Long-term outcome in new onset refractory status epilepticus: a retrospective study.

BACKGROUND: New onset refractory status epilepticus (NORSE) is a neurologic emergency without an immediately identifiable cause. The complicated and long ICU stay of the patients can lead to perceiving a prolongation of therapies as futile. However, a recovery is possible even in severe cases. This retrospective study investigates ICU treatments, short- and long-term outcome and ethical decisions of a case series of patients with NORSE. METHODS: Overall, 283 adults were admitted with status epilepticus (SE) to the Neurocritical Care Unit of the University Hospital Zurich, Switzerland, between 01.2010 and 12.2022. Of them, 25 had a NORSE. We collected demographic, clinical, therapeutic and outcome data. Descriptive statistics was performed. RESULTS: Most patients were female (68%), previously healthy (Charlson comorbidity index 1 [0-4]) and relatively young (54 ± 17 years). 96% presented with super-refractory SE. Despite extensive workup, the majority (68%) of cases remained cryptogenic. Most patients had a long and complicated ICU stay. The in-hospital mortality was 36% (n = 9). The mortality at last available follow-up was 56% (n = 14) on average 30 months after ICU admission. The cause of in-hospital death for 89% (n = 8) of the patients was the withholding/withdrawing of therapies. Medical staff except for one patient triggered the decision. The end of life (EOL) decision was taken 29 [12-51] days after the ICU admission. Death occurred on day 6 [1-8.5] after the decision was taken. The functional outcome improved over time for 13/16 (81%) hospital survivors (median mRS at hospital discharge 4 [3.75-5] vs. median mRS at last available follow-up 2 [1.75-3], p < 0.001). CONCLUSIONS: Our data suggest that the long-term outcome can still be favorable in NORSE survivors, despite a prolonged and complicated ICU stay. Clinicians should be careful in taking EOL decisions to avoid the risk of a self-fulfilling prophecy. Our results encourage clinicians to continue treatment even in initially refractory cases.

The split apparent diffusion coefficient sign: A novel magnetic resonance imaging biomarker for cortical pathology with possible implications in autoimmune encephalitis.

INTRODUCTION: MRI is the imaging modality of choice for assessing patients with encephalopathy. In this context, we discuss a novel biomarker, the "split ADC sign," where the cerebral cortex demonstrates restricted diffusion (high DWI signal and low ADC) and the underlying white matter demonstrates facilitated diffusion (high or low DWI signal and high ADC). We hypothesize that this sign can be used as a biomarker to suggest either acute encephalitis onset or to raise the possibility of an autoimmune etiology. MATERIALS AND METHODS: A full-text radiological information system search of radiological reports was performed for all entities known to produce restricted diffusion in the cortex excluding stroke between January 2012 and June 2022. Initial MRI studies performed upon onset of clinical symptoms were screened for the split ADC sign. RESULTS: 25 subjects were encountered with a positive split ADC sign (15 female; median age = 57 years, range 18-82). Diagnosis included six herpes simplex encephalitis, three peri-ictal MRI changes, eight PRES, two MELAS, and six autoimmune (3 anti-GABAAR, two seronegative, and one anti-Ma2/Ta). Subjects were imaged at a mean 1.8 days after the onset of symptoms (range 0-8). DISCUSSION: We present a novel visual MRI biomarker, the split ADC sign, and highlight its potential usefulness in subjects with encephalopathy to suggest acute disease onset or to raise the possibility of an autoimmune etiology when location-based criteria are applied. When positive, the sign was present on the initial MRI and can therefore be used to help focus further clinical and laboratory workup.

Identification of different MRI atrophy progression trajectories in epilepsy by subtype and stage inference.

Artificial intelligence (AI)-based tools are widely employed, but their use for diagnosis and prognosis of neurological disorders is still evolving. Here we analyse a cross-sectional multicentre structural MRI dataset of 696 people with epilepsy and 118 control subjects. We use an innovative machine-learning algorithm, Subtype and Stage Inference, to develop a novel data-driven disease taxonomy, whereby epilepsy subtypes correspond to distinct patterns of spatiotemporal progression of brain atrophy.In a discovery cohort of 814 individuals, we identify two subtypes common to focal and idiopathic generalized epilepsies, characterized by progression of grey matter atrophy driven by the cortex or the basal ganglia. A third subtype, only detected in focal epilepsies, was characterized by hippocampal atrophy. We corroborate external validity via an independent cohort of 254 people and confirm that the basal ganglia subtype is associated with the most severe epilepsy.Our findings suggest fundamental processes underlying the progression of epilepsy-related brain atrophy. We deliver a novel MRI- and AI-guided epilepsy taxonomy, which could be used for individualized prognostics and targeted therapeutics.

The role of neuronal antibodies in cryptogenic new onset refractory status epilepticus.

Most cases with new onset refractory status epilepticus (NORSE) remain cryptogenic despite extensive diagnostic workup. The aim of this study was to analyze the etiology and clinical features of NORSE and investigate known or potentially novel autoantibodies in cryptogenic NORSE (cNORSE). We retrospectively assessed the medical records of adults with status epilepticus at a Swiss tertiary referral center between 2010 and 2021. Demographic, diagnostic, therapeutic, and outcome parameters were characterized. We performed post hoc screening for known or potentially novel autoantibodies including immunohistochemistry (IHC) on rat brain with cerebrospinal fluid (CSF) and serum samples of cNORSE. Twenty patients with NORSE were identified. Etiologies included infections (n = 4), Creutzfeldt-Jakob disease (n = 1), CASPR2 autoimmune encephalitis (n = 1), and carotid artery stenosis with recurrent perfusion deficit (n = 1). Thirteen cases (65%) were cryptogenic despite detailed evaluation. A posteriori IHC for neuronal autoantibodies yielded negative results in all available serum (n = 11) and CSF (n = 9) samples of cNORSE. Our results suggest that neuronal antibodies are unlikely to play a major role in the pathogenesis of cNORSE. Future studies should rather focus on other-especially T-cell- and cytokine-mediated-mechanisms of autoinflammation in this devastating disease, which is far too poorly understood so far.

Association of Mortality and Risk of Epilepsy With Type of Acute Symptomatic Seizure After Ischemic Stroke and an Updated Prognostic Model.

Importance: Acute symptomatic seizures occurring within 7 days after ischemic stroke may be associated with an increased mortality and risk of epilepsy. It is unknown whether the type of acute symptomatic seizure influences this risk. Objective: To compare mortality and risk of epilepsy following different types of acute symptomatic seizures. Design, Setting, and Participants: This cohort study analyzed data acquired from 2002 to 2019 from 9 tertiary referral centers. The derivation cohort included adults from 7 cohorts and 2 case-control studies with neuroimaging-confirmed ischemic stroke and without a history of seizures. Replication in 3 separate cohorts included adults with acute symptomatic status epilepticus after neuroimaging-confirmed ischemic stroke. The final data analysis was performed in July 2022. Exposures: Type of acute symptomatic seizure. Main Outcomes and Measures: All-cause mortality and epilepsy (at least 1 unprovoked seizure presenting >7 days after stroke). Results: A total of 4552 adults were included in the derivation cohort (2547 male participants [56%]; 2005 female [44%]; median age, 73 years [IQR, 62-81]). Acute symptomatic seizures occurred in 226 individuals (5%), of whom 8 (0.2%) presented with status epilepticus. In patients with acute symptomatic status epilepticus, 10-year mortality was 79% compared with 30% in those with short acute symptomatic seizures and 11% in those without seizures. The 10-year risk of epilepsy in stroke survivors with acute symptomatic status epilepticus was 81%, compared with 40% in survivors with short acute symptomatic seizures and 13% in survivors without seizures. In a replication cohort of 39 individuals with acute symptomatic status epilepticus after ischemic stroke (24 female; median age, 78 years), the 10-year risk of mortality and epilepsy was 76% and 88%, respectively. We updated a previously described prognostic model (SeLECT 2.0) with the type of acute symptomatic seizures as a covariate. SeLECT 2.0 successfully captured cases at high risk of poststroke epilepsy. Conclusions and Relevance: In this study, individuals with stroke and acute symptomatic seizures presenting as status epilepticus had a higher mortality and risk of epilepsy compared with those with short acute symptomatic seizures or no seizures. The SeLECT 2.0 prognostic model adequately reflected the risk of epilepsy in high-risk cases and may inform decisions on the continuation of antiseizure medication treatment and the methods and frequency of follow-up.

Amygdala dismantled: the role of amygdala subregions in epilepsy.

This scientific commentary refers to: 'Amygdala subnuclear volumes in temporal lobe epilepsy with hippocampal sclerosis and in non-lesional patients' by Ballerini et al. (https://doi.org/10.1093/braincomms/fcac225).

Antiseizure medication withdrawal risk estimation and recommendations: A survey of American Academy of Neurology and EpiCARE members.

OBJECTIVE: Choosing candidates for antiseizure medication (ASM) withdrawal in well-controlled epilepsy is challenging. We evaluated (a) the correlation between neurologists' seizure risk estimation ("clinician predictions") vs calculated predictions, (b) how viewing calculated predictions influenced recommendations, and (c) barriers to using risk calculation. METHODS: We asked US and European neurologists to predict 2-year seizure risk after ASM withdrawal for hypothetical vignettes. We compared ASM withdrawal recommendations before vs after viewing calculated predictions, using generalized linear models. RESULTS: Three-hundred and forty-six neurologists responded. There was moderate correlation between clinician and calculated predictions (Spearman coefficient 0.42). Clinician predictions varied widely, for example, predictions ranged 5%-100% for a 2-year seizure-free adult without epileptiform abnormalities. Mean clinician predictions exceeded calculated predictions for vignettes with epileptiform abnormalities (eg, childhood absence epilepsy: clinician 65%, 95% confidence interval [CI] 57%-74%; calculated 46%) and surgical vignettes (eg, focal cortical dysplasia 6-month seizure-free mean clinician 56%, 95% CI 52%-60%; calculated 28%). Clinicians overestimated the influence of epileptiform EEG findings on withdrawal risk (26%, 95% CI 24%-28%) compared with calculators (14%, 95% 13%-14%). Viewing calculated predictions slightly reduced willingness to withdraw (-0.8/10 change, 95% CI -1.0 to -0.7), particularly for vignettes without epileptiform abnormalities. The greatest barrier to calculator use was doubting its accuracy (44%). SIGNIFICANCE: Clinicians overestimated the influence of abnormal EEGs particularly for low-risk patients and overestimated risk and the influence of seizure-free duration for surgical patients, compared with calculators. These data may question widespread ordering of EEGs or time-based seizure-free thresholds for surgical patients. Viewing calculated predictions reduced willingness to withdraw particularly without epileptiform abnormalities.

Verbal fluency functional magnetic resonance imaging detects anti-seizure effects and affective side effects of perampanel in people with focal epilepsy.

Perampanel, a noncompetitive antagonist of the postsynaptic a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor, is effective for controlling focal to bilateral tonic-clonic seizures but is also known to increase feelings of anger. Using statistical parametric mapping-derived measures of activation and task-modulated functional connectivity (psychophysiologic interaction), we investigated 14 people with focal epilepsy who had verbal fluency functional magnetic resonance imaging (fMRI) twice, before and after the add-on treatment of perampanel. For comparison, we included 28 people with epilepsy, propensity-matched for clinical characteristics, who had two scans but no change in anti-seizure medication (ASM) regimen in-between. After commencing perampanel, individuals had higher task-related activations in left orbitofrontal cortex (OFC), fewer task-related activations in the subcortical regions including the left thalamus and left caudate, and lower task-related thalamocaudate and caudate-subtantial nigra connectivity. Decreased task-related connectivity is observed between the left OFC and precuneus and left medial frontal lobe. Our results highlight the brain regions associated with the beneficiary therapeutic effects on focal to bilateral tonic-clonic seizures (thalamus and caudate) but also the undesired affective side effects of perampanel with increased anger and aggression (OFC).

Predictive models for starting antiseizure medication withdrawal following epilepsy surgery in adults.

More than half of adults with epilepsy undergoing resective epilepsy surgery achieve long-term seizure freedom and might consider withdrawing antiseizure medications. We aimed to identify predictors of seizure recurrence after starting postoperative antiseizure medication withdrawal and develop and validate predictive models. We performed an international multicentre observational cohort study in nine tertiary epilepsy referral centres. We included 850 adults who started antiseizure medication withdrawal following resective epilepsy surgery and were free of seizures other than focal non-motor aware seizures before starting antiseizure medication withdrawal. We developed a model predicting recurrent seizures, other than focal non-motor aware seizures, using Cox proportional hazards regression in a derivation cohort (n = 231). Independent predictors of seizure recurrence, other than focal non-motor aware seizures, following the start of antiseizure medication withdrawal were focal non-motor aware seizures after surgery and before withdrawal [adjusted hazard ratio (aHR) 5.5, 95% confidence interval (CI) 2.7-11.1], history of focal to bilateral tonic-clonic seizures before surgery (aHR 1.6, 95% CI 0.9-2.8), time from surgery to the start of antiseizure medication withdrawal (aHR 0.9, 95% CI 0.8-0.9) and number of antiseizure medications at time of surgery (aHR 1.2, 95% CI 0.9-1.6). Model discrimination showed a concordance statistic of 0.67 (95% CI 0.63-0.71) in the external validation cohorts (n = 500). A secondary model predicting recurrence of any seizures (including focal non-motor aware seizures) was developed and validated in a subgroup that did not have focal non-motor aware seizures before withdrawal (n = 639), showing a concordance statistic of 0.68 (95% CI 0.64-0.72). Calibration plots indicated high agreement of predicted and observed outcomes for both models. We show that simple algorithms, available as graphical nomograms and online tools (predictepilepsy.github.io), can provide probabilities of seizure outcomes after starting postoperative antiseizure medication withdrawal. These multicentre-validated models may assist clinicians when discussing antiseizure medication withdrawal after surgery with their patients.

Contribution of the µ-opioid receptor system to affective disorders in temporal lobe epilepsy: A bidirectional relationship?

OBJECTIVE: Affective disorders are frequent comorbidities of temporal lobe epilepsy (TLE). The endogenous opioid system has been implicated in both epilepsy and affective disorders, and may play a significant role in their bidirectional relationship. In this cross-sectional study, we investigated the association between µ-opioid receptor binding and affective disorders in patients with TLE. METHODS: Nine patients with TLE and depression/anxiety underwent 11 C-carfentanil positron emission tomography (CFN PET) and neuropsychiatric assessment, including the Hospital Anxiety and Depression Scale and the Positive and Negative Affect Schedule. The normalized CFN PET scans were compared with those of 26 age-matched healthy controls. Correlation analyses with affective symptoms were performed by region of interest-based analysis focusing on the limbic circuit and orbitofrontal cortex. RESULTS: We observed widely reduced CFN binding potential (BP) in bilateral frontal lobes and striata in patients with TLE compared to healthy controls. In the TLE group, more severe anxiety and negative affect were associated with decreased CFN BP in the posterior cingulate gyrus. SIGNIFICANCE: In patients with TLE, interictally reduced binding in the opioid system was associated with higher levels of anxiety and negative affect. We speculate that seizure-related agonist-driven desensitization and downregulation of opioid receptors could be a potential underlying pathomechanism.

In Vivo N-Methyl-d-Aspartate Receptor (NMDAR) Density as Assessed Using Positron Emission Tomography During Recovery From NMDAR-Antibody Encephalitis.

This case-control study uses a radiotracer and positron emission tomography to assess N-methyl-d-aspartate receptor (NMDAR) density changes during recovery from NMDAR-antibody encephalitis.

Mapping neurotransmitter systems to the structural and functional organization of the human neocortex.

Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macro-scale neuroanatomy and how they shape emergent function remain poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from more than 1,200 healthy individuals to construct a whole-brain three-dimensional normative atlas of 19 receptors and transporters across nine different neurotransmitter systems. We found that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting-state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncovered a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we found both expected and novel associations between receptor distributions and cortical abnormality patterns across 13 disorders. We replicated all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.

New-onset refractory status epilepticus due to autoimmune encephalitis after vaccination against SARS-CoV-2: First case report.

Background: Vaccination against SARS-CoV-2 has been conducted frequently to limit the pandemic but may rarely be associated with postvaccinal autoimmune reactions or disorders. Case presentation: We present a 35-year-old woman who developed fever, skin rash, and headache 2 days after the second SARS-CoV-2 vaccination with BNT162b2 (Pfizer/Biontech). Eight days later, she developed behavioral changes and severe recurrent seizures that led to sedation and intubation. Cerebral magnetic resonance imaging showed swelling in the (para-) hippocampal region predominantly on the left hemisphere and bilateral subcortical subinsular FLAIR hyperintensities. Cerebrospinal fluid analysis revealed a lymphocytic pleocytosis of 7 cells/µl and normal protein and immunoglobulin parameters. Common causes of encephalitis or encephalopathy such as viral infections, autoimmune encephalitis with well-characterized autoantibodies, paraneoplastic diseases, and intoxications were ruled out. We made a diagnosis of new-onset refractory status epilepticus (NORSE) due to seronegative autoimmune encephalitis. The neurological deficits improved after combined antiepileptic therapy and immunomodulatory treatment including high-dose methylprednisolone and plasma exchange. Conclusions: Although a causal relationship cannot be established, the onset of symptoms shortly after receiving the SARS-CoV-2 vaccine suggests a potential association between the vaccination and NORSE due to antibody-negative autoimmune encephalitis. After ruling out other etiologies, early immunomodulatory treatment may be considered in such cases.

Postoperative progression of brain metastasis is associated with seizures.

Seizures in patients with brain metastases have an impact on morbidity and quality of life. The influence of tumor growth on the risk of seizures in these patients is not well defined. In this cohort study, we evaluated adult patients from the University Hospital of Zurich following resection of brain metastases from solid tumors, with or without preoperative seizures, at 3, 6, 9, and 12 months postoperatively. Brain magnetic resonance imaging was assessed for tumor progression using the Response Assessment in Neuro-Oncology criteria. The quarterly risk of unprovoked seizures was modeled with mixed effects logistic regression. We analyzed 444 time frames in 220 patients. Progression of brain metastases was independently associated with seizures during the respective quarterly follow-up period (odds ratio = 3.9, 95% confidence interval = 1.3-11.3, p = .014). Complete resection of brain metastases was associated with a lower risk of seizures (odds ratio = .2, 95% confidence interval = .04-.7, p = .015). Postoperative progression of brain metastases quadrupled the risk of seizures; therefore, vigorous follow-up may be useful to identify tumor progression and gauge the risk of seizures. The identification of patients at high seizure risk may have implications for treatment decisions and influence aspects of daily life. Breakthrough seizures may indicate brain metastases progression.

Volumetric analysis of the piriform cortex in temporal lobe epilepsy.

The piriform cortex, at the confluence of the temporal and frontal lobes, generates seizures in response to chemical convulsants and electrical stimulation. Resection of more than 50% of the piriform cortex in anterior temporal lobe resection for refractory temporal lobe epilepsy (TLE) was associated with a 16-fold higher chance of seizure freedom. The objectives of the current study were to implement a robust protocol to measure piriform cortex volumes and to quantify the correlation of these volumes with clinical characteristics of TLE. Sixty individuals with unilateral TLE (33 left) and 20 healthy controls had volumetric analysis of left and right piriform cortex and hippocampi. A protocol for segmenting and measuring the volumes of the piriform cortices was implemented, with good inter-rater and test-retest reliability. The right piriform cortex volume was consistently larger than the left piriform cortex in both healthy controls and patients with TLE. In controls, the mean volume of the right piriform cortex was 17.7% larger than the left, and the right piriform cortex extended a mean of 6 mm (Range: -4 to 12) more anteriorly than the left. This asymmetry was also seen in left and right TLE. In TLE patients overall, the piriform cortices were not significantly smaller than in controls. Hippocampal sclerosis was associated with decreased ipsilateral and contralateral piriform cortex volumes. The piriform cortex volumes, both ipsilateral and contralateral to the epileptic temporal lobe, were smaller with a longer duration of epilepsy. There was no significant association between piriform cortex volumes and the frequency of focal seizures with impaired awareness or the number of anti-seizure medications taken. Implementation of robust segmentation will enable consistent neurosurgical resection in anterior temporal lobe surgery for refractory TLE..

Event-based modeling in temporal lobe epilepsy demonstrates progressive atrophy from cross-sectional data.

OBJECTIVE: Recent work has shown that people with common epilepsies have characteristic patterns of cortical thinning, and that these changes may be progressive over time. Leveraging a large multicenter cross-sectional cohort, we investigated whether regional morphometric changes occur in a sequential manner, and whether these changes in people with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS) correlate with clinical features. METHODS: We extracted regional measures of cortical thickness, surface area, and subcortical brain volumes from T1-weighted (T1W) magnetic resonance imaging (MRI) scans collected by the ENIGMA-Epilepsy consortium, comprising 804 people with MTLE-HS and 1625 healthy controls from 25 centers. Features with a moderate case-control effect size (Cohen d ≥ .5) were used to train an event-based model (EBM), which estimates a sequence of disease-specific biomarker changes from cross-sectional data and assigns a biomarker-based fine-grained disease stage to individual patients. We tested for associations between EBM disease stage and duration of epilepsy, age at onset, and antiseizure medicine (ASM) resistance. RESULTS: In MTLE-HS, decrease in ipsilateral hippocampal volume along with increased asymmetry in hippocampal volume was followed by reduced thickness in neocortical regions, reduction in ipsilateral thalamus volume, and finally, increase in ipsilateral lateral ventricle volume. EBM stage was correlated with duration of illness (Spearman ρ = .293, p = 7.03 × 10-16 ), age at onset (ρ = -.18, p = 9.82 × 10-7 ), and ASM resistance (area under the curve = .59, p = .043, Mann-Whitney U test). However, associations were driven by cases assigned to EBM Stage 0, which represents MTLE-HS with mild or nondetectable abnormality on T1W MRI. SIGNIFICANCE: From cross-sectional MRI, we reconstructed a disease progression model that highlights a sequence of MRI changes that aligns with previous longitudinal studies. This model could be used to stage MTLE-HS subjects in other cohorts and help establish connections between imaging-based progression staging and clinical features.

Measurement of Midregional Pro-Atrial Natriuretic Peptide to Discover Atrial Fibrillation in Patients With Ischemic Stroke.

BACKGROUND: Midregional pro-atrial natriuretic peptide (MR-proANP) is a promising biomarker to differentiate the underlying etiology of acute ischemic stroke (AIS). OBJECTIVES: This study aimed to determine the role of MR-proANP for classification as cardioembolic (CE) stroke, identification of newly diagnosed atrial fibrillation (NDAF), and risk assessment for major adverse cardiovascular events (MACE). METHODS: This study measured MR-proANP prospectively collected within 24 hours after symptom-onset in patients with AIS from the multicenter BIOSIGNAL (Biomarker Signature of Stroke Aetiology) cohort study. Primary outcomes were CE stroke etiology and NDAF after prolonged cardiac monitoring, as well as a composite outcome of MACE (recurrent cerebrovascular events, myocardial infarction, or cardiovascular death) within 1 year. Logistic/Poisson and subproportional hazard regression were applied to evaluate the association between MR-proANP levels and outcomes. Additionally, a model for prediction of NDAF was derived and validated as a decision tool for immediate clinical application. RESULTS: Between October 1, 2014, and October 31, 2017, this study recruited 1,759 patients. Log10MR-proANP levels were associated with CE stroke (OR: 7.96; 95% CI: 4.82-13.14; risk ratio: 3.12; 95% CI: 2.23-4.37), as well as NDAF (OR: 35.3; 95% CI: 17.58-71.03; risk ratio: 11.47; 95% CI: 6.74-19.53), and MACE (subdistributional HR: 2.02; 95% CI: 1.32-3.08) during follow-up. The model to predict NDAF including only age and MR-proANP levels had a good discriminatory capacity with an area under the curve of 0.81 (95% CI: 0.76-0.86), was well calibrated (calibration in the large: -0.086; calibration slope 1.053), and yielded higher net-benefit compared with validated scores to predict NDAF (AS5F score, CHA2DS2-VASc [Congestive Heart Failure, Hypertension, Age ≥65 or ≥75, Diabetes, Prior Cardioembolic Event, (female) Sex, or Vascular Disease] score). CONCLUSIONS: MR-proANP is a valid biomarker to determine risk of NDAF and MACE in patients with AIS and can be used as a decision tool to identify patients for prolonged cardiac monitoring. (Biomarker Signature of Stroke Aetiology Study: The BIOSIGNAL study [BIOSIGNAL]; NCT02274727).