Orbital Inflammation Research Articles

Ophthalmologic manifestations of the granulomatosis with polyangiitis (Wegener)

PurposeWegener's granulomatosis (WG) is a severe focal granulomatous inflammation with variable ophthalmic manifestationsMethodsPatients with a confirmed WG, seen in a single tertiary center between 2008 and 2014 were included retrospectively. WG was proven based on biological or histological analysisResultsFive patients (3W/2M) aged 26–55 years, were included. Clinical features included one scleritis with dacryoadenitis, one bilateral episcleritis complicated with uveo‐scleritis, one bilateral Mooren's ulcer and two orbital inflammatory pseudotumor. Time between the onset of symptoms and the diagnosis was 100 months (range: 1–276 months). All patients had anti‐cytoplasm antibodies to polynuclear neutrophils and underwent biopsies. Histological features included vasculitis inflammatory necrotizing granulomas. Extraocular features were pulmonary lesions (100%), rhinosinusal involvment (80%), renal disease (40%), neurological injury (40%). All patients were initially treated with high‐dose corticosteroids, wich were progressively decreased and received maintenance immunosupressive drugs. Immunosuppressive treatment was initiated on average 64 months after the onset of signs (range: 1–276 months)ConclusionsWG‘s ophthalmologic symptoms are variable. Scleritis remains the most common manifestation, followed by orbital inflammation. Atypical manifestations such as Mooren's ulcer or uveitis can delay the diagnosis. A multidisciplinary approach is mandatory to control this life threatening condition. WG should be considered in all cases of chronic orbital inflammation, scleritis or keratitis to ensure prompt diagnosis and improve the systemic prognosis.

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

BackgroundAlthough 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.MethodsAn 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.ResultsPrincipal 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.ConclusionThis 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.

Recurrent, alternating orbital inflammation

Recurrent, alternating orbital inflammation

Lacrimal Gland Volume Changes in Unilateral Primary Acquired Nasolacrimal Obstruction.

To investigate whether unilateral primary acquired nasolacrimal duct obstruction (PANDO) causes Schirmer score and lacrimal gland volume changes in the contralateral non-PANDO eye. Sixteen unilateral female PANDO and 16 female controls were enrolled in the study. Exclusion criteria were orbital trauma, inflammation, infection, tumor involvement or infiltrative diseases, history of ocular surgery, ocular surface disorder, systemic drug use that interferes with tear secretion, and chronic use of topical eye drops. Bilateral lacrimal gland volumes were measured in computed tomography (CT) images of the participants. A Schirmer test without anesthesia was also performed on each participant. As there was no significant difference between the right and left eye values for Schirmer and gland size (P > 0.05), both eyes of the control group were enrolled in the study. The groups were age matched and the mean lacrimal gland was 0.479 cm3 in the PANDO as well as the contralateral non-PANDO side, which was statistically smaller compared to the control eyes (0.580 cm3) (P = 0.04). The mean Schirmer scores in the same order were 18.5 ± 7.1 mm, 13.2 ± 8.9 mm, and 21.3 ± 10.5 mm, respectively. Non-PANDO side Schirmer scores were lower compared to the other two groups, but statistical significance was present for the control group (P = 0.04). Compared to the control group, lacrimal gland volumes were bilaterally smaller in unilateral PANDO patients. Schirmer scores were statistically lower in the contralateral non-PANDO side compared to the controls.

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.

Biodegradable Fixation of the Orbital Rim After Lateral Orbitotomy.

To describe authors' experience with repair of the lateral orbital rim with poly-L/DL-lactic acid (PDLLA) biodegradable plates using ultrasonic pin fixation after lateral orbitotomy with bone flap. The authors retrospectively reviewed all patients who underwent a lateral orbitotomy with bone flap for biopsy of orbital tumors at their institution from January 2010 to May 2013. All patients underwent an orbitotomy by either a lateral eyelid crease incision or lateral canthotomy/cantholysis approach. A lateral bone flap was fashioned in the usual manner, extending from the frontozygomatic suture down the lateral rim for approximately 2 cm. The bone flap was repaired in each case with either a 6 or 7 hole PDLLA plate and secured with ultrasonic PDLLA pin fixation. Twenty-four patients were identified who underwent a lateral orbitotomy with bone flap. Of these patients, 10 were repaired with PDLLA plates. The average age of the patients with PDLLA bone flap fixation was 55 years (range 5-85). The average follow-up time was 12.9 months (range 4-42). Indications included 4 lacrimal gland tumors, 4 intraconal tumors, and 2 lateral orbital tumors. Final diagnosis included lymphoma (3), squamous cell carcinoma (1), neuroblastoma (1), amyloid (1), fibrous tissue (1), sarcoidosis (1), cavernous hemangioma (1), and idiopathic orbital inflammation (1). Three patients had edema of the surrounding soft tissues after surgery, all but 1 resolved by postop month 3. There were 2 cases of transient temporal numbness that resolved by postop month 1. There were no cases of vision loss, extraocular motility deficit, infection, or need for removal of the implant before absorption. PDLLA biodegradable plates with ultrasonic pin placement provide a safe, effective means for lateral rim fixation after orbitotomy with bone flap.

Fibrosis, gene expression and orbital inflammatory disease

Background/aimsTo 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.MethodsWe collected...

IgG4-Related Ophthalmic Disease: Pooling of Published Cases and Literature Review

In recent years, IgG4-related ophthalmic disease (IgG4-ROD) has emerged as a common cause of orbital inflammation, accounting for a substantial proportion of idiopathic orbital inflammation and lymphoid hyperplasia. The last pooled analysis of published cases was conducted in 2012, but a large number of new cases have been added to the literature since then. In this review, we present the demographic, clinical, histological, and treatment data for 172 published cases of biopsy-confirmed IgG4-ROD. Results are accompanied by a review of the relevant literature.

Idiopathic Orbital Myositis in a 9-Year-Old Girl: A Case Report.

Idiopathic Orbital Myositis in a 9-Year-Old Girl: A Case Report.

IgG4-associated orbital and ocular inflammation.

BackgroundIgG4-associated orbital and ocular inflammation is a relatively unknown entity characterized by sclerosing inflammation with infiltration of IgG4-positive plasma cells. Some so-called idiopathic inflammation syndromes are being re-classified as IgG4-associated inflammation with histopathologic evaluation.FindingsWe report three cases with differing manifestations of IgG4-associated ocular and orbital inflammation: a case of recurrent, treatment-refractory sclero-uveitis that was diagnosed as granulomatosis with polyangiitis with an IgG4-related component, a case of pachymeningitis with optic neuritis that resulted in permanent visual loss, and a case of orbital inflammatory pseudotumor. All three would have been incompletely diagnosed without thorough histopathologic evaluation (including immunohistochemistry).ConclusionsIgG4-associated disease is an idiopathic, multi-organ inflammatory state that can manifest as chronic, relapsing, sclerosing inflammation in virtually any organ system. There is a wide range of presentations in ocular and orbital inflammation. Ophthalmologists should keep IgG4-associated inflammation in mind when examining chronic, sclerofibrosing inflammation with multi-system involvement. The histology of biopsy specimens is crucial in making the correct diagnosis. Timely assessment may lead to fewer diagnostic tests and more targeted therapy.

IgG4-related disease in idiopathic sclerosing orbital inflammation

AimsTo investigate the frequency of IgG4-related disease (IgG4-RD) among patients previously diagnosed with idiopathic sclerosing orbital inflammation (ISOI), and to compare the clinical features and treatment outcomes of patients with...

IgG4-Related Ophthalmic Disease. Part II: Clinical Aspects.

To review the current state of knowledge of IgG4-related ophthalmic disease (IgG4-ROD). A review of the literature and personal experience of the authors. IgG4-related disease is a recently recognized fibroinflammatory disorder that may affect 1 or more organs. It is characterized by lymphoplasmacytic infiltrates with large numbers of IgG4 positive plasma cells, storiform fibrosis, obliterative phlebitis, and eosinophil infiltration as well as peripheral eosinophilia, and in some cases, elevated serum levels of IgG4. These features are not always seen, and the diagnosis should be made by integrating clinical, imaging, and histopathological data, with reference to recently defined diagnostic criteria. IgG4-ROD forms a significant proportion of what has previously been labeled "idiopathic orbital inflammation" or reactive lymphoid hyperplasia. Orbital disease may occur alone, at the same time as disease elsewhere, or metachronously with systemic disease. Although almost any ocular adnexal tissue may be affected, there are several commoner recognizable patterns of IgG4-ROD: (1) sclerosing dacryoadenitis; 2) enlargement of orbital nerves (most commonly the infraorbital nerve) associated with orbital myositis and lacrimal gland disease, often in combination with paranasal sinus disease, eosinophilia, and systemic involvement; and 3) sclerosing orbital inflammation. Patients with IgG4-ROD should be investigated and monitored for other organ involvement. Some patients with IgG4-related disease may develop lymphoma, usually marginal zone lymphoma of mucosa-associated lymphoid tissue type. Treatment of IgG4-ROD includes the use of corticosteroids and other immunosuppressants. Rituximab has been shown to be very effective. Longer term studies on the natural course and treatment of IgG4-ROD are needed. Patients presenting with orbital inflammatory lesions should have biopsies obtained whenever possible. The examining pathologist should routinely look for features of IgG4-ROD, and if found, the patient should be investigated for other organ involvement. Early treatment may prevent destructive changes in affected tissues.

Increased CD40+ Fibrocytes in Patients With Idiopathic Orbital Inflammation.

To investigate the phenotypic and functional characteristics of peripheral and tissue-infiltrating stem cells called fibrocytes in patients with idiopathic orbital inflammation (IOI). Seven patients with IOI were studied. In the 3 patients requiring orbital biopsy, fibrocytes were identified in orbital tissue from patients with IOI compared with healthy controls using immunohistochemistry. Fibrocytes from the peripheral blood of all 7 patients and controls were quantified and phenotyped by flow cytometry and immunofluorescence for expression of CD34, alpha smooth muscle actin, CD40, and collagen 1. Quantitation of CD40-mediated interleukin-6 (IL-6) production was measured using enzyme-linked immunosorbent assay. Orbital biopsy specimens from patients with IOI demonstrate tissue infiltration by fibrocytes (n = 3). Fibrocytes are present in the peripheral blood of IOI patients (n = 7) but are scarce in healthy donors (n = 19). Fibrocytes from IOI patients express substantial levels of CD40, and ligation of CD40 increases IL-6 expression. Fibrocytes are present in the peripheral blood and orbital tissues of patients with IOI and constitutively express CD40 and express IL-6 in response to ligation. This site-specific predilection of CD34(+) fibrocytes to sites of orbital inflammation and fibrosis may suggest a role in IOI. Moreover, CD40-mediated activation cytokine production may contribute to the proinflammatory and profibrotic features of IOI and may provide a mechanism for future targeted therapy.

Ipilimumab-induced Ocular and Orbital Inflammation—A Case Series and Review of the Literature

Purpose: Ipilimumab, a monoclonal antibody directed against the immune protein cytotoxic T-lymphocyte antigen-4 (CTLA-4), characteristically induces side effects called “immune-related adverse events” (IRAE). Although ophthalmic involvement is rare, we report 7 cases of eye and orbit complications related to ipilimumab therapy.Methods: We performed a retrospective review of patients with metastatic melanoma who developed ipilimumab-related ocular or orbital inflammation who were seen at our institutions.Results: Seven patients were identified: 4 patients had orbital inflammation, 2 had uveitis, and 1 had peripheral ulcerative keratitis. Four patients developed inflammation after the second ipilimumab infusion, 2 after the third infusion and 1 after the first infusion. All 4 patients with orbital inflammation were treated with systemic corticosteroids. Two patients with uveitis were treated with topical steroids, but were also treated with systemic corticosteroids for other IRAE, including colitis and hypophysitis. The patient with keratitis was treated with topical corticosteroids alone with resolution of inflammation. All 7 patients discontinued ipilimumab therapy, 5 due to systemic IRAE and 2 due to tumor progression. Five of 7 patients had tumor progression on ipilimumab therapy.Conclusions: Ocular and orbital inflammation may occur in patients with metastatic melanoma receiving ipilimumab, is frequently accompanied by other IRAEs, and resolves with corticosteroid treatment, often leaving no long-term sequelae.

IgG4-related ophthalmic disease. Part I: background and pathology.

To review the current state of knowledge of IgG4-related ophthalmic disease (IgG4-ROD). A review of the literature and personal experience of the authors. IgG4-related disease is a recently recognized fibroinflammatory disorder that may affect 1 or more organs. It is characterized by lymphoplasmacytic infiltrates with large numbers of IgG4 positive plasma cells, storiform fibrosis, obliterative phlebitis, and eosinophil infiltration as well as peripheral eosinophilia, and in some cases, elevated serum levels of IgG4. These features are not always seen, and the diagnosis should be made by integrating clinical, imaging, and histopathological data, with reference to recently defined diagnostic criteria. IgG4-ROD forms a significant proportion of what has previously been labeled "idiopathic orbital inflammation" or reactive lymphoid hyperplasia. Orbital disease may occur alone, at the same time as disease elsewhere, or metachronously with systemic disease. Although almost any ocular adnexal tissue may be affected, there are several more common recognizable patterns of IgG4-ROD: 1) sclerosing dacryoadenitis; 2) enlargement of orbital nerves (most commonly the infraorbital nerve) associated with orbital myositis and lacrimal gland disease, often in combination with paranasal sinus disease, eosinophilia, and systemic involvement; and 3) sclerosing orbital inflammation. Patients presenting with orbital inflammatory lesions should have biopsies obtained whenever possible. The examining pathologist should routinely look for features of IgG4-ROD, and if found, the patient should be investigated for other organ involvement. Early treatment may prevent destructive changes in affected tissues.

Sarcoidosis in the National Veteran Population: Association of Ocular Inflammation and Mortality

To describe the distribution of ocular sarcoidosis in the veteran population and to determine the association between ocular disease and all-cause mortality. Retrospective review. The Veterans Health Administration National Patient Care Database information on medical diagnoses, date of diagnosis, age, race, gender, and Veterans Administration medical center station number for site-specific calculations for fiscal years 2010 through 2012 was collected. Mortality data were obtained from the Beneficiary Identification Records Locator Subsystem. The patient cohort was identified with a primary diagnosis of sarcoidosis using International Classification of Disease, ninth edition, code of 135 in outpatient treatment files for the study period. The sarcoidosis patients were divided into those with uveitis or orbital inflammation (defined as ocular inflammation for this study) and those without uveitis or orbital inflammation. Survival analysis was performed using the Cox proportional hazard method. Association between ocular inflammation and 1-year mortality. Of 15 130 subjects with sarcoidosis, 3364 (22.2%) were evaluated in an eye clinic within a Veterans Administration Medical Center. Most patients were diagnosed with anterior uveitis (n = 1013; 80.7% of ocular inflammation), and the least common diagnosis was orbital granuloma (n = 28; 2.2% of ocular inflammation). Male gender was protective to the development of uveitis (estimate, 0.76; 95% confidence interval, 0.65-0.88; P = 0.0005). The overall 1-year all-cause mortality for all patients with a diagnosis of sarcoidosis was 2.0%. Ocular inflammation was associated with a decrease in 1-year all-cause mortality (simple model: hazard ratio, 0.36; P = 0.0015; complex model: hazard ratio, 0.35; P = 0.013). Veterans with ocular inflammation had significantly lower 1-year all-cause mortality than those without documented ocular inflammation. The reason for this finding remains to be established.

Molecular diagnosis of orbital inflammatory disease

Orbital inflammatory diseases include thyroid eye disease (TED), granulomatosis with polyangiitis (GPA), sarcoidosis, and nonspecific orbital inflammation (NSOI). Histopathological diagnosis usually relies on the clinical context and is not always definitive. Gene expression profiling provides diagnostic and therapeutic information in several malignancies, but its role in evaluating nonmalignant disease is relatively untested. We hypothesized that gene expression profiling could provide diagnostic information for NSOI. We collected formalin-fixed, paraffin-embedded orbital biopsies from 10 institutions and 83 subjects including 25 with thyroid eye disease, 25 nonspecific orbital inflammation, 20 healthy controls, 6 with granulomatosis with polyangiitis, and 7 with sarcoidosis. Tissues were divided into discovery and validation sets. Gene expression was quantified using Affymetrix U133 Plus 2.0 microarrays. A random forest statistical algorithm based on data from 39 probe sets identified controls, GPA, or TED with an average accuracy of 76% (p=0.02). Random forest analysis indicated that 52% of tissues from patients with nonspecific inflammation were consistent with a diagnosis of GPA. Molecular diagnosis by gene expression profiling will augment clinical data and histopathology in differentiating forms of orbital inflammatory disease.

Sclerosing Lesions of the Orbit: A Review.

Orbital sclerosing inflammation is a distinct group of pathologies characterized by indolent growth with minimal or no signs of inflammation. However, contrary to earlier classifications, it should not be considered a chronic stage of acute inflammation. Although rare, orbital IgG4-related disease has been associated with systemic sclerosing pseudotumor-like lesions. Possible mechanisms include autoimmune and IgG4 related defective clonal proliferation. Currently, there is no specific treatment protocol for IgG4-related disease although the response to low dose steroid provides a good response as compared to non-IgG4 sclerosing pseudotumor. Specific sclerosing inflammations (e.g. Wegener's disease, sarcoidosis, Sjogren's syndrome) and neoplasms (lymphoma, metastatic breast carcinoma) should be ruled out before considering idiopathic sclerosing inflammation as a diagnosis.

Orbital Complications of Acute Sinusitis: Evaluation, Management, and Results

Introduction Even though orbital complications in acute rhinosinusitis are not very common, they can be very severe complications, with high mortality rates, due to infection spreading to orbital and intracranial tissues (1). Especially due to intracranial complications, acute rhinosinusitis is considered in the life-threatening disease group. As per Chandler et al. (2), orbital complications are classified into five groups according to the severity of complications: preseptal cellulitis, orbital cellulitis, subperiosteal abscess, orbital abscess, and cavernous sinus thrombosis. Although orbital complications are clinically rare, they are more common in children than in adults. Orbital septum acts as a barrier that prevents the spread of inflammation from the preseptal region towards the orbital space. Along with proptosis, limitation of eye movements, and decrease in vision, the presence of redness, edema, and local temperature increase in the eyelids, i.e., infectious pathology of orbital region, suggest intraorbital propagation. Especially in the childhood period, compared to adult age groups, infections in the preseptal region that did not receive proper treatment can spread easily in the orbits and cause serious complications such as brain abscess, meningitis, and cavernous sinus thrombosis (1-4). Although antibiotic use reduces the incidence of sinus infections and complications, acute sinusitis is still the leading cause of orbital inflammation and impaired vision. Particularly after frequent upper respiratory infections during the childhood, the infection that spreads easily to the nose and sinuses sets the ground for orbital complications (4-6). In our study, accompanied by diagnosis, treatment, and follow-up symptoms of 11 patients who developed orbital complications of rhinosinusitis, treatment and follow-up algorithm of orbital complications have been revised with literature data. 131

A complicated case of orbital cellulitis: When the fog doesn't clear.

Orbital cellulitis is a potential sight-threatening infection of the ocular adnexal structures posterior to the orbital septum. Acute bacterial sinusitis remains the most common cause of orbital cellulitis in the paediatric age group. Simultaneous intracranial and orbital complications from orbital cellulitis are rare. We describe a case of orbital cellulitis, which proceeded to sub-periosteal abscess formation and intracranial abscess within days of the initial presentation. The specific features of this case including the rapid progression of the orbital inflammation, failure of improvement over 48 h despite maximal medical treatment and incorrect initial reporting of computed tomography imaging all contributed to the complications seen in this case.