A Case of a Non-Specific Orbital Inflammation

Editor, In August 2013, a 17-year-old girl presented with progression of severe headaches accompanied with double vision for 2 weeks. Ophthalmologic examination showed bilateral papilledema and right-sided abducens paresis. Whilst extensive neurological screening (CT and MRI) showed no abnormalities, lumbar puncture revealed an increased intracranial pressure (>50 cm H2O, with normal CSF constituency) supporting the diagnosis of idiopathic intracranial hypertension (IIH). A successful ventriculo-peritoneal shunt was placed. Two years later however, the patient returned with a painful and red left eye. Ophthalmologic examination revealed impaired abduction caused by a diffuse swelling of the left medial rectus muscle (Fig. 1A,B). After exclusion of systemic involvement, the patient was diagnosed with non-specific orbital inflammation (NSOI) and successfully treated with oral prednisolone. In November 2013, the identical twin presented with severe pain on eye movement of the left eye. Examination showed a significant proptosis and MRI revealed an enlargement of the left medial rectus muscle, exactly at the same location as her sister (Fig. 1C,D). Without abnormalities in systemic workup, the diagnosis of NSOI was established. Treatment was initiated with 3-day IV methylprednisolone (500 mg) followed by oral prednisolone, with a good response. In contrast to her sister, multiple relapses occurred for which additional therapies were given, including methotrexate, biologics, radiotherapy and IV immunoglobulins with minimal results. Eighteen months after diagnosis, the patient returned with a diffuse headache, decreased visual acuity and papilledema bilaterally. CT and MRI of the cranium showed no abnormalities, but lumbar puncture revealed an increased intracranial pressure (>50 cm H2O, with normal CSF constituency). Similar to her sister, a ventriculo-peritoneal shunt was placed. Until today, oral prednisone is needed for treatment of her NSOI. No other family members were affected by any of the symptoms or diagnoses. NSOI is a benign, non-infectious, inflammatory disease of which the diagnosis is based on exclusion of specific local or systemic causes (Yuen & Rubin 2003). A biopsy should be performed when malignancy is suspected or no effect of treatment is noticed (Bijlsma et al. 2012). Relapses after treatment occur frequently and NSOI can remain refractory (Yuen & Rubin 2003). IIH is a disorder with signs and symptoms of raised intracranial pressure, with no established pathogenesis (Markey et al. 2016). The predominant clinical feature of IIH is headache, although diagnosis is made through a combination of increased intracranial pressure with either papilledema or a 6th nerve palsy (Markey et al. 2016). Treatment consists of lifestyle, pharmaceutical and/or surgical interventions. Early and adequate treatment is needed to prevent permanent visual loss. IIH and NSOI can have overlapping clinical features complicating individual diagnosis. A clinical tool for differentiation is the distinction between paresis and mechanical limitation of eye movement. Within literature, no cases of coexisting IIH and NSOI have previously been reported, and the conditions were previously considered unrelated. Several reports in families suggest possible (epi)genetic factors that confer risk for developing these conditions (Yuen & Rubin 2003, Jacob et al. 2007, Markey et al. 2016). However, no genetic loci have yet been linked to either conditions. The co-occurrence of IIH and NSOI reported here in twins, with presentation in reversed order within a time period of 2 years, suggests possible shared disease mechanisms. An association between IIH and NSOI can be used in future research for both conditions.

This systematic review of biopsy proven cases of non specific orbital inflammation and sclerosing variant from 2010-2016 attempts to elucidate new findings regarding the demographic profile of the diseases. Discussion of histopathology is emphasized, as to describe the most common presenting features of non-specific orbital inflammation as well as to discuss its molecular make-up . This review also discusses the therapeutic approach and discusses the “steroids vs. biopsy first” controversy regarding non-specific orbital inflammation. The incidence of IgG4 and its relationship to non-specific orbital inflammation is also discussed.

Non-specific orbital inflammation (NSOI) and IgG4-related orbital disease (IgG4-ROD) are often challenging to differentiate. Furthermore, it is still uncertain how chronic inflammation, such as IgG4-ROD, can lead to mucosa-associated lymphoid tissue (MALT) lymphoma. Therefore, we aimed to evaluate the diagnostic value of gene expression analysis to differentiate orbital autoimmune diseases and elucidate genetic overlaps. First, we established a database of NSOI, relapsing NSOI, IgG4-ROD and MALT lymphoma patients of our orbital center (2000–2019). In a consensus process, three typical patients of the above mentioned three groups (mean age 56.4 ± 17 years) at similar locations were selected. Afterwards, RNA was isolated using the RNeasy FFPE kit (Qiagen) from archived paraffin-embedded tissues. The RNA of these 12 patients were then subjected to gene expression analysis (NanoString nCounter®), including a total of 1364 target genes. The most significantly upregulated and downregulated genes were used for a machine learning algorithm to distinguish entities. This was possible with a high probability (p < 0.0001). Interestingly, gene expression patterns showed a characteristic overlap of lymphoma with IgG4-ROD and NSOI. In contrast, IgG4-ROD shared only altered expression of one gene regarding NSOI. To validate our potential biomarker genes, we isolated the RNA of a further 48 patients (24 NSOI, 11 IgG4-ROD, 13 lymphoma patients). Then, gene expression pattern analysis of the 35 identified target genes was performed using a custom-designed CodeSet to assess the prediction accuracy of the multi-parameter scoring algorithms. They showed high accuracy and good performance (AUC ROC: IgG4-ROD 0.81, MALT 0.82, NSOI 0.67). To conclude, genetic expression analysis has the potential for faster and more secure differentiation between NSOI and IgG4-ROD. MALT-lymphoma and IgG4-ROD showed more genetic similarities, which points towards progression to lymphoma.

Ulcerative colitis (UC) is an increasingly prevalent inflammatory condition affecting the intestinal mucosa, while nonspecific orbital inflammation (NSOI) is a common non-neoplastic orbital disorder. Exploring the molecular interplay between UC and NSOI may help physicians make earlier diagnoses and enhance treatment approaches. We analyzed gene expression datasets (GSE58331, GSE105149, GSE206285, and GSE179285) for UC and NSOI from the GEO database. Using WGCNA and differential expression analysis, we identified genes commonly altered in both diseases. GO enrichment, PPI networks, and transcription factor prediction were performed using Cytoscape plugins (cytoHubba and iRegulon). Machine learning techniques were employed to assess transcription factor activity and evaluate potential therapeutic targets among the hub genes. We conducted an association analysis using the TwoSampleMR package in R to explore potential causal relationships between NSOI and UC. A total of 85 intersecting genes between NSOI and UC were identified, and enrichment analyses revealed their roles in immune and inflammatory processes. Key biomarkers, including CXCL10, CXCR4, CXCL9, CD27, SELL, MMP9, CD79A, CD3E, GZMK, and CCL19, were highlighted, linking them to processes such as leukocyte migration, viral response, and monocyte differentiation. STAT1 was identified as a shared transcription factor influencing both diseases. Machine learning algorithms identified eight potential genes for diagnostic and therapeutic use, with CXCL10 emerging as a key player in the pathogenesis of NSOI and UC. CXCL10 likely regulates CXCR4, LCK, CCR7, and other genes involved in pathways such as cytokine-cytokine receptor interactions, HIV-1 infection, and Epstein-Barr virus infection. This study offers insights into the co-pathogenic mechanisms of UC and NSOI, providing a foundation for further mechanistic research and therapeutic development.

BackgroundTo present the very rare comorbidity of developing non-specific orbital inflammation (NSOI) in two patients with histories of definite thyroid eye disease (TED).Case presentationBoth patients complained of new-onset progressive proptosis although their thyroid disease was controlled and computed tomography scan revealed an intraorbital inflammatory mass. The pathological assessment indicated that both patients had developed fibrosing NSOI. Therefore, intravenous corticosteroids were administered. The mass regressed and the amount of proptosis was decreased in both patients.ConclusionsWe reviewed all related cases in the literature and extracted their clinical and radiological characteristics for this paper. Ophthalmologists should consider TED and NSOI in patients with a new-onset complaint of proptosis. Despite rare comorbidity of TED and NSOI, it should be considered especially in patients with refractory proptosis, and lead to its further evaluation and prompt management.

Background: Nonspecific Orbital Inflammation (NSOI) remains a perplexing enigma among proliferative inflammatory disorders. Its etiology is idiopathic, characterized by distinctive and polymorphous lymphoid infiltration within the orbital region. Preliminary investigations suggest that PALMD localizes within the cytosol, potentially playing a crucial role in cellular processes, including plasma membrane dynamics and myogenic differentiation. The potential of PALMD as a biomarker for NSOI warrants meticulous exploration. Methods: PALMD was identified through the intersection analysis of common DEGs from datasets GSE58331 and GSE105149 from the GEO database, alongside immune-related gene lists from the ImmPort database, using Lasso regression and SVM-RFE analysis. GSEA and GSVA were conducted with gene sets co-expressed with PALMD. To further investigate the correlation between PALMD and immune-related biological processes, the CIBERSORT algorithm and ESTIMATE method were employed to evaluate immune microenvironment characteristics of each sample. The expression levels of PALMD were subsequently validated using GSE105149. Results: Among the 314 DEGs identified, several showed significant differences. Lasso and SVM-RFE algorithms pinpointed 15 hub genes. Functional analysis of PALMD emphasized its involvement in cell-cell adhesion, leukocyte migration, and leukocyte-mediated immunity. Enrichment analysis revealed that gene sets positively correlated with PALMD were enriched in immune-related pathways. Immune infiltration analysis indicated that resting dendritic cells, resting mast cells, activated NK cells, and plasma cells positively associate with PALMD expression. Conversely, naive B cells, activated dendritic cells, M0 and M1 macrophages, activated mast cells, activated CD4 memory T cells, and naive CD4 T cells showed a negative correlation with PALMD expression. PALMD demonstrated significant diagnostic potential in differentiating NSOI. Conclusions: This study identifies PALMD as a potential biomarker linked to NSOI, providing insights into its pathogenesis and offering new avenues for tracking disease progression.

PurposeAcute orbital inflammation can lead to irreversible vision loss in serious cases. Treatment thus far has been limited to systemic steroids or surgical decompression of the orbit. An animal model that mimics the characteristic features of acute orbital inflammation as found in thyroid eye disease can be used to explore novel treatment modalities.MethodsWe developed a murine model of orbital inflammation by injecting oxazolone into the mouse orbit. The mice underwent magnetic resonance imaging (MRI) and were euthanized at various time points for histologic examination. Immunofluorescence studies of specific inflammatory cells and cytokine arrays were performed.ResultsWe found clinical and radiographic congruity between the murine model and human disease. After 72 hours, sensitized mice exhibited periorbital dermatitis and inflammation in the eyelids of the injected side. By one week, increased proptosis in the injected eye with significant eyelid edema was appreciated. By four weeks, inflammation and proptosis were decreased. At all three time points, the mice demonstrated exophthalmos and periorbital edema. Histopathologically, populations of inflammatory cells including T cells, macrophages, and neutrophils shared similarities with patient samples in thyroid eye disease. Proteomic changes in the levels of inflammatory and angiogenic markers correlated to the expected angiogenic, inflammatory, and fibrotic responses observed in patients with thyroid eye disease.ConclusionsA murine model of orbital inflammation created using oxazolone recapitulates some of the clinical features of thyroid eye disease and potentially other nonspecific orbital inflammation, typified by inflammatory cell infiltration, orbital tissue expansion and remodeling, and subsequent fibrosis.Translational RelevanceThis animal model could serve as a viable platform with which to understand the underlying mechanisms of acute orbital inflammation and to investigate potential new, targeted treatments.

Nonspecific orbital inflammation (NSOI) is a term used to describe nonmalignant inflammation of the orbit characterized by a polymorphous lymphoid infiltrate with varying degrees of fibrosis, without a known local or systemic cause. The emphasis is on lack of finding a known cause. Orbital inflammation itself is not a diagnosis, but rather a description of a tissue response to some underlying problem, such as infection, irritation, or injury, which has triggered the immune system. The injured cells release chemical factors stimulating the inflammatory response which is characterized by symptoms of pain, redness, swelling, warmth, and possible dysfunction of the tissues involved. In the case of the orbit, it is infiltration of orbital soft tissues by chronic inflammatory cells that causes findings such as proptosis, eyelid swelling, chemosis, pain, diplopia, or visual loss. Every effort must first be made to identify a specific cause of the inflammation. Navigating through the differential diagnosis of diseases that can cause or simulate orbital inflammation is challenging; however, adhering to a methodical history and exam will help facilitate the process. Only once all other specific etiologies have been eliminated can one conclude with the diagnosis of nonspecific orbital inflammation, which only means that the causative pathogen or trigger could not be identified.

PurposeImmunogenic causes of inflammation may be difficult to differentiate in the work-up of orbital inflammatory disease. The study aims to investigate the utility of autoimmune markers in the screening for orbital inflammation. Markers studied included angiotensin-converting enzyme (ACE), antinuclear antibody (ANA), anti-neutrophilic cytoplasmic autoantibodies (ANCA), extractable nuclear antigen (ENA), anti-cyclic citrullinated peptide (Anti-CCP) and anti-double stranded DNA antibody (Anti-dsDNA antibody).MethodsA retrospective single-centre study of consecutive patients with non-infective orbital inflammation screened for autoimmune markers at presentation. Serology was interpreted alongside clinical course and other investigations (e.g. radiographic features and histopathology). Tabulated data and Pearson’s Chi-square allowed analysis of trends between serology, diagnosis and the decision to biopsy.Results79 patients, between 1999 and 2021, were included (50 females, mean age was 50.4 ± 17.4 years). 28 (34.6%) patients had specific orbital inflammation and 53 (65.4%) patients had non-specific orbital inflammation (NSOI). Of the 12 patients with positive serology and a specific diagnosis, only 5 (41.7%) patients had concordant serological results. There was no association between serology results and the patient undergoing biopsy (P = 0.651). Serology was unable to exclude nor differentiate NSOI from other specific conditions and ANA had limited discriminatory value between specific conditions and NSOI.ConclusionSerological testing alone may not provide a clear direction for further investigation of orbital inflammation and a biopsy may occur independently of the serological results. The value of autoimmune markers may lie in subsequent follow-up as patients may develop suggestive symptoms after an indeterminate positive result or initially seronegative disease.

Nonspecific Orbital Inflammation

IgG4-related sclerosing disease is a recently described systemic inflammatory disease that should be considered when evaluating patients with nonspecific orbital inflammation (pseudotumor). Orbital biopsy is necessary to establish a diagnosis and demonstrates lymphoplasmacytic infiltration, fibrosis, obliterative phlebitis of medium and small veins, and variable degrees of eosinophilia. We report the clinical and histopathological findings of 2 patients who developed chronic orbital inflammation as a manifestation of IgG4-related sclerosing disease. The 2 cases illustrate the widely varying clinical characteristics of this elusive disease.

Idiopathic sclerosing orbital inflammation (ISOI) has been categorized by some authors as a unique clinicopathologic entity, separate from the heterogeneous group of disorders known collectively as nonspecific orbital inflammation. Histologic similarity and clinical association with other fibrosclerosing conditions has been shown. The authors present a case of ISOI in conjunction with autoimmune hemolytic anemia. A 59-year-old woman with a history of hemolytic anemia had left upper lid swelling, periocular pain, proptosis, and restriction of ocular motility. Magnetic resonance imaging (MRI) showed a homogeneously enhancing lateral orbital mass. Biopsy revealed dense fibrous connective tissue with a paucicellular infiltrate, consistent with ISOI, and treatment with prednisolone 60 mg/day was instituted. At 4-week review, the proptosis had settled and the patient regained full range of extraocular movements. At 14 months, the response was sustained and repeat MRI showed a 70% reduction in size of the mass. The first known case of ISOI and hemolytic anemia is presented. Despite dense fibrosis histologically, steroid responsiveness can be encountered in cases of ISOI. An early, aggressive approach to management is recommended, and corticosteroids should be considered as a treatment option.

Orbital Floor Fracture Reconstruction using Conchal Auricular Cartilage Graft

ultrasonographic and/or serological evidence of autoimmune thyroid disease makes diagnosis of GO even more uncertain. Thus, if in typical cases imaging is confirmatory, then in doubtful circumstances it is mandatory. Many conditions may cause exophthalmos and/or extraocular muscle enlargement mimicking GO. Table 1 offers a list of these conditions, for some of which etiology is uncertain. IgG4-related disease is a recently described fibroinflammatory multiorgan disorder characterized by tumefactive lesions, lymphoplasmacytic infiltration with abundant IgG4-positive plasma cells, storiform fibrosis and frequently (but not always) elevated serum IgG4 levels (see [4] for an excellent and exhaustive review of this disease). Initially described in the context of autoimmune pancreatitis, IgG4-related disease may indeed affect several extrapancreatic sites, including the thyroid and the orbit. Riedel’s (fibrosclerosing) thyroiditis has been shown immunohistochemically to be comprised within the spectrum of IgG4-related disease [5]. The fibrous variant of Hashimoto’s thyroiditis might also be closely related to IgG4-related disease [6]. Graves’-like orbitopathy was described in a patient with autoimmune pancreatitis and very high serum IgG4 concentrations, in the absence of thyroid autoimmune disease or related thyroid dysfunction [7]. Clinical features were similar to those of moderate-to-severe and active GO. Imaging was characterized by enlarged extraocular muscles (with tendon sparing) and lacrimal gland, and expansion of the adipose tissue; there was an excellent response of orbital changes to intravenous glucocorticoids and orbital radiotherapy [7]. An additional case was described at the Mayo Clinic: the patient had a longlasting diagnosis of “GO”, treated many times with oral glucocorticoids because of repeated recurrences [8]. The patient was eventually submitted to orbital Graves’ orbitopathy (GO) affects about 25 % of patients with hyperthyroidism due to Graves’ disease [1], is usually mild and infrequently progressive [2, 3], although moderate-to-severe or (rare) sight-threatening forms do exist and require aggressive treatments [1]. In most cases, the onset of GO is temporally related to the onset of hyperthyroidism, but in some instances the orbital disease may precede or follow the onset of hyperthyroidism by months or years [1]. In addition, it is known that GO may less frequently develop in patients with euthyroid or hypothyroid Hashimoto’s thyroiditis [1]. The diagnosis of GO is simple and straightforward in the typical patient who, in addition to signs and symptoms of hyperthyroidism, has positive TSHreceptor antibody tests, bilateral eye symptoms (lacrimation, grittiness, photophobia, diplopia) and signs (exophthalmos, periorbital soft tissue swelling, ocular dysmotility, rarely visual defects). Diagnosis is confirmed by imaging studies showing enlarged extraocular muscles (with tendon sparing) and/or expansion of the orbital fibroadipose tissue [1]. Diagnostic problems arise particularly in those patients who are not hyperthyroid and have asymmetrical or unilateral orbital involvement. The presence of euthyroid/hypothyroid chronic autoimmune thyroiditis does not guarantee that orbital disease be related to GO; the absence of thyroid

To examine the radiological differences between bacterial orbital cellulitis (OC) and diffuse non-specific orbital inflammation (DNSOI) on magnetic resonance imaging (MRI). Retrospective study of patients with OC and DNSOI with an MRI orbital scan. Localised orbital inflammation (e.g., idiopathic dacryoadenitis and myositis), quiescent orbital inflammation and pre-septal cellulitis were excluded. Thirty-two patients presenting between 2008 and 2023, including twenty-one OC patients (mean age: 42.5 ± 24.9 years old, male: 6), and eleven DNSOI patients (mean age: 52.3 ± 17.8 years old, male: 16). Both OC and DNSOI demonstrate orbital fat contrast-enhancement. However, whilst OC demonstrated a hyperintense T2 signal (P < 0.001), variable signal was observed in DNSOI, with a hypointense T2 signal more suggestive of DNSOI (P = 0.012). When the lacrimal glands were involved, indistinct margins were more likely in OC (P < 0.001), whilst gross enlargement and contrast-enhancement was observed in DNSOI (P = 0.032 and 0.017, respectively). Peripheral contrast-enhancement of the extraocular muscle (EOM) (P = 0.002) was more common in OC, whilst DNSOI demonstrated variable contrast-enhancement throughout the affected EOM (P < 0.001). The presence of contralateral abnormalities, such as lacrimal gland enlargement and EOM involvement, are more suggestive of DNSOI. Several MRI features, beyond overt sinogenic disease, may help to differentiate OC from DNSOI, including the orbital fat signal intensity, EOM and/or lacrimal gland involvement, and contralateral orbital abnormalities. However, these features may not be specific, and thus highlights the ongoing radiological dilemma clinicians are faced when tasked with differentiating between infectious and non-infectious orbital inflammatory disease.