Confounders for prognostic accuracy of neuron-specific enolase after cardiac arrest: A retrospective cohort study.

AIM: To evaluate neuron-specific enolase (NSE) thresholds for prediction of neurological outcome after cardiac arrest and to analyze the influence of hemolysis and confounders. METHODS: Retrospective analysis from a cardiac arrest registry. Determination of NSE serum concentration and hemolysis-index (h-index) 48-96 hours after cardiac arrest. Evaluation of neurological outcome using the Cerebral Performance Category score (CPC) at hospital discharge. Separate analyses considering CPC 1-3 and CPC 1-2 as good neurological outcome. Analysis of specificity and sensitivity for poor and good neurological outcome prediction with and without exclusion of hemolytic samples (h-index larger than 50). RESULTS: Among 356 survivors three days after cardiac arrest, hemolysis was detected in 28 samples (7.9%). At a threshold of 60 µg/L, NSE predicted poor neurological outcome (CPC 4-5) in all samples with a specificity of 92% (86-95%) and sensitivity of 73% (66-79%). In non-hemolytic samples, specificity was 94% (89-97%) and sensitivity 70% (62-76%). At a threshold of 100 µg/L, specificity was 98% (95-100%, all samples) and 99% (95-100%, non-hemolytic samples), and sensitivity 58% (51-65%) and 55% (47-63%), respectively. Possible confounders for elevated NSE in patients with good neurological outcome were ECMO, malignancies, blood transfusions and acute brain diseases. Nine patients with NSE below 17 µg/L had CPC 5, all had plausible death causes other than hypoxic-ischemic encephalopathy. CONCLUSIONS: NSE concentrations higher than 100 µg/L predicted poor neurological outcome with high specificity. An NSE less than 17 µg/L indicated absence of severe hypoxic-ischemic encephalopathy. Hemolysis and other confounders need to be considered. INSTITUTIONAL PROTOCOL NUMBER: The local ethics committee (board name: Ethikkommission der Charité) approved this study by the number: EA2/066/23, approval date: 28th June 2023, study title "'ROSC' - Resuscitation Outcome Study."

Cortical somatosensory evoked potential amplitudes and clinical outcome after cardiac arrest: a retrospective multicenter study.

OBJECTIVE: Bilaterally absent cortical somatosensory evoked potentials (SSEPs) reliably predict poor outcome in comatose cardiac arrest (CA) patients. Cortical SSEP amplitudes are a recent prognostic extension; however, amplitude thresholds, inter-recording, and inter-rater agreement remain uncertain. METHODS: In a retrospective multicenter cohort study, we determined cortical SSEP amplitudes of comatose CA patients using a standardized evaluation pathway. We studied inter-recording agreement in repeated SSEPs and inter-rater agreement by four raters independently determining 100 cortical SSEP amplitudes. Primary outcome was assessed using the cerebral performance category (CPC) upon intensive care unit discharge dichotomized into good (CPC 1-3) and poor outcome (CPC 4-5). RESULTS: Of 706 patients with SSEPs with median 3 days after CA, 277 (39.2%) had good and 429 (60.8%) poor outcome. Of patients with bilaterally absent cortical SSEPs, one (0.8%) survived with CPC 3 and 130 (99.2%) had poor outcome. Otherwise, the lowest cortical SSEP amplitude in good outcome patients was 0.5 µV. 184 (42.9%) of 429 poor outcome patients had lower cortical SSEP amplitudes. In 106 repeated SSEPs, there were 6 (5.7%) with prognostication-relevant changes in SSEP categories. Following a standardized evaluation pathway, inter-rater agreement was almost perfect with a Fleiss' kappa of 0.88. INTERPRETATION: Bilaterally absent and cortical SSEP amplitudes below 0.5 µV predicted poor outcome with high specificity. A standardized evaluation pathway provided high inter-rater and inter-recording agreement. Regain of consciousness in patients with bilaterally absent cortical SSEPs rarely occurs. High-amplitude cortical SSEP amplitudes likely indicate the absence of severe brain injury.

Hypoxic-Ischemic Encephalopathy Evaluated by Brain Autopsy and Neuroprognostication After Cardiac Arrest.

Importance: Neuroprognostication studies are potentially susceptible to a self-fulfilling prophecy as investigated prognostic parameters may affect withdrawal of life-sustaining therapy. Objective: To compare the results of prognostic parameters after cardiac arrest (CA) with the histopathologically determined severity of hypoxic-ischemic encephalopathy (HIE) obtained from autopsy results. Design, Setting, and Participants: In a retrospective, 3-center cohort study of all patients who died following cardiac arrest during their intensive care unit stay and underwent autopsy between 2003 and 2015, postmortem brain histopathologic findings were compared with post-CA brain computed tomographic imaging, electroencephalographic (EEG) findings, somatosensory-evoked potentials, and serum neuron-specific enolase levels obtained during the intensive care unit stay. Data analysis was conducted from 2015 to 2020. Main Outcomes and Measures: The severity of HIE was evaluated according to the selective eosinophilic neuronal death (SEND) classification and patients were dichotomized into categories of histopathologically severe and no/mild HIE. Results: Of 187 included patients, 117 were men (63%) and median age was 65 (interquartile range, 58-74) years. Severe HIE was found in 114 patients (61%) and no/mild HIE was identified in 73 patients (39%). Severe HIE was found in all 21 patients with bilaterally absent somatosensory-evoked potentials, all 15 patients with gray-white matter ratio less than 1.10 on brain computed tomographic imaging, all 9 patients with suppressed EEG, 15 of 16 patients with burst-suppression EEG, and all 29 patients with neuron-specific enolase levels greater than 67 µg/L more than 48 hours after CA without confounders. Three of 7 patients with generalized periodic discharges on suppressed background and 1 patient with burst-suppression EEG had a SEND 1 score (<30% dead neurons) in the cerebral cortex, but higher SEND scores (>30% dead neurons) in other oxygen-sensitive brain regions. Conclusions and Relevance: In this study, histopathologic findings suggested severe HIE after cardiac arrest in patients with bilaterally absent cortical somatosensory-evoked potentials, gray-white matter ratio less than 1.10, highly malignant EEG, and serum neuron-specific enolase concentration greater than 67 µg/L.

Timing of brain computed tomography and accuracy of outcome prediction after cardiac arrest.

AIM: Gray-white-matter ratio (GWR) calculated from head CT is a radiologic index of tissue changes associated with hypoxic-ischemic encephalopathy after cardiac arrest (CA). Evidence from previous studies indicates high specificity for poor outcome prediction at GWR thresholds of 1.10-1.20. We aimed to determine the relationship between accuracy of neurologic prognostication by GWR and timing of CT. METHODS: We included 195 patients admitted to the ICU following CA. GWR was calculated from CT radiologic densities in 16 regions of interest. Outcome was determined upon intensive care unit discharge using the cerebral performance category (CPC). Accuracy of outcome prediction of GWR was compared for 3 epochs (<6, 6-24, and >24 h after CA). RESULTS: 125 (64%) patients had poor (CPC4-5) and 70 (36%) good outcome (CPC1-3). Irrespective of timing, specificity for poor outcome prediction was 100% at a GWR threshold of 1.10. Among 50 patients with both early and late CT, GWR decreased significantly over time (p = 0.002) in patients with poor outcome, sensitivity for poor outcome prediction was 12% (7-20%) with early CTs (<6 h) and 48% (38-58%) for late CTs (>24 h). Across all patients, sensitivity of early and late CT was 17% (9-28%) and 39% (28-51%), respectively. CONCLUSION: A GWR below 1.10 predicts poor outcome (CPC4-5) in patients after CA with high specificity irrespective of time of acquisition of CT. Because GWR decreases over time in patients with severe HIE, sensitivity for prediction of poor outcome is higher for late CTs (>24 h after CA) as compared to early CTs (<6 h after CA).

Unresponsive wakefulness or coma after cardiac arrest-A long-term follow-up study.

OBJECTIVE: To investigate the clinical course and early prognostic markers in cardiac arrest (CA) patients discharged from the intensive care unit (ICU) in an unresponsive wakefulness syndrome (UWS) or coma. METHODS: 89 patients were identified from a prospective CA database. Follow-up was conducted by telephone interviews with legal guardians, evaluation of re-admission and rehabilitation reports assessing core elements of the coma recovery scale-revised (CRS-R). Somatosensory evoked potential (SSEP) and electroencephalography (EEG) original recordings were re-analyzed, the gray-white-matter ratio (GWR) was determined from brain computed tomography (CT) and neuron-specific enolase (NSE) serum concentrations were retrieved. RESULTS: Follow-up was successful for 32/50 (64%) patients admitted between 2001-2009 and 31/39 (79%) between 2009-2015. Median ICU stay was 27 days (IQR 20-36). Neurological improvement beyond UWS was found in 2 of 63 patients. Among 61 patients with successful follow-up and no improvement, NSE serum concentrations within the reference range, SSEP amplitudes above 2.5 µV or continuous reactive EEG were found in 5%, 3% and 2% of those tested. NSE > 90 µg/L, SSEP ≤ 0.3 µV, highly malignant EEG or GWR < 1.10 were found in 44%, 49%, 35% and 22% of those tested. CONCLUSIONS: Neurological recovery was rare in CA patients discharged in UWS after prolonged ICU treatment. Status epilepticus requiring prolonged deep sedation is one potential reason for delayed awakening. Sensitivity for established poor outcome parameters to predict persistent UWS early after CA was moderate. SSEP, EEG and NSE may indicate absence of severe HIE early after CA.

View-Independent Working Memory Representations of Artificial Shapes in Prefrontal and Posterior Regions of the Human Brain.

Traditional views of visual working memory postulate that memorized contents are stored in dorsolateral prefrontal cortex using an adaptive and flexible code. In contrast, recent studies proposed that contents are maintained by posterior brain areas using codes akin to perceptual representations. An important question is whether this reflects a difference in the level of abstraction between posterior and prefrontal representations. Here, we investigated whether neural representations of visual working memory contents are view-independent, as indicated by rotation-invariance. Using functional magnetic resonance imaging and multivariate pattern analyses, we show that when subjects memorize complex shapes, both posterior and frontal brain regions maintain the memorized contents using a rotation-invariant code. Importantly, we found the representations in frontal cortex to be localized to the frontal eye fields rather than dorsolateral prefrontal cortices. Thus, our results give evidence for the view-independent storage of complex shapes in distributed representations across posterior and frontal brain regions.

Cortical somatosensory evoked high-frequency (600Hz) oscillations predict absence of severe hypoxic encephalopathy after resuscitation.

OBJECTIVE: Following cardiac arrest (CA), hypoxic encephalopathy (HE) frequently occurs and hence reliable neuroprognostication is crucial to decide on the extent of intensive care. Several investigations predict severe HE leading to persistent unresponsive wakefulness or death, with high specificity. Only few studies attempted to predict absence of severe HE. Cortical somatosensory evoked high-frequency (600Hz) oscillation (HFO) bursts indicate the presence of highly synchronized spiking activity in the primary somatosensory cortex. Since global neuronal damage characterizes severe HE preserved cortical HFOs may early exclude severe HE. METHODS: We determined amplitudes of early and late HFO bursts in 302 comatose CA patients after median nerve somatosensory evoked potential (SSEPs) and clinical outcome upon intensive care unit discharge using the cerebral performance category (CPC) scale. RESULTS: We detected significant early HFO bursts in 146 patients and late HFO bursts in 95 patients. Only one of 27 unresponsive wakefulness patients had a late HFO burst amplitude above 70nV and all seventeen patients who died despite higher amplitudes died from non-neurological causes. CONCLUSIONS: High-frequency SSEP components can reliably be studied in comatose CA patients using standard equipment. SIGNIFICANCE: Late HFO burst amplitudes above 70nV largely exclude severe HE incompatible with regaining consciousness.

Amplitudes of SSEP and outcome in cardiac arrest survivors: A prospective cohort study.

OBJECTIVE: To investigate the relationship between somatosensory evoked potential (SSEP) amplitudes and neurologic outcome after cardiac arrest. METHODS: We prospectively studied SSEPs, recorded 24 hours to 4 days after cardiac arrest, in patients with targeted temperature management. SSEP amplitude was defined pragmatically as the highest short-latency amplitude of 4 cortical recordings (2 per side, CP3/CP4 vs Fz) at least 4.5 ms after the spinal SSEP. Cerebral performance category (CPC) was determined upon intensive care unit discharge. CPC 1-3 was defined as good, CPC 4-5 as poor outcome. RESULTS: Of 318 patients, 25 had incomplete recordings, no reproducible spinal SSEP, or high noise level. Of the remaining 293 patients, 137 (47%) had poor and 156 (53%) good outcome. The lowest amplitude in a survivor with good outcome was 0.62 µV. All 78 patients with lower amplitudes had poor outcome. None of 27 patients with CPC 4 (unresponsive wakefulness) had amplitudes above 2.5 µV. In the majority of 24 patients who died despite amplitudes above 2.5 µV, clinical course and other prognostic parameters argued against severe hypoxic encephalopathy. CONCLUSIONS: The prognostic value of SSEPs extends beyond an absent/present dichotomy. Absent and very low amplitude SSEPs appear to be highly predictive of poor outcome after cardiac arrest. Prospective external validation of the lower threshold found in our study is necessary. SSEP recordings should not be used for prognostication if noise could mask potentials with critically low amplitudes. High SSEP amplitudes argue against severe hypoxic encephalopathy.

Comments on "Backpropagation algorithms for a broad class of dynamic networks".

In a recent paper, De Jesús proposed a general framework for describing dynamic neural networks. Gradient and Jacobian calculations were discussed based on backpropagation-through-time (BPTT) algorithm and real-time recurrent learning (RTRL). Some errors in the paper of De Jesús bring difficulties for other researchers who want to implement the algorithms. This comments paper shows the critical parts of the publication and gives errata to facilitate understanding and implementation.