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The increase in neuronal activity induced by a single seizure is supported by a rise in the cerebral blood flow and tissue oxygenation, a mechanism called neurovascular coupling (NVC). Whether cerebral and systemic hemodynamics are able to match neuronal activity during recurring seizures is unclear, as data from rodent models are at odds with human studies. In order to clarify this issue, we used an invasive brain and systemic monitoring to study the effects of chemically induced non-convulsive seizures in sheep. Despite an increase in neuronal activity as seizures repeat (Spearman’s ρ coefficient 0.31, P  < 0.001), ictal variations of cerebral blood flow remained stable while it progressively increased in the inter-ictal intervals (ρ = 0.06, P  = 0.44 and ρ = 0.22; P  = 0.008). We also observed a progressive reduction in the inter-ictal brain tissue oxygenation (ρ =  − 0.18; P  = 0.04), suggesting that NVC was unable to compensate for the metabolic demand of these closely repeating seizures. At the systemic level, there was a progressive reduction in blood pressure and a progressive rise in cardiac output (ρ =  − 0.22; P  = 0.01 and ρ = 0.22; P  = 0.01, respectively), suggesting seizure-induced autonomic dysfunction.

Background Sepsis-associated encephalopathy (SAE) is frequent in septic patients. Electroencephalography (EEG) is very sensitive to detect early epileptic abnormalities, such as seizures and periodic discharges (PDs), and to quantify their duration (the so-called burden). However, the prevalence of these EEG abnormalities in septic patients, as well as their effect on morbidity and mortality, are still unclear. The aims of this study were to assess whether the presence of electrographic abnormalities (i.e. the absence of reactivity, the presence and burden of seizures and PDs) was associated with functional outcome and mortality in septic patients and whether these abnormalities were associated with sepsis-associated encephalopathy (SAE). Methods We prospectively included septic patients, without known chronic or acute intracranial disease or pre-existing acute encephalopathy, requiring ICU admission in a tertiary academic centre. Continuous EEG monitoring was started within 72 h after inclusion and performed for up to 7 days. A comprehensive assessment of consciousness and delirium was performed twice daily by a trained neuropsychologist. Primary endpoints were unfavourable functional outcome (UO, defined as a Glasgow Outcome Scale-Extended—GOSE—score < 5), and mortality collected at hospital discharge and secondary endpoint was the association of PDs with SAE. Mann–Whitney, Fisher’s exact and χ 2 tests were used to assess differences in variables between groups, as appropriate. Multivariable logistic regression analysis with in-hospital mortality, functional outcome, SAE or PDs as the dependent variables were performed. Results We included 92 patients. No seizures were identified. Nearly 25% of patients had PDs. The presence of PDs and PDs burden was associated with UO in univariate ( n  = 15 [41%], p  = 0.005 and p  = 0.008, respectively) and, for PDs presence, also in multivariate analysis after correcting for disease severity (OR 3.82, IC 95% [1.27–11.49], p  = 0.02). The PDs burden negatively correlated with GOSE (Spearman’s coefficient ρ  = − 0.2, p  = 0.047). The presence of PDs was also independently associated with SAE (OR 8.98 [1.11–72.8], p  = 0.04). Reactivity was observed in the majority of patients and was associated with outcomes ( p = 0.044 for both functional outcome and mortality). Conclusion Our findings suggest that PDs and PDs burden are associated with SAE and might affect outcome in septic patients.

Introduction Prognosis after resuscitation from cardiac arrest (CA) remains poor, with high morbidity and mortality as a result of extensive cardiac and brain injury and lack of effective treatments. Hypertonic sodium lactate (HSL) may be beneficial after CA by buffering severe metabolic acidosis, increasing brain perfusion and cardiac performance, reducing cerebral swelling, and serving as an alternative energetic cellular substrate. The aim of this study was to test the effects of HSL infusion on brain and cardiac injury in an experimental model of CA. Methods After a 10-min electrically induced CA followed by 5 min of cardiopulmonary resuscitation maneuvers, adult swine ( n  = 35) were randomly assigned to receive either balanced crystalloid (controls, n  = 11) or HSL infusion started during cardiopulmonary resuscitation (CPR, Intra-arrest, n  = 12) or after return of spontaneous circulation (Post-ROSC, n  = 11) for the subsequent 12 h. In all animals, extensive multimodal neurological and cardiovascular monitoring was implemented. All animals were treated with targeted temperature management at 34 °C. Results Thirty-four of the 35 (97.1%) animals achieved ROSC; one animal in the Intra-arrest group died before completing the observation period. Arterial pH, lactate and sodium concentrations, and plasma osmolarity were higher in HSL-treated animals than in controls ( p  < 0.001), whereas potassium concentrations were lower ( p  = 0.004). Intra-arrest and Post-ROSC HSL infusion improved hemodynamic status compared to controls, as shown by reduced vasopressor requirements to maintain a mean arterial pressure target > 65 mmHg ( p  = 0.005 for interaction; p  = 0.01 for groups). Moreover, plasma troponin I and glial fibrillary acid protein (GFAP) concentrations were lower in HSL-treated groups at several time-points than in controls. Conclusions In this experimental CA model, HSL infusion was associated with reduced vasopressor requirements and decreased plasma concentrations of measured biomarkers of cardiac and cerebral injury.

Non-convulsive seizures and status epilepticus are frequent and associated with increased mortality in septic patients. However, the mechanism through which seizures impact outcome in these patients is unclear. As previous studies yielded an alteration of neurovascular coupling (NVC) during sepsis, we hypothesized that non-convulsive seizures, might further impair NVC, leading to brain tissue hypoxia. We used a previously developed ovine model of sepsis. Animals were allocated to sham procedure or sepsis; septic animals were studied either during the hyperdynamic phase (sepsis group) or after septic shock occurrence (septic shock group). After allocation, seizures were induced by cortical application of penicillin. We recorded a greater seizure-induced increase in the EEG gamma power in the sepsis group than in sham. Using a neural mass model, we also found that the theoretical activity of the modeled inhibitory interneurons, thought to be important to reproduce gamma oscillations, were relatively greater in the sepsis group. However, the NVC was impaired in sepsis animals, despite a normal brain tissue oxygenation. In septic shock animals, it was not possible to induce seizures. Cortical activity declined in case of septic shock, but it did not differ between sham or sepsis animals. As the alteration in NVC preceded cortical activity reduction, we suggest that, during sepsis progression, the NVC inefficiency could be partially responsible for the alteration of brain function, which might prevent seizure occurrence during septic shock. Moreover, we showed that cardiac output decreased during seizures in sepsis animals instead of increasing as in shams. The alteration of the seizure-induced systemic hemodynamic variations in sepsis might further affect cerebrovascular response to neuronal activation. Our findings support the hypothesis that anomalies in the cerebral blood flow regulation may contribute to the sepsis-associated encephalopathy and that seizures might be dangerous in such a vulnerable setting.

BackgroundAlteration of the mechanisms of cerebral blood flow (CBF) regulation might contribute to the pathophysiology of sepsis-associated encephalopathy (SAE). However, previous clinical studies on dynamic cerebral autoregulation (dCA) in sepsis had several cofounders. Furthermore, little is known on the potential impairment of neurovascular coupling (NVC) in sepsis. The aim of our study was to determine the presence and time course of dCA and NVC alterations in a clinically relevant animal model and their potential impact on the development of SAE.MethodsThirty-six anesthetized, mechanically ventilated female sheep were randomized to sham procedures (sham, n = 15), sepsis (n = 14), or septic shock (n = 7). Blood pressure, CBF, and electrocorticography were continuously recorded. Pearson’s correlation coefficient Lxa and transfer function analysis were used to estimate dCA. NVC was assessed by the analysis of CBF variations induced by cortical gamma activity (Eγ) peaks and by the magnitude-squared coherence (MSC) between the spontaneous fluctuations of CBF and Eγ. Cortical function was estimated by the alpha-delta ratio. Wilcoxon signed rank and rank sum tests, Friedman tests, and RMANOVA test were used as appropriate.ResultsSepsis and sham animals did not differ neither in dCA nor in NVC parameters. A significant impairment of dCA occurred only after septic shock (Lxa, p = 0.03, TFA gain p = 0.03, phase p = 0.01). Similarly, NVC was altered during septic shock, as indicated by a lower MSC in the frequency band 0.03–0.06 Hz (p < 0.001). dCA and NVC impairments were associated with cortical dysfunction (reduction in the alpha-delta ratio (p = 0.03)).ConclusionsA progressive loss of dCA and NVC occurs during septic shock and is associated with cortical dysfunction. These findings indicate that the alteration of mechanisms controlling cortical perfusion plays a late role in the pathophysiology of SAE and suggest that alterations of CBF regulation mechanisms in less severe phases of sepsis reported in clinical studies might be due to patients’ comorbidities or other confounders. Furthermore, a mean arterial pressure targeting therapy aiming to optimize dCA might not be sufficient to prevent neuronal dysfunction in sepsis since it would not improve NVC.

Background Cardiac arrest (CA) remains a leading cause of mortality and long-term neurological disability. In cases of refractory CA, extracorporeal cardiopulmonary resuscitation (ECPR) may be implemented as a salvage therapy to mitigate hypoxic-ischemic brain injury and improve outcomes. However, the optimal target temperature in the specific context of ECPR remains uncertain. The objective of this study was to evaluate the impact of hypothermia on brain function using a controlled experimental model of ECPR. Methods Twelve pigs were subjected to 5 min of untreated ventricular fibrillation, followed by 25 min of conventional cardiopulmonary resuscitation (CPR). At 30 min, veno-arterial extracorporeal membrane oxygenation support was initiated, and defibrillation attempts were performed until the achievement of return of spontaneous circulation (ROSC). Following ROSC, animals were randomly assigned to one of two groups: hypothermia (HT), targeting a core body temperature of 33–34 °C, or controlled normothermia (NT), targeting 37–38 °C. All animals underwent continuous multimodal neurological and cardiovascular monitoring. Blood samples were collected at predefined time points to assess circulating biomarkers of organ injury. The primary outcome was the change of brain tissue oxygen tension (PbtO 2 ) over time. Other neurological and hemodynamical parameters were treated as secondary analyses. At 12 h post-ROSC, animals were euthanized via intracardiac injection of potassium chloride. Brain tissues were immediately harvested and appropriately stored for molecular analyses. Results A total of 12 pigs were included in the study, with six animals allocated to each group. Baseline characteristics were comparable between the groups and ROSC was achieved in all animals. Throughout the experiment, PbtO₂ gradually declined and intracranial pressure (ICP) increased in both groups; however, no significant differences were observed between groups. Similarly, there were no significant differences in cerebral metabolites, cortical activity, or gene expression in either frontal or parietal brain tissues. Notably, neurofilament light chain (NfL) concentrations were significantly lower at the end of the observation period in the HT group compared to NT ( p  = 0.04), while neuron-specific enolase (NSE) and glial fibrillary acidic protein (GFAP) levels did not differ significantly between the two groups. Conclusions HT did not improve cerebral perfusion or metabolic parameters in this refractory cardiac arrest ECPR model; the early decrease in NfL levels requires cautious interpretation and further investigation.

Background Anoxic brain injuries represent the main determinant of poor outcome after cardiac arrest (CA). Large animal models have been described to investigate new treatments during CA and post‐resuscitation phase, but a detailed model that includes extensive neuromonitoring is lacking. Method Before an electrically‐induced 10‐minute CA and resuscitation, 46 adult pigs underwent neurosurgery for placement of a multifunctional probe (intracranial pressure or ICP, tissue oxygen tension or PbtO2 and cerebral temperature) and a bolt‐based technique for the placement and securing of a regional blood flow probe and two sEEG electrodes; two modified cerebral microdialysis (CMD) probes were also inserted in the frontal lobes and accidental misplacement was prevented using a perforated head support. Result 42 animals underwent the CA procedure and 41 achieved the return of spontaneous circulation (ROSC). In 4 cases (8.6%) an adverse event took place during preparation, but only in two cases (4.3%) this was related to the neurosurgery. In 6 animals (13.3%) the minor complications that occurred resolved after probe repositioning. Conclusion Herein we provide a detailed comprehensive neuromonitoring approach in a large animal model of CA that might help future research. The figures displays multiple neuromonitoring devices in place to allow simultaneous measurements of multiple brain‐derived parameters during cardiac arrest and post‐resuscitation period.

Keywords: Neurofibrillary tangles, Tau pathology, FTLD-tau, MAPT

Brain metastasis (BM) is a frequent complication of systemic cancer usually associated with poor prognosis. Survival depends on numerous factors, which complicates prognosis and treatment. It has been suggested that BM growing from previously dormant disseminated tumour cells (DTCs) may exhibit a milder phenotype than BM derived from continuously progressing metastatic cells; however, to the best of our knowledge, the prognosis of patients presenting with BM from dormant DTCs is unknown. The present study retrospectively compared survival data, collected from a single neurosurgical centre, between patients presenting with BM from previously dormant DTCs and patients with non-dormant BM. A total of 262 medical records were reviewed. In the univariate Cox regression analysis, the median survival of the dormant BM group was statistically longer than that of the non-dormant group (P=0.048); a trend towards a longer survival persisted after correcting for age, presence of breast cancer and treatment options (P=0.057), which are all factors known to influence outcome. The improved outcome of these patients could be considered in models for prognostication. Moreover, the development of therapies able to eradicate dormant DTCs could provide a new promising strategy to prolong the survival of patients with a favourable prognosis.

Aims Cerebral complications after cardiac arrest (CA) remain a major problem worldwide. The aim was to test the effects of sodium-ß-hydroxybutyrate (SBHB) infusion on brain injury in a clinically relevant swine model of CA. Results CA was electrically induced in 20 adult swine. After 10 min, cardiopulmonary resuscitation was performed for 5 min. After return of spontaneous circulation (ROSC), the animals were randomly assigned to receive an infusion of balanced crystalloid (controls, n = 11) or SBHB (theoretical osmolarity 1189 mOsm/l, n = 8) for 12 h. Multimodal neurological and cardiovascular monitoring were implemented in all animals. Nineteen of the 20 animals achieved ROSC. Blood sodium concentrations, osmolarity and circulating KBs were higher in the treated animals than in the controls. SBHB infusion was associated with significantly lower plasma biomarkers of brain injury at 6 (glial fibrillary acid protein, GFAP and neuron specific enolase, NSE) and 12 h (neurofilament light chain, NFL, GFAP and NSE) compared to controls. The amplitude of the stereoelectroencephalograph (sEEG) increased in treated animals after ROSC compared to controls. Cerebral glucose uptake was lower in treated animals. Conclusions In this experimental model, SBHB infusion after resuscitated CA was associated with reduced circulating markers of cerebral injury and increased sEEG amplitude.