The OSCAR-MP Consensus Criteria for Quality Assessment of Retinal Optical Coherence Tomography Angiography

Consensus; Angiography; RetinaConsenso; Angiografía; RetinaConsens; Angiografia; RetinaBackground and Objectives Optical coherence tomography angiography (OCTA) is a noninvasive high-resolution imaging technique for assessing the retinal vasculature and is increasingly used in various ophthalmologic, neuro-ophthalmologic, and neurologic diseases. To date, there are no validated consensus criteria for quality control (QC) of OCTA. Our study aimed to develop criteria for OCTA quality assessment. Methods To establish criteria through (1) extensive literature review on OCTA artifacts and image quality to generate standardized and easy-to-apply OCTA QC criteria, (2) application of OCTA QC criteria to evaluate interrater agreement, (3) identification of reasons for interrater disagreement, revision of OCTA QC criteria, development of OCTA QC scoring guide and training set, and (4) validation of QC criteria in an international, interdisciplinary multicenter study. Results We identified 7 major aspects that affect OCTA quality: (O) obvious problems, (S) signal strength, (C) centration, (A) algorithm failure, (R) retinal pathology, (M) motion artifacts, and (P) projection artifacts. Seven independent raters applied the OSCAR-MP criteria to a set of 40 OCTA scans from people with MS, Sjogren syndrome, and uveitis and healthy individuals. The interrater kappa was substantial (κ 0.67). Projection artifacts were the main reason for interrater disagreement. Because artifacts can affect only parts of OCTA images, we agreed that prior definition of a specific region of interest (ROI) is crucial for subsequent OCTA quality assessment. To enhance artifact recognition and interrater agreement on reduced image quality, we designed a scoring guide and OCTA training set. Using these educational tools, 23 raters from 14 different centers reached an almost perfect agreement (κ 0.92) for the rejection of poor-quality OCTA images using the OSCAR-MP criteria. Discussion We propose a 3-step approach for standardized quality control: (1) To define a specific ROI, (2) to assess the occurrence of OCTA artifacts according to the OSCAR-MP criteria, and (3) to evaluate OCTA quality based on the occurrence of different artifacts within the ROI. OSCAR-MP OCTA QC criteria achieved high interrater agreement in an international multicenter study and is a promising QC protocol for application in the context of future clinical trials and studies.R. Wicklein received an intramural research grant from the Technical University of Munich, School of Medicine, and was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC-2145 - SyNergy ID 390857198). C. Yam's PhD fellowship is funded by the UCL Queen Square Institute of Neurology and Cleveland Clinic London PhD Neuroscience Fellowship. C. Noll received a research scholarship from the Gemeinnützige Hertie Foundation. L. Aly received travel and research support by Novartis. N. Banze received no funding. E. Feodora Romahn received no funding. E. Wolf received no funding. Bernhard Hemmer received funding for the study by the European Union's Horizon 2020 Research and Innovation Program [grant MultipleMS, EU RIA 733161] and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology [EXC 2145 SyNergy - ID 390857198]. F.C. Oertel received research support by the National MS Society, American Academy of Neurology and Hertie foundation, all outside of the submitted work. H.G. Zimmermann received intramural funding from the Berlin Center for Translational Vascular Biomedicine (VasBioBerlin). P. Albrecht received no funding. M. Ringelstein received no funding. C. Baumann has no financial disclosures and no conflicting relationship. N. Feucht received no funding. J. Penkava received no funding. J. Havla reports grants from the Friedrich-Baur-Stiftung, Merck, and Horizon. C. Mardin is a medical advisor to Heidelberg Engineering, Heidelberg, Germany, receives lecture honorarium by Heidelberg Engineering, Bayer AG, Leverkusen, Germany, and is partially funded by Federal Ministry of Education and Research and Bavarian Ministry of Health. J.A. Gernert received a research grant from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; SFB/TRR 274, ID 408885537). E. Vasileiou did not receive any funding. A. van der Walt did not receive any funding. O. Al-Louzi did not receive any funding. S. Cabello did not receive any funding. A. Vidal-Jordana has received support for contracts Juan Rodes (JR16/00024) and from Fondo de Investigación en Salud (PI17/02162 and PI22/01589) from Instituto de Salud Carlos III, Spain. J. Krämer did not receive any funding. Heinz Wiendl did not receive any funding. J.L. Preiningerova was funded by Charles University Cooperation Program in Neuroscience, and General University Hospital in Prague project MH CZ-DRO-VFN64165…. O. Ciccarelli was funded by NIHR RP-2017-08-ST2-004 and supported by researchers at the National Institute for Health and Care Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Center (BRC) including OC. E. Garcia-Martin received grant support: PI20/00437 (Carlos III Health Institute) and Inflammatory Disease Network (RICORS) (RD21/0002/0050) (Carlos III Health Institute). V. Kana received funding from the Swiss National Foundation and a Filling the Gap protected research time grant (University of Zurich), all outside of the submitted work. P.A. Calabresi reports no funding. F. Paul reports no funding. S. Saidha reports no funding. A. Petzold reports no funding. A. Toosy is supported by recent awards from the MRC (MR/S026088/1), NIHR BRC (541/CAP/OC/818837) and RoseTrees Trust (A1332 and PGL21/10079), and MSIF. B. Knier was funded by the Else Kröner-Fresenius-Stiftung (Else Kröner-Fresenius Exzellenzstipendium 2019_EKES.09) and the Gemeinnützige Hertie Foundation (medMS program) and received a research award from Novartis

Retinal inner nuclear layer volume reflects inflammatory disease activity in multiple sclerosis: a longitudinal OCT study

Inner nuclear layer; Multiple sclerosis; Optical coherence tomographyCapa nuclear interna; Esclerosis múltiple; Tomografía de coherencia ópticaCapa nuclear interior; Esclerosi múltiple; Tomografia de coherència òpticaBackground: The association of peripapillary retinal nerve fibre layer (pRNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness with neurodegeneration in multiple sclerosis (MS) is well established. The relationship of the adjoining inner nuclear layer (INL) with inflammatory disease activity is less well understood. Objective: The objective of this paper is to investigate the relationship of INL volume changes with inflammatory disease activity in MS. Methods In this longitudinal, multi-centre study, optical coherence tomography (OCT) and clinical data (disability status, relapses and MS optic neuritis (MSON)) were collected in 785 patients with MS (68.3% female) and 92 healthy controls (63.4% female) from 11 MS centres between 2010 and 2017 and pooled retrospectively. Data on pRNFL, GCIPL and INL were obtained at each centre. Results: There was a significant increase in INL volume in eyes with new MSON during the study (N=61/1562, β=0.01mm3, p<.001). Clinical relapses (other than MSON) were significantly associated with increased INL volume (β=0.005, p=.025). INL volume was independent of disease progression (β=0.002mm3, p=.474). Conclusion: Our data demonstrate that an increase in INL volume is associated with MSON and the occurrence of clinical relapses. Therefore, INL volume changes may be useful as an outcome marker for inflammatory disease activity in MSON and MS treatment trials

Deciphering Multiple Sclerosis Progression

Esclerosi múltiple; NeurodegeneracióEsclerosis múltiple; NeurodegeneraciónMultiple sclerosis; NneurodegenerationMultiple sclerosis (MS) is primarily an inflammatory and degenerative disease of the central nervous system, triggered by unknown environmental factors in patients with predisposing genetic risk profiles. The prevention of neurological disability is one of the essential goals to be achieved in a patient with MS. However, the pathogenic mechanisms driving the progressive phase of the disease remain unknown. It was described that the pathophysiological mechanisms associated with disease progression are present from disease onset. In daily practice, there is a lack of clinical, radiological, or biological markers that favor an early detection of the disease's progression. Different definitions of disability progression were used in clinical trials. According to the most descriptive, progression was defined as a minimum increase in the Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 from a baseline level of 0, 1.0–5.0, and 5.5, respectively. Nevertheless, the EDSS is not the most sensitive scale to assess progression, and there is no consensus regarding any specific diagnostic criteria for disability progression. This review document discusses the current pathophysiological concepts associated with MS progression, the different measurement strategies, the biomarkers associated with disability progression, and the available pharmacologic therapeutic approaches

Role of high mobility group box protein 1 (HMGB1) in peripheral blood from patients with multiple sclerosis

Altres ajuts: The authors thank the 'Red Española de Esclerosis Múltiple (REEM)' sponsored by the 'Fondo de Investigación Sanitaria' (FIS), Ministry of Science and Innovation, Spain, and the 'Ajuts per donar Suport als Grups de Recerca de Catalunya,' sponsored by the 'Agència de Gestió d'Ajuts Universitaris i de Recerca' (AGAUR), Generalitat de Catalunya, Spain.High mobility group box protein 1 (HMGB1) is a transcriptional regulator that is receiving increasing attention in autoimmune disorders including multiple sclerosis (MS). Here, we investigated the role of HMGB1 in the peripheral blood compartment from MS patients. HMGB1 mRNA expression levels were determined by PCR in peripheral blood mononuclear cells (PBMC) of 29 healthy controls and 57 untreated MS patients (26 with relapsing-remitting MS - RRMS, 13 with secondary progressive MS - SPMS, and 18 with primary progressive MS - PPMS). HMGB1 protein levels were measured by ELISA in serum samples from 18 HC and 37 untreated MS patients (13 with RRMS, 14 with SPMS, and 10 with PPMS). HMGB1 expression levels were increased in PBMC from the whole MS group compared with controls (P = 0.03). Further stratification of the MS group revealed higher expression levels in PBMC from patients with relapse-onset MS, and differences were statistically significant for RRMS patients compared with PPMS patients and controls (P = 4 × 10 −5 and P = 0.005, respectively) and also for SPMS patients compared with PPMS patients (P = 0.001). HMGB1 serum levels were increased in the whole MS group compared with controls (P = 2 × 10 −4). In MS clinical forms, the highest HMGB1 serum levels were observed in RRMS patients, and differences were statistically significant compared to PPMS patients (P = 5 × 10 −5), SPMS patients (P = 0.001), and controls (P = 0.001). These results point to a role of HMGB1 mRNA and protein levels as disease activity biomarkers to discriminate the more inflammatory relapse-onset MS forms, particularly RRMS, from the less inflammatory PPMS form of the disease. The online version of this article (doi:10.1186/s12974-015-0269-9) contains supplementary material, which is available to authorized users

Cognitive impairment in multiple sclerosis: diagnosis and monitoring

Multiple sclerosis; Neurophysiological monitoring; Neuropsychological testsEsclerosi múltiple; Monitorització neurofisiològica; Proves neuropsicològiquesEsclerosis múltiple; Monitoreo neurofisiológico; Pruebas neuropsicológicasIntroduction Cognitive impairment (CI) has a prevalence of 45–70% in people with multiple sclerosis (MS), producing a negative impact on their quality of life, personal life, and work. Early detection of CI has become an important aspect to be considered for an adequate follow-up, to optimize social adaptation and to implement specific cognitive rehabilitation strategies. The aim of this work is to propose a suitable cognitive evaluation of patients with MS based on available and efficient tools for diagnosis and monitoring purposes well supported by literature review and clinical experience. Methods A multidisciplinary panel of professionals from the field of neurology, neuropsychology, and neuroimaging performed a literature review of the topic of cognitive impairment assessment. This was combined and completed with their clinical experience to produce a set of recommendations. Results Some limitations to cognitive evaluation are described: shortage of time and resources during the neurology consultation, scarceness or absence of specialized professionals’ availability, importance of tests adaptation, and doubts about its use to define therapeutic efficiency. We recommend a baseline and annual screening evaluation, and we suggest a baseline and periodic neuropsychological assessment. The latter ought to change to a recommendation with the presence of either positive screening test, or subjective to cognitive complaints, screening-test results and patient or family report mismatch, or in specific social/work situations. Conclusions Cognitive evaluation should be performed on all patients diagnosed with MS and throughout follow-up. It is necessary to support the creation of multidisciplinary MS teams to optimize the evaluation and follow-up of MS patients

Detection of lesions in the optic nerve with magnetic resonance imaging using a 3D convolutional neural network

Deep learning; Multiple sclerosis, Optic nerveAprendizaje profundo; Esclerosis múltiple; Nervio ópticoAprenentatge profund; Esclerosi múltiple; Nervi òpticBackground Optic neuritis (ON) is one of the first manifestations of multiple sclerosis, a disabling disease with rising prevalence. Detecting optic nerve lesions could be a relevant diagnostic marker in patients with multiple sclerosis. Objectives We aim to create an automated, interpretable method for optic nerve lesion detection from MRI scans. Materials and Methods We present a 3D convolutional neural network (CNN) model that learns to detect optic nerve lesions based on T2-weighted fat-saturated MRI scans. We validated our system on two different datasets (N = 107 and 62) and interpreted the behaviour of the model using saliency maps. Results The model showed good performance (68.11% balanced accuracy) that generalizes to unseen data (64.11%). The developed network focuses its attention to the areas that correspond to lesions in the optic nerve. Conclusions The method shows robustness and, when using only a single imaging sequence, its performance is not far from diagnosis by trained radiologists with the same constraint. Given its speed and performance, the developed methodology could serve as a first step to develop methods that could be translated into a clinical setting.This project was developed as a part of Gerard Martí-Juan ECTRIMS Research Fellowship Program 2021–2022. This study was partially supported by the Projects (PI18/00823, PI19/00950), from the Fondo de Investigación Sanitaria (FIS), Instituto de Salud Carlos III

T1/T2-weighted ratio in multiple sclerosis: A longitudinal study with clinical associations

Clinically isolated syndrome; Magnetic resonance imaging; Multiple sclerosisSíndrome clínicamente aislado; Imágenes por resonancia magnética; Esclerosis múltipleSíndrome clínicament aïllat; Imatges per ressonància magnètica; Esclerosi múltipleBackground T1w/T2-w ratio has been proposed as a clinically feasible MRI biomarker to assess tissue integrity in multiple sclerosis. However, no data is available in the earliest stages of the disease and longitudinal studies analysing clinical associations are scarce. Objective To describe longitudinal changes in T1-w/T2-w in patients with clinically isolated syndrome (CIS) and multiple sclerosis, and to investigate their clinical associations. Methods T1-w/T2-w images were generated and the mean value obtained in the corresponding lesion, normal-appearing grey (NAGM) and white matter (NAWM) masks. By co-registering baseline to follow-up MRI, evolved lesions were assessed; and by placing the mask of new lesions to the baseline study, the pre-lesional tissue integrity was measured. Results We included 171 CIS patients and 22 established multiple sclerosis patients. In CIS, evolved lesions showed significant T1-w/T2-w increases compared to baseline (+7.6%, P < 0.001). T1-w/T2-w values in new lesions were lower than in pre-lesional tissue (-28.2%, P < 0.001), and pre-lesional tissue was already lower than baseline NAWM (-7.8%, P < 0.001). In CIS at baseline, higher NAGM T1-w/T2-w was associated with multiple sclerosis diagnosis, and longitudinal decreases in NAGM and NAWM T1-w/T2-w were associated with disease activity. In established multiple sclerosis, T1-w/T2-w was inversely correlated with clinical disability and disease duration. Conclusion A decrease in T1-w/T2-w ratio precedes lesion formation. In CIS, higher T1-w/T2-w was associated with multiple sclerosis diagnosis. In established multiple sclerosis, lower T1-w/T2-w values were associated with clinical disability. The possible differential impact of chronic inflammation, iron deposition and demyelination should be considered to interpret these findings.This project was developed as a part of Mateus Boaventura ECTRIMS Clinical Training Fellowship Programme 2018–2019. This study was partially supported by the Project PI18/00823, from the Fondo de Investigación Sanitaria (FIS), Instituto de Salud Carlos III

CSF Chitinase 3–Like 2 Is Associated With Long-term Disability Progression in Patients With Progressive Multiple Sclerosis

Multiple Sclerosis; ChitinaseEsclerosis múltiple; QuitinasaEsclerosi múltiple; QuitinasaObjective This study aimed to identify long-term prognostic protein biomarkers associated with disease progression in patients with progressive multiple sclerosis (MS). Methods CSF samples were collected from a discovery cohort of 28 patients with progressive MS who participated in a clinical trial with interferon beta. Patients were classified into high and low disability progression phenotypes according to numeric progression rates (NPR) and step-based progression rates (SPR) after a mean follow-up time of 12 years. Protein abundance was measured by shotgun proteomics. Selected proteins from the discovery cohort were quantified by parallel reaction monitoring in CSF samples from an independent validation cohort of 41 patients with progressive MS classified also into high and low disability progression phenotypes after a mean follow-up time of 7 years. Results Of 2,548 CSF proteins identified in the discovery cohort, 10 were selected for validation based on their association with long-term disability progression: SPATS2-like protein, chitinase 3–like 2 (CHI3L2), plasma serine protease inhibitor, metallothionein-3, phospholipase D4, beta-hexosaminidase, neurexophilin-1, adipocyte enhancer-binding protein 1, cathepsin L1, and lipopolysaccharide-binding protein. Only CHI3L2 was validated, and patients with high disability progression exhibited significantly higher CSF protein levels compared with patients with low disability progression (p = 0.03 for NPR and p = 0.02 for SPR). CHI3L2 levels showed good performance to discriminate between high and low disability progression in patients with progressive MS (area under the curve 0.73; sensitivity 90% and specificity 63%). Conclusions Although further confirmatory studies are needed, we propose CSF CHI3L2 as a prognostic protein biomarker associated with long-term disability progression in patients with progressive MS.This work was funded by grants from the International Progressive MS Alliance (grant no. PA0020), Asociación Esclerosis Múltiple (EME)—Red Española de Esclerosi múltiple (REEM), REEM (RD16/0015/002 and RD16/0015/003) cofunded by the Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (FEDER, Otra manera de hacer Europa)

Lesion topographies in multiple sclerosis diagnosis

To assess the contributions of cortico-juxtacortical and corpus callosum lesions to multiple sclerosis diagnosis and to compare the value of ≥1 vs ≥3 periventricular lesions in clinically isolated syndromes (CIS). Step 1: We evaluated lesion topography classifications in 657 patients with CIS with stepwise Cox proportional hazards regression models considering second attack as the outcome. Step 2: We established 2 dissemination in space (DIS) versions according to the periventricular lesion cutoffs of ≥1 and ≥3 and assessed their performance at 10 years with second attack as the outcome, first individually and then combined with dissemination in time (DIT) in all cases (n = 326), by age, and by CIS topography. Step 1: The models (hazard ratios [95% confidence interval]) favored ≥1 over ≥3 periventricular lesions (2.5 [1.7-3.6]) and cortico-juxtacortical over juxtacortical lesions (1.4 [1.0-1.8]). Callosal lesions were not selected. Step 2: DIS specificity with ≥1 periventricular lesions was slightly lower than with ≥3 (59.1 vs 61.4) and the same after adding DIT (88.6). Regarding age, ≥3 periventricular lesions improved DIS specificity over ≥1 lesions in the 40-49 years of age bracket (66.7 vs 58.3). This difference disappeared when adding DIT (83.3). Optic neuritis had a similar pattern when evaluating CIS topographies. Our results comply with the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) consensus recommendation of combining cortical and juxtacortical lesions into a single term when possible. Concerning periventricular lesions, maintaining the current ≥1 cutoff in the McDonald criteria does not compromise specificity in typical CIS cases, but attention should be paid to older patients or optic neuritis cases

Oral contraceptives do not modify the risk of a second attack and disability accrual in a prospective cohort of women with a clinically isolated syndrome and early multiple sclerosis

To evaluate whether oral contraceptive (OC) use is associated with the risk of a second attack and disability accrual in women with a clinically isolated syndrome (CIS) and early multiple sclerosis (MS). Reproductive information from women included in the Barcelona CIS prospective cohort was collected through a self-reported cross-sectional survey. We examined the relationship of OC exposure with the risk of a second attack and confirmed Expanded Disability Status Scale of 3.0 using multivariate Cox regression models, adjusted by age, topography of CIS, oligoclonal bands, baseline brain T2 lesions, body size at menarche, smoking, and disease-modifying treatment (DMT). OC and DMT exposures were considered as time-varying variables. Findings were confirmed with sensitivity analyses using propensity score models. A total of 495 women were included, 389 (78.6%) referred to ever use OC and 341 (68.9%) started OC before the CIS. Exposure to OC was not associated with a second attack (adjusted hazard ratio (aHR) = 0.73, 95% confidence interval (CI) = 0.33-1.61) or disability accrual (aHR = 0.81, 95% CI = 0.17-3.76). Sensitivity analyses confirmed these results. OC use does not modify the risk of second attack or disability accrual in patients with CIS and early MS, once considered as a time-dependent exposure and adjusted by other potential confounders