MSJ765666_supplementary_figure_1 – Supplemental material for Serum neurofilament light chain is a biomarker of acute and chronic neuronal damage in early multiple sclerosis

Supplemental material, MSJ765666_supplementary_figure_1 for Serum neurofilament light chain is a biomarker of acute and chronic neuronal damage in early multiple sclerosis by Nelly Siller, Jens Kuhle, Muthuraman Muthuraman, Christian Barro, Timo Uphaus, Sergiu Groppa, Ludwig Kappos, Frauke Zipp and Stefan Bittner in Multiple Sclerosis Journal

Endovascular Stroke Treatment and Risk of Intracranial Hemorrhage in Anticoagulated Patients

Background and Purpose— We aimed to determine the safety and mortality after mechanical thrombectomy in patients taking vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs). Methods— In a multicenter observational cohort study, we used multiple logistic regression analysis to evaluate associations of symptomatic intracranial hemorrhage (sICH) with VKA or DOAC prescription before thrombectomy as compared with no anticoagulation. The primary outcomes were the rate of sICH and all-cause mortality at 90 days, incorporating sensitivity analysis regarding confirmed therapeutic anticoagulation. Additionally, we performed a systematic review and meta-analysis of literature on this to…

NfL predicts relapse-free progression in a longitudinal multiple sclerosis cohort study

Background: Easily accessible biomarkers enabling the identification of those patients with multiple sclerosis (MS) who will accumulate irreversible disability in the long term are essential to guide early therapeutic decisions. We here examine the utility of serum neurofilament light chain (sNfL) for forecasting relapse-free disability progression and conversion to secondary progressive MS (SPMS) in the prospective Neurofilament and longterm outcome in MS (NaloMS) cohort. Methods: The predictive ability of sNfL at Baseline and sNfL follow-up (FU)/ Baseline (BL) ratio with regard to disability progression was assessed within a development cohort (NaloMS, n=196 patients with relapsing-remitt…

Health-related quality of life, anxiety and depression up to 12 months post-stroke: Influence of sex, age, stroke severity and atrial fibrillation - A longitudinal subanalysis of the Find-AF

Abstract Background Stroke can negatively impact the health-related quality of life (HRQoL). Anxiety or depression after stroke have been associated with poorer HRQoL, higher mortality and greater dependence in activities of daily living. We aimed to analyze HRQoL, anxiety and depressive symptoms in patients with and without atrial fibrillation (AF) up to 12 months post-stroke. Methods Find-AFRANDOMISED was a prospective, randomized multicenter study, which included 398 patients ≥60 years with acute cerebral ischemia. HRQoL data were collected using the 3-level EuroQol-5D (EQ-5D-3L) and Stroke Impact Scale (SIS-16). Anxiety and depressive symptoms were measured using the Hospital Anxiety an…

Clinical implications of serum neurofilament in newly diagnosed MS patients: a longitudinal multicentre cohort study

Abstract Background We aim to evaluate serum neurofilament light chain (sNfL), indicating neuroaxonal damage, as a biomarker at diagnosis in a large cohort of early multiple sclerosis (MS) patients. Methods In a multicentre prospective longitudinal observational cohort, patients with newly diagnosed relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS) were recruited between August 2010 and November 2015 in 22 centers. Clinical parameters, MRI, and sNfL levels (measured by single molecule array) were assessed at baseline and up to four-year follow-up. Findings Of 814 patients, 54.7% (445) were diagnosed with RRMS and 45.3% (369) with CIS when applying 2010 McDonald criteria (R…

Brain Natriuretic Peptide and Discovery of Atrial Fibrillation After Stroke

Background and Purpose— Diagnosing paroxysmal atrial fibrillation (pAF) can be challenging after acute ischemic stroke. Enhanced and prolonged Holter-ECG monitoring (EPM) improves the detection rate but is not feasible for all patients. We hypothesized that brain natriuretic peptide (BNP) may help to identify patients with stroke at high risk for pAF to select patients for EPM more effectively. Methods— Patients with acute cerebral ischemia ≥60 years presenting in sinus rhythm and without history of AF were included into a prospective, randomized multicenter study to receive either EPM (3× 10-day Holter-ECG) or usual stroke care diagnostic work-up. BNP plasma levels were measured on random…

Serum neurofilament levels reflect outer retinal layer changes in multiple sclerosis

Background: Serum neurofilament light chain (sNfL) and distinct intra-retinal layers are both promising biomarkers of neuro-axonal injury in multiple sclerosis (MS). We aimed to unravel the association of both markers in early MS, having identified that neurofilament has a distinct immunohistochemical expression pattern among intra-retinal layers. Methods: Three-dimensional (3D) spectral domain macular optical coherence tomography scans and sNfL levels were investigated in 156 early MS patients (female/male: 109/47, mean age: 33.3 ± 9.5 years, mean disease duration: 2.0 ± 3.3 years). Out of the whole cohort, 110 patients had no history of optic neuritis (NHON) and 46 patients had a previous…

Abstract TMP17: Revacept, an Inhibitor of Platelet Adhesion in Patients With Symptomatic Carotid Artery Stenosis. Safety Data From the International Randomized Multicenter Revacept CS02 Phase 2 Study

Introduction: Revacept is a novel vascular lesion-directed inhibitor of platelet adhesion and thrombus formation, exhibiting no effects on the homeostatic functions of circulating platelets. Objective: The effects of Revacept on plaque-mediated thrombosis were investigated in patients with symptomatic stenosis of the internal carotid artery (at least 50%, following ECST-criteria). Methods: Within an international, prospective, multicenter (n=16), randomized trial 158 patients could be randomized to receive placebo, or 40/120 mg Revacept by intravenous infusion over 20 minutes. Cerebrovascular events and cardiovascular complications were followed up to 3 months. Results: 158 patients were f…

NfL (Neurofilament Light Chain) Levels as a Predictive Marker for Long-Term Outcome After Ischemic Stroke

Background and Purpose— Ischemic stroke causes major disability as a consequence of neuronal loss and recurrent ischemic events. Biomarkers predicting tissue damage or stroke recurrence might be useful to guide an individualized stroke therapy. NfL (neurofilament light chain) is a promising biomarker that might be used for this purpose. Methods— We used individual data of patients with an acute ischemic stroke and clinical long term follow-up. Serum NfL (sNfL) was quantified within 24 hours after admission and after 1 year and compared with other biomarkers (GDF15 [growth differentiation factor 15], S100, NT-proBNP [N-terminal pro-B-type natriuretic peptide], ANP [atrial natriuretic peptid…

Stroke Care Within the COVID-19 Pandemic—Increasing Awareness of Transient and Mild Stroke Symptoms Needed

Background: The COVID-19 pandemic might affect health care resources and alter patient admission to hospital in case of stroke or transient ischemic attack (TIA). We aim to determine whether the COVID-19 pandemic is affecting utilization of recanalization procedures and numbers of patients with stroke and TIA admitted to a primary care stroke center.Methods: In this retrospective observational study, we compared patients admitted from January 2019 until February 2020 with patients admitted during the COVID-19 pandemic (March/April 2020) in Germany. We included patients with stroke (hemorrhagic or ischemic) or TIA as classified by International Statistical Classification of Diseases and Rela…

Abstract WP200: Development and Validation of a Score to Detect Paroxysmal Atrial Fibrillation During Long-term Holter-monitoring After Acute Ischemic Stroke

Introduction: Atrial fibrillation remains one of the most common causes of ischemic stroke. The diagnosis of paroxysmal atrial fibrillation (pAF) frequently escapes routine diagnostic due to its intermittent and asymptomatic occurrence. Currently prolonged monitoring times (72h) are recommended, but did not find their way into everyday practice. Therefore an individual patient selection for prolonged ECG-monitoring might increase the diagnostic yield of pAF in a resource-saving and cost-effective manner. Methods: We used individual patient data from three prospective studies (n total =1556) which performed a prolonged Holter ECG-monitoring (at least 72 h) and centralized data evaluation af…

Secondary Progression in Multiple Sclerosis: Neuronal Exhaustion or Distinct Pathology?

Prevention of progression in neurological diseases, particularly in multiple sclerosis (MS) but also in neurodegenerative diseases, remains a significant challenge. MS patients switch from a relapsing-remitting to a progressive disease course, but it is not understood why and how this conversion occurs and why some patients never experience disease progression. Do aging and accumulation of neuronal damage induce progression, or do cognitive symptoms and accelerated grey matter (GM) atrophy point to distinct processes affecting networks? This review weighs accepted dogma against real data on the secondary progressive phase of the disease, highlighting current challenges in this important fie…

Safety of endovascular treatment in acute stroke patients taking oral anticoagulants

International journal of stroke 12(4), 412-415 (2017). doi:10.1177/1747493016677986

Automatic detection of paroxysmal atrial fibrillation in patients with ischaemic stroke: better than routine diagnostic workup?

Background and purpose Prolonged electrocardiogram (ECG) monitoring after ischaemic stroke increases the diagnostic yield of paroxysmal atrial fibrillation (pAF). In order to facilitate the additional workload involved in ECG analysis due to prolonged monitoring times, we investigated the effectiveness of pAF detection with an automated software algorithm (SA) in comparison to the routine staff-based analysis (RA) during standard stroke-unit care. Therefore, patients with acute ischaemic stroke or transitory ischaemic attack presenting with sinus rhythmus on the admission ECG and no history of atrial fibrillation were prospectively included. Methods A 24-h Holter ECG assessment was performe…

Revacept, an Inhibitor of Platelet Adhesion in Symptomatic Carotid Artery Stenosis: Design and Rationale of a Randomized Phase II Clinical Trial

AbstractPatients with stroke or transient ischemic attacks (TIAs) and internal carotid artery stenosis harbor an increased risk of recurrent stroke especially within 2 weeks after the first event. In addition, the revascularization procedure itself (carotid endarterectomy [CEA] or carotid artery stenting [CAS]) is associated with both clinically apparent and silent brain infarctions, mainly caused by the embolic nature of the ruptured carotid plaque. The glycoprotein VI (GPVI) fusion protein Revacept is a highly specific antithrombotic drug without direct inhibition of systemic platelet function that might reduce periprocedural distal embolization from the vulnerable ruptured plaque located…

EGFL7 - a potential therapeutic target for multiple sclerosis?

Association of intrathecal pleocytosis and IgG synthesis with axonal damage in early MS

ObjectiveTo investigate the association of serum neurofilament light chain (sNfL) levels with CSF parameters in clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS), taking into account radiologic and clinical parameters of disease activity.MethodsSimultaneously collected serum and CSF samples of 112 untreated patients newly diagnosed with CIS or RRMS were included in this cross-sectional study. CSF parameters were obtained as part of routine diagnostic tests. sNfL levels of patients and of 62 healthy donors were measured by highly sensitive single molecule array (SiMoA) immunoassay.ResultsPatients with RRMS (n = 91, median 10.13 pg/mL, interquartile range [IQR] 6.67–1…

Response by Uphaus et al to Letter Regarding Article, “NfL (Neurofilament Light Chain) Levels as a Predictive Marker for Long-Term Outcome After Ischemic Stroke”

Serum neurofilament light chain is a biomarker of acute and chronic neuronal damage in early multiple sclerosis.

Background: Monitoring neuronal injury remains one key challenge in early relapsing-remitting multiple sclerosis (RRMS) patients. Upon axonal damage, neurofilament – a major component of the neuro-axonal cytoskeleton – is released into the cerebrospinal fluid (CSF) and subsequently peripheral blood. Objective: To investigate the relevance of serum neurofilament light chain (sNfL) for acute and chronic axonal damage in early RRMS. Methods: sNfL levels were determined in 74 patients (63 therapy-naive) with recently diagnosed clinically isolated syndrome (CIS) or RRMS using Single Molecule Array technology. Standardized 3 T magnetic resonance imaging (MRI) was performed at baseline and 1–3 con…

Treatment response to dimethyl fumarate is characterized by disproportionate CD8+ T cell reduction in MS

Background: The effect of dimethyl fumarate (DMF) on circulating lymphocyte subsets and their contribution as predictors of clinical efficacy have not yet been investigated in multiple sclerosis (MS). Objective: To evaluate lymphocytes and lymphocyte subsets (analyzed 6 months after DMF start) in MS patients with and without disease activity after 1 year of treatment in a retrospective study. Methods: Peripheral blood lymphocyte subsets were analyzed by flow cytometry. Untreated MS patients ( n = 40) were compared to those 6 months after onset of DMF treatment ( n = 51). Clinical and magnetic resonance imaging (MRI) disease activity of DMF-treated patients were assessed in the first year un…

Translational Value of CSF and Blood Markers of Autoimmunity and Neurodegeneration

Increased frequency of proinflammatory CD4 T cells and pathological levels of serum neurofilament light chain in adult drug-resistant epilepsy

OBJECTIVE: Adult drug-resistant epilepsy (DRE) is associated with significant morbidity. Infiltration of immune cells is observed in DRE epileptic foci; however, the relation between DRE and the peripheral immune cell compartment remains only partially understood. We aimed to investigate differences in immune cell populations, cytokines, and neurodegenerative biomarkers in the peripheral blood of subjects with epilepsy versus healthy controls, and in DRE compared to well-controlled epilepsy (WCE). METHODS: Peripheral blood mononuclear cells and serum from >120 age- and sex-matched adults suffering from focal onset epilepsy and controls were analyzed by multipanel flow cytometry, multiplex i…

Software-based analysis of 1-hour Holter ECG to select for prolonged ECG monitoring after stroke.

Abstract Objective Identification of ischemic stroke patients at high risk for paroxysmal atrial fibrillation (pAF) during 72 hours Holter ECG might be useful to individualize the allocation of prolonged ECG monitoring times, currently not routinely applied in clinical practice. Methods In a prospective multicenter study, the first analysable hour of raw ECG data from prolonged 72 hours Holter ECG monitoring in 1031 patients with acute ischemic stroke/TIA presenting in sinus rhythm was classified by an automated software (AA) into “no risk of AF” or “risk of AF” and compared to clinical variables to predict AF during 72 hours Holter‐ECG. Results pAF was diagnosed in 54 patients (5.2%; mean …

Automatic Holter electrocardiogram analysis in ischaemic stroke patients to detect paroxysmal atrial fibrillation : ready to replace physicians?

Background and purpose The detection of paroxysmal atrial fibrillation (pAF) in patients presenting with ischaemic stroke shifts secondary stroke prevention to oral anticoagulation. In order to deal with the time- and resource-consuming manual analysis of prolonged electrocardiogram (ECG)-monitoring data, we investigated the effectiveness of pAF detection with an automated algorithm (AA) in comparison to a manual analysis with software support within the IDEAS study [study analysis (SA)]. Methods We used the dataset of the prospective IDEAS cohort of patients with acute ischaemic stroke/transient ischaemic attack presenting in sinus rhythm undergoing prolonged 72-h Holter ECG with central a…