Plasma calcitonin gene-related peptide levels in idiopathic intracranial hypertension: an exploratory study.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a debilitating condition characterized by increased intracranial pressure often presenting with chronic migraine-like headache. Calcitonin gene-related peptide (CGRP) plays an important pathophysiological role in primary headaches such as migraine, whilst its role in IIH has not yet been established. METHODS: This longitudinal exploratory study included patients with IIH, episodic migraine (EM) in a headache-free interval and healthy controls (HC). Blood samples were collected from a cubital vein and plasma CGRP (pCGRP) levels were measured by standardized ELISA. RESULTS: A total of 26 patients with IIH (mean age 33.2 years [SD 9.2], 88.5% female, median BMI 34.8 kg/m2 [IQR 30.0-41.4]), 30 patients with EM (mean age 27.6 years [7.5], 66.7% female) and 57 HC (mean age 25.3 years [5.2], 56.1% female) were included. pCGRP levels displayed a wide variation in IIH as well as in EM and HC on a group-level. Within IIH, those with migraine-like headache had significantly higher pCGRP levels than those with non-migraine-like headache (F(2,524) = 84.79; p < 0.001) and headache absence (F(2,524) = 84.79; p < 0.001) throughout the observation period, explaining 14.7% of the variance in pCGRP levels. CGRP measurements showed strong intraindividual agreement in IIH (ICC 0.993, 95% CI 0.987-0.996, p < 0.001). No association was found between pCGRP levels and ophthalmological parameters. CONCLUSIONS: Although interindividual heterogeneity of pCGRP levels is generally high, migraine-like headache seems to be associated with higher pCGRP levels. CGRP may play a role in the headache pathophysiology at least in a subgroup of IIH.

An interdisciplinary integrated specialized one-stop outpatient clinic for idiopathic intracranial hypertension - an assessment of sick leave, presenteeism, and health care utilization.

BACKGROUND: Management of idiopathic intracranial hypertension (IIH) is complex requiring contributions from multiple specialized disciplines. In practice, this creates considerable organizational and communicational challenges. To meet those challenges, we established an interdisciplinary integrated outpatient clinic for IIH with a central coordination and a one-stop- concept. Here, we aimed to evaluate effects of this concept on sick leave, presenteeism, and health care utilization. METHODS: In a retrospective cohort study, we compared the one-stop era with integrated care (IC, 1-JUL-2021 to 31-DEC-2022) to a reference group receiving standard care (SC, 1-JUL-2018 to 31-DEC-2019) regarding economic outcome parameters assessed over 6 months. Multivariate binary logistic regression models were used to adjust for confounders. RESULTS: Baseline characteristics of the IC group (n = 85) and SC group (n = 81) were comparable (female: 90.6% vs. 90.1%; mean age: 33.6 vs. 32.8 years, educational level: ≥9 years of education 60.0% vs. 59.3%; located in Vienna 75.3% vs. 76.5%). Compared to SC, the IC group showed significantly fewer days with sick leave or presenteeism (-5 days/month), fewer unscheduled contacts for IIH-specific problems (-2.3/month), and fewer physician or hospital contacts in general (-4.1 contacts/month). Subgroup analyses of patients with migration background and language barrier consistently indicated stronger effects of the IC concept in these groups. CONCLUSIONS: Interdisciplinary integrated management significantly improves the burden of IIH in terms of sick leave, presenteeism and healthcare consultations - particularly in socioeconomically underprivileged patient groups.

The additive value of complementing diagnostic idiopathic intracranial hypertension criteria by MRI - an external validation study.

BACKGROUND: Recently, diagnostic criteria including a standardized MRI criterion were presented to identify patients suffering from idiopathic intracranial hypertension (IIH) proposing that IIH might be defined by two out of three objective findings (papilledema, ≥ 25 cm cerebrospinal fluid opening pressure (CSF-OP) and ≥ 3/4 neuroimaging signs). METHODS: To provide independent external validation, we retrospectively applied the proposed diagnostic criteria to our cohort of patients with clinical suspicion of IIH from the Vienna IIH database. Neuroimaging was reevaluated for IIH signs according to standardized definitions by a blinded expert neuroradiologist. We determined isolated diagnostic accuracy of the neuroimaging criterion (≥ 3/4 signs) as well as overall accuracy of the new proposed criteria. RESULTS: We included patients with IIH (n = 102) and patients without IIH (no-IIH, n = 23). Baseline characteristics were balanced between IIH and no-IIH groups, but papilledema and CSF-OP were significantly higher in IIH. For the presence of ≥ 3/4 MRI signs, sensitivity was 39.2% and specificity was 91.3% with positive predictive value (PPV) of 95.2% and negative predictive value (NPV) 25.3%. Reclassifying our cohort according to the 2/3 IIH definition correctly identified 100% of patients without IIH, with definite IIH and suggested to have IIH without papilledema by Friedman criteria, respectively. CONCLUSION: The standardized neuroimaging criteria are easily applicable in clinical routine and provide moderate sensitivity and excellent specificity to identify patients with IIH. Defining IIH by 2/3 criteria significantly simplifies diagnosis without compromising accuracy.

Anomaly guided segmentation: Introducing semantic context for lesion segmentation in retinal OCT using weak context supervision from anomaly detection.

Automated lesion detection in retinal optical coherence tomography (OCT) scans has shown promise for several clinical applications, including diagnosis, monitoring and guidance of treatment decisions. However, segmentation models still struggle to achieve the desired results for some complex lesions or datasets that commonly occur in real-world, e.g. due to variability of lesion phenotypes, image quality or disease appearance. While several techniques have been proposed to improve them, one line of research that has not yet been investigated is the incorporation of additional semantic context through the application of anomaly detection models. In this study we experimentally show that incorporating weak anomaly labels to standard segmentation models consistently improves lesion segmentation results. This can be done relatively easy by detecting anomalies with a separate model and then adding these output masks as an extra class for training the segmentation model. This provides additional semantic context without requiring extra manual labels. We empirically validated this strategy using two in-house and two publicly available retinal OCT datasets for multiple lesion targets, demonstrating the potential of this generic anomaly guided segmentation approach to be used as an extra tool for improving lesion detection models.

Treatment with GLP-1 receptor agonists is associated with significant weight loss and favorable headache outcomes in idiopathic intracranial hypertension.

BACKGROUND: In idiopathic intracranial hypertension (IIH), sustained weight loss is the main pillar in modifying disease course, whereby glucagon-like peptide-1 receptor agonists (GLP-1-RAs) could present an attractive treatment option. METHODS: In this open-label, single-center, case-control pilot study, patients with IIH (pwIIH) and a body mass index (BMI) of ≥ 30 kg/m2 were offered to receive a GLP-1-RA (semaglutide, liraglutide) in addition to the usual care weight management (UCWM). Patients electing for UCWM only served as a control group matched for age-, sex- and BMI (1:2 ratio). The primary endpoint was the percentage weight loss at six months (M6) compared to baseline. Secondary endpoints included the rate of patients with a weight loss of ≥ 10%, monthly headache days (MHD), the rate of patients with a ≥ 30% and ≥ 50% reduction in MHD, visual outcome parameters, and adverse events (AEs). RESULTS: We included 39 pwIIH (mean age 33.6 years [SD 8.0], 92.3% female, median BMI 36.3 kg/m2 [IQR 31.4-38.3]), with 13 patients being treated with GLP-1-RAs. At M6, mean weight loss was significantly higher in the GLP-1-RA group (-12.0% [3.3] vs. -2.8% [4.7]; p < 0.001). Accordingly, weight loss of ≥ 10% was more common in this group (69.2% vs. 4.0%; p < 0.001). Median reduction in MHD was significantly higher in the GLP-1-RA group (-4 [-10.5, 0.5] vs. 0 [-3, 1]; p = 0.02), and the 50% responder rate was 76.9% vs. 40.0% (p = 0.04). Visual outcome parameters did not change significantly from baseline to M6. Median reduction in acetazolamide dosage was significantly higher in the GLP-1-RA group (-16.5% [-50, 0] vs. 0% [-25, 50]; p = 0.04). AEs were mild or moderate and attributed to gastrointestinal symptoms in 9/13 patients. None of the AEs led to premature treatment discontinuation. CONCLUSIONS: This open-label, single-center pilot study suggests that GLP-1-RAs are an effective and safe treatment option for achieving significant weight loss with a favorable effect on headache, leading to reduced acetazolamide dosage in pwIIH.

A systematic evaluation of human expert agreement on optical coherence tomography biomarkers using multiple devices.

OBJECTIVES: To assess the agreement in evaluating optical coherence tomography (OCT) variables in the leading macular diseases such as neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DMO) and retinal vein occlusion (RVO) among OCT-certified graders. METHODS: SD-OCT volume scans of 356 eyes were graded by seven graders. The grading included presence of intra- and subretinal fluid (IRF, SRF), pigment epithelial detachment (PED), epiretinal membrane (ERM), conditions of the vitreomacular interface (VMI), central retinal thickness (CRT) at the foveal centre-point (CP) and central millimetre (CMM), as well as height and location of IRF/SRF/PED. Kappa statistics (κ) and intraclass correlation coefficient (ICC) were used to report categorical grading and measurement agreement. RESULTS: The overall agreement on the presence of IRF/SRF/PED was κ = 0.82/0.85/0.81; κ of VMI condition was 0.77, that of ERM presence 0.37. ICC for CRT measurements at CP and CMM was excellent with an ICC of 1.00. Height measurements of IRF/SRF/PED showed robust consistency with ICC = 0.85-0.93. There was substantial to almost perfect agreement in locating IRF/SRF/PED with κ = 0.67-0.86. Between diseases, κ of IRF/SRF presence was 0.69/0.80 for nAMD, 0.64/0.83 for DMO and 0.86/0.89 for RVO. CONCLUSION: Even in the optimized setting, featuring certified graders, standardized image acquisition and the use of a professional reading platform, there is a disease dependent variability in biomarker evaluation that is most pronounced for IRF in nAMD as well as DMO. Our findings highlight the variability in the performance of human expert OCT grading and the need for AI-based automated feature analyses.

THE IMPACT OF THE VITREOMACULAR INTERFACE ON FUNCTIONAL AND ANATOMICAL OUTCOMES IN DIABETIC MACULAR EDEMA TREATED WITH THREE DIFFERENT ANTI-VEGF AGENTS: Post Hoc Analysis of The Protocol T Study.

PURPOSE: To investigate the impact of baseline vitreomacular interface status on treatment outcomes in patients treated with three different anti-vascular endothelial growth factors for diabetic macular edema. METHODS: Post hoc analysis from patients enrolled in the DRCR.net Protocol T study. Optical coherence tomography images were analyzed at baseline and at the end of follow-up to identify the presence of complete vitreomacular adhesion, partial vitreomacular adhesion, vitreomacular traction syndrome, and complete posterior vitreous detachment. RESULTS: Six hundred and twenty-nine eyes were eligible for the study based on the study criteria. Complete adhesion eyes gained on average +3.7 more ETDRS letters compared with the complete posterior vitreous detachment group at the end of the 12 months follow-up ( P < 0.001). Baseline vitreomacular interface status had no significant influence on central subfield thickness at 12 months ( P = 0.144). There was no difference between the treatment arms based on effect of baseline vitreomacular interface status on best-corrected visual acuity gain. CONCLUSION: This study provides evidence that vitreomacular interface status affects functional outcomes in diabetic macular edema patients treated with anti-vascular endothelial growth factor injections. The presence of complete or partial vitreomacular adhesion at baseline may be associated with a larger treatment benefit than those with complete posterior vitreous detachment.

VALIDATION OF AN AUTOMATED FLUID ALGORITHM ON REAL-WORLD DATA OF NEOVASCULAR AGE-RELATED MACULAR DEGENERATION OVER FIVE YEARS.

BACKGROUND/PURPOSE: To apply an automated deep learning automated fluid algorithm on data from real-world management of patients with neovascular age-related macular degeneration for quantification of intraretinal/subretinal fluid volumes in optical coherence tomography images. METHODS: Data from the Vienna Imaging Biomarker Eye Study (VIBES, 2007-2018) were analyzed. Databases were filtered for treatment-naive neovascular age-related macular degeneration with a baseline optical coherence tomography and at least one follow-up and 1,127 eyes included. Visual acuity and optical coherence tomography at baseline, Months 1 to 3/Years 1 to 5, age, sex, and treatment number were included. Artificial intelligence and certified manual grading were compared in a subanalysis of 20%. Main outcome measures were fluid volumes. RESULTS: Intraretinal/subretinal fluid volumes were maximum at baseline (intraretinal fluid: 21.5/76.6/107.1 nL; subretinal fluid 13.7/86/262.5 nL in the 1/3/6-mm area). Intraretinal fluid decreased to 5 nL at M1-M3 (1-mm) and increased to 11 nL (Y1) and 16 nL (Y5). Subretinal fluid decreased to a mean of 4 nL at M1-M3 (1-mm) and remained stable below 7 nL until Y5. Intraretinal fluid was the only variable that reflected VA change over time. Comparison with human expert readings confirmed an area under the curve of >0.9. CONCLUSION: The Vienna Fluid Monitor can precisely quantify fluid volumes in optical coherence tomography images from clinical routine over 5 years. Automated tools will introduce precision medicine based on fluid guidance into real-world management of exudative disease, improving clinical outcomes while saving resources.

Automated quantification of macular fluid in retinal diseases and their response to anti-VEGF therapy.

AIM: To objectively assess disease activity and treatment response in patients with retinal vein occlusion (RVO), neovascular age-related macular degeneration (nAMD) and centre-involved diabetic macular oedema (DME), using artificial intelligence-based fluid quantification. METHODS: Posthoc analysis of 2311 patients (11 151 spectral-domain optical coherence tomography volumes) from five clinical, multicentre trials, who received a flexible antivascular endothelial growth factor (anti-VEGF) therapy over a 12-month period. Fluid volumes were measured with a deep learning algorithm at baseline/months 1, 2, 3 and 12, for three concentric circles with diameters of 1, 3 and 6 mm (fovea, paracentral ring and pericentral ring), as well as four sectors surrounding the fovea (superior, nasal, inferior and temporal). RESULTS: In each disease, at every timepoint, most intraretinal fluid (IRF) per square millimetre was present at the fovea, followed by the paracentral ring and pericentral ring (p<0.0001). While this was also the case for subretinal fluid (SRF) in RVO/DME (p<0.0001), patients with nAMD showed more SRF in the paracentral ring than at the fovea up to month 3 (p<0.0001). Between sectors, patients with RVO/DME showed the highest IRF volumes temporally (p<0.001/p<0.0001). In each disease, more SRF was consistently found inferiorly than superiorly (p<0.02). At month 1/12, we measured the following median reductions of initial fluid volumes. For IRF: RVO, 95.9%/97.7%; nAMD, 91.3%/92.8%; DME, 37.3%/69.9%. For SRF: RVO, 94.7%/97.5%; nAMD, 98.4%/99.8%; DME, 86.3%/97.5%. CONCLUSION: Fully automated localisation and quantification of IRF/SRF over time shed light on the fluid dynamics in each disease. There is a specific anatomical response of IRF/SRF to anti-VEGF therapy in all diseases studied.

SYSTEMATIC CORRELATION OF CENTRAL SUBFIELD THICKNESS WITH RETINAL FLUID VOLUMES QUANTIFIED BY DEEP LEARNING IN THE MAJOR EXUDATIVE MACULAR DISEASES.

PURPOSE: To investigate the correlation of volumetric measurements of intraretinal (IRF) and subretinal fluid obtained by deep learning and central retinal subfield thickness (CSFT) based on optical coherence tomography in retinal vein occlusion, diabetic macular edema, and neovascular age-related macular degeneration. METHODS: A previously validated deep learning-based approach was used for automated segmentation of IRF and subretinal fluid in spectral domain optical coherence tomography images. Optical coherence tomography volumes of 2.433 patients obtained from multicenter studies were analyzed. Fluid volumes were measured at baseline and under antivascular endothelial growth factor therapy in the central 1, 3, and 6 mm. RESULTS: Patients with neovascular age-related macular degeneration generally demonstrated the weakest association between CSFT and fluid volume measurements in the central 1 mm (0.107-0.569). In patients with diabetic macular edema, IRF correlated moderately with CSFT (0.668-0.797). In patients with retinal vein occlusion, IRF volumes showed a moderate correlation with CSFT (0.603-0.704). CONCLUSION: The correlation of CSFT and fluid volumes depends on the underlying pathology. Although the amount of central IRF seems to partly drive CSFT in diabetic macular edema and retinal vein occlusion, it has only a limited impact on patients with neovascular age-related macular degeneration. Our findings do not support the use of CSFT as a primary or secondary outcome measure for the quantification of exudative activity or treatment guidance.

The impact of structural optical coherence tomography changes on visual function in retinal vein occlusion.

PURPOSE: We aimed to determine the correlation between optical coherence tomography (OCT)- and demographic features and baseline best corrected visual acuity (BCVA) in treatment-naïve patients with retinal vein occlusion (RVO). METHODS: This was a cross-sectional posthoc analysis of OCT images that included RVO patients from two prospective, open-label, multicentre studies. The morphological grading was done manually, in the standardized setting of a reading centre. Main outcome measure was the estimated difference in Early Treatment Diabetic Retinopathy Study letters associated with each individual biomarker. RESULTS: Included were 381/301 treatment-naïve patients with BRVO/CRVO. For BRVO, statistically significant correlations with BCVA were seen for a 100 µm increase in central subfield thickness (CST; -3.1 letters), intraretinal cysts at centre point (CP; +4.1), subretinal fluid (SRF) at CP (+3.0) and hyperreflective foci (HRF) at the central B-scan (-2.2). In CRVO, a 100 µm increase in CST was associated with a loss of -3.4 letters. In the total cohort, 100 µm increase in CST, SRF at CP and HRF at the central B-scan correlated with a difference of -3.2,+3.2 and -2.0 letters. A 10-year increase in age and female gender yielded a -2.0 and -2.5 letter decrease in the total cohort. Adjusted multiple R2 for the respective group was 18.3%/26.3%/23.5%. CONCLUSIONS: Of all parameters studied, only CST and age were consistently associated with worse BCVA in treatment-naïve RVO patients. Morphology on OCT explained only a modest part of functional loss in this patient cohort.

N-triazinyl derivatives of 1- and 9-aminoanthracene: synthesis and photo-physical properties.

New N-triazinyl derivatives were synthesized by reaction of cyanuric chloride with 1- and 9-aminoanthracenes and subsequent nucleophilic substitution of chlorine atoms on triazinyl ring with methoxy and/or phenylamino groups. The compounds were characterized by (1)H and (13)C NMR and mass spectra. The influence of the chemical structure and solvent polarity on the UV/Vis absorption and fluorescence spectra and fluorescence quantum yields were investigated. Semi-empirical computations revealed highly polar CT states in singlet excited state manifold connected with charge-transfer from the hydrocarbon moiety to the triazinyl ring. The relationships between the CT-to-emitting state energy gap, solvent polarity and fluorescence quantum yield were discussed.

Fluorescence anisotropy of branched molecules containing 1-aminopyrene chromophores.

Fluorescence anisotropy measurements were performed on a set of multichromophoric compounds, which contain a different number of aminopyrenyl moieties linked to a triazine ring, in order to reveal the nature of both the electronic excited states and relaxation pathways of the compounds. Our experimental results complement quantum chemical calculations. We propose that the lowest excited state from which fluorescence proceeds is localized on a single individual aminopyrene moiety. In contrast, excitation to a higher excited state is likely followed by a migration of energy to another nearby aminopyrene chromophore before the internal conversion to the emitting state takes place. We suggest that this migration is responsible for the experimentally measured decrease of fluorescence anisotropy of the studied compounds.

Ultrafast intramolecular electronic energy transfer in rigidly linked aminopyrenyl-aminobenzanthronyl dyads--a femtosecond study.

Ultrafast electronic excitation transfer (EET) followed by structural and vibrational relaxation (VER) of the acceptor have been characterised using transient absorption and transient lens techniques.