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.

Subciliary Rotating Sutures Combined With Modified Hotz Procedure for Correction of Congenital Lower Eyelid Entropion.

PURPOSE: Standard techniques for the treatment of congenital lower eyelid entropion may not yield suitable outcomes or may result in overcorrection if disinsertion of the lower eyelid retractors is not the primary cause. Herein, we propose and evaluate a technique using subciliary rotating sutures combined with a modified Hotz procedure for repair of lower eyelid congenital entropion that addresses these concerns. METHODS: A retrospective chart review was conducted of all patients who underwent lower eyelid congenital entropion repair by a single surgeon using subciliary rotating sutures combined with a modified Hotz procedure between 2016 and 2020. Study variables included patient demographics, follow-up period, postoperative complications, operative success, and recurrence. RESULTS: Twelve patients (19 eyelids) met the study inclusion criteria. The mean patient age was 7.1 ± 6.1 years (range, 0.2-22 years). Nine of the patients were female (75%) and 3 were male (25%). The distribution of eyelids was 8 right (42%) and 11 left (58%). The mean follow-up time was 19.5 ± 15 (range 2.5-45) months. There were two eyelids (11%) that had entropion recurrence after initial repair in patients with concomitant compound disease processes. Repeated repair resulted in success with no recurrence at last follow-up. Overall, the described entropion repair technique was successful and without recurrence in 17 eyelids (89%). There were no cases of ectropion, lid retraction, or other complications. CONCLUSIONS: Subciliary rotating sutures combined with a modified Hotz procedure are effective for correction of congenital lower eyelid entropion. As the technique does not manipulate the posterior layer of the lower eyelid retractors, it may be useful for when retractor reinsertion does not yield adequate improvement and may also reduce the risk of eyelid retraction and overcorrection in particular cases.

Orbital cellulitis and cavernous sinus thrombosis with contralateral sinus disease in a COVID-19 positive adolescent patient.

Patients with COVID-19 have been reported to have elevated coagulation factors, which is a well-documented cause of venous thromboembolism events such as deep vein thrombosis and pulmonary embolism. Other venous thrombotic events, however, such as cavernous sinus thrombosis (CST) have been less commonly observed, specifically in combination with primary orbital cellulitis. Due to its unique anatomic location, the cavernous sinus is susceptible to thrombophlebitis processes including septic thrombosis and thrombosis most commonly from sinusitis. Many studies have shown that in the antibiotic era thromboembolic events of the cavernous sinus are less common due to infection spread from the orbit or facial region. This case report describes a 17-year-old COVID-19 positive male who presented with a left-sided primary orbital cellulitis with CST without radiographic evidence of ipsilateral sinus disease.

Factors Influencing Fellowship Training Among Ophthalmology Residents: A Pilot Study.

Objective: There has been an increase in ophthalmology fellowship training programs and applicants. The current ophthalmology literature lacks any recent study examining factors influencing residents' decisions to pursue subspecialty fellowship training. Methods: An anonymous, 16-item survey was distributed to residents from a convenience sample of ophthalmology residency programs by their program directors or administrators. Results: A total of 72 residents and 9 interns from 9 distinct programs completed the survey. Eighty-two percent of respondents reported they have either applied or will apply for a fellowship position. Gender and race showed no significant association with fellowship application. Respondents perceived that obtaining a fellowship position would be easier (61%) than obtaining an ophthalmology residency. The desire for additional clinical and surgical training were the 2 primary factors for the pursuit of fellowship training. Half of those pursuing fellowship training (49%) indicated they still desired to practice comprehensive ophthalmology. None of the respondents indicated they wished to practice in a rural area. Conclusion: The data collected in this pilot study elicited factors and variable associations that provide a sound basis for informing revisions and improvements to the data collection tool for a follow-up prospective, longitudinal study involving all ACGME ophthalmology training programs. The results indicate some of the essential factors associated with the pursuit of fellowship training by the current generation of residents. The results also highlight potential trends related to residents' views of their training and desired practice patterns.

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.

Antibody Development in Patients Treated Long-Term With OnabotulinumtoxinA for Benign Essential Blepharospasm and Hemifacial Spasm.

BACKGROUND: Report the development of onabotulinumtoxinA neutralizing antibodies in patients treated consecutively for 20 years or longer for benign essential blepharospasm (BEB), hemifacial spasm (HFS), and Meige Syndrome. METHODS: Prospective, randomized, cross-sectional study of 12 randomly selected patients from a single clinical practice that have been treated consecutively for 20 or more years with onabotulinumtoxinA for BEB, HFS, or Meige Syndrome. Serum samples were collected from each subject and analyzed for neutralizing antibody formation using the Mouse Protection Assay. RESULTS: None of the tested patients (0%) displayed neutralizing antibodies to onabotulinumtoxinA. The mean duration of treatment was 27.5 years (range 22.1-34.1, SD 3.1, 95% confidence interval 25.45-29.50). Nine of the patients had a diagnosis of BEB, 2 HFS, and one Meige. Eleven of the 12 patients were women. There was no statistically significant difference in treatment dosage or interval over the course of treatment. CONCLUSIONS: The data support previous studies showing low incidence of antibody formation for botulinum A toxins with this subset of long-term treated patients. The results also provide further evidence for studies that have suggested increased onabotulinumtoxinA treatment volumes and/or decreased intervals between treatments are not due to neutralizing antibody formation and secondary non-response, but rather study designs that do not consider the titration phase of initial treatments. This study is specific to long-term treated patients, and the results cannot be generalized to patients naive to treatment.

Visible Meibomian Gland Structure Increases After Vectored Thermal Pulsation Treatment in Dry Eye Disease Patients with Meibomian Gland Dysfunction.

PURPOSE: To assess the effect of vectored thermal pulsation treatment (VTP) on visible meibomian gland structure (VGS) in patients with meibomian gland dysfunction (MGD). SETTING: Private group practice (A.T.E.). DESIGN: Retrospective, single-blinded cohort study. METHODS: Visible meibomian gland structure was evaluated at baseline and at 1-year in treatment (30 patients, 48 eyes) and control (13 patients, 22 eyes) groups. Meibography images were captured using dynamic meibomian imaging. Images were assessed using a novel morphometric analysis technique and analyzed for change in area of VGS (pixels). Additional outcomes measured include tear break up time, corneal staining, tear osmolarity, matrix metalloproteinase-9 (MMP-9), meibography grading, and meibomian gland evaluation. RESULTS: As high as 69% of eyes in the treatment group showed an improvement in VGS versus 27% of eyes in the control group. As high as 31% of eyes in the treatment group showed a decline in VGS versus 73% of eyes in the control group. TBUT (p = 0.0001), corneal staining (p = 0.0063), and meibomian gland evaluation scores (p = 0.0038) all significantly improved after VTP treatment. However, SPEED scores, MMP-9, tear osmolarity, and meiboscale scores were not significantly improved 1-year post treatment. CONCLUSION: A morphometric analysis protocol of meibography provides clinically meaningful information that is undetectable with the standard semiquantitative method of grading meibomian gland structure. This is the first report indicating that gland structure may increase post-VTP relative to untreated controls, thus presenting significant implications regarding benefits and timing of VTP therapy. The described protocol is currently more appropriate for research than for clinical practice.

Transitioning from a gold weight to an "enhanced" palpebral spring in the management of paralytic lagophthalmos secondary to facial nerve palsy.

PURPOSE: To analyze the outcomes of patients who transitioned from a weight to a spring. METHODS: Case series original investigation. Five consecutive patients undergoing "enhanced" palpebral spring insertion status post gold weight insertion were identified. Outcome measures included visual acuity, lagophthalmos, margin reflex distance 1, and corneal epithelial defects. Subjective outcomes included need for eye lubrication, closure and rapid blink, and symptoms of discomfort and dryness. This study was reviewed by an accredited Institutional Review Board (IRB) and granted exempt status according to federal regulations. RESULTS: Mean visual acuity post weight versus spring was 20/200 (logMAR 1.0, Std Dev. -0.6) and 20/25 (logMAR 0.1, Std Dev. -0.1), respectively (p = 0.0214, CI 0.231 to 1.670). Mean lagophthalmos post weight (3.5 mm, Std Dev. -2.8) versus post spring (0.2 mm, Std Dev. -0.5). Margin reflex distance 1 improved by a mean of 1.4 mm (gold wt -0.6, Std Dev. -0.5/spring -2.0, Std Dev. -0.4) (p = 0.0016, CI -1.773 to -0.977). Superficial punctate keratopathy was present in all patients with weights and present in no patients post transition (p = 0.0079). Post transition, three of five patients rarely required lubrication and experienced a more satisfactory blink rate. CONCLUSION: Patients with lagophthalmos due to cranial nerve seven palsy who have undergone gold weight placement but continue to exhibit objective and subjective corneal symptoms may have symptomatic improvement with the transition to a palpebral spring.

Quantification of the Aesthetically Desirable Female Midface Position.

BACKGROUND: The purpose of this study was to attempt to determine a reliable method of evaluating midface position. We assessed a novel parameter called WIZDOM (Width of the Interzygomatic Distance of the Midface) and its relationship to other facial metrics. OBJECTIVES: The goal was to evaluate midfacial position quantitatively in women by examining 2-dimensional photographs of a subset of women with idealized facial proportions. METHODS: Three examiners analyzed stock photographs of nonsmiling female model faces. Numerous parameters were analyzed for each photograph, including: interpupillary distance, medial canthus (MC) to lip, brow length, WIZDOM, WIZDOM to MC, WIZDOM to hairline, WIZDOM to chin vertical, and lateral brow to WIZDOM. Meaningful relationships between various parameters were statistically analyzed. Examiner measurements were assessed for interobserver reliability. RESULTS: Fifty-five female model photographs were included in the analysis. The average interpupillary distance was 59.2 mm ± 3.54 (range, 50.5-67.3 mm). The WIZDOM average was 108 mm ± 5.81 (range, 93-127 mm) and brow length was 107 mm ± 5.87 (range, 96.7-124 mm). The difference between brow length and WIZDOM was not statistically different (P = 0.834). The interobserver reliability between the 3 examiners was excellent for all parameters (P < 0.01), ranging from 0.718 (WIZDOM-MC) to 0.993 (interpupillary distance). The WIZDOM measurement was reproducible with an interobserver coefficient of 0.939. CONCLUSIONS: WIZDOM can be used to quantify aesthetically desirable midfacial position in patients and can be used as a measurement to aid in assessment and as an ideal to achieve balanced aesthetic results in midface restorative procedures-lifting or volumization-in females.

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.

Canthal cutdown for emergent treatment of orbital compartment syndrome.

This article evaluates the use of a "canthal cutdown" technique in orbital compartment syndrome in a cadaveric model. Twelve cadaver orbits were used to simulate orbital compartment syndrome using a blood analog solution. Two pressure probes, in different orbital locations, were used to monitor orbital pressure. Pressure was monitored during successive procedures: canthotomy, cantholysis, and canthal cutdown. Orbits were then re-injected with solution, simulating an active orbital hemorrhage, and pressure measurements were recorded over a 10-minute duration. No statistically significant difference was found between the two orbital pressure monitoring devices at each measurement point (p = 0.99). Significant pressure reductions, for both probes, were observed after canthal cutdown compared to initial measurement after injection of 20 mL blood analog (p < 0.001 and p = 0.005). When comparing the orbital pressure following canthotomy and inferior cantholysis versus canthal cutdown, the cutdown procedure provided an additional 74% in orbital pressure reduction (p =0.01). After re-injection of 10 mL of solution and 10 minutes of egress, pressure returned to baseline (probe 1: baseline 7 mm Hg vs. post-cutdown at 10 minutes 7 mm Hg; p = 0.83; and probe 2: 5 mm Hg vs. 5 mm Hg; p = 0.83). The canthal cutdown technique provides further reduction in orbital pressure versus canthotomy and cantholysis alone. The technique may be effective for treatment of static orbital compartment syndrome and temporizing treatment of compartment syndrome from active orbital hemorrhages.

Neomycin, polymyxin B, and dexamethasone allergic reactions following periocular surgery.

BACKGROUND: The aim of this study was to evaluate the rate of periocular allergic skin reactions to topical neomycin, polymyxin B, and dexamethasone (NPD) ophthalmic ointment. METHODS: A consecutive patient prospective study was performed. A total of 522 patients who had a procedure involving incision of the periocular skin with subsequent postoperative application of NPD ophthalmic ointment were included. Patients were evaluated for signs of allergy at 1 week postoperatively or prior if the patient had complaints. A periocular allergic reaction was defined as any periocular skin pruritus, erythema, edematous papules, vesicles, or plaques at the site of ointment application beyond that of the typical postprocedure presentation. The patients continued to be monitored for 30 days postoperatively. RESULTS: Of the 522 patients who completed the study, eight (1.5%) had a definitive periocular allergic contact dermatitis to the NPD ophthalmic ointment. Allergic presentation ranged from postoperative day 3 to 14. CONCLUSIONS: The rate of periocular allergic reactions to NPD ophthalmic ointment is significantly lower than reported in the literature for other topical preparations of neomycin and polymyxin B. The low rate of allergy in this study suggests that NPD ophthalmic ointment can safely be applied to the periocular skin with a very minimal risk of inciting an allergic reaction.

Piezosurgery in External Dacryocystorhinostomy.

BACKGROUND: Dacryocystorhinostomy (DCR) can be performed via an external or endoscopic approach. The use of ultrasonic or piezosurgery has been well described for endoscopic DCRs but is lacking for external DCRs. This study presents a case series of external DCRs performed using piezosurgery evaluating results and complications. METHODS: Prospective, consecutive case series of patients undergoing primary external DCR for lacrimal drainage insufficiency. A standard external DCR technique was used using 1 of 2 piezosurgery systems for all bone incision. All patients received silicone intubation to the lacrimal system. Surgical outcome was measured in terms of patient-reported epiphora as follows: 1) complete resolution, 2) improvement >50%, 3) improvement <50%, and 4) No improvement. Intra and postoperative complications were also recorded. RESULTS: Fifty-two patients, 14 male and 38 female, were included in the study, with 2 patients having bilateral surgery. The average age of the patients was 55.8 years. The average length of follow up was 221 days. Surgical outcomes showed 72% of patients with complete resolution of epiphora and 21% with >50% improvement. There were 4 patients (7%) who had <50% improvement. There was 1 (2%) intraoperative complication and 2 (4%) postoperative complications recorded. CONCLUSIONS: Piezourgery is a viable modality for performing external DCRs. The lack of surgical complications shows a potential for decreased soft tissues damage. The surgical success rate based on patient-reported epiphora is similar to those published for mechanical external DCRs. This modality may benefit the novice surgeon in the reduction of soft and mucosal tissue damage.

Use of Kaolin-impregnated Gauze for Improvement of Intraoperative Hemostasis and Postoperative Wound Healing in Blepharoplasty.

PURPOSE: Kaolin is a mineral shown to be effective in controlling hemorrhage when combined with standard gauze and applied to wounds. This study investigates the application of kaolin to control intraoperative bleeding and promote wound healing in eyelid surgery. METHODS: This prospective, randomized, double-blind study recruited patients who underwent eyelid surgery. Following skin incision, kaolin-impregnated gauzewas placed in one eyelid wound bed and cotton gauze in the other, then removed. Distinct, individual areas of bleeding were recorded. Standardized photographs were obtained postoperatively on Day 1, 4, and 7. Photographs were graded for edema and ecchymosis by four blinded observers. Patients also completed a survey inquiring which side had more bruising, swelling, and pain at each return visit. RESULTS: A total of 46 patients completed the study. The number of intraoperative bleeding sites for kaolin versus plain gauze was not significantly different (p=0.96). Photographic grading by blinded observers did not identify any statistically significant differences in postoperative edema at any time point between lids. There was a statistically significant difference for ecchymosis at postoperative Day 4 (p=0.009) and Day 7 (p=0.016). Patient surveys did not show any difference in perceived edema, ecchymosis, or pain between lids. CONCLUSION: Intraoperative hemostasis was not affected by the use of kaolin-impregnated gauze. The effectiveness of kaolin in wound healing showed improved ecchymosis at Days 4 and 7 when assessed by blinded observers. Patients did not notice any improvement in postoperative edema, ecchymosis, or pain.

Nasolacrimal System Aeration on Computed Tomographic Imaging: Sex and Age Variation.

PURPOSE: To investigate variation in aeration of the nasolacrimal drainage system between age groups and genders, and to report the reliability of repeated aeration grading and nasolacrimal canal measurements on CT. METHODS: Retrospective review of CT images from 92 individuals, 60 female and 32 male, was conducted by 3 independent reviewers for the presence of air within the nasolacrimal drainage system. Diameter and area measurements were also obtained at the smallest identifiable portion of the nasolacrimal canal by 2 independent reviewers. RESULTS: When air is present on CT, it is seen more fully throughout the nasolacrimal system in men as compared to women. Age data demonstrate that patients from the third and fourth decade have significantly more aeration than older patients. Diameter and area of the nasolacrimal duct within the canal at its narrowest point revealed no correlation with sex, age, or nasolacrimal system aeration. Inter-reviewer reliability shows strong repeatability of aeration grading and nasolacrimal duct measurements between multiple reviewers. CONCLUSIONS: The results suggest CT is reliable and repeatable modality to assess nasolacrimal system aeration and nasolacrimal duct diameter. Decreased aeration of the nasolacrimal system in females and the elderly mirrors epidemiologic trends for those at risk to develop primary acquired nasolacrimal duct obstruction. Variables in nasolacrimal drainage system anatomy, specifically nasolacrimal duct diameter and area, did not vary between sexes or age groups, suggesting aeration may be an overlooked variable in nasolacrimal system function.

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.

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.