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.

Predictability of the Phenylephrine Test With Regard to Eyelid Skin Appearance in Patients Who Undergo Müller Muscle-Conjunctival Resection Without Blepharoplasty.

PURPOSE: To evaluate the ability of preoperative phenylephrine testing to predict postoperative upper eyelid tarsal platform show in patients undergoing Müller muscle-conjunctival resection (MMCR) ptosis repair without concurrent blepharoplasty. METHODS: A retrospective chart review was performed on 52 eyelids of patients who underwent MMCR without external skin incision. Photographs were reviewed to objectively and subjectively compare the results of phenylephrine testing to postoperative appearance. Only patients who underwent successful MMCR were included in the study. The authors defined successful MMCR as having a resulting marginal reflex distance within 1 mm of that predicted by phenylephrine testing. For objective analysis, the tarsal platform show was measured using computer software. For subjective analysis, 2 experienced examiners were asked to grade the correlation in appearance on a scale of 1-5 (1 being poor correlation and 5 being excellent correlation). RESULTS: The mean tarsal platform show in the phenylephrine test photographs and the postoperative photographs was 3.8 and 3.63 mm, respectively (mean = 0.17; standard deviation = 0.71). The difference between the means was not statistically significant (p > 0.05). The mean difference in tarsal platform show between phenylephrine testing and postoperative was 0.17 mm (standard deviation = 0.71). The difference was not statistically significant (t[51] = 0.09; p > 0.05; 2 tailed). The mean subjective correlation score comparing phenylephrine testing photographs to postoperative photographs was 4.4 out of possible 5. CONCLUSIONS: Phenylephrine testing exhibits good predictability with regard to eyelid appearance after successful MMCR without external skin incision and, therefore, may assist the surgeon when trying to decide if blepharoplasty or eyelid crease formation is necessary at the time of MMCR.

Conjunctivodacryocystorhinostomy with Jones tube: a history and update.

PURPOSE OF REVIEW: Current opinions and trends in the management of upper lacrimal obstruction include design variations on the original Lester Jones tube and updated awareness and management of the problems associated with the tubes. This article includes a brief review of the fascinating history of the development of the Jones tube, which sets the perspective for the current scientific dialog. RECENT FINDINGS: First, many design modifications have been proposed to reduce the risk of tube migration and extrusion, with no consensus on the best tube. Second, the issue of retrograde airflow through the Jones tube with the use of continuous positive airway pressure is an increasingly common and challenging problem. Third, bacterial biofilms on the surface of the Jones tube can play a role in recalcitrant infections. Jones tubes can be cleaned or replaced in the office setting with topical anesthesia. SUMMARY: Conjunctivodacryocystorhinostomy (CDCR) with placement of a Jones tube remains the gold standard for management of upper lacrimal obstruction. This article provides an updated perspective on issues with extrusion or migration of the tube, bothersome retrograde airflow with the use of a continuous positive airway pressure device, and management of crusting and possible infectious biofilms on the tube.

Morgellons Disease Presenting As an Eyelid Lesion.

Morgellons disease is characterized by complaints of uncomfortable skin sensations and fibers emanating from nonhealing skin lesions. Morgellons disease is well-known in the dermatology and psychiatry literature, where it is typically considered a subtype of delusional parasitosis, but it has not yet been described in the ophthalmology literature. A patient with self-reported Morgellons disease is presented, who was referred for evaluation of left lower eyelid ectropion. She reported that her skin was infested with fibers that were "trying to get down into the eyelid." On examination, she had ectropion of the left lower eyelid, broken cilia, and an ulcerated left upper eyelid lesion concerning for carcinoma. Biopsy of the lesion was consistent with excoriation. Treatment of her ectropion was deferred out of concern for wound dehiscence, given the patient's aggressive excoriation behavior. This case is presented to make the ophthalmologist aware of this disorder and to highlight the appropriate clinical management.

Orbital pseudotumor can be a localized form of granulomatosis with polyangiitis as revealed by gene expression profiling.

Biopsies and ANCA testing for limited forms of granulomatosis with polyangiitis (GPA) are frequently non-diagnostic. We characterized gene expression in GPA and other causes of orbital inflammation. We tested the hypothesis that a sub-set of patients with non-specific orbital inflammation (NSOI, also known as pseudotumor) mimics a limited form of GPA. Formalin-fixed, paraffin-embedded orbital biopsies were obtained from controls (n=20) and patients with GPA (n=6), NSOI (n=25), sarcoidosis (n=7), or thyroid eye disease (TED) (n=20) and were divided into discovery and validation sets. Transcripts in the tissues were quantified using Affymetrix U133 Plus 2.0 microarrays. Distinct gene expression profiles for controls and subjects with GPA, TED, or sarcoidosis were evident by principal coordinate analyses. Compared with healthy controls, 285 probe sets had elevated signals in subjects with GPA and 1472 were decreased (>1.5-fold difference, false discovery rate adjusted p<0.05). The immunoglobulin family of genes had the most dramatic increase in expression. Although gene expression in GPA could be readily distinguished from gene expression in TED, sarcoidosis, or controls, a comparison of gene expression in GPA versus NSOI found no statistically significant differences. Thus, forms of orbital inflammation can be distinguished based on gene expression. NSOI/pseudotumor is heterogeneous but often may be an unrecognized, localized form of GPA.

Dermis fat graft implantation after unilateral enucleation for retinoblastoma in pediatric patients.

PURPOSE: To evaluate the efficacy of dermis fat graft (DFG) as a primary implant technique in pediatric patients requiring unilateral enucleation due to retinoblastoma. METHODS: A retrospective chart review of 14 consecutive pediatric patients who underwent dermis fat graft implantation after unilateral enucleation for retinoblastoma by 1 surgeon (E.A.S.) was performed to evaluate graft efficacy with regard to orbital volume growth and any associated morbidity. Patients who received chemotherapy or external beam radiation were excluded. Demographic information was recorded. Serial MRIs were used to measure orbital volumes to compare the surgical and contralateral orbits over time. The main outcome measure was the difference in bony orbital volume between enucleated and contralateral, uninvolved orbits. Mann-Whitney U test was used to compare orbital volume measurements between surgical and nonsurgical orbits. Correlation testing was performed to determine the effect of age, sex, and follow-up time on the orbital volume changes. RESULTS: There was no statistical difference between the MRI volume measured for surgical and nonsurgical orbits over time. This was the case at all measured time points and for all ages and genders. All patients were under the age of 4 years at the time of surgery. The median difference in orbital volumes between surgical and nonsurgical orbits was -0.095 cm (range -1.26 to 1.01 cm; quartiles -0.32 to 0.07 cm; mean ± SD, -0.144 ± 0.0522 cm; 95% confidence interval, -0.247 to -0.0419 cm). The median follow-up time from surgery date to the most recent clinical examination was 38.5 months (range, 13 to 70 months; quartiles, 28.75 to 45.5 months; mean ± standard deviation [SD], 38.43 ± 17.21 months; 95% confidence interval, 29.41 to 47.45 months). CONCLUSIONS: In pediatric patients below 4 years of age with unilateral retinoblastoma treated with enucleation and primary dermis fat graft implantation, there was no statistically significant difference in bony orbital volume between the surgical and nonsurgical orbits during the follow-up period.

Idiopathic lymphoplasmacellular mucositis-dermatitis of the eyelid.

Idiopathic lymphoplasmacellular mucositis-dermatitis is a rare mucosal or cutaneous disorder characterized clinically by papules or plaques with variable erosion and microscopically by dense dermal inflammatory cell infiltrates with numerous plasma cells. It has been described in the oral and upper aerodigestive tracts, male and female genitalia, and other mucosal surfaces. In this article, the authors describe a case of idiopathic lymphoplasmacellular mucositis-dermatitis occurring in the skin of the eyelid that was removed by excisional biopsy and has not recurred in the 19-month follow-up period.

Tattoo granuloma of the eyelid mimicking carcinoma.

A 68-year-old woman was referred to the Oculofacial Plastic and Reconstructive Surgery service for evaluation of a left upper eyelid lesion that was worrisome for carcinoma. The mass measured 8 × 8 mm; it was well-circumscribed, pink, and firm with distortion of the eyelid margin, central ulceration, and loss of the lashes. The patient denied previous surgery or trauma in this area, but she had a history of blepharopigmentation (tattoo eyeliner) of all 4 eyelids approximately 7 years prior. Incisional biopsy revealed inflammatory changes consistent with a localized reaction to the tattoo pigment granules. Local kenalog injection was attempted with improvement of the overall appearance but with persistent deformity including irregularity of the margin and loss of lashes. The persistent abnormal appearance was worrisome for an underlying carcinoma missed on the initial incisional biopsy and prompted a full-thickness wedge resection and reconstruction of the abnormal area. The results of biopsy of the excised tissue confirmed absence of malignant neoplasm and showed changes consistent with tattoo granuloma. Tattoo granuloma of the eyelid should be considered in the differential diagnosis of eyelid lesions worrisome for carcinoma in patients with a history of blepharopigmentation.

Orbital decompression to alleviate intermittent globe subluxation due to massive optic nerve sheath enlargement from chronic hydrocephalus.

A 59-year-old man with a history of chronic hydrocephalus and lifelong poor vision was referred to the oculoplastic surgery service for the management of symptomatic proptosis and intermittent globe subluxation of his OD. Imaging studies of his orbits revealed massively enlarged and calcified optic nerve sheaths. Neurosurgical consultation recommended against violation of the cerebrospinal fluid space given the chronic compensated hydrocephalus. Three-wall bony orbital decompression was therefore performed without complication and resulted in improved symptomatic and cosmetic outcomes.

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.

Non-specific orbital inflammation: Current understanding and unmet needs.

Non-specific orbital inflammation (NSOI) is a noninfectious inflammatory condition of the orbit. Although it is generally considered the most common diagnosis derived from an orbital biopsy, it is a diagnosis of exclusion, meaning that the diagnosis requires exclusion of a systemic process or another identifiable etiology of orbital inflammation. The clinical diagnosis of NSOI is ill-defined, but it is typically characterized by acute orbital signs and symptoms, including pain, proptosis, periorbital edema, chemosis, diplopia, and less commonly visual disturbance. NSOI poses a diagnostic and therapeutic challenge: The clinical presentations and histological findings are heterogeneous, and there are no specific diagnostic criteria or treatment guidelines. The etiology and pathogenesis of NSOI are poorly understood. Here we recapitulate our current clinical understanding of NSOI, with an emphasis on the most recent findings on clinical characteristics, imaging findings, and treatment outcomes. Furthermore, gene expression profiling of NSOI and its implications are presented and discussed.

Radiologic imaging shows variable accuracy in diagnosing orbital inflammatory disease and assessing its activity.

Radiologic orbital imaging provides important information in the diagnosis and management of orbital inflammation. However, the diagnostic value of orbital imaging is not well elucidated. This study aimed to investigate the diagnostic accuracy of orbital imaging to diagnose orbital inflammatory diseases and its ability to detect active inflammation. We collected 75 scans of 52 patients (49 computed tomography (CT) scans; 26 magnetic resonance (MR) imaging scans). Clinical diagnoses included thyroid eye disease (TED) (41 scans, 31 patients), non-specific orbital inflammation (NSOI) (22 scans, 14 patients), sarcoidosis (4 scans, 3 patients), IgG4-related ophthalmic disease (IgG4-ROD) (5 scans, 3 patients), and granulomatosis with polyangiitis (GPA) (3 scans, 1 patient). Two experienced neuroradiologists interpreted the scans, offered a most likely diagnosis, and assessed the activity of inflammation, blinded to clinical findings. The accuracy rate of radiological diagnosis compared to each clinical diagnosis was evaluated. Sensitivity and specificity in detecting active inflammation were analyzed for TED and NSOI. The accuracy rate of radiologic diagnosis was 80.0% for IgG4-ROD, 77.3% for NSOI, and 73.2% for TED. Orbital imaging could not diagnose sarcoidosis. Orbital CT had a sensitivity of 50.0% and a specificity of 75.0% to predict active TED using clinical assessment as the gold standard. The sensitivity/specificity of orbital MR was 83.3/16.7% for the detection of active NSOI. In conclusion, orbital imaging is accurate for the diagnosis of IgG4, NSOI, and TED. Further studies with a large number of cases are needed to confirm this finding, especially with regard to uncommon diseases. Orbital CT showed moderate sensitivity and good specificity for identifying active TED.

An Update on Endocrine Mucin-producing Sweat Gland Carcinoma: Clinicopathologic Study of 63 Cases and Comparative Analysis.

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare, low-grade adnexal neoplasm with predilection for the periorbital skin of older women. Histologically and immunophenotypically, EMPSGC is analogous to another neoplasm with neuroendocrine differentiation, solid papillary carcinoma of the breast. Both lesions are spatially associated with neuroendocrine mucinous adenocarcinomas of the skin and breast, respectively. EMPSGC is ostensibly a precursor of neuroendocrine-type mucinous sweat gland adenocarcinoma (MSC), a lesion of uncertain prognosis. Non-neuroendocrine MSC has been deemed locally aggressive with metastatic potential, and previous works speculated that EMPSGC-associated (neuroendocrine-type) MSC had similar recurrence and metastatic potential with implications for patient follow-up. Only 96 cases of EMPSGC have been reported (12 cases in the largest case series). Herein, we present 63 cases diagnosed as "EMPSGC" in comparison with aggregated results from known published EMPSGC cases. We aim to clarify the clinicopathologic features and prognostic significance of the neuroendocrine differentiation of EMPSGC and its associated adenocarcinoma and to determine the nosological relevance of EMPSGC association in the spectrum of MSC histopathogenesis. Results established an overall female predominance (66.7%) and average presenting age of 64 years. EMPSGC lesions were associated with adjacent MSC in 33.3% of cases. The recurrence rate for neuroendocrine-type MSC was ~21%, less than the reported 30% for non-neuroendocrine MSC. There were no cases of metastasis. EMPSGC and neuroendocrine-type MSC are distinct entities with more indolent behavior than previously reported, supporting a favorable prognosis for patients.

Conjunctivodacryocystorhinostomy with the frosted jones pyrex tube.

PURPOSE: To report the results of conjunctivodacryocystorhinostomy with primary placement of a frosted Jones Pyrex tube in the treatment of epiphora from upper lacrimal dysfunction. METHODS: A retrospective chart review was performed for patients who had undergone conjunctivodacryocystorhinostomy with primary placement of a frosted Jones Pyrex tube performed by a single surgeon (R.A.D.). All patients with at least 6 months of follow-up were included in the study. Efficacy was judged by patient report of resolution of tearing and charts were reviewed for complications. RESULTS: Five conjunctivodacryocystorhinostomy procedures were performed with primary placement of a frosted Jones Pyrex tube. Four of the surgeries were performed for a diagnosis of flaccid canaliculi and one for a congenital upper lacrimal obstruction that had been unsuccessfully treated with previous surgery at another institution. Three of the surgeries were performed with an endoscopic approach and 2 were performed with an external approach. Follow-up ranged from 29 to 34 weeks (mean, 31.2 weeks). All patients reported complete resolution of tearing and no complications were noted, including no evidence of tube migration or extrusion. CONCLUSIONS: Primary placement of frosted Jones Pyrex tubes in patients undergoing conjunctivodacryocystorhinostomy seems to retain the efficacy of a standard Jones Pyrex tube while reducing the likelihood of tube extrusion, which is the main complication of this surgery.

Comparison of injection pain of articaine and lidocaine in eyelid surgery.

PURPOSE: To compare the pain induced by tissue infiltration of lidocaine 2% with epinephrine 1:100,000 versus articaine 4% with epinephrine 1:100,000 for eyelid surgery. METHODS: Thirty patients undergoing bilateral eyelid surgery were enrolled in a prospective, randomized, double-masked study. Each subject received injections of lidocaine 2% with epinephrine 1:100,000 (Xylocaine) on one side and articaine 4% with epinephrine 1:100,000 (Septocaine) on the other for surgical anesthesia. The patients rated the pain of infiltration using a 100-mm visual analogue scale immediately after receiving each injection. The pain scores were compared using the paired t test. RESULTS: Twenty-two of the 30 patients (73.3%) rated the articaine injection as less painful than the lidocaine injection. The mean pain score for lidocaine was 42.60 +/- 24.74 and the pain score for articaine was 31.85 +/- 20.28 (p = 0.011). CONCLUSIONS: In this study, infiltration of articaine was less painful than lidocaine for eyelid surgery, making articaine an attractive alternative for local anesthesia.

The management of large-angle esotropia in Graves ophthalmopathy with combined medial rectus recession and lateral rectus resection.

PURPOSE: To describe surgical management and outcomes for large-angle esotropia of ≥50Δ secondary to Graves ophthalmopathy using combined initial nonadjustable medial rectus recessions and lateral rectus resections. METHODS: The medical records of consecutive patients undergoing strabismus surgery for large-angle esotropia secondary to Graves ophthalmopathy from 1995 to 2012 by a single surgeon at each of two institutions was performed. Patient characteristics, surgical technique, and pre- and postoperative measurements of ocular alignment were analyzed. A modified Gorman diplopia scale was used to assess outcome. RESULTS: Of 38 patients, 36 had bilateral nonadjustable medial rectus recessions and lateral rectus resections as initial treatment for esotropia, and 6 patients underwent simultaneous vertical muscle surgery. Mean preoperative horizontal deviation was 60Δ and mean preoperative vertical deviation was 10Δ. Of the 38 patients, 19 (50%) reached the primary outcome, including 5 of 6 (85%) who had no preoperative vertical strabismus. The indications for reoperation were vertical strabismus in 13 of 21 patients (62%), residual esotropia in 7 of 21 (33%), and consecutive exotropia in 1 of 21 (5%). With a median follow-up of 13.2 months after first surgery, 32 of 38 patients (84%) reached the secondary outcome. CONCLUSIONS: Combining nonadjustable medial rectus recessions with lateral rectus resections can be a beneficial primary treatment for large-angle esotropia in patients with Graves ophthalmopathy, especially in those patients with small or no associated vertical strabismus.

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.

The Role of the Immune Response in the Pathogenesis of Thyroid Eye Disease: A Reassessment.

BACKGROUND: Although thyroid eye disease is a common complication of Graves' disease, the pathogenesis of the orbital disease is poorly understood. Most authorities implicate the immune response as an important causal factor. We sought to clarify pathogenesis by using gene expression microarray. METHODS: An international consortium of ocular pathologists and orbital surgeons contributed formalin fixed orbital biopsies. RNA was extracted from orbital tissue from 20 healthy controls, 25 patients with thyroid eye disease (TED), 25 patients with nonspecific orbital inflammation (NSOI), 7 patients with sarcoidosis and 6 patients with granulomatosis with polyangiitis (GPA). Tissue was divided into a discovery set and a validation set. Gene expression was quantified using Affymetrix U133 Plus 2.0 microarrays which include 54,000 probe sets. RESULTS: Principal component analysis showed that gene expression from tissue from patients with TED more closely resembled gene expression from healthy control tissue in comparison to gene expression characteristic of sarcoidosis, NSOI, or granulomatosis with polyangiitis. Unsupervised cluster dendrograms further indicated the similarity between TED and healthy controls. Heat maps based on gene expression for cytokines, chemokines, or their receptors showed that these inflammatory markers were associated with NSOI, sarcoidosis, or GPA much more frequently than with TED. CONCLUSION: This is the first study to compare gene expression in TED to gene expression associated with other causes of exophthalmos. The juxtaposition shows that inflammatory markers are far less characteristic of TED relative to other orbital inflammatory diseases.

Fibrosis, gene expression and orbital inflammatory disease.

BACKGROUND/AIMS: To clarify the pathogenesis of fibrosis in inflammatory orbital diseases, we analysed the gene expression in orbital biopsies and compared our results with those reported for idiopathic pulmonary fibrosis. METHODS: We collected 140 biopsies from 138 patients (58 lacrimal glands; 82 orbital fat). Diagnoses included healthy controls (n=27), non-specific orbital inflammation (NSOI) (n=61), thyroid eye disease (TED) (n=29), sarcoidosis (n=14) and granulomatosis with polyangiitis (GPA) (n=7). Fibrosis was scored on a 0-3 scale by two experts, ophthalmic pathologists. Gene expression was quantified using Affymetrix U133 plus 2.0 microarray. RESULTS: Within orbital fat, fibrosis was greatest among subjects with GPA (2.75±0.46) and significantly increased in tissue from subjects with GPA, NSOI or sarcoidosis (p<0.01), but not for TED, compared with healthy controls (1.13±0.69). For lacrimal gland, the average score among controls (1.36±0.48) did not differ statistically from any of the four disease groups. Seventy-three probe sets identified transcripts correlating with fibrosis in orbital fat (false discovery rate <0.05) after accounting for batch effects, disease type, age and sex. Transcripts with increased expression included fibronectin, lumican, thrombospondin and collagen types I and VIII, each of which has been reported upregulated in pulmonary fibrosis. CONCLUSIONS: A pathologist's recognition of fibrosis in orbital tissue correlates well with increased expression of transcripts that are considered essential in fibrosis. Many transcripts implicated in orbital fibrosis have been previously implicated in pulmonary fibrosis. TED differs from other causes of orbital fat inflammation because fibrosis is not a major component. Marked fibrosis is less common in the lacrimal gland compared with orbital adipose tissue.