Inflammation and Fibrosis in Orbital Inflammatory Disease: A Histopathologic Analysis.

PURPOSE: The purpose of this study was to compare the histopathologic inflammation and fibrosis of orbital adipose tissue in orbital inflammatory disease (OID) specimens. METHODS: In this retrospective cohort study, inflammation, and fibrosis in orbital adipose tissue from patients with thyroid-associated orbitopathy (TAO), granulomatosis with polyangiitis (GPA), sarcoidosis, nonspecific orbital inflammation (NSOI), and healthy controls were scored by 2 masked ocular pathologists. Both categories were scored on a scale of 0 to 3 with scoring criteria based on the percentage of specimens containing inflammation or fibrosis, respectively. Tissue specimens were collected from oculoplastic surgeons at 8 international centers representing 4 countries. Seventy-four specimens were included: 25 with TAO, 6 with orbital GPA, 7 with orbital sarcoidosis, 24 with NSOI, and 12 healthy controls. RESULTS: The mean inflammation and fibrosis scores for healthy controls were 0.0 and 1.1, respectively. Orbital inflammatory disease groups' inflammation (I) and fibrosis (F) scores, formatted [I, F] with respective p -values when compared to controls, were: TAO [0.2, 1.4] ( p = 1, 1), GPA [1.9, 2.6] ( p = 0.003, 0.009), sarcoidosis [2.4, 1.9] ( p = 0.001, 0.023), and NSOI [1.3, 1.8] ( p ≤ 0.001, 0.018). Sarcoidosis had the highest mean inflammation score. The pairwise analysis demonstrated that sarcoidosis had a significantly higher mean inflammation score than NSOI ( p = 0.036) and TAO ( p < 0.0001), but no difference when compared to GPA. GPA had the highest mean fibrosis score, with pairwise analysis demonstrating a significantly higher mean fibrosis score than TAO ( p = 0.048). CONCLUSIONS: Mean inflammation and fibrosis scores in TAO orbital adipose tissue samples did not differ from healthy controls. In contrast, the more "intense" inflammatory diseases such as GPA, sarcoidosis, and NSOI did demonstrate higher histopathologic inflammation and fibrosis. This has implications in prognosis, therapeutic selection, and response monitoring in orbital inflammatory disease.

Necrobiotic Xanthogranuloma With Associated Monoclonal Gammopathy Presenting as an Eyelid Nodule.

Necrobiotic xanthogranuloma (NXG) is a progressive non-Langerhans cell histiocytosis with a predilection for the periorbital area. NXG is most commonly associated with monoclonal gammopathy and ophthalmic complications. The authors present a 69-year-old man who was evaluated for a left upper eyelid nodule and plaques on the lower extremities, trunk, abdomen, and right upper extremity. Biopsy of the eyelid was supportive for NXG. Serum protein electrophoresis was positive for a monoclonal gammopathy, IgG light chain kappa. MRI showed preseptal involvement. The periocular nodules cleared with a high dose of prednisone; however, the other skin lesions persisted. Bone marrow biopsy showed kappa-restricted 6% plasma cells and he was treated with intravenous immunoglobulin. This case illustrates the importance of clinicopathologic correlations to render an NXG diagnosis.

Orbital MALT lymphoma with amyloid deposition.

MALT lymphoma is a commonly encountered orbital tumor, and primary amyloidosis is frequently found to be an independent orbital lesion. Orbital MALT lymphoma with associated amyloid deposition is considered rare, with only 12 cases previously published. We describe a 33-year-old man, the youngest patient reported to-date, with a mass in the superonasal quadrant of the right anterior orbit. Pathology demonstrated extranodal marginal zone lymphoma in mucosa-associated lymphoid tissue with associated amyloid deposition. Systemic work-up revealed no other site of either lymphoma or amyloidosis. The patient underwent local irradiation and subsequent surgical resection of the residual mass. Persistent lymphoma was found and treated with rituximab.

Pediatric Orbital Cellulitis/Abscess: Microbiology and Pattern of Antibiotic Prescribing.

INTRODUCTION: The treatment for pediatric orbital cellulitis/abscess is trending towards intravenous antibiotic management alone in appropriate cases. Without cultures to guide therapy, knowing the local microbiology is of utmost importance in managing these patients. METHODS: We conducted a retrospective case series for patients age 2 months to 17 years, who were hospitalized between January 1, 2013, and December 31, 2019, to evaluate the local microbiology and pattern of antibiotic prescribing in pediatric orbital cellulitis. RESULTS AND DISCUSSION: Of 95 total patients, 69 (73%) received intravenous antibiotics only and 26 (27%) received intravenous antibiotics plus surgery. The most common organism cultured was Streptococcus anginosus, followed by Staphylococcus aureus, and group A streptococcus. Methicillin-resistant Staphylococcus aureus (MRSA) prevalence was 9%. MRSA-active antibiotics remain the most frequently used antibiotics.

Enrichment of IGF-1R and PPARγ signalling pathways in orbital inflammatory diseases: steps toward understanding pathogenesis.

BACKGROUND: Orbital inflammatory disease (OID) encompasses a wide range of pathology including thyroid-associated orbitopathy (TAO), granulomatosis with polyangiitis (GPA), sarcoidosis and non-specific orbital inflammation (NSOI), accounting for up to 6% of orbital diseases. Understanding the underlying pathophysiology of OID can improve diagnosis and help target therapy. AIMS: To test the hypothesis that shared signalling pathways are activated in different forms of OID. METHODS: In this secondary analysis, pathway analysis was performed on the previously reported differentially expressed genes from orbital adipose tissue using patients with OID and healthy controls who were characterised by microarray. For the original publications, tissue specimens were collected from oculoplastic surgeons at 10 international centres representing four countries (USA, Canada, Australia and Saudi Arabia). Diagnoses were independently confirmed by two masked ocular pathologists (DJW, HEG). Gene expression profiling analysis was performed at the Oregon Health & Science University. Eighty-three participants were included: 25 with TAO, 6 with orbital GPA, 7 with orbital sarcoidosis, 25 with NSOI and 20 healthy controls. RESULTS: Among the 83 subjects (mean (SD) age, 52.8 (18.3) years; 70% (n=58) female), those with OID demonstrated perturbation of the downstream gene expressions of the IGF-1R (MAPK/RAS/RAF/MEK/ERK and PI3K/Akt/mTOR pathways), peroxisome proliferator-activated receptor-γ (PPARγ), adipocytokine and AMPK signalling pathways compared with healthy controls. Specifically, GPA samples differed from controls in gene expression within the insulin-like growth factor-1 receptor (IGF-1R, PI3K-Akt (p=0.001), RAS (p=0.005)), PPARγ (p=0.002), adipocytokine (p=0.004) or AMPK (p=<0.001) pathways. TAO, sarcoidosis and NSOI samples were also found to have statistically significant differential gene expression in these pathways. CONCLUSIONS: Although OID includes a heterogenous group of pathologies, TAO, GPA, sarcoidosis and NSOI share enrichment of common gene signalling pathways, namely IGF-1R, PPARγ, adipocytokine and AMPK. Pathway analyses of gene expression suggest that other forms of orbital inflammation in addition to TAO may benefit from blockade of IGF-1R signalling pathways.

Management of periocular cutaneous squamous cell carcinoma with perineural invasion: a case series and literature review.

PURPOSE: To review and elucidate the complex, multimodal management of periocular cutaneous squamous cell carcinoma (SCC) with perineural invasion (PNI), and offer practical, evidence-based patient care recommendations. METHODS: Three exemplary cases of high-risk periocular cutaneous SCC with PNI were selected from a single surgeon's experience. The clinical courses, management, and clinical outcomes, with follow-up intervals of 19, 19, and 24 months after presentation, were reviewed. The English-language literature on PNI, with attention to the management of cutaneous SCC of the head and neck (SCCHN), was reviewed. RESULTS: PNI of cutaneous SCCHN portends aggressive tumor behavior and a worsened prognosis. Treatment is multimodal, with varied combinations of surgical excision, radiotherapy (RT), and systemic chemotherapy. Retrospective reports from multiple institutions involve heterogenous patient populations, treatment strategies, and confounding variables that preclude formulation of a standardized treatment paradigm. Newer, comparative studies of advanced RT techniques (e.g., hyper-fractionation), novel systemic chemotherapeutic agents (e.g., cetuximab, cemiplimab), and varied integrative regimens are providing additional insights. Prompt initiation of adjuvant therapies (within 6-8 weeks of surgery), and careful evaluation of lymphatic basins can increase oncologic control. Utilizing deep-tissue fixation of advancement flaps and eyelid stabilization can enhance functional and aesthetic results. CONCLUSIONS: Management of cutaneous SCC with PNI remains complex and in most cases requires combined-modality therapy directed by a multidisciplinary tumor board. With novel therapies and new treatment patterns, optimal combinations and intensities of individual modalities require further elucidation. The oculofacial plastic surgeon plays a pivotal role - in diagnosis, coordination of interdisciplinary management, thoughtful surgical reconstruction, and postoperative surveillance.

Teprotumumab Efficacy, Safety, and Durability in Longer-Duration Thyroid Eye Disease and Re-treatment: OPTIC-X Study.

PURPOSE: To evaluate teprotumumab safety/efficacy in patients with thyroid eye disease (TED) who were nonresponsive or who experienced a disease flare. DESIGN: The Treatment of Graves' Orbitopathy to Reduce Proptosis with Teprotumumab Infusions in an Open-Label Clinical Extension Study (OPTIC-X) is a teprotumumab treatment and re-treatment trial following the placebo-controlled teprotumumab Phase 3 Treatment of Graves' Orbitopathy (Thyroid Eye Disease) to Reduce Proptosis with Teprotumumab Infusions in a Randomized, Placebo-Controlled, Clinical Study (OPTIC) trial. PARTICIPANTS: Patients who previously received placebo (n = 37) or teprotumumab (n = 14) in OPTIC. METHODS: OPTIC nonresponders or those who flared (≥2-mm increase in proptosis, ≥2-point increase in clinical activity score [CAS], or both) during follow-up were treated for the first time (previous placebo patients) or re-treated with teprotumumab in OPTIC-X with 8 infusions over 24 weeks. MAIN OUTCOME MEASURES: Proptosis response and safety. Secondary outcomes included proptosis, CAS, subjective diplopia, and quality-of-life. RESULTS: Thirty-three of 37 placebo-treated OPTIC patients (89.2%) became proptosis responders (mean ± standard deviation, -3.5 ± 1.7 mm) when treated with teprotumumab in OPTIC-X. The responses were equivalent to the OPTIC study. In these responders, proptosis, CAS of 0 or 1, and diplopia responses were maintained in 29 of 32 patients (90.6%), 20 of 21 patients (95.2%), and 12 of 14 patients (85.7%), respectively, at follow-up week 48. The median TED duration was 12.9 months versus 6.3 months in those treated with teprotumumab in the OPTIC study. Of the 5 OPTIC teprotumumab nonresponders re-treated in OPTIC-X, 2 responded, 1 showed a proptosis reduction of 1.5 mm from OPTIC baseline, and 2 discontinued treatment early. Of the OPTIC teprotumumab responders who experienced flare, 5 of 8 patients (62.5%) responded when re-treated (mean proptosis reduction, 1.9 ± 1.2 mm from OPTIC-X baseline and 3.3 ± 0.7 mm from OPTIC baseline). Compared with published double-masked trials and their integrated follow-up, no new safety signals were identified. Mild hearing impairment was reported; 4 events occurred during the first course of treatment, and 2 events reoccurred after re-treatment. CONCLUSIONS: Patients with TED of longer disease duration responded similarly to those treated earlier in the disease course. Patients with an insufficient initial response or flare may benefit from additional teprotumumab therapy. No new safety risk was identified; however additional postmarketing pharmacovigilance is ongoing.

Evaluation and Medical Management of the Pediatric Patient With Orbital Cellulitis/Abscess: A Systematic Review.

BACKGROUND AND OBJECTIVES: Pediatric orbital cellulitis/abscess (OCA) can lead to vision loss, intracranial extension of infection, or cavernous thrombosis if not treated promptly. No widely recognized guidelines exist for the medical management of OCA. The objective of this review was to summarize existing evidence regarding the role of inflammatory markers in distinguishing disease severity and need for surgery; the role of imaging in OCA evaluation; and the microbiology of OCA over the past 2 decades. METHODS: This review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Searches were performed in MEDLINE (Ovid), Web of Science Core Collection, Scopus, CINAHL (EBSCO), and Cochrane Central Register of Controlled Trials (CENTRAL), most recently on February 9, 2021. RESULTS: A total of 63 studies were included. Most were descriptive and assessed to have poor quality with high risk of bias. The existing publications evaluating inflammatory markers in the diagnosis of OCA have inconsistent results. Computed tomography imaging remains the modality of choice for evaluating orbital infection. The most common organisms recovered from intraoperative cultures are Streptococcus species (Streptococcus anginosus group, group A Streptococcus, and pneumococcus) and Staphylococcus aureus. Methicillin-resistant S aureus in culture-positive cases had a median prevalence of 3% (interquartile range, 0%-13%). CONCLUSION: This systematic review summarizes existing literature concerning inflammatory markers, imaging, and microbiology for OCA evaluation and management. High-quality evidence is still needed to define the optimal medical management of OCA.

Case Report: Idiopathic Sclerosing Orbital Inflammation.

SIGNIFICANCE: Idiopathic sclerosing orbital inflammation (ISOI) is characterized by insidious, chronic, progressive inflammation and fibrosis that damage ocular structures and produce a mass effect. This case highlights the challenges in diagnosis and management of ISOI, as well as the associated ocular morbidities, including potential vision loss. PURPOSE: The purpose of this study was to provide education regarding a rare condition that exhibits variable presentation and has an unpredictable success rate with regard to treatment paradigm. Improved therapeutic options are promising. Ultimately, early detection and management are key and may allow for better visual outcome. CASE REPORT: A 46-year-old woman presented with complaints of chronic right-sided facial headaches and eye pain and gradual right globe prominence over the previous 6 months. Worsening vision and decreased right peripheral visual field were also noted. Upon examination, an afferent pupillary defect and florid disc edema were evident. Imaging studies revealed an orbital and extraorbital infiltrative mass involving the right orbital apex, inferior orbital fissure, pterygopalatine fossa, and cavernous sinus. Right anterior orbitotomy with biopsy revealed fragments of fibroconnective and adipose tissue with sclerosis and chronic focal inflammation, consistent with ISOI. Treatment included intravenous methylprednisone, followed by oral prednisone, beginning at 60 mg/d with a slow taper thereafter. Signs and symptoms improved dramatically and eventually resolved. Vision significantly improved, and the afferent pupillary defect resolved. The patient remained asymptomatic at 3-month follow-up. CONCLUSIONS: Idiopathic sclerosing orbital inflammation is difficult to diagnose and manage. No large studies exist because of the rare nature of the disease. Slowly progressive, nonspecific signs and symptoms may delay recognition and treatment. Orbital imaging and histopathologic analysis are critical for definitive diagnosis. Conventional treatment with corticosteroids is not uniformly successful, but newer combined therapy options can improve outcomes. Early identification and treatment are key to management and ultimate preservation of function and vision.

Teprotumumab in Clinical Practice: Recommendations and Considerations From the OPTIC Trial Investigators.

BACKGROUND: Thyroid eye disease (TED) is a vision-threatening and debilitating condition that until very recently had no Food and Drug Administration (FDA)-approved medical therapies. Teprotumumab has recently been approved to treat TED. We aim to provide guidance for its use, based on the input of the US investigators who participated in Phase 2 and Phase 3 clinical trials. METHODS: An expert panel was convened on October 11th and November 16th of 2019. All panel members had extensive experience as investigators in the Phase 2 and/or Phase 3 clinical trials of teprotumumab. Consensus among those investigators was reached to determine patient characteristics most appropriate for teprotumumab treatment. Safety guidelines were also reviewed and agreed on. RESULTS: The authors recommend that teprotumumab be considered first-line therapy for patients with clinically significant ophthalmopathy, including those with disease duration exceeding 9 months. The clinical activity score (CAS) may be useful for longitudinal monitoring but should not be used to determine treatment eligibility. Criteria will likely be expanded after more experience with the drug. Using teprotumumab for patients with TED with substantial signs, symptoms, or morbidity without a CAS score of >4 (e.g., progressive proptosis, diplopia, and early compressive optic neuropathy) or more, could be considered. Diabetes mellitus and inflammatory bowel disease comorbidities should not be exclusionary, but stringent monitoring in these patients is recommended. Drug dosing, administration interval, and duration should adhere to the study protocol: 8 infusions, separated by 3 weeks. Patients with more severe disease may benefit from additional doses. Corticosteroids can be used before or during teprotumumab therapy. Clinical and laboratory monitoring should be consistent with good clinical practice for patients receiving teprotumumab. CONCLUSIONS: Confirming the efficacy of teprotumumab usage outside the narrow parameters of the completed clinical trials will require rigorous scientific validation. As a step in that direction, we believe its on-label usage is appropriately applied to all patients with TED with substantial symptoms or morbidity, as judged by their physician.

Fate and Management of Incompletely Excised Solitary Fibrous Tumor of the Orbit: A Case Series and Literature Review.

PURPOSE: There is an imperfect correlation between the histology and behavior of solitary fibrous tumor (SFT). In addition, recurrence is common, and dedifferentiation may occur over time. Preferred primary treatment is intact excision, but friable pseudocapsules and tenacious attachments can thwart this goal in the crowded, visually sensitive orbit. This study addresses the fate and appropriate management of incompletely excised orbital SFT. METHODS: Among a single surgeon's 7-case experience with orbital SFT, 3 cases involved incomplete primary excision, either before (2 cases) or after (1 case) referral. We reviewed the clinicopathologic data in these 3 cases, with follow-up intervals of 18, 21, and 52 years after initial presentation. We reviewed the English-language literature on SFT, with special attention to evolving nomenclature, orbital involvement, recurrence, malignant transformation, and management options. RESULTS: Benign versus malignant designations of SFT vary with histological and behavioral criteria. Approximately 150 orbital cases have been reported. Published rates of primary malignancy and recurrence across all histologic categories are 6% to 12% and 30% to 37%, respectively. We identified 43 well-documented recurrences (range, 6 months-33 years; median, 3 years) and 10 cases of histological dedifferentiation (range, 14 months-33 years). Because of SFT's rarity and needed follow-up intervals, the value of adjuvant therapy is not yet proven. In follow up of 18, 21, and 52 years after initial presentation, our 3 cases with incomplete excision showed either no recurrence (Case 1) or no morphological dedifferentiation (Cases 2, 3). CONCLUSION: A treatment algorithm is predicated on the completeness of surgical excision and histological features. However, we recommend case-by-case multidisciplinary decisions in a tumor-board setting.

Teprotumumab for the Treatment of Active Thyroid Eye Disease.

BACKGROUND: Thyroid eye disease is a debilitating, disfiguring, and potentially blinding periocular condition for which no Food and Drug Administration-approved medical therapy is available. Strong evidence has implicated the insulin-like growth factor I receptor (IGF-IR) in the pathogenesis of this disease. METHODS: In a randomized, double-masked, placebo-controlled, phase 3 multicenter trial, we assigned patients with active thyroid eye disease in a 1:1 ratio to receive intravenous infusions of the IGF-IR inhibitor teprotumumab (10 mg per kilogram of body weight for the first infusion and 20 mg per kilogram for subsequent infusions) or placebo once every 3 weeks for 21 weeks; the last trial visit for this analysis was at week 24. The primary outcome was a proptosis response (a reduction in proptosis of ≥2 mm) at week 24. Prespecified secondary outcomes at week 24 were an overall response (a reduction of ≥2 points in the Clinical Activity Score plus a reduction in proptosis of ≥2 mm), a Clinical Activity Score of 0 or 1 (indicating no or minimal inflammation), the mean change in proptosis across trial visits (from baseline through week 24), a diplopia response (a reduction in diplopia of ≥1 grade), and the mean change in overall score on the Graves' ophthalmopathy-specific quality-of-life (GO-QOL) questionnaire across trial visits (from baseline through week 24; a mean change of ≥6 points is considered clinically meaningful). RESULTS: A total of 41 patients were assigned to the teprotumumab group and 42 to the placebo group. At week 24, the percentage of patients with a proptosis response was higher with teprotumumab than with placebo (83% [34 patients] vs. 10% [4 patients], P<0.001), with a number needed to treat of 1.36. All secondary outcomes were significantly better with teprotumumab than with placebo, including overall response (78% of patients [32] vs. 7% [3]), Clinical Activity Score of 0 or 1 (59% [24] vs. 21% [9]), the mean change in proptosis (-2.82 mm vs. -0.54 mm), diplopia response (68% [19 of 28] vs. 29% [8 of 28]), and the mean change in GO-QOL overall score (13.79 points vs. 4.43 points) (P≤0.001 for all). Reductions in extraocular muscle, orbital fat volume, or both were observed in 6 patients in the teprotumumab group who underwent orbital imaging. Most adverse events were mild or moderate in severity; two serious events occurred in the teprotumumab group, of which one (an infusion reaction) led to treatment discontinuation. CONCLUSIONS: Among patients with active thyroid eye disease, teprotumumab resulted in better outcomes with respect to proptosis, Clinical Activity Score, diplopia, and quality of life than placebo; serious adverse events were uncommon. (Funded by Horizon Therapeutics; OPTIC ClinicalTrials.gov number, NCT03298867, and EudraCT number, 2017-002763-18.).

The spectrum of orbital dermoid cysts and their surgical management.

PURPOSE: The purpose of this study is to describe a spectrum of surgical approaches to orbital dermoid cysts, influenced by the anatomic location of the expanded cyst wall and other factors. METHODS: In this retrospective case series, we reviewed cases of dermoid cysts surgically excised during a 39-year period (1977-2016). Cysts were categorized according to the location of the expanded cyst wall and other considerations. The impact of these factors on surgical management was determined. RESULTS: We identified six dermoid cyst growth patterns based on the anatomic location of the expanded cyst wall that influence the surgical approach: anterior to the frontozygomatic suture (FZS), superior to the FZS, medial to the FZS and other lateral wall sutures, traversing the FZS and other lateral wall sutures, nasoglabellar, and sinus tract from the orbit to the skin. Two additional factors influencing surgical methodology included satellite inflammatory pseudocysts and recurrence after surgical resection. CONCLUSION: Orbital dermoid cysts are not monolithic lesions. Functional and aesthetic outcomes can benefit from considering the anatomic pattern of cyst wall expansion and other factors in their surgical management.

Surgical Management of a Recurrent Odontogenic Keratocyst With Orbital and Temporal Fossa Invasion.

Odontogenic keratocyst is a benign locally aggressive odontogenic cyst with a high recurrence rate. This report presents an unusual case of a recurrent odontogenic keratocyst with zygomatic bone involvement and orbital and temporal extension resulting in globe compression. Odontogenic keratocyst is reviewed, and surgical management of the cyst is discussed.The authors present a case of a recurrent odontogenic keratocyst involving the zygoma with orbital and temporal invasion; aggressive surgical resection and reconstruction was required.

Surgical Timing for Congenital Ptosis Should Not Be Determined Solely by the Presence of Anisometropia.

PURPOSE: Timing of surgery in children with congenital ptosis is a critical component of care, and anisometropia is frequently cited as an indication for early intervention. The purpose of this study is to evaluate the change in refractive error following surgery for congenital ptosis to better inform decisions regarding the timing of surgery. METHODS: A retrospective review of clinical records was performed on patients who underwent surgical correction of congenital ptosis in an academic oculoplastic surgery practice from 2002 to 2017. Patients with complete preoperative and postoperative refractive data were included in the study. Changes in refractive error following surgery were analyzed. RESULTS: Among 184 pediatric patients who underwent ptosis surgery during the study period, 56 patients (71 eyes) met inclusion criteria. The mean age at surgery was 5.1 years. Mean refractive error change in all the operated eyes was a 0.82 D decrease in spherical equivalent (p = 0.1920) and a 0.40 D increase in cylinder (p = 0.0255). There were no statistically significant changes in spherical equivalent or cylinder in the control eyes. CONCLUSIONS: The authors data did not show movement toward normalization of refractive error following ptosis surgery. In fact, it showed a statistically significant worsening of astigmatism following surgery. Because refractive error does not improve following surgery, anisometropia should not be the sole indication for early surgery in congenital ptosis.

Herpes Zoster Ophthalmicus With Orbital Findings Preceding Skin Rash.

The authors describe 2 patients who presented with orbital findings and later developed vesicular lesions that were positive for varicella zoster virus and consistent with Herpes Zoster ophthalmicus. One case is the first to involve dacryoadenitis and orbital myositis preceding disseminated Herpes Zoster. In the other case, a patient developed zoster orbital syndrome leading to elevated intraocular pressure, loss of vision, and afferent pupillary defect. Canthotomy and cantholysis were required to restore vision. In both cases, the orbital syndrome developed prior to the vesicular rash. These cases highlight the need to consider Herpes Zoster ophthalmicus in patients with orbital syndrome not responding to conventional treatment.

Gene Expression Profiling and Heterogeneity of Nonspecific Orbital Inflammation Affecting the Lacrimal Gland.

Importance: Although a variety of well-characterized diseases, such as sarcoidosis and granulomatosis with polyangiitis, affect the lacrimal gland, many patients with dacryoadenitis are diagnosed as having nonspecific orbital inflammation (NSOI) on the basis of histology and systemic disease evaluation. The ability to further classify the disease in these patients should facilitate selection of effective therapies. Objective: To test the a priori hypothesis that gene expression profiles would complement clinical and histopathologic evaluations in identifying well-characterized diseases and in subdividing NSOI into clinically relevant groups. Design, Setting, and Participants: In this cohort study, gene expression levels in biopsy specimens of inflamed and control lacrimal glands were measured with microarrays. Stained sections of the same biopsy specimens were used for evaluation of histopathology. Tissue samples of patients were obtained from oculoplastic surgeons at 7 international centers representing 4 countries (United States, Saudi Arabia, Canada, and Taiwan). Gene expression analysis was done at Oregon Health & Science University. Participants were 48 patients, including 3 with granulomatosis with polyangiitis, 28 with NSOI, 7 with sarcoidosis, 4 with thyroid eye disease, and 6 healthy controls. The study dates were March 2012 to April 2017. Main Outcomes and Measures: The primary outcome was subdivision of biopsy specimens based on gene expression of a published list of approximately 40 differentially expressed transcripts in blood, lacrimal gland, and orbital adipose tissue from patients with sarcoidosis. Stained sections were evaluated for inflammation (none, mild, moderate, or marked), granulomas, nodules, or fibrosis by 2 independent ocular pathologists masked to the clinical diagnosis. Results: Among 48 patients (mean [SD] age, 41.6 [19.0] years; 32 [67%] female), the mclust algorithm segregated the biopsy specimens into 4 subsets, with the differences illustrated by a heat map and multidimensional scaling plots. Most of the sarcoidosis biopsy specimens were in subset 1, which had the highest granuloma score. Three NSOI biopsy specimens in subset 1 had no apparent granulomas. Thirty-two percent (9 of 28) of the NSOI biopsy specimens could not be distinguished from biopsy specimens of healthy controls in subset 4, while other examples of NSOI tended to group with gene expression resembling granulomatosis with polyangiitis or thyroid eye disease. The 4 subsets could also be partially differentiated by their fibrosis, granulomas, and inflammation pathology scores but not their lymphoid nodule scores. Conclusions and Relevance: Gene expression profiling discloses clear heterogeneity among patients with lacrimal inflammatory disease. Comparison of the expression profiles suggests that a subset of patients with nonspecific dacryoadenitis might have a limited form of sarcoidosis, while other patients with NSOI cannot be distinguished from healthy controls.

Consensus on Diagnostic Criteria of Idiopathic Orbital Inflammation Using a Modified Delphi Approach.

Importance: Current practice to diagnose idiopathic orbital inflammation (IOI) is inconsistent, leading to frequent misdiagnosis of other orbital entities, including cancer. By specifying criteria, diagnosis of orbital inflammation will be improved. Objective: To define a set of criteria specific for the diagnosis of IOI. Design, Setting, and Participants: A 3-round modified Delphi process with an expert panel was conducted from June 8, 2015, to January 25, 2016. Fifty-three orbital scientist experts, identified through membership in the Orbital Society, were invited to participate in on online survey and they scored, using 5-point Likert scales, items that are eligible as diagnostic criteria from the literature and from personal experience. The items were clustered around the anatomic subtypes of IOI: idiopathic dacryoadenitis and idiopathic orbital fat inflammation (2 nonmyositic IOIs), and idiopathic orbital myositis (myositic IOI). Items with dissensus were rescored in the second round, and all items with consensus (median, ≥4; interquartile range, ≤1) were ranked by importance in the third round. Main Outcomes and Measures: Consensus on items to be included in the criteria. Results: Of the 53 experts invited to participate, a multinational panel of 35 (66%) individuals with a mean (SD) years of experience of 31 (11) years were included. Consensus was achieved on 7 of 14 clinical and radiologic items and 5 of 7 pathologic items related to diagnosis of nonmyositic IOI, and 11 of 14 clinical and radiologic items and 1 of 5 pathologic items for myositic IOI. There was agreement among panelists to focus on surgical tissue biopsy results in the diagnosis of nonmyositic IOI and on a trial with systemic corticosteroids in myositic IOI. Panelists agreed that a maximum number of 30 IgG4-positive plasma cells per high-power field in the orbital tissue is compatible with the diagnosis of IOI. Conclusions and Relevance: An international panel of experts endorsed consensus diagnostic criteria of IOI. These criteria define a level of exclusion suggested for diagnosis and include tissue biopsy for lesions not confined to the extraocular muscles. This consensus is a step toward developing guidelines for the management of IOI, which needs to be followed by validation studies of the criteria.

Teprotumumab for Thyroid-Associated Ophthalmopathy.

BACKGROUND: Thyroid-associated ophthalmopathy, a condition commonly associated with Graves' disease, remains inadequately treated. Current medical therapies, which primarily consist of glucocorticoids, have limited efficacy and present safety concerns. Inhibition of the insulin-like growth factor I receptor (IGF-IR) is a new therapeutic strategy to attenuate the underlying autoimmune pathogenesis of ophthalmopathy. METHODS: We conducted a multicenter, double-masked, randomized, placebo-controlled trial to determine the efficacy and safety of teprotumumab, a human monoclonal antibody inhibitor of IGF-IR, in patients with active, moderate-to-severe ophthalmopathy. A total of 88 patients were randomly assigned to receive placebo or active drug administered intravenously once every 3 weeks for a total of eight infusions. The primary end point was the response in the study eye. This response was defined as a reduction of 2 points or more in the Clinical Activity Score (scores range from 0 to 7, with a score of ≥3 indicating active thyroid-associated ophthalmopathy) and a reduction of 2 mm or more in proptosis at week 24. Secondary end points, measured as continuous variables, included proptosis, the Clinical Activity Score, and results on the Graves' ophthalmopathy-specific quality-of-life questionnaire. Adverse events were assessed. RESULTS: In the intention-to-treat population, 29 of 42 patients who received teprotumumab (69%), as compared with 9 of 45 patients who received placebo (20%), had a response at week 24 (P<0.001). Therapeutic effects were rapid; at week 6, a total of 18 of 42 patients in the teprotumumab group (43%) and 2 of 45 patients in the placebo group (4%) had a response (P<0.001). Differences between the groups increased at subsequent time points. The only drug-related adverse event was hyperglycemia in patients with diabetes; this event was controlled by adjusting medication for diabetes. CONCLUSIONS: In patients with active ophthalmopathy, teprotumumab was more effective than placebo in reducing proptosis and the Clinical Activity Score. (Funded by River Vision Development and others; ClinicalTrials.gov number, NCT01868997 .).