Serum neurofilament measurement improves clinical risk scores for outcome prediction after cardiac arrest: results of a prospective study

Abstract Background A recent study found serum neurofilament light chain (NfL) levels to be strongly associated with poor neurological outcome in patients after cardiac arrest. Our aim was to confirm these findings in an independent validation study and to investigate whether NfL improves the prognostic value of two cardiac arrest-specific risk scores. Methods This prospective, single-center study included 164 consecutive adult after out-of-hospital cardiac arrest (OHCA) patients upon intensive care unit admission. We calculated two clinical risk scores (OHCA, CAHP) and measured NfL on admission within the first 24 h using the single molecule array NF-light® assay. The primary endpoint was neurological outcome at hospital discharge assessed with the cerebral performance category (CPC) score. Results Poor neurological outcome (CPC > 3) was found in 60% (98/164) of patients, with 55% (91/164) dying within 30 days of hospitalization. Compared to patients with favorable outcome, NfL was 14-times higher in patients with poor neurological outcome (685 ± 1787 vs. 49 ± 111 pg/mL), with an adjusted odds ratio of 3.4 (95% CI 2.1 to 5.6, p < 0.001) and an area under the curve (AUC) of 0.82. Adding NfL to the clinical risk scores significantly improved discrimination of both the OHCA score (from AUC 0.82 to 0.89, p < 0.001) and CAHP score (from AUC 0.89 to 0.92, p < 0.05). Adding NfL to both scores also resulted in significant improvement in reclassification statistics with a Net Reclassification Index (NRI) of 0.58 (p < 0.001) for OHCA and 0.83 (p < 0.001) for CAHP. Conclusions Admission NfL was a strong outcome predictor and significantly improved two clinical risk scores regarding prognostication of neurological outcome in patients after cardiac arrest. When confirmed in future outcome studies, admission NfL should be considered as a standard laboratory measures in the evaluation of OHCA patients.

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Serum Neurofilament Measurement Improves Clinical Risk Score for Outcome Prediction After Cardiac Arrest: Results of A Prospective Study

10.21203/rs.3.rs-92711/v1 ◽

2020 ◽

Author(s):

Sabina Hunziker ◽

Adrian Quinto ◽

Maja Ramin-Wright ◽

Christoph Becker ◽

Katharina Beck ◽

...

Keyword(s):

Cardiac Arrest ◽

Single Molecule ◽

Neurological Outcome ◽

Outcome Prediction ◽

Cerebral Performance Category ◽

Neuron Specific Enolase ◽

Risk Scores ◽

Neurofilament Light Chain ◽

Clinical Risk ◽

Poor Neurological Outcome

Abstract Background: A recent study found serum neurofilament light chain (NfL) levels to be strongly associated with poor neurological outcome in patients after cardiac arrest. Our aim was to confirm these findings in an independent validation study and to investigate whether NfL improves the prognostic value of two cardiac arrest risk scores.Methods: This prospective, single-center study included 164 consecutive adult cardiac arrest patients upon intensive care unit admission. We calculated two clinical risk scores (OHCA, CAHP) and measured NfL on admission using the single molecule array NF-light® assay. The primary endpoint was neurological outcome at hospital discharge assessed with the cerebral performance category (CPC) score.Results: Poor neurological outcome (CPC≥3) was found in 60% (98/164) of patients, and 55% (91/164) died. Compared to patients with favorable outcome, NfL was 14-times higher in patients with poor neurological outcome (685±1787 vs. 49±111pg/mL), with an adjusted odds ratio of 3.4 (95%CI 2.1 to 5.6, p<0.001) and an area under the curve (AUC) of 0.82. Adding NfL to the clinical risk scores significantly improved discrimination of both the OHCA score (from AUC 0.82 to 0.89, p<0.001) and CAHP score (from AUC 0.89 to 0.92, p<0.05). Admission NfL showed better outcome prediction compared to neuron-specific enolase (NSE) (AUC 0.84 vs.0.69, p=0.01).Conclusions: This study confirms the high performance of admission NfL alone and in combination with two clinical risk scores to prognosticate clinical outcome in patients after cardiac arrest. NfL should be considered as a standard laboratory measures in the evaluation of cardiac arrest patients.

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Proteomics-based Multimarker Model Improves Neurofilament Light Chain for Predicting Neurological Outcome after Cardiac Arrest

10.21203/rs.3.rs-108273/v1 ◽

2020 ◽

Author(s):

Raphael Wurm ◽

Henrike Arfsten ◽

Besnik Muqaku ◽

Markus Ponleitner ◽

Andrea Bileck ◽

...

Keyword(s):

Cardiac Arrest ◽

Single Molecule ◽

Light Chain ◽

Neurological Outcome ◽

Cerebral Performance Category ◽

Predictive Ability ◽

Small Sample ◽

Clinical Markers ◽

Neurofilament Light Chain ◽

Neurofilament Light

Abstract Background: Out of hospital cardiac arrest (OHCA) is a life-threatening event. Continuous advances in management increased initial survival, but the rate of favorable neurological outcome remains low. We have previously shown the usefulness of proteomics to identify novel biomarkers to predict this outcome. Neurofilament light chain (NfL), a marker of axonal damage, has since emerged as a promising single marker. The aim of this study was thus to assess the predictive value of NfL and compare it to our established model.Methods: NfL was measured in plasma samples from OHCA drawn at 48 hours after the event using single molecule assays. Neurological function at discharge from ICU was recorded on the cerebral performance category (CPC) scale. Predictive ability was assessed for NfL and compared to an established multimarker model.Results: Seventy patients were included into this analysis, of whom 21 (30%) showed a favorable outcome (CPC 1-2) compared to 49 (70%) with an unfavorable outcome (CPC 3 - 5). NfL increased from CPC 1 to 5 (16.5 pg/ml to 641 pg/ml, p<0.001). NfL alone performed moderately well with an area under the ROC (AUROC) of 79.4%. Prediction was significantly improved by combination of NfL with the established best performing model (F = 6.83, p = 0.01) with an AUROC to 89.7% (p for comparison = 0.017).Conclusion:The combination of NfL with other plasma and clinical markers is superior to that of either model alone and achieves a very good AUROC in this relatively small sample. Trial registration: ClinicalTrials.gov NCT01960699. Registered 08 October 2013.

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Performance of clinical risk scores to predict mortality and neurological outcome in cardiac arrest patients

Resuscitation ◽

10.1016/j.resuscitation.2018.10.022 ◽

2019 ◽

Vol 136 ◽

pp. 21-29 ◽

Cited By ~ 13

Author(s):

Cyril Isenschmid ◽

Tanja Luescher ◽

Roshaani Rasiah ◽

Jeanice Kalt ◽

Theresa Tondorf ◽

...

Keyword(s):

Cardiac Arrest ◽

Neurological Outcome ◽

Risk Scores ◽

Clinical Risk

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A Practical Risk-Score for Early Prediction of Neurological Outcome after Out-of-Hospital Cardiac Arrest –MIRA2CLE2

10.1101/2020.04.12.20045146 ◽

2020 ◽

Author(s):

Nilesh Pareek ◽

Peter Kordis ◽

Nicholas Beckley-Hoelscher ◽

Dominic Pimenta ◽

Spela Tadel Kocjancic ◽

...

Keyword(s):

Cardiac Arrest ◽

Risk Score ◽

Neurological Outcome ◽

Heart Attack ◽

Primary Outcome ◽

Cerebral Performance Category ◽

Epinephrine Administration ◽

Poor Outcome ◽

Poor Neurological Outcome ◽

Hospital Cardiac Arrest

AimsThe purpose of this study was to develop a practical risk−score to predict poor neurological outcome after out−of−hospital cardiac arrest (OOHCA) for use on arrival to a Heart Attack Centre.Methods and ResultsBetween May 2012 and December 2017, 1055 patients had OOHCA in our region, of whom 373 patients were included in the King's Out of Hospital Cardiac Arrest Registry (KOCAR). We performed prediction modelling with multi-variable logistic regression to identify factors independently predictive of the primary outcome in order to derive a risk score. This was externally validated in two independent cohorts comprising 474 patients. The primary outcome was poor neurological function at 6−month follow−up (Cerebral Performance Category 3-−). Seven independent variables for prediction of outcome were identified: Missed (Unwitnessed) arrest, Initial non-shockable rhythm, non-Reactivity of pupils, Age, Changing intra-arrest rhythms, Low pH<;7.20 and Epinephrine administration. From these variables, the MIRA2CLE2 score was developed which had an AUC of 0.90 in the development and 0.85 and 0.89 in the validation cohorts. 3 risk groups of the MIRA2CLE2 were defined − Low risk (≤2−5.6% risk of poor outcome; Intermediate risk (3−4−55.4% of poor outcome) and high risk (≥5−92.3% risk of poor outcome). The risk-score performance was equivalent in a sub-group of patients referred for early angiography and revascularisation where appropriate.ConclusionsThe MIRA2CLE2 score is a practical risk score for early accurate prediction of poor neurological outcome after OOHCA, which has been developed for simplicity of use on admission to a Heart Attack Centre.

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Blood-based NfL

Neurology ◽

10.1212/wnl.0000000000003680 ◽

2017 ◽

Vol 88 (10) ◽

pp. 930-937 ◽

Cited By ~ 156

Author(s):

Oskar Hansson ◽

Shorena Janelidze ◽

Sara Hall ◽

Nadia Magdalinou ◽

Andrew J. Lees ◽

...

Keyword(s):

Diagnostic Accuracy ◽

Single Molecule ◽

Area Under The Curve ◽

Diagnostic Workup ◽

Healthy Controls ◽

Class Iii ◽

Early Disease ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Parkinsonian Disorders

Objective:To determine if blood neurofilament light chain (NfL) protein can discriminate between Parkinson disease (PD) and atypical parkinsonian disorders (APD) with equally high diagnostic accuracy as CSF NfL, and can therefore improve the diagnostic workup of parkinsonian disorders.Methods:The study included 3 independent prospective cohorts: the Lund (n = 278) and London (n = 117) cohorts, comprising healthy controls and patients with PD, progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), as well as an early disease cohort (n = 109) of patients with PD, PSP, MSA, or CBS with disease duration ≤3 years. Blood NfL concentration was measured using an ultrasensitive single molecule array (Simoa) method, and the diagnostic accuracy to distinguish PD from APD was investigated.Results:We found strong correlations between blood and CSF concentrations of NfL (ρ ≥ 0.73–0.84, p ≤ 0.001). Blood NfL was increased in patients with MSA, PSP, and CBS (i.e., all APD groups) when compared to patients with PD as well as healthy controls in all cohorts (p < 0.001). Furthermore, in the Lund cohort, blood NfL could accurately distinguish PD from APD (area under the curve [AUC] 0.91) with similar results in both the London cohort (AUC 0.85) and the early disease cohort (AUC 0.81).Conclusions:Quantification of blood NfL concentration can be used to distinguish PD from APD. Blood-based NfL might consequently be included in the diagnostic workup of patients with parkinsonian symptoms in both primary care and specialized clinics.Classification of evidence:This study provides Class III evidence that blood NfL levels discriminate between PD and APD.

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Assessment of Procalcitonin to Predict Outcome in Hypothermia-Treated Patients after Cardiac Arrest

Critical Care Research and Practice ◽

10.1155/2011/631062 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 6

Author(s):

Pascal Stammet ◽

Yvan Devaux ◽

Francisco Azuaje ◽

Christophe Werer ◽

Christiane Lorang ◽

...

Keyword(s):

Cardiac Arrest ◽

Neurological Outcome ◽

Outcome Prediction ◽

Cerebral Performance Category ◽

Area Under The Curve ◽

Simplified Acute Physiology Score ◽

Induced Hypothermia ◽

Neurological Sequelae ◽

Performance Category ◽

Good Outcome

Objective. Determine the potential of procalcitonin (PCT) to predict neurological outcome after hypothermia treatment following cardiac arrest.Methods. Retrospective analysis of patient data over a 2-year period. Mortality and neurological outcome of survivors were determined 6 months after cardiac arrest using the Cerebral Performance Category (CPC) score.Results. Data from 53 consecutive patients were analyzed. Median age was 63 (54–71) and 79% were male. Twenty-seven patients had good outcome (CPC ≤ 2) whereas 26 had severe neurological sequelae or died (CPC 3–5). At 48 h, after regaining normothermia, PCT was significantly higher in patients with bad outcome compared to those with good outcome: 3.38 (1.10–24.48) versus 0.28 (0–0.75) ng/mL (). PCT values correlated with bad neurological outcome (, ) and predicted outcome with an area under the curve of 0.84 (95% CI 0.73–0.96). A cutoff point of 1 ng/mL provided a sensitivity of 85% and a specificity of 81%. Above a PCT level of 16 ng/mL, no patient regained consciousness. PCT provided an additive value over simplified acute physiology score II.Conclusions. PCT might be an ancillary marker for outcome prediction after cardiac arrest treated by induced hypothermia.

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Circulating Levels of miR-574-5p Are Associated with Neurological Outcome after Cardiac Arrest in Women: A Target Temperature Management (TTM) Trial Substudy

Disease Markers ◽

10.1155/2019/1802879 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Adeline Boileau ◽

Antonio Salgado Somoza ◽

Josef Dankiewicz ◽

Pascal Stammet ◽

Patrik Gilje ◽

...

Keyword(s):

Cardiac Arrest ◽

Neurological Outcome ◽

Cerebral Performance Category ◽

Temperature Management ◽

Target Temperature Management ◽

Target Temperature ◽

Circulating Micrornas ◽

Performance Category ◽

Poor Neurological Outcome ◽

Circulating Levels

Purpose. Postresuscitation neuroprognostication is guided by neurophysiological tests, biomarker measurement, and clinical examination. Recent investigations suggest that circulating microRNAs (miRNA) may help in outcome prediction after cardiac arrest. We assessed the ability of miR-574-5p to predict neurological outcome after cardiac arrest, in a sex-specific manner. Methods. In this substudy of the Target Temperature Management (TTM) Trial, we enrolled 590 cardiac arrest patients for which blood samples were available. Expression levels of miR-574-5p were measured by quantitative PCR in plasma samples collected 48 h after cardiac arrest. The endpoint of the study was poor neurological outcome at 6 months (cerebral performance category scores 3 to 5). Results. Eighty-one percent of patients were men, and 49% had a poor neurological outcome. Circulating levels of miR-574-5p at 48 h were higher in patients with a poor neurological outcome at 6 months (p<0.001), both in women and in men. Circulating levels of miR-574-5p were univariate predictors of neurological outcome (odds ratio (OR) [95% confidence interval (CI)]: 1.5 [1.26-1.78]). After adjustment with clinical variables and NSE, circulating levels of miR-574-5p predicted neurological outcome in women (OR [95% CI]: 1.9 [1.09-3.45]), but not in men (OR [95% CI]: 1.0 [0.74-1.28]). Conclusion. miR-574-5p is associated with neurological outcome after cardiac arrest in women.

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Neuromarkers and neurological outcome in out-of-hospital cardiac arrest patients treated with therapeutic hypothermia–experience from the HAnnover COoling REgistry (HACORE)

PLoS ONE ◽

10.1371/journal.pone.0245210 ◽

2021 ◽

Vol 16 (1) ◽

pp. e0245210

Author(s):

Muharrem Akin ◽

Vera Garcheva ◽

Jan-Thorben Sieweke ◽

John Adel ◽

Ulrike Flierl ◽

...

Keyword(s):

Cardiac Arrest ◽

Therapeutic Hypothermia ◽

Neurological Outcome ◽

Clinical Decision Making ◽

Cerebral Performance Category ◽

Neuron Specific Enolase ◽

Clinical Decision ◽

St Segment Elevation ◽

Poor Neurological Outcome ◽

Hospital Cardiac Arrest

Background Neuron-specific enolase (NSE) and S-100b have been used to assess neurological damage following out-of-hospital cardiac arrest (OHCA). Cut-offs were derived from small normothermic cohorts. Whether similar cut-offs apply to patients treated with hypothermia remained undetermined. Methods We investigated 251 patients with OHCA treated with hypothermia but without routine prognostication. Neuromarkers were determined at day 3, neurological outcome was assessed after hospital discharge by cerebral performance category (CPC). Results Good neurological outcome (CPC≤2) was achieved in 41%. Elevated neuromarkers, older age and absence of ST-segment elevation after ROSC were associated with increased mortality. Poor neurological outcome in survivors was additionally associated with history of cerebrovascular events, sepsis and higher admission lactate. Mean NSE was 33μg/l [16–94] vs. 119μg/l [25–406]; p<0.001, for survivors vs. non-survivors, and 21μg/l [16–29] vs. 40μg/l [23–98], p<0.001 for good vs. poor neurological outcome. S-100b was 0.127μg/l [0.063–0.360] vs. 0.772μg/l [0.121–2.710], p<0.001 and 0.086μg/l [0.061–0.122] vs. 0.138μg/l [0.090–0.271], p = 0.009, respectively. For mortality, thresholds of 36μg/l for NSE and 0.128μg/l for S-100b could be determined; for poor neurological outcome 33μg/l (NSE) and 0.123μg/l (S-100b), respectively. Positive predictive value for NSE was 81% (74–88) and 79% (71–85) for S-100b. Conclusions Thresholds for NSE and S-100b predicting mortality and poor neurological outcome are similar in OHCA patients receiving therapeutic hypothermia as in those reported before the era of hypothermia. However, both biomarkers do not have enough specificity to predict mortality or poor neurological outcome on their own and should only be additively used in clinical decision making.

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Promising Diagnostic Accuracy of Plasma GFAP and NfL Within The AD Continuum

10.21203/rs.3.rs-634853/v1 ◽

2021 ◽

Author(s):

Tandis Parvizi ◽

Theresa Koenig ◽

Raphael Wurm ◽

Sara Silvaieh ◽

Patrick Altmann ◽

...

Keyword(s):

Risk Factors ◽

Single Molecule ◽

Plasma Concentrations ◽

Area Under The Curve ◽

Roc Curves ◽

Subjective Cognitive Decline ◽

Amyloid Pet ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Visual Rating

Abstract Background: Blood-based biomarkers may add a great benefit in detecting the earliest neuropathological changes in patients with Alzheimer’s disease (AD). We examined the utility of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in plasma and cerebrospinal fluid (CSF) regarding clinical diagnosis and amyloid positivity in an outpatient memory clinic - based cohort. Methods: In this retrospective analysis, we included a total of 185 patients, 141 patients along clinical the AD continuum, i.e. subjective cognitive decline (SCD, n=18), mild cognitive impairment (MCI, n=63), AD (n=60) and 44 age-matched healthy controls (HC). CSF and plasma concentrations of NfL and GFAP were measured with single molecule array (SIMOAâ) technology using the Neurology 2-Plex B kit from Quanterix. Amyloid-PET was performed in 75 patients and graded as amyloid positive and negative by visual rating. To assess the discriminatory potential of different biomarkers, age- and sex-adjusted receiver operating characteristic (ROC) curves were calculated and the area under the curve (AUC) of each model was compared using DeLong’s test for correlated AUC curves.Results: We constructed a panel combining plasma NfL and GFAP with known AD risk factors (age+sex+APOE4+GFAP+NfL panel). Using this panel, AUC was 91.6% for HC vs. AD, 81.7% for HC vs. MCI, 85% for SCD vs. AD, 81.3% for SCD vs. MCI, 77.7% for HC vs. SCD and 72.3% for MCI vs. AD. In terms of predicting amyloid PET status, we computed an AUC of 88.4%. Conclusion: The combination of plasma GFAP and NfL with well-established risk factors could contribute crucially to the identification of patients at risk, and thereby facilitate inclusion of patients in clinical trials for disease modifying therapies.

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Post-resuscitation partial pressure of arterial carbon dioxide and outcome in patients with out-of-hospital cardiac arrest: a multicenter retrospective cohort study

10.21203/rs.3.rs-882819/v1 ◽

2021 ◽

Author(s):

Nobunaga Okada ◽

Tasuku Matsuyama ◽

Yohei Okada ◽

Asami Okada ◽

Kenji Kandori ◽

...

Keyword(s):

Cardiac Arrest ◽

Neurological Outcome ◽

Cerebral Performance Category ◽

Multivariate Logistic Regression Analysis ◽

Spontaneous Circulation ◽

Performance Category ◽

Neurological Outcomes ◽

Significant Difference ◽

Poor Neurological Outcome ◽

Hospital Cardiac Arrest

Abstract We aimed to estimate the association between PaCO2 level in the patient after out-of-hospital cardiac arrest (OHCA) resuscitation with patient outcome based on a multicenter prospective cohort registry in Japan between June 2014 and December 2015.Based on the PaCO2 within 24-h after return of spontaneous circulation (ROSC), patients were divided into six groups as follow; severe hypocapnia (<25mmHg), mild hypocapnia (25–35mmHg,), normocapnia (35–45mmHg), mild hypercapnia (45–55mmHg), severe hypercapnia (>55mmHg), exposure to both hypocapnia and hypercapnia. Multivariate logistic regression analysis was conducted to calculate the adjusted odds ratios (aORs) and 95% confidence interval (CI) for the 1-month poor neurological outcome (Cerebral Performance Category ≥3). Among the 13491 OHCA patients, 607 were included. Severe hypocapnia, mild hypocapnia, severe hypercapnia, and exposure to both hypocapnia and hypercapnia were associated with a higher rate of 1-month poor neurological outcome compared with mild hypercapnia (aOR 6.68 [95% CI 2.16–20.67], 2.56 [1.30–5.04], 2.62 [1.06–6.47], 5.63 [2.21–14.34]; respectively). There was no significant difference between the outcome of patients with normocapnia and mild hypercapnia. In conclusion, maintaining normocapnia and mild hypercapnia during the 24-h after ROSC was associated with better neurological outcomes than other PaCO2 abnormalities in this study.

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