Orbital inflammatory diseases are a heterogenic group of conditions that often entail a difficult diagnostic process and many patients are treatment resistant. Inflammatory diseases can be visualized by Zirconium-89-labelled rituximab PET-CT (89Zr-rituximab PET/CT). In this study, we describe our experience and possible potential of the 89Zr-rituximab PET/CT for diagnostic and therapeutic management of refractory orbital inflammation. Retrospectively, 89Zr-rituximab uptake was assessed and related to clinical data. The main outcome measures were the characteristics of the scan and the clinical relation of uptake with the diagnostic process and treatment effectivity. Twelve patients with thyroid eye disease (TED) and suspected idiopathic orbital inflammation (IOI) were scanned. Six patients had a strong 89Zr-rituximab uptake and showed a focal distribution within the lesion. Four patients (one TED, three IOI) responded well to rituximab treatment after a positive scan. 89Zr-rituximab PET/CT was essential to the diagnosis of optic nerve meningioma in one patient. 89Zr-rituximab PET/CT has the potential to be a powerful tool for the detection of B cell-mediated disease within the orbit and ocular adnexa. This technique can be a valuable addition for diagnosing diseases around the eye and can potentially predict rituximab treatment response in patients with refractory inflammation.

Objective: Preventive unruptured intracranial aneurysm occlusion can reduce the risk of subarachnoid hemorrhage, but both endovascular and microneurosurgical treatment carry a risk of serious complications. To improve individualized management decisions, we developed risk scores for complications of endovascular and microneurosurgical treatment based on easily retrievable patient, aneurysm, and treatment characteristics. Methods: For this multicenter cohort study, we combined individual patient data from unruptured intracranial aneurysm patients ≥18 years undergoing preventive endovascular treatment (standard, balloon-assisted or stent-assisted coiling, Woven EndoBridge-device, or flow-diverting stent) or microneurosurgical clipping at one of 10 participating centers from three continents between 2000-2018. The primary outcome was death from any cause or clinical deterioration from neurological complications ≤30 days. We selected predictors based on previous knowledge about relevant risk factors and predictor performance and studied the association between predictors and complications with logistic regression. We assessed model performance with calibration plots and concordance (c) statistics. Results: Of 1282 included patients, 94 (7.3%) had neurological symptoms that resolved <30 days, 140 (10.9%) had persisting neurological symptoms, and 6 died (0.5%)). At 30 days, 52 patients (4.1%) were dead or dependent. Predictors of procedural complications were: size of aneurysm, aneurysm location, familial subarachnoid hemorrhage, earlier atherosclerotic disease, treatment volume, endovascular modality (for endovascular treatment) or extra aneurysm configuration factors (for microneurosurgical treatment; branching artery from aneurysm neck or unfavorable dome-to-neck ratio), and age (acronym: SAFETEA). For endovascular treatment (n=752), the c-statistic was 0.72 (95%CI:0.67-0.77) and the absolute complication risk ranged from 3.2% (95%CI:1.6%-14.9%;≤1 point) to 33.1% (95%CI:25.4%-41.5%;≥6 points). For microneurosurgical treatment (n=530), the c-statistic was 0.72 (95%CI:0.67-0.77) and the complication risk ranged from 4.9% (95%CI:1.5%-14.9%;≤1 point) to 49.9% (95%CI:39.4%-60.6%;≥6 points). Conclusions: The SAFETEA risk scores for endovascular and microneurosurgical treatment are based on seven easily retrievable risk factors to predict the absolute risk of procedural complications in patients with unruptured intracranial aneurysms. The scores need external validation before the predicted risks can be properly used to support decision making in clinical practice.

Non‐Hodgkin orbital lymphoma (NHOL) and idiopathic orbital inflammation (IOI) are common orbital conditions with largely unknown pathophysiology that can be difficult to diagnose. In this study we aim to identify serum miRNAs associated with NHOL and IOI. We performed OpenArray^® miRNA profiling in 33 patients and controls. Differentially expressed miRNAs were technically validated across technology platforms and replicated in an additional cohort of 32 patients and controls. We identified and independently validated a serum miRNA profile of NHOL that was remarkably similar to IOI and characterized by an increased expression of a cluster of eight miRNAs. Pathway enrichment analysis indicated that the miRNA‐cluster is associated with immune‐mediated pathways, which we supported by demonstrating the elevated expression of this cluster in serum of patients with other inflammatory conditions. The cluster contained miR‐148a, a key driver of B‐cell tolerance, and miR‐365 that correlated with serum IgG and IgM concentrations. In addition, miR‐29a and miR‐223 were associated with blood lymphocyte and neutrophil populations, respectively. NHOL and IOI are characterized by an abnormal serum miRNA‐cluster associated with immune pathway activation and linked to B cell and neutrophil dysfunction.

Non‐Hodgkin orbital lymphoma (NHOL) and idiopathic orbital inflammation (IOI) are common orbital conditions with largely unknown pathophysiology. To investigate the immune cell composition of these diseases, we performed standardized 29 parameter flow cytometry phenotyping in peripheral blood mononuclear cells of 18 NHOL patients, 21 IOI patients, and 41 unaffected controls. Automatic gating by FlowSOM revealed decreased abundance of meta‐clusters containing dendritic cells in patients, which we confirmed by manual gating. A decreased percentage of (HLA‐DR⁺CD303⁺CD123⁺) plasmacytoid dendritic cells (pDC) in the circulation of IOI patients and decreased (HLA‐DR⁺CD11c⁺CD1c⁺) conventional dendritic cells (cDC) type‐2 for IOI patients were replicated in an independent cohort of patients and controls. Meta‐analysis of both cohorts demonstrated that pDCs are also decreased in blood of NHOL patients and highlighted that the decrease in blood cDC type‐2 was specific for IOI patients compared to NHOL or controls. Deconvolution‐based estimation of immune cells in transcriptomic data of 48 orbital biopsies revealed a decrease in the abundance of pDC and cDC populations within the orbital microenvironment of IOI patients. Collectively, these data suggest a previously underappreciated role for dendritic cells in orbital disorders.

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