关键词： COVID-19   SARS-CoV-2   Neurological manifestations   Systematic review   Inflammation  

摘要： Background Coronavirus disease 2019 (COVID-19) has become a global pandemic, affecting millions of people. However, clinical research on its neurological manifestations is thus far limited. In this study, we aimed to systematically collect and investigate the clinical manifestations and evidence of neurological involvement in COVID-19. Methods Three medical (Medline, Embase, and Scopus) and two preprints (BioRxiv and MedRxiv) databases were systematically searched for all published articles on neurological involvement in COVID-19 since the outbreak. All included studies were systematically reviewed, and selected clinical data were collected for meta-analysis via random-effects. Results A total of 41 articles were eligible and included in this review, showing a wide spectrum of neurological manifestations in COVID-19. The meta-analysis for unspecific neurological symptoms revealed that the most common manifestations were fatigue (33.2% [23.1-43.3]), anorexia (30.0% [23.2-36.9]), dyspnea/shortness of breath (26.9% [19.2-34.6]), and malaise (26.7% [13.3-40.1]). The common specific neurological symptoms included olfactory (35.7-85.6%) and gustatory (33.3-88.8%) disorders, especially in mild cases. Guillain-Barre syndrome and acute inflammation of the brain, spinal cord, and meninges were repeatedly reported after COVID-19. Laboratory, electrophysiological, radiological, and pathological evidence supported neurologic involvement of COVID-19. Conclusions Neurological manifestations are various and prevalent in COVID-19. Emerging clinical evidence suggests neurological involvement is an important aspect of the disease. The underlying mechanisms can include both direct invasion and maladaptive inflammatory responses. More studies should be conducted to explore the role of neurological manifestations in COVID-19 progression and to verify their underlying mechanisms.

关键词： Critical care   Stroke   Cerebral infarction   Intracerebral hemorrhage   Coagulopathy  

摘要： Background Little is known about newly developed stroke in patients admitted to the intensive care unit (ICU). Objective This study aimed to investigate characteristics and outcomes of newly developed stroke in patients admitted to the non-neurological intensive care units (ICU-onset stroke, IOS). Methods A consecutive series of adult patients who were admitted to the non-neurological ICU were included in this study. We compared neurological profiles, risk factors, and mortality rates between patients with IOS and those without IOS. Results Of 18,604 patients admitted to the ICU for non-neurological illness, 218 (1.2%) developed stroke (ischemic, n = 182;hemorrhagic, n = 36). The most common neurological presentation was altered mental status (n = 149), followed by hemiparesis (n = 55), and seizures (n = 28). The most common etiology of IOS was cardioembolism (50% [91/182]) for ischemic IOS and coagulopathy (67% [24/36]) for hemorrhagic IOS. In multivariable analysis, the Acute Physiology and Chronic Health Evaluation II (APACHE II) score (adjusted odds ratio [AOR] = 1.04, 95% CI = 1.03-1.06, P < 0.001), prothrombin time (AOR = 0.99, 95% CI = 0.98-0.99, P = 0.013), cardiovascular surgery (AOR = 1.84, 95% CI = 1.34-2.50, P < 0.001), mechanical ventilation (AOR = 6.75, 95% CI = 4.87-9.45, P < 0.001), and extracorporeal membrane oxygenation (AOR = 2.77, 95% CI = 1.62-4.55, P < 0.001) were related to the development of IOS. Stroke was associated with increased 3-month mortality after hospital discharge (AOR, 2.20;95% CI, 1.58-3.05;P < 0.001), after adjustment for APACHE II and comorbidities. Conclusions Patients who developed IOS had characteristics of initial critical illness and managements performed in the ICU as well as neurological presentations. The occurrence of IOS was related to high morbidity and mortality.

关键词： Cardiac arrest   Prognostication   Guideline algorithm   Prognostic accuracy   Coma  

摘要： Purpose To assess the performance of a 4-step algorithm for neurological prognostication after cardiac arrest recommended by the European Resuscitation Council (ERC) and the European Society of Intensive Care Medicine (ESICM). Methods Retrospective descriptive analysis with data from the Target Temperature Management (TTM) Trial. Associations between predicted and actual neurological outcome were investigated for each step of the algorithm with results from clinical neurological examinations, neuroradiology (CT or MRI), neurophysiology (EEG and SSEP) and serum neuron-specific enolase. Patients examined with Glasgow Coma Scale Motor Score (GCS-M) on day 4 (72-96 h) post-arrest and available 6-month outcome were included. Poor outcome was defined as Cerebral Performance Category 3-5. Variations of the ERC/ESICM algorithm were explored within the same cohort. Results The ERC/ESICM algorithm identified poor outcome patients with 38.7% sensitivity (95% CI 33.1-44.7) and 100% specificity (95% CI 98.8-100) in a cohort of 585 patients. An alternative cut-off for serum neuron-specific enolase, an alternative EEG-classification and variations of the GCS-M had minor effects on the sensitivity without causing false positive predictions. The highest overall sensitivity, 42.5% (95% CI 36.7-48.5), was achieved when prognosticating patients irrespective of GCS-M score, with 100% specificity (95% CI 98.8-100) remaining. Conclusion The ERC/ESICM algorithm and all exploratory multimodal variations thereof investigated in this study predicted poor outcome without false positive predictions and with sensitivities 34.6-42.5%. Our results should be validated prospectively, preferably in patients where withdrawal of life-sustaining therapy is uncommon to exclude any confounding from self-fulfilling prophecies.

关键词： Hemorrhagic transformation (HT)   High mobility group box protein 1 (HMGB1)   Glycyrrhizin   Peroxynitrite (ONOO-)   Tissue plasminogen activator (t-PA)  

摘要： Peroxynitrite (ONOO-) and high mobility group box 1 protein (HMGB1) are important cytotoxic factors contributing to cerebral ischemia-reperfusion injury. However, the roles of ONOO- in mediating HMGB1 expression and its impacts on hemorrhagic transformation (HT) in ischemic brain injury with delayed t-PA treatment remain unclear. In the present study, we tested the hypothesis that ONOO- could directly mediate the activation and release of HMGB1 in ischemic brains with delayed t-PA treatment. With clinical studies, we found that plasma nitrotyrosine (NT, a surrogate marker of ONOO-) was positively correlated with HMGB1 level in acute ischemic stroke patients. Hemorrhagic transformation and t-PA-treated ischemic stroke patients had increased levels of nitrotyrosine and HMGB1 in plasma. In animal experiments, we found that FeTmPyP, a representative ONOO- decomposition catalyst (PDC), significantly reduced the expression of HMGB1 and its receptor TLR2, and inhibited MMP-9 activation, preserved collagen IV and tight junction claudin-5 in ischemic rat brains with delayed t-PA treatment. ONOO- donor SIN-1 directly induced expression of HMGB1 and its receptor TLR2 in naive rat brains in vivo and induced HMGB1 in brain microvascular endothelial ***3 cells in vitro. Those results suggest that ONOO- could activate HMGB1/TLR2/MMP-9 signaling. We then addressed whether glycyrrhizin, a natural HMGB1 inhibitor, could inhibit ONOO- production and the antioxidant properties of glycyrrhizin contribute to the inhibition of HMGB1 and the neuroprotective effects on attenuating hemorrhagic transformation in ischemic stroke with delayed t-PA treatment. Glycyrrhizin treatment downregulated the expressions of NADPH oxidase p47 phox and p67 phox and iNOS, inhibited superoxide and ONOO- production, reduced the expression of HMGB1, TLR2, MMP-9, preserved type IV collagen and claudin-5 in ischemic brains. Furthermore, glycyrrhizin significantly decreased the mortality rate, attenuated hemorrh

关键词： acute ischaemic stroke   early neurological deterioration   nomogram  

摘要： Background and purpose Acute ischaemic stroke (AIS) is a vital cause of mortality and morbidity in China. Many AIS patients develop early neurological deterioration (END). This study aimed to construct a nomogram to predict END in AIS patients. Methods Acute ischaemic stroke patients in Nanjing First Hospital were recruited as the training cohort. Additional patients in Nantong Third People's Hospital were enrolled as the validation cohort. Multivariate logistic regression was utilized to establish the nomogram. Discrimination and calibration performance of the nomogram were tested by concordance index and calibration plots. Decision curve analysis was employed to assess the utility of the nomogram. Results In all, 1889 and 818 patients were recruited in the training and validation cohorts, respectively. Age [odds ratio (OR) 1.075;95% confidence interval (CI) 1.059-1.091], diabetes mellitus (OR 1.673;95% CI 1.181-2.370), atrial fibrillation (OR 3.297;95% CI 2.005-5.421), previous antiplatelet medication (OR 0.473;95% CI 0.301-0.744), hyper-sensitive C-reactive protein (OR 1.049;95% CI 1.036-1.063) and baseline National Institutes of Health Stroke Scale (OR 1.071;95% CI 1.045-1.098) were associated with END and incorporated in the nomogram. The concordance index was 0.826 (95% CI 0.785-0.885) and 0.798 (95% CI 0.749-0.847) in the training and validation cohorts. By decision curve analysis, the model was relevant between thresholds of 0.06 and 0.90 in the training cohort and 0.08 and 0.77 in the validation cohort. Conclusions The nomogram composed of hyper-sensitive C-reactive protein, age, diabetes mellitus, atrial fibrillation, previous antiplatelet medication and baseline National Institutes of Health Stroke Scale may predict the risk of END in AIS patients.

关键词： COVID-19   meningitis   neurological symptoms  

摘要： There has been a global outbreak of coronavirus disease 2019 (COVID-19) since December 2019. In clinical practice, not only fever and respiratory tract symptoms but also multiple organ symptoms are observed in patients diagnosed with COVID-19. Herein, we report a rare case of a patient diagnosed with COVID-19 who manifested with concomitant neurological symptoms. The patient developed fever and respiratory symptoms at disease onset, followed by muscle soreness, and subsequently altered consciousness and psychiatric symptoms, with positive signs based on neurological examination. The patient tested positive for the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) nucleic acid (throat swab). Further, chest computed tomography (CT) revealed typical COVID-19 findings, and head CT did not reveal significant abnormalities. The patient recovered after treatment and was discharged. This rare case indicates that SARS-CoV-2 can invade the central nervous system, thus causing neurological symptoms and signs. This article is protected by copyright. All rights reserved.

关键词： endocannabinoid system   neurological diseases   cardiac functions   metabolic diseases   immune functions  

摘要： The identification of the human cannabinoid receptors and their roles in health and disease, has been one of the most significant biochemical and pharmacological advancements to have occurred in the past few decades. In spite of the major strides made in furthering endocannabinoid research, therapeutic exploitation of the endocannabinoid system has often been a challenging task. An impaired endocannabinoid tone often manifests as changes in expression and/or functions of type 1 and/or type 2 cannabinoid receptors. It becomes important to understand how alterations in cannabinoid receptor cellular signaling can lead to disruptions in major physiological and biological functions, as they are often associated with the pathogenesis of several neurological, cardiovascular, metabolic, and inflammatory diseases. This review focusses mostly on the pathophysiological roles of type 1 and type 2 cannabinoid receptors, and it attempts to integrate both cellular and physiological functions of the cannabinoid receptors. Apart from an updated review of pre-clinical and clinical studies, the adequacy/inadequacy of cannabinoid-based therapeutics in various pathological conditions is also highlighted. Finally, alternative strategies to modulate endocannabinoid tone, and future directions are also emphasized.

关键词： Biomarkers   Mortality   Neurological recovery   Perforin-2   Sudden cardiac arrest  

摘要： Background: Biomarkers involved in inflammation and stress response were implicated in patients who were successfully resuscitated from out of hospital cardiac arrest (sR-OHCA). Here we report that macrophage-expressed gene, perforin-2, an evolutionarily conserved protein with membrane attack domain, is associated with poor neurological outcomes and mortality after sR-OHCA. Objectives: To examine the association between circulating perforin-2 protein measured within 6-h of sR-OHCA, mortality and neurological outcomes. Methods: We prospectively enrolled 144 sR-OHCA patients from 4 different tertiary care centers. We measured perforin-2 and other conventional clinical biomarkers and compared between survivors vs. non-survivors. The neurological outcomes were dichotomized as poor- or good-according to the cereberal performance score. Results: At the end of the hospital stay, 45% of the patients had died and 46% had poor neurological outcomes. Serum perforin-2 levels were significantly higher in patients with poor neurological recovery, compared to the ones with goodneurological recovery (ng/mL, 13.7 +/- 45.9 vs. 1.2 +/- 7.0, p = 0.01). There were no differences in other routinely measured biomarkers and left ventricular ejection fraction. On multivariate logistic regression, elevated perforin-2 (OR: 12.78, 95% CI: 1.0-17.8, p = 0.02), comatose on presentation (OR: 27.82, 95% CI: 0.2-19.5, p = 0.02) and non-shockable rhythm (OR: 17.04, 95% CI: 0.7-15.7, p = 0.01) were the significant predictors of poor neurological outcome. Conclusions: This study reports a novel macrophage-expressed circulating biomarker perforin-2 to be strongly associated with reduced survival and poor neurological outcomes in sR-OHCA. These data can guide clinicians to prognosticate survival and neurological outcomes in sR-OHCA, and also form the basis for future therapeutic approaches.