 months), 8 out of 9 patients were still alive. Recurrence occurred in two patients with conjunctival melanoma (CM), and they were again treated with wide excision. Postoperative visual acuity remained stable or improved. CONCLUSION: This retrospective case series demonstrates that globe-sparing excisional surgery can be considered in selected cases of periocular malignancies other than BCC with anterior orbital invasion, thus avoiding cosmetic disfigurement and loss of vision due to orbital exenteration.

Bone metastasis in a case of primary acquired melanosis with atypia resulting from conjunctiva melanoma.

A 66-year-old woman presented to a tertiary referral centre with a diagnosis of limbal stem cell deficiency secondary to multiple treatments for primary acquired melanosis (PAM) by her referring ophthalmologists. She was known with primary acquired melanosis with severe atypia of the right eye which had been treated with several excisions, cryotherapy and topical chemotherapy. She had PAM over 360° of alternating intensity. Throughout the follow-up period, she developed a cataract and subsequent a retinal detachment for which she underwent a phacovitrectomy on the right eye. There was no nodule present nor did the routine lymph nodes inspection show any enlargement. No abnormalities were observed on intranasal examination. Seven years after the last excision, a metastasis to the spine (Th3) was diagnosed. A complete systemic work-up and a pathological examination did not show any alternative primary melanoma in the body. The original histological material was reviewed again by an ophthalmopathologist. After a new round of stains and immunohistochemistry, the presence of atypical melanocytes in both the epithelium and stroma were found in a scar region leading to a renewed conclusion that the PAM in question was actually the primary melanoma.

miR-196b-5p and miR-107 Expression Differentiates Ocular Sebaceous Carcinoma from Squamous Cell Carcinoma of the Conjunctiva.

An Ocular Sebaceous Carcinoma (OSC) is a rare malignant tumor for which initial clinical and pathological diagnosis is often incorrect. OSCs can mimic Squamous Cell Carcinomas of the Conjunctiva (SCCC). The aim of this study was to find microRNA biomarkers to distinguish OSCs and SCCCs from normal tissue and from each other. Clinical OSC and SCCC case files and the corresponding histopathological slides were collected and reviewed. Micro dissected formalin-fixed paraffin-embedded tumor and control tissues were subjected to semi-high throughput microRNA profiling. MicroRNA expression distinguishes OSCs and SCCCs from corresponding control tissues. Selected differentially expressed miRNAs were validated using single RT-PCR assays. No prognostic miRNAs could be identified that reliably predict SCCC metastasis or OSC recurrence. A comparison between OSCs (n = 14) and SCCCs (n = 18) revealed 38 differentially expressed microRNAs (p < 0.05). Differentially expressed miRNAs were selected for validation in the discovery cohort and an independent validation cohort (OSCs, n = 11; SCCCs, n = 12). At least two miRNAs, miR-196b-5p (p ≤ 0.05) and miR-107 (p ≤ 0.001), displayed a statistically significant differential expression between OSCs and SCCCs with miR-196b-5p upregulated in SCCCs and miR-107 upregulated in OSCs. In the validation cohort, microRNA miR-493-3p also showed significant upregulation in SCCCs when compared to OSCs (p ≤ 0.05). ROC analyses indicated that the combined miR-196b-5p and miR-107 expression levels predicted OSCs with 90.0% sensitivity and 83.3% specificity. In conclusion, the combined testing of miR-196b-5p and miR-107, can be of additional use in routine diagnostics to discriminate OSCs from SCCCs.

Is Tissue Still the Issue? The Promise of Liquid Biopsy in Uveal Melanoma.

Uveal melanoma (UM) is the second most frequent type of melanoma. Therapeutic options for UM favor minimally invasive techniques such as irradiation for vision preservation. As a consequence, no tumor material is obtained. Without available tissue, molecular analyses for gene expression, mutation or copy number analysis cannot be performed. Thus, proper patient stratification is impossible and patients' uncertainty about their prognosis rises. Minimally invasive techniques have been studied for prognostication in UM. Blood-based biomarker analysis has become more common in recent years; however, no clinically standardized protocol exists. This review summarizes insights in biomarker analysis, addressing new insights in circulating tumor cells, circulating tumor DNA, extracellular vesicles, proteomics, and metabolomics. Additionally, medical imaging can play a significant role in staging, surveillance, and prognostication of UM and is addressed in this review. We propose that combining multiple minimally invasive modalities using tumor biomarkers should be the way forward and warrant more attention in the coming years.

Outcome after treatment for sebaceous carcinoma: A multicenter study.

BACKGROUND: Sebaceous carcinoma (SC) is a rare malignant tumour whereby, comprehensive long-term data are scarce. This study aimed to assess the outcome of patients treated with resection for SC. METHODS: Patients treated at four tertiary centres were included. Cumulative incidence curves were calculated for recurrences. RESULTS: A total of 100 patients (57 males, 57%) were included with 103 SCs. The median age was 72 (range, 15-95) years with a median follow-up of 52 (interquartile range [IQR], 24-93) months. Most SCs were located (peri)ocular (49.5%). Of all SCs, 17 locally recurred (16.5%) with a median time to recurrence of 19 (IQR, 8-29) months. The cumulative incidence probability for recurrence was statistically higher for (peri)ocular tumours (p = 0.005), and for positive resection margins (p = 0.001). Two patients presented with lymph node metastases and additional seven patients (8.7%) developed lymph node metastases during follow-up with a median time to metastases of 8 (IQR, 0.5-28) months. Three patients had concurrent in-transit metastases and one patient also developed liver and bone metastases during follow-up. CONCLUSION: SC is a rare, yet locally aggressive tumour. Positive resection margins and (peri)ocular SCs are more frequently associated with local recurrence. SC infrequently presents with locoregional or distant metastases.

A pilot study on the use of prednisolone-encapsulated liposomes for the treatment of moderate-to-severe Graves' orbitopathy with reduced systemic steroid exposure.

PURPOSE: To demonstrate that long-circulating PEGylated liposomal prednisolone is a safe and effective therapy in patients with active moderate-to-severe Graves' orbitopathy. METHODS: Open-label, proof-of-concept, multicentre pilot study. Ten patients with moderate-to-severe Graves's orbitopathy, who were euthyroid for at least three months. Long-circulating PEGylated liposomal prednisolone 150 mg was administered intravenously twice, with 2-week interval. Total follow-up was 12 months, with visits at baseline, week 2, 6, 13, 26 and 52. Physical, laboratory and ophthalmological examinations were performed. Response to treatment was defined as a reduction in Clinical Activity Score by ≥2 points; palpebral aperture by ≥3 mm; soft tissue signs by ≥2 grades; exophthalmos by ≥2 mm; and motility by >8 degrees or improvement in diplopia score. A response was sustained when equally observed at weeks 6 and 13. RESULTS: One patient achieved a sustained response according to the predetermined definition. All patients showed a decrease in Clinical Activity Score after one infusion, with a mean decrease of two points. The Clinical Activity Score was ≤1 at week 52 for all patients. Improvement was also observed in the soft tissue signs. Most of the adverse events were mild and of a transient nature. Two patients required further treatment with intravenous methylprednisolone. CONCLUSION: This pilot study showed a positive effect of long-circulating PEGylated liposomal prednisolone on the Clinical Activity Score in patients with moderate-to-severe Graves's orbitopathy, resulting in fewer hospital visits and possibly less glucocorticoid-related side-effects.

Results of surgical correction of upper eyelid retraction in Graves' Orbitopathy.

INTRODUCTION: Anterior levator disinsertion/reinsertion and Müllerectomy (ALDM) is generally performed to correct upper eyelid retraction in patients with Graves' orbitopathy (GO). We studied the outcome of this procedure and its correlation with clinical parameters. PATIENTS AND METHODS: Retrospective analysis of results of ALDM in 305 consecutive euthyroid patients with burnt-out GO treated in our hospital between 1 January 2000 and 1 January 2016. From the patient files, we recorded data on age, gender, laterality of surgery, smoking history and previous interventions. For outcome analysis, we used a qualitative scoring system with subdivision into three categories (good (MRD-1 of 4-5 mm, smooth upper eyelid contour and left-right difference of < 1 mm); acceptable (MRD-1 of 3-<4 or> 5-6 mm), smooth upper eyelid contour and left-right difference of < 2 mm; poor: if none of the above criteria was met). We analysed the outcome per eyelid as well as per patient. RESULTS: Of the 305 patients (471 eyelids), 166 underwent bilateral and 139 unilateral surgery. Regarding eyelids, the outcome of surgery was good in 71.6% (337/471) acceptable in 15.7% (74/471) and poor in 12.7% (60/471). Regarding patients, the outcome was good in 64.3% (196/305), acceptable in 15.7% (48/305) and poor in 20% (61/305). Concerning bilateral and unilateral surgery, the outcome was good in 60.8% (101/166) and acceptable in 16.9% (28/166) of patients after bilateral surgery, and good in 68.3% (95/139) and acceptable in 14.4% (20/139) of the patients after unilateral surgery (p = 0.17). Reoperation was performed in 16% (75 of 471) of eyelids and in 22 % (66 of 305) of patients. After secondary surgery, the cumulative success percentage was good in 78.6% (370/471) of eyelids and in 79% (241/305) of patients. We found no relation between surgical outcome and any other studied parameter, such as age, gender, smoking history and previous intervention such as extraocular muscle surgery and/or orbital decompression. CONCLUSION: Correction of upper eyelid retraction yields a good result in 64.3% of patients and 71.6% of eyelids. With one additional procedure, the procedure proved was successful in 79% of patients and eyelids. We found no relation between the outcome of surgery and any other parameter, such as previous disease severity, previous interventions or smoking history. For comparative analysis, we recommend to report the outcome per patient rather than per eyelid.

Retrospective study in 608 cases on the rate of surgical site infections after orbital surgery without prophylactic systemic antibiotics.

OBJECTIVE: To determine postoperative surgical site infection (SSI) rates in three separate patient groups who underwent orbital surgery without prophylactic systemic antibiotics. STUDY DESIGN: Single-centre retrospective descriptive case series. STUDY POPULATION: We studied the notes of 639 consecutive patients who had undergone orbital surgery in our hospital from 2009 through 2013. All patients belonged to either of three groups: (1) clean orbital surgery (n=226); (2) clean orbital surgery with implant (n=290); (3) clean-contaminated surgery (n=92). Thirty-one patients were excluded. RESULTS: Of the total of 608 patients, without systemic antibiotic prophylaxis, only five were diagnosed with SSI 5/608 (0.82%): 1/226 in the 'clean' group, 3/290 in the 'clean-with-implant' group and 1/92 in the 'clean-contaminated' group. All five patients with SSI were effectively treated with antibiotics. CONCLUSION: In this study 'clean', 'clean-with-implant' and 'clean-contaminated' orbital surgery was safely performed without prophylactic antibiotics. Where postoperative infection did occur, the patients were effectively treated with systemic antibiotics. We suggest to restrict the administration of systemic antibiotic prophylaxis in orbital surgery.

Silent squamous cell carcinoma invading the orbit following the course of the zygomaticotemporal nerve.

PURPOSE: To evaluate the clinical and histopathological characteristics of silent skin squamous cell carcinomas (SCC) with invasion routes to the orbit. METHODS: Retrospective case studies. Clinical records and histopathological material, therapy and complications were evaluated, together with MRI imaging analyses and literature review on the anatomy of the lateral orbital wall in relation to the zygomatico-temporal nerve channel. RESULTS: Two recent cases of metastatic SCC from het lateral zygomatic region to het orbit are reported. Originally the skin tumors of the first case was diagnosed as benign, but a review of the pathology of these skin tumors showed an invasive SCC. The second case was diagnosed as an atypical SCC. Analysis of possible invasion routes, using both computer tomography (CT) and magnetic resonance imaging (MRI), indicated neither skin nor bone involvement. However, the lateral temporal fossa near the entrance of the zygomatico-temporal channel showed small tumors and pseudo-cysts. The original skin tumor specimens did not show malignant tissue in the surgical margins nor intra- or perineural invasion. CONCLUSIONS: Because the course of the zygomatico-temporal nerve bundle was exactly in line with the original skin tumor, the channel and the orbital tumors, this route should be considered when malignant orbital tumors have a history of or a relation with a periorbital skin-tumor.