Prediction of cognitive outcome based on the progression of auditory discrimination during coma.

To date, no clinical test is able to predict cognitive and functional outcome of cardiac arrest survivors. Improvement of auditory discrimination in acute coma indicates survival with high specificity. Whether the degree of this improvement is indicative of recovery remains unknown. Here we investigated if progression of auditory discrimination can predict cognitive and functional outcome. We prospectively recorded electroencephalography responses to auditory stimuli of post-anoxic comatose patients on the first and second day after admission. For each recording, auditory discrimination was quantified and its evolution over the two recordings was used to classify survivors as "predicted" when it increased vs. "other" if not. Cognitive functions were tested on awakening and functional outcome was assessed at 3 months using the Cerebral Performance Categories (CPC) scale. Thirty-two patients were included, 14 "predicted survivors" and 18 "other survivors". "Predicted survivors" were more likely to recover basic cognitive functions shortly after awakening (ability to follow a standardized neuropsychological battery: 86% vs. 44%; p=0.03 (Fisher)) and to show a very good functional outcome at 3 months (CPC 1: 86% vs. 33%; p=0.004 (Fisher)). Moreover, progression of auditory discrimination during coma was strongly correlated with cognitive performance on awakening (phonemic verbal fluency: rs=0.48; p=0.009 (Spearman)). Progression of auditory discrimination during coma provides early indication of future recovery of cognitive functions. The degree of improvement is informative of the degree of functional impairment. If confirmed in a larger cohort, this test would be the first to predict detailed outcome at the single-patient level

Prediction of awakening from hypothermic post anoxic coma based on auditory discrimination.

OBJECTIVE: Most of the available clinical tests for prognosis of post-anoxic coma are informative of poor outcome. Previous work has shown that an improvement in auditory discrimination over the first days of coma is predictive of awakening. Here, we aimed at evaluating this test on a large cohort of patients undergoing therapeutic hypothermia and at investigating its added value on existing clinical measures. METHODS: We recorded electroencephalography responses to auditory stimuli in 94 comatose patients, under hypothermia and after re-warming to normal temperature. Auditory discrimination was semi-automatically quantified by decoding electroencephalography responses to frequently repeated vs. rare sounds. Outcome prediction was based on the change of decoding performance from hypothermia to normothermia. RESULTS: An increase in auditory discrimination from hypothermia to normothermia was observed for 33 out of 94 patients. Among them, 27 awoke from coma, resulting in a positive predictive value of awakening of 82% (95% confidence interval: 0.65-0.93). Most non-survivors showing an improvement in auditory discrimination had incident status epilepticus. By excluding them, 27 out of 29 patients with improvement in auditory discrimination survived, resulting in a considerable improvement of the predictive value for awakening (93%, with 95% confidence interval: 0.77-0.99). Importantly, this test predicted the awakening of 13 out of 51 patients for which the outcome was uncertain based on current tests. INTERPRETATION: The progression of auditory discrimination from hypothermia to normothermia has a high predictive value for awakening. This quantitative measure provides an added value to existing clinical tests and encourages the maintenance of life support. This article is protected by copyright. All rights reserved

Evidence of trace conditioning in comatose patients revealed by the reactivation of EEG responses to alerting sounds.

Trace conditioning refers to a learning process occurring after repeated presentation of a neutral conditioned stimulus (CS+) and a salient unconditioned stimulus (UCS) separated by a temporal gap. Recent studies have reported that trace conditioning can occur in humans in reduced levels of consciousness by showing a transfer of the unconditioned autonomic response to the CS+ in healthy sleeping individuals and in vegetative state patients. However, no previous studies have investigated the neural underpinning of trace conditioning in the absence of consciousness in humans. In the present study, we recorded the EEG activity of 29 post-anoxic comatose patients while presenting a trace conditioning paradigm using neutral tones as CS+ and alerting sounds as UCS. Most patients received therapeutic hypothermia and all were deeply unconscious according to standardized clinical scales. After repeated presentation of the CS+ and UCS couple, learning was assessed by measuring the EEG activity during the period where the UCS is omitted after CS+ presentation. Specifically we assessed the 'reactivation' of the neural response to UCS omission by applying a decoding algorithm derived from the statistical model of the EEG activity in response to the UCS presentation. The same procedure was used in a group of 12 awake healthy controls. We found a reactivation of the UCS response in absence of stimulation in eight patients (five under therapeutic hypothermia) and four healthy controls. Additionally, the reactivation effect was temporally specific within trials since it manifested primarily at the specific latency of UCS presentation and significantly less before or after this period. Our results show for the first time that trace conditioning may manifest as a reactivation of the EEG activity related to the UCS and even in the absence of consciousness

Progression of auditory discrimination based on neural decoding predicts awakening from coma

Auditory evoked potentials are informative of intact cortical functions of comatose patients. The integrity of auditory functions evaluated using mismatch negativity paradigms has been associated with their chances of survival. However, because auditory discrimination is assessed at various delays after coma onset, it is still unclear whether this impairment depends on the time of the recording. We hypothesized that impairment in auditory discrimination capabilities is indicative of coma progression, rather than of the comatose state itself and that rudimentary auditory discrimination remains intact during acute stages of coma. We studied 30 post-anoxic comatose patients resuscitated from cardiac arrest and five healthy, age-matched controls. Using a mismatch negativity paradigm, we performed two electroencephalography recordings with a standard 19-channel clinical montage: the first within 24 h after coma onset and under mild therapeutic hypothermia, and the second after 1 day and under normothermic conditions. We analysed electroencephalography responses based on a multivariate decoding algorithm that automatically quantifies neural discrimination at the single patient level. Results showed high average decoding accuracy in discriminating sounds both for control subjects and comatose patients. Importantly, accurate decoding was largely independent of patients' chance of survival. However, the progression of auditory discrimination between the first and second recordings was informative of a patient's chance of survival. A deterioration of auditory discrimination was observed in all non-survivors (equivalent to 100% positive predictive value for survivors). We show, for the first time, evidence of intact auditory processing even in comatose patients who do not survive and that progression of sound discrimination over time is informative of a patient's chance of survival. Tracking auditory discrimination in comatose patients could provide new insight to the chance of awakening in a quantitative and automatic fashion during early stages of com

Neural detection of complex sound sequences in the absence of consciousness.

The neural response to a violation of sequences of identical sounds is a typical example of the brain's sensitivity to auditory regularities. Previous literature interprets this effect as a pre-attentive and unconscious processing of sensory stimuli. By contrast, a violation to auditory global regularities, i.e. based on repeating groups of sounds, is typically detectable when subjects can consciously perceive them. Here, we challenge the notion that global detection implies consciousness by testing the neural response to global violations in a group of 24 patients with post-anoxic coma (three females, age range 45-87 years), treated with mild therapeutic hypothermia and sedation. By applying a decoding analysis to electroencephalographic responses to standard versus deviant sound sequences, we found above-chance decoding performance in 10 of 24 patients (Wilcoxon signed-rank test, P < 0.001), despite five of them being mildly hypothermic, sedated and unarousable. Furthermore, consistently with previous findings based on the mismatch negativity the progression of this decoding performance was informative of patients' chances of awakening (78% predictive of awakening). Our results show for the first time that detection of global regularities at neural level exists despite a deeply unconscious state

Auditory stimulation and deep learning predict awakening from coma after cardiac arrest.

Assessing the integrity of neural functions in coma after cardiac arrest remains an open challenge. Prognostication of coma outcome relies mainly on visual expert scoring of physiological signals, which is prone to subjectivity and leaves a considerable number of patients in a 'grey zone', with uncertain prognosis. Quantitative analysis of EEG responses to auditory stimuli can provide a window into neural functions in coma and information about patients' chances of awakening. However, responses to standardized auditory stimulation are far from being used in a clinical routine due to heterogeneous and cumbersome protocols. Here, we hypothesize that convolutional neural networks can assist in extracting interpretable patterns of EEG responses to auditory stimuli during the first day of coma that are predictive of patients' chances of awakening and survival at 3 months. We used convolutional neural networks (CNNs) to model single-trial EEG responses to auditory stimuli in the first day of coma, under standardized sedation and targeted temperature management, in a multicentre and multiprotocol patient cohort and predict outcome at 3 months. The use of CNNs resulted in a positive predictive power for predicting awakening of 0.83 ± 0.04 and 0.81 ± 0.06 and an area under the curve in predicting outcome of 0.69 ± 0.05 and 0.70 ± 0.05, for patients undergoing therapeutic hypothermia and normothermia, respectively. These results also persisted in a subset of patients that were in a clinical 'grey zone'. The network's confidence in predicting outcome was based on interpretable features: it strongly correlated to the neural synchrony and complexity of EEG responses and was modulated by independent clinical evaluations, such as the EEG reactivity, background burst-suppression or motor responses. Our results highlight the strong potential of interpretable deep learning algorithms in combination with auditory stimulation to improve prognostication of coma outcome

How Do You Feel? Subjective Perception of Recovery as a Reliable Surrogate of Cognitive and Functional Outcome in Cardiac Arrest Survivors.

To show that subjective estimate of patient's condition is related to objective cognitive and functional outcome in cardiac arrest survivors. Longitudinal cohort study. ICU and Neuropsychology Service in two hospitals in Switzerland. Fifty survivors included from a prospective cohort of 138 patients admitted at the ICU for cardiopulmonary arrest. Comprehensive cognitive and functional evaluation at 6 months follow-up. Subjectively, 70% of survivors reported satisfactory recovery and 29% reported no complaints. Objectively, 76% were classified as good neurologic outcome (Cerebral Performance Category 1), 26% as having no symptoms (modified Rankin Scale 0), and 38% as upper good recovery (Glasgow Outcome Scale Extended 1). Cognitive assessment detected substantial cognitive impairment in 26%, primarily concerning processing speed, language, long-term memory, and executive functions. Subjective complaints severity correlated significantly with objective cognitive impairment (rS = 0.64; p < 0.001). Finally, patients reporting unsatisfactory recovery displayed lower functional scores than those reporting satisfactory recovery (e.g., quality of life satisfaction: 64% vs 81%; Z = 2.18; p = 0.03) and more cognitive impairment (three vs one cognitive domains impaired; Z = -3.21; p < 0.001), concerning in particular learning and long-term verbal and visual memory. Long-term subjective and objective outcome appears good in the majority of cardiac arrest survivors. Specific functional and cognitive impairments were found in patients reporting unsatisfactory recovery. Subjective recovery was strongly correlated with objective assessment

Auditory discrimination improvement predicts awakening of postanoxic comatose patients treated with targeted temperature management at 36°C.

Outcome prognostication in postanoxic comatose patients is more accurate in predicting poor than good recovery. Using electroencephalography recordings in patients treated with targeted temperature management at 33°C (TTM 33), we have previously shown that improvement in auditory discrimination over the first days of coma predicted awakening. Given the increased application of a 36°C temperature target (TTM 36), here we aimed at validating the predictive value of auditory discrimination in the TTM 36 setting. In this prospective multicenter study, we analyzed the EEG responses to auditory stimuli from 60 consecutive patients from the first and second coma day. A semiautomatic decoding analysis was applied to single patient data to quantify discrimination performance between frequently repeated and deviant sounds. The decoding change from the first to second day was used for predicting patient outcome. We observed an increase in auditory discrimination in 25 out of 60 patients. Among them, 17 awoke from coma (68% positive predictive value; 95% confidence interval: 0.46-0.85). By excluding patients with electroencephalographic epileptiform features, 15 of 18 exhibited improvement in auditory discrimination (83% positive predictive value; 95% confidence interval: 0.59-0.96). Specificity of good outcome prediction increased after adding auditory discrimination to EEG reactivity. These results suggest that tracking of auditory discrimination over time is informative of good recovery independent of the temperature target. This quantitative test provides complementary information to existing clinical tools by identifying patients with high chances of recovery and encouraging the maintenance of life support

Detection of tuberculosis drug resistance a comparison by Mycobacterium tuberculosis MLPA assay versus Genotype®MTBDRplus

BACKGROUND: To cope with the emergence of multidrug-resistant tuberculosis (MDR-TB), new molecular methods that can routinely be used to screen for a wide range of drug resistance related genetic markers in the Mycobacterium tuberculosis genome are urgently needed. OBJECTIVE: To evaluate the performance of multiplex ligaton-dependent probe amplification (MLPA) against Genotype® MTBDRplus to detect resistance to isoniazid (INHr) and rifampicin (RIFr). METHOD: 96 culture isolates characterised for identification, drug susceptibility testing (DST) and sequencing of rpoB, katG, and inhA genes were evaluated by the MLPA and Genotype®MTBDRplus assays. RESULTS: With sequencing as a reference standard, sensitivity (SE) to detect INHr was 92.8% and 85.7%, and specificity (SP) was 100% and 97.5%, for MLPA and Genotype®MTBDRplus, respectively. In relation to RIFr, SE was 87.5% and 100%, and SP was 100% and 98.8%, respectively. Kappa value was identical between Genotype®MTBDRplus and MLPA compared with the standard DST and sequencing for detection of INHr [0.83 (0.75-0.91)] and RIFr [0.93 (0.88-0.98)]. CONCLUSION: Compared to Genotype®MTBDRplus, MLPA showed similar sensitivity to detect INH and RIF resistance. The results obtained by the MLPA and Genotype®MTBDRplus assays indicate that both molecular tests can be used for the rapid detection of drug-resistant TB with high accuracy. MLPA has the added value of providing information on the circulating M. tuberculosis lineages.publishersversionpublishe