Spreading depolarizations in ischaemia after subarachnoid haemorrhage, a diagnostic phase III study.

Focal brain damage after aneurysmal subarachnoid haemorrhage predominantly results from intracerebral haemorrhage, and early and delayed cerebral ischaemia. The prospective, observational, multicentre, cohort, diagnostic phase III trial, DISCHARGE-1, primarily investigated whether the peak total spreading depolarization-induced depression duration of a recording day during delayed neuromonitoring (delayed depression duration) indicates delayed ipsilateral infarction. Consecutive patients (n = 205) who required neurosurgery were enrolled in six university hospitals from September 2009 to April 2018. Subdural electrodes for electrocorticography were implanted. Participants were excluded on the basis of exclusion criteria, technical problems in data quality, missing neuroimages or patient withdrawal (n = 25). Evaluators were blinded to other measures. Longitudinal MRI, and CT studies if clinically indicated, revealed that 162/180 patients developed focal brain damage during the first 2 weeks. During 4.5 years of cumulative recording, 6777 spreading depolarizations occurred in 161/180 patients and 238 electrographic seizures in 14/180. Ten patients died early; 90/170 developed delayed infarction ipsilateral to the electrodes. Primary objective was to investigate whether a 60-min delayed depression duration cut-off in a 24-h window predicts delayed infarction with >0.60 sensitivity and >0.80 specificity, and to estimate a new cut-off. The 60-min cut-off was too short. Sensitivity was sufficient [= 0.76 (95% confidence interval: 0.65-0.84), P = 0.0014] but specificity was 0.59 (0.47-0.70), i.e. <0.80 (P < 0.0001). Nevertheless, the area under the receiver operating characteristic (AUROC) curve of delayed depression duration was 0.76 (0.69-0.83, P < 0.0001) for delayed infarction and 0.88 (0.81-0.94, P < 0.0001) for delayed ischaemia (reversible delayed neurological deficit or infarction). In secondary analysis, a new 180-min cut-off indicated delayed infarction with a targeted 0.62 sensitivity and 0.83 specificity. In awake patients, the AUROC curve of delayed depression duration was 0.84 (0.70-0.97, P = 0.001) and the prespecified 60-min cut-off showed 0.71 sensitivity and 0.82 specificity for reversible neurological deficits. In multivariate analysis, delayed depression duration (ß = 0.474, P < 0.001), delayed median Glasgow Coma Score (ß = -0.201, P = 0.005) and peak transcranial Doppler (ß = 0.169, P = 0.016) explained 35% of variance in delayed infarction. Another key finding was that spreading depolarization-variables were included in every multiple regression model of early, delayed and total brain damage, patient outcome and death, strongly suggesting that they are an independent biomarker of progressive brain injury. While the 60-min cut-off of cumulative depression in a 24-h window indicated reversible delayed neurological deficit, only a 180-min cut-off indicated new infarction with >0.60 sensitivity and >0.80 specificity. Although spontaneous resolution of the neurological deficit is still possible, we recommend initiating rescue treatment at the 60-min rather than the 180-min cut-off if progression of injury to infarction is to be prevented.

Spatial and Temporal Comparisons of Calcium Channel and Intrinsic Signal Imaging During in Vivo Cortical Spreading Depolarizations in Healthy and Hypoxic Brains.

BACKGROUND: Spreading depolarizations (SDs) can be viewed at a cellular level using calcium imaging (CI), but this approach is limited to laboratory applications and animal experiments. Optical intrinsic signal imaging (OISI), on the other hand, is amenable to clinical use and allows viewing of large cortical areas without contrast agents. A better understanding of the behavior of OISI-observed SDs under different brain conditions is needed. METHODS: We performed simultaneous calcium and OISI of SDs in GCaMP6f mice. SDs propagate through the cortex as a pathological wave and trigger a neurovascular response that can be imaged with both techniques. We imaged both mechanically stimulated SDs (sSDs) in healthy brains and terminal SDs (tSDs) induced by system hypoxia and cardiopulmonary failure. RESULTS: We observed a lag in the detection of SDs in the OISI channels compared with CI. sSDs had a faster velocity than tSDs, and tSDs had a greater initial velocity for the first 400 µm when observed with CI compared with OISI. However, both imaging methods revealed similar characteristics, including a decrease in the sSD (but not tSD) velocities as the wave moved away from the site of initial detection. CI and OISI also showed similar spatial propagation of the SD throughout the image field. Importantly, only OISI allowed regional ischemia to be detected before tSDs occurred. CONCLUSIONS: Altogether, data indicate that monitoring either neural activity or intrinsic signals with high-resolution optical imaging can be useful to assess SDs, but OISI may be a clinically applicable way to predict, and therefore possibly mitigate, hypoxic-ischemic tSDs.

Remote and Persistent Alterations in Glutamate Receptor Subunit Composition Induced by Spreading Depolarizations in Rat Brain.

Spreading depolarizations (SDs) are massive breakdowns of ion homeostasis in the brain's gray matter and are a necessary pathologic mechanism for lesion development in various injury models. However, injury-induced SDs also propagate into remote, healthy tissue where they do not cause cell death, yet their functional long-term effects are unknown. Here we induced SDs in uninjured cortex and hippocampus of Sprague-Dawley rats to study their impact on glutamate receptor subunit expression after three days. We find that both cortical and hippocampal tissue exhibit changes in glutamate receptor subunit expression, including GluA1 and GluN2B, suggesting that SDs in healthy brain tissue may have a role in plasticity. This study is the first to show prolonged effects of SDs on glutamate signaling and has implications for neuroprotection strategies aimed at SD suppression.

Spreading Diffusion-Restriction Events in the Gyrencephalic Brain After Subarachnoid Hemorrhage Revealed by Continuous Magnetic Resonance Imaging.

BACKGROUND: How widely spreading depolarizations (SDs) propagate through the gyrencephalic brain, including sulci and deeper cortical areas, remains an important clinical question. Here, we investigated SDs that occur spontaneously after subarachnoid placement of autologous blood clots in sulci of the juvenile swine brain. METHODS: To investigate the three-dimensional spread of waves, animals underwent continuous diffusion-weighted magnetic resonance imaging (DW-MRI) for up to 6 h following clot placement. SD is the mechanism of the cytotoxic edema of developing infarction that is diagnosed by DW-MRI, and DW-MRI also captures transient diffusion restriction caused by SD in less injured or healthy brains. Here, images (b = 0, 375, and 750) were acquired across five coronal slices with 1.25 × 1.25-mm in-plane resolution and 5-mm slice thickness, and the protocol was repeated every 6.83-9.15 s. Spatial drift correction, temporal smoothing, and signal intensity normalization were applied to generate videos of diffusion signal intensity changes for each coronal slice. RESULTS: Review of video data from five animals revealed ten discrete events consisting of focal diffusion restriction that propagated through cerebral cortex. All events originated in the cortex surrounding the sulcal clot, either in the gyrus (n = 4) or in the sulcal depth (n = 6). In six cases, two to three independent waves spread simultaneously in medial, lateral, and antero-posterior directions. Waves traveled within sulcal walls, traversed the depths of sulci to re-emerge on the adjacent gyrus, and, in three cases, spread fully around the dorsolateral convexity. One event spread deep to olfactory regions along midline cortex, and no events were observed contralateral to the subarachnoid clot. CONCLUSIONS: Together, these results suggest that SDs in the injured gyrencephalic brain originate near the injury focus and can spread extensively through the cortex to wide and deep uninjured regions. These findings have implications for transient neurologic deficits in the neurocritically ill patient and relevance to patient monitoring and therapeutics.

Seizures and Cognitive Outcome After Traumatic Brain Injury: A Post Hoc Analysis.

INTRODUCTION: Seizures and abnormal periodic or rhythmic patterns are observed on continuous electroencephalography monitoring (cEEG) in up to half of patients hospitalized with moderate to severe traumatic brain injury (TBI). We aimed to determine the impact of seizures and abnormal periodic or rhythmic patterns on cognitive outcome 3 months following moderate to severe TBI. METHODS: This was a post hoc analysis of the multicenter randomized controlled phase 2 INTREPID2566 clinical trial conducted from 2010 to 2016 across 20 United States Level I trauma centers. Patients with nonpenetrating TBI and postresuscitation Glasgow Coma Scale scores 4-12 were included. Bedside cEEG was initiated per protocol on admission to intensive care, and the burden of ictal-interictal continuum (IIC) patterns, including seizures, was quantified. A summary global cognition score at 3 months following injury was used as the primary outcome. RESULTS: 142 patients (age mean + / - standard deviation 32 + / - 13 years; 131 [92%] men) survived with a mean global cognition score of 81 + / - 15; nearly one third were considered to have poor functional outcome. 89 of 142 (63%) patients underwent cEEG, of whom 13 of 89 (15%) had severe IIC patterns. The quantitative burden of IIC patterns correlated inversely with the global cognition score (r = - 0.57; p = 0.04). In multiple variable analysis, the log-transformed burden of severe IIC patterns was independently associated with the global cognition score after controlling for demographics, premorbid estimated intelligence, injury severity, sedatives, and antiepileptic drugs (odds ratio 0.73, 95% confidence interval 0.60-0.88; p = 0.002). CONCLUSIONS: The burden of seizures and abnormal periodic or rhythmic patterns was independently associated with worse cognition at 3 months following TBI. Their impact on longer-term cognitive endpoints and the potential benefits of seizure detection and treatment in this population warrant prospective study.

The Relationship Between Seizures and Spreading Depolarizations in Patients with Severe Traumatic Brain Injury.

BACKGROUND: Both seizures and spreading depolarizations (SDs) are commonly detected using electrocorticography (ECoG) after severe traumatic brain injury (TBI). A close relationship between seizures and SDs has been described, but the implications of detecting either or both remain unclear. We sought to characterize the relationship between these two phenomena and their clinical significance. METHODS: We performed a post hoc analysis of a prospective observational clinical study of patients with severe TBI requiring neurosurgery at five academic neurotrauma centers. A subdural electrode array was placed intraoperatively and ECoG was recorded during intensive care. SDs, seizures, and high-frequency background characteristics were quantified offline using published standards and terminology. The primary outcome was the Glasgow Outcome Scale-Extended score at 6 months post injury. RESULTS: There were 138 patients with valid ECoG recordings; the mean age was 47 ± 19 years, and 104 (75%) were men. Overall, 2,219 ECoG-detected seizures occurred in 38 of 138 (28%) patients in a bimodal pattern, with peak incidences at 1.7-1.8 days and 3.8-4.0 days post injury. Seizures detected on scalp electroencephalography (EEG) were diagnosed by standard clinical care in only 18 of 138 (13%). Of 15 patients with ECoG-detected seizures and contemporaneous scalp EEG, seven (47%) had no definite scalp EEG correlate. ECoG-detected seizures were significantly associated with the severity and number of SDs, which occurred in 83 of 138 (60%) of patients. Temporal interactions were observed in 17 of 24 (70.8%) patients with both ECoG-detected seizures and SDs. After controlling for known prognostic covariates and the presence of SDs, seizures detected on either ECoG or scalp EEG did not have an independent association with 6-month functional outcome but portended worse outcome among those with clustered or isoelectric SDs. CONCLUSIONS: In patients with severe TBI requiring neurosurgery, seizures were half as common as SDs. Seizures would have gone undetected without ECoG monitoring in 20% of patients. Although seizures alone did not influence 6-month functional outcomes in this cohort, they were independently associated with electrographic worsening and a lack of motor improvement following surgery. Temporal interactions between ECoG-detected seizures and SDs were common and held prognostic implications. Together, seizures and SDs may occur along a dynamic continuum of factors critical to the development of secondary brain injury. ECoG provides information integral to the clinical management of patients with TBI.

The Critical Role of Spreading Depolarizations in Early Brain Injury: Consensus and Contention.

BACKGROUND: When a patient arrives in the emergency department following a stroke, a traumatic brain injury, or sudden cardiac arrest, there is no therapeutic drug available to help protect their jeopardized neurons. One crucial reason is that we have not identified the molecular mechanisms leading to electrical failure, neuronal swelling, and blood vessel constriction in newly injured gray matter. All three result from a process termed spreading depolarization (SD). Because we only partially understand SD, we lack molecular targets and biomarkers to help neurons survive after losing their blood flow and then undergoing recurrent SD. METHODS: In this review, we introduce SD as a single or recurring event, generated in gray matter following lost blood flow, which compromises the Na+/K+ pump. Electrical recovery from each SD event requires so much energy that neurons often die over minutes and hours following initial injury, independent of extracellular glutamate. RESULTS: We discuss how SD has been investigated with various pitfalls in numerous experimental preparations, how overtaxing the Na+/K+ ATPase elicits SD. Elevated K+ or glutamate are unlikely natural activators of SD. We then turn to the properties of SD itself, focusing on its initiation and propagation as well as on computer modeling. CONCLUSIONS: Finally, we summarize points of consensus and contention among the authors as well as where SD research may be heading. In an accompanying review, we critique the role of the glutamate excitotoxicity theory, how it has shaped SD research, and its questionable importance to the study of early brain injury as compared with SD theory.

Questioning Glutamate Excitotoxicity in Acute Brain Damage: The Importance of Spreading Depolarization.

BACKGROUND: Within 2 min of severe ischemia, spreading depolarization (SD) propagates like a wave through compromised gray matter of the higher brain. More SDs arise over hours in adjacent tissue, expanding the neuronal damage. This period represents a therapeutic window to inhibit SD and so reduce impending tissue injury. Yet most neuroscientists assume that the course of early brain injury can be explained by glutamate excitotoxicity, the concept that immediate glutamate release promotes early and downstream brain injury. There are many problems with glutamate release being the unseen culprit, the most practical being that the concept has yielded zero therapeutics over the past 30 years. But the basic science is also flawed, arising from dubious foundational observations beginning in the 1950s METHODS: Literature pertaining to excitotoxicity and to SD over the past 60 years is critiqued. RESULTS: Excitotoxicity theory centers on the immediate and excessive release of glutamate with resulting neuronal hyperexcitation. This instigates poststroke cascades with subsequent secondary neuronal injury. By contrast, SD theory argues that although SD evokes some brief glutamate release, acute neuronal damage and the subsequent cascade of injury to neurons are elicited by the metabolic stress of SD, not by excessive glutamate release. The challenge we present here is to find new clinical targets based on more informed basic science. This is motivated by the continuing failure by neuroscientists and by industry to develop drugs that can reduce brain injury following ischemic stroke, traumatic brain injury, or sudden cardiac arrest. One important step is to recognize that SD plays a central role in promoting early neuronal damage. We argue that uncovering the molecular biology of SD initiation and propagation is essential because ischemic neurons are usually not acutely injured unless SD propagates through them. The role of glutamate excitotoxicity theory and how it has shaped SD research is then addressed, followed by a critique of its fading relevance to the study of brain injury. CONCLUSIONS: Spreading depolarizations better account for the acute neuronal injury arising from brain ischemia than does the early and excessive release of glutamate.

Development and Evaluation of a Method for Automated Detection of Spreading Depolarizations in the Injured Human Brain.

BACKGROUND: Spreading depolarizations (SDs) occur in some 60% of patients receiving intensive care following severe traumatic brain injury and often occur at a higher incidence following serious subarachnoid hemorrhage and malignant hemisphere stroke (MHS); they are independently associated with worse clinical outcome. Detection of SDs to guide clinical management, as is now being advocated, currently requires continuous and skilled monitoring of the electrocorticogram (ECoG), frequently extending over many days. METHODS: We developed and evaluated in two clinical intensive care units (ICU) a software routine capable of detecting SDs both in real time at the bedside and retrospectively and also capable of displaying patterns of their occurrence with time. We tested this prototype software in 91 data files, each of approximately 24 h, from 18 patients, and the results were compared with those of manual assessment ("ground truth") by an experienced assessor blind to the software outputs. RESULTS: The software successfully detected SDs in real time at the bedside, including in patients with clusters of SDs. Counts of SDs by software (dependent variable) were compared with ground truth by the investigator (independent) using linear regression. The slope of the regression was 0.7855 (95% confidence interval 0.7149-0.8561); a slope value of 1.0 lies outside the 95% confidence interval of the slope, representing significant undersensitivity of 79%. R2 was 0.8415. CONCLUSIONS: Despite significant undersensitivity, there was no additional loss of sensitivity at high SD counts, thus ensuring that dense clusters of depolarizations of particular pathogenic potential can be detected by software and depicted to clinicians in real time and also be archived.

Proceedings of the First Curing Coma Campaign NIH Symposium: Challenging the Future of Research for Coma and Disorders of Consciousness.

Coma and disorders of consciousness (DoC) are highly prevalent and constitute a burden for patients, families, and society worldwide. As part of the Curing Coma Campaign, the Neurocritical Care Society partnered with the National Institutes of Health to organize a symposium bringing together experts from all over the world to develop research targets for DoC. The conference was structured along six domains: (1) defining endotype/phenotypes, (2) biomarkers, (3) proof-of-concept clinical trials, (4) neuroprognostication, (5) long-term recovery, and (6) large datasets. This proceedings paper presents actionable research targets based on the presentations and discussions that occurred at the conference. We summarize the background, main research gaps, overall goals, the panel discussion of the approach, limitations and challenges, and deliverables that were identified.

What Should a Clinician Do When Spreading Depolarizations are Observed in a Patient?

The International Conference on Spreading Depolarizations (iCSD) held in Boca Raton, Florida, in the September of 2018 devoted a section to address the question, "What should a clinician do when spreading depolarizations are observed in a patient?" Discussants represented a wide range of expertise, including neurologists, neurointensivists, neuroradiologists, neurosurgeons, and pre-clinical neuroscientists, to provide both clinical and basic pathophysiology perspectives. A draft summary of viewpoints offered was then written by a multidisciplinary writing group of iCSD members, based on a transcript of the session. Feedback of all discussants was formally collated, reviewed, and incorporated into the final document which was subsequently approved by all authors.

Which Spreading Depolarizations Are Deleterious To Brain Tissue?

Spreading depolarizations (SDs) are profound disruptions of cellular homeostasis that slowly propagate through gray matter and present an extraordinary metabolic challenge to brain tissue. Recent work has shown that SDs occur commonly in human patients in the neurointensive care setting and have established a compelling case for their importance in the pathophysiology of acute brain injury. The International Conference on Spreading Depolarizations (iCSD) held in Boca Raton, Florida, in September of 2018 included a discussion session focused on the question of "Which SDs are deleterious to brain tissue?" iCSD is attended by investigators studying various animal species including invertebrates, in vivo and in vitro preparations, diseases of acute brain injury and migraine, computational modeling, and clinical brain injury, among other topics. The discussion included general agreement on many key issues, but also revealed divergent views on some topics that are relevant to the design of clinical interventions targeting SDs. A draft summary of viewpoints offered was then written by a multidisciplinary writing group of iCSD members, based on a transcript of the session. Feedback of all discussants was then formally collated, reviewed and incorporated into the final document. It is hoped that this report will stimulate collection of data that are needed to develop a more nuanced understanding of SD in different pathophysiological states, as the field continues to move toward effective clinical interventions.

The Curing Coma Campaign: Framing Initial Scientific Challenges-Proceedings of the First Curing Coma Campaign Scientific Advisory Council Meeting.

Coma and disordered consciousness are common manifestations of acute neurological conditions and are among the most pervasive and challenging aspects of treatment in neurocritical care. Gaps exist in patient assessment, outcome prognostication, and treatment directed specifically at improving consciousness and cognitive recovery. In 2019, the Neurocritical Care Society (NCS) launched the Curing Coma Campaign in order to address the "grand challenge" of improving the management of patients with coma and decreased consciousness. One of the first steps was to bring together a Scientific Advisory Council including coma scientists, neurointensivists, neurorehabilitationists, and implementation experts in order to address the current scientific landscape and begin to develop a framework on how to move forward. This manuscript describes the proceedings of the first Curing Coma Campaign Scientific Advisory Council meeting which occurred in conjunction with the NCS Annual Meeting in October 2019 in Vancouver. Specifically, three major pillars were identified which should be considered: endotyping of coma and disorders of consciousness, biomarkers, and proof-of-concept clinical trials. Each is summarized with regard to current approach, benefits to the patient, family, and clinicians, and next steps. Integration of these three pillars will be essential to the success of the Curing Coma Campaign as will expanding the "curing coma community" to ensure broad participation of clinicians, scientists, and patient advocates with the goal of identifying and implementing treatments to fundamentally improve the outcome of patients.

Continuous Electroencephalography After Moderate to Severe Traumatic Brain Injury.

OBJECTIVES: After traumatic brain injury, continuous electroencephalography is widely used to detect electrographic seizures. With the development of standardized continuous electroencephalography terminology, we aimed to describe the prevalence and burden of ictal-interictal patterns, including electrographic seizures after moderate-to-severe traumatic brain injury and to correlate continuous electroencephalography features with functional outcome. DESIGN: Post hoc analysis of the prospective, randomized controlled phase 2 multicenter INTREPID study (ClinicalTrials.gov: NCT00805818). Continuous electroencephalography was initiated upon admission to the ICU. The primary outcome was the 3-month Glasgow Outcome Scale-Extended. Consensus electroencephalography reviews were performed by raters certified in standardized continuous electroencephalography terminology blinded to clinical data. Rhythmic, periodic, or ictal patterns were referred to as "ictal-interictal continuum"; severe ictal-interictal continuum was defined as greater than or equal to 1.5 Hz lateralized rhythmic delta activity or generalized periodic discharges and any lateralized periodic discharges or electrographic seizures. SETTING: Twenty U.S. level I trauma centers. PATIENTS: Patients with nonpenetrating traumatic brain injury and postresuscitation Glasgow Coma Scale score of 4-12 were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 152 patients with continuous electroencephalography (age 34 ± 14 yr; 88% male), 22 (14%) had severe ictal-interictal continuum including electrographic seizures in four (2.6%). Severe ictal-interictal continuum burden correlated with initial prognostic scores, including the International Mission for Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (r = 0.51; p = 0.01) and Injury Severity Score (r = 0.49; p = 0.01), but not with functional outcome. After controlling clinical covariates, unfavorable outcome was independently associated with absence of posterior dominant rhythm (common odds ratio, 3.38; 95% CI, 1.30-9.09), absence of N2 sleep transients (3.69; 1.69-8.20), predominant delta activity (2.82; 1.32-6.10), and discontinuous background (5.33; 2.28-12.96) within the first 72 hours of monitoring. CONCLUSIONS: Severe ictal-interictal continuum patterns, including electrographic seizures, were associated with clinical markers of injury severity but not functional outcome in this prospective cohort of patients with moderate-to-severe traumatic brain injury. Importantly, continuous electroencephalography background features were independently associated with functional outcome and improved the area under the curve of existing, validated predictive models.

Terminal spreading depolarization and electrical silence in death of human cerebral cortex.

OBJECTIVE: Restoring the circulation is the primary goal in emergency treatment of cerebral ischemia. However, better understanding of how the brain responds to energy depletion could help predict the time available for resuscitation until irreversible damage and advance development of interventions that prolong this span. Experimentally, injury to central neurons begins only with anoxic depolarization. This potentially reversible, spreading wave typically starts 2 to 5 minutes after the onset of severe ischemia, marking the onset of a toxic intraneuronal change that eventually results in irreversible injury. METHODS: To investigate this in the human brain, we performed recordings with either subdural electrode strips (n = 4) or intraparenchymal electrode arrays (n = 5) in patients with devastating brain injury that resulted in activation of a Do Not Resuscitate-Comfort Care order followed by terminal extubation. RESULTS: Withdrawal of life-sustaining therapies produced a decline in brain tissue partial pressure of oxygen (pti O2 ) and circulatory arrest. Silencing of spontaneous electrical activity developed simultaneously across regional electrode arrays in 8 patients. This silencing, termed "nonspreading depression," developed during the steep falling phase of pti O2 (intraparenchymal sensor, n = 6) at 11 (interquartile range [IQR] = 7-14) mmHg. Terminal spreading depolarizations started to propagate between electrodes 3.9 (IQR = 2.6-6.3) minutes after onset of the final drop in perfusion and 13 to 266 seconds after nonspreading depression. In 1 patient, terminal spreading depolarization induced the initial electrocerebral silence in a spreading depression pattern; circulatory arrest developed thereafter. INTERPRETATION: These results provide fundamental insight into the neurobiology of dying and have important implications for survivable cerebral ischemic insults. Ann Neurol 2018;83:295-310.

The negative ultraslow potential, electrophysiological correlate of infarction in the human cortex.

Spreading depolarizations are characterized by abrupt, near-complete breakdown of the transmembrane ion gradients, neuronal oedema, mitochondrial depolarization, glutamate excitotoxicity and activity loss (depression). Spreading depolarization induces either transient hyperperfusion in normal tissue; or hypoperfusion (inverse coupling = spreading ischaemia) in tissue at risk for progressive injury. The concept of the spreading depolarization continuum is critical since many spreading depolarizations have intermediate characteristics, as opposed to the two extremes of spreading depolarization in either severely ischaemic or normal tissue. In animals, the spreading depolarization extreme in ischaemic tissue is characterized by prolonged depolarization durations, in addition to a slow baseline variation termed the negative ultraslow potential. The negative ultraslow potential is initiated by spreading depolarization and similar to the negative direct current (DC) shift of prolonged spreading depolarization, but specifically refers to a negative potential component during progressive recruitment of neurons into cell death in the wake of spreading depolarization. We here first quantified the spreading depolarization-initiated negative ultraslow potential in the electrocorticographic DC range and the activity depression in the alternate current range after middle cerebral artery occlusion in rats. Relevance of these variables to the injury was supported by significant correlations with the cortical infarct volume and neurological outcome after 72 h of survival. We then identified negative ultraslow potential-containing clusters of spreading depolarizations in 11 patients with aneurysmal subarachnoid haemorrhage. The human platinum/iridium-recorded negative ultraslow potential showed a tent-like shape. Its amplitude of 45.0 (39.0, 69.4) mV [median (first, third quartile)] was 6.6 times larger and its duration of 3.7 (3.3, 5.3) h was 34.9 times longer than the negative DC shift of spreading depolarizations in less compromised tissue. Using Generalized Estimating Equations applied to a logistic regression model, we found that negative ultraslow potential displaying electrodes were significantly more likely to overlie a developing ischaemic lesion (90.0%, 27/30) than those not displaying a negative ultraslow potential (0.0%, 0/20) (P = 0.004). Based on serial neuroimages, the lesions under the electrodes developed within a time window of 72 (56, 134) h. The negative ultraslow potential occurred in this time window in 9/10 patients. It was often preceded by a spreading depolarization cluster with increasingly persistent spreading depressions and progressively prolonged DC shifts and spreading ischaemias. During the negative ultraslow potential, spreading ischaemia lasted for 40.0 (28.0, 76.5) min, cerebral blood flow fell from 57 (53, 65) % to 26 (16, 42) % (n = 4) and tissue partial pressure of oxygen from 12.5 (9.2, 15.2) to 3.3 (2.4, 7.4) mmHg (n = 5). Our data suggest that the negative ultraslow potential is the electrophysiological correlate of infarction in human cerebral cortex and a neuromonitoring-detected medical emergency.awy102media15775596049001.

Lasting s-ketamine block of spreading depolarizations in subarachnoid hemorrhage: a retrospective cohort study.

OBJECTIVE: Spreading depolarizations (SD) are characterized by breakdown of transmembrane ion gradients and excitotoxicity. Experimentally, N-methyl-D-aspartate receptor (NMDAR) antagonists block a majority of SDs. In many hospitals, the NMDAR antagonist s-ketamine and the GABAA agonist midazolam represent the current second-line combination treatment to sedate patients with devastating cerebral injuries. A pressing clinical question is whether this option should become first-line in sedation-requiring individuals in whom SDs are detected, yet the s-ketamine dose necessary to adequately inhibit SDs is unknown. Moreover, use-dependent tolerance could be a problem for SD inhibition in the clinic. METHODS: We performed a retrospective cohort study of 66 patients with aneurysmal subarachnoid hemorrhage (aSAH) from a prospectively collected database. Thirty-three of 66 patients received s-ketamine during electrocorticographic neuromonitoring of SDs in neurointensive care. The decision to give s-ketamine was dependent on the need for stronger sedation, so it was expected that patients receiving s-ketamine would have a worse clinical outcome. RESULTS: S-ketamine application started 4.2 ± 3.5 days after aSAH. The mean dose was 2.8 ± 1.4 mg/kg body weight (BW)/h and thus higher than the dose recommended for sedation. First, patients were divided according to whether they received s-ketamine at any time or not. No significant difference in SD counts was found between groups (negative binomial model using the SD count per patient as outcome variable, p = 0.288). This most likely resulted from the fact that 368 SDs had already occurred in the s-ketamine group before s-ketamine was given. However, in patients receiving s-ketamine, we found a significant decrease in SD incidence when s-ketamine was started (Poisson model with a random intercept for patient, coefficient - 1.83 (95% confidence intervals - 2.17; - 1.50), p < 0.001; logistic regression model, odds ratio (OR) 0.13 (0.08; 0.19), p < 0.001). Thereafter, data was further divided into low-dose (0.1-2.0 mg/kg BW/h) and high-dose (2.1-7.0 mg/kg/h) segments. High-dose s-ketamine resulted in further significant decrease in SD incidence (Poisson model, - 1.10 (- 1.71; - 0.49), p < 0.001; logistic regression model, OR 0.33 (0.17; 0.63), p < 0.001). There was little evidence of SD tolerance to long-term s-ketamine sedation through 5 days. CONCLUSIONS: These results provide a foundation for a multicenter, neuromonitoring-guided, proof-of-concept trial of ketamine and midazolam as a first-line sedative regime.

Neurostereologic Lesion Volumes and Spreading Depolarizations in Severe Traumatic Brain Injury Patients: A Pilot Study.

BACKGROUND: Spreading depolarizations (SDs) occur in 50-60% of patients after surgical treatment of severe traumatic brain injury (TBI) and are independently associated with unfavorable outcomes. Here we performed a pilot study to examine the relationship between SDs and various types of intracranial lesions, progression of parenchymal damage, and outcomes. METHODS: In a multicenter study, fifty patients (76% male; median age 40) were monitored for SD by continuous electrocorticography (ECoG; median duration 79 h) following surgical treatment of severe TBI. Volumes of hemorrhage and parenchymal damage were estimated using unbiased stereologic assessment of preoperative, postoperative, and post-ECoG serial computed tomography (CT) studies. Neurologic outcomes were assessed at 6 months by the Glasgow Outcome Scale-Extended. RESULTS: Preoperative volumes of subdural and subarachnoid hemorrhage, but not parenchymal damage, were significantly associated with the occurrence of SDs (P's < 0.05). Parenchymal damage increased significantly (median 34 ml [Interquartile range (IQR) - 2, 74]) over 7 (5, 8) days from preoperative to post-ECoG CT studies. Patients with and without SDs did not differ in extent of parenchymal damage increase [47 ml (3, 101) vs. 30 ml (- 2, 50), P = 0.27], but those exhibiting the isoelectric subtype of SDs had greater initial parenchymal damage and greater increases than other patients (P's < 0.05). Patients with temporal clusters of SDs (≥ 3 in 2 h; n = 10 patients), which included those with isoelectric SDs, had worse outcomes than those without clusters (P = 0.03), and parenchymal damage expansion also correlated with worse outcomes (P = 0.01). In multivariate regression with imputation, both clusters and lesion expansion were significant outcome predictors. CONCLUSIONS: These results suggest that subarachnoid and subdural blood are important primary injury factors in provoking SDs and that clustered SDs and parenchymal lesion expansion contribute independently to worse patient outcomes. These results warrant future prospective studies using detailed quantification of TBI lesion types to better understand the relationship between anatomic and physiologic measures of secondary injury.

A case report of delayed cortical infarction adjacent to sulcal clots after traumatic subarachnoid hemorrhage in the absence of proximal vasospasm.

BACKGROUND: Cortical ischemic lesions represent the predominant pathomorphological pattern of focal lesions after aneurysmal subarachnoid hemorrhage (aSAH). Autopsy studies suggest that they occur adjacent to subarachnoid blood and are related to spasm of small cortical rather than proximal arteries. Recent clinical monitoring studies showed that cortical spreading depolarizations, which induce cortical arterial spasms, are involved in lesion development. If subarachnoid blood induces adjacent cortical lesions, it would be expected that (i) they also develop after traumatic subarachnoid hemorrhage (tSAH), and (ii) lesions after tSAH can occur in absence of angiographic vasospasm, as was found for aSAH. CASE PRESENTATION: An 86-year-old woman was admitted to our hospital with fluctuating consciousness after hitting her head during a fall. The initial computed tomography (CT) was significant for tSAH in cortical sulci. On day 8, the patient experienced a secondary neurological deterioration with reduced consciousness and global aphasia. Whereas the CT scan on day 9 was still unremarkable, magnetic resonance imaging (MRI) on day 10 revealed new cortical laminar infarcts adjacent to sulcal blood clots. Proximal vasospasm was ruled out using MR and CT angiography and Doppler sonography. CT on day 14 confirmed the delayed infarcts. CONCLUSIONS: We describe a case of delayed cortical infarcts around sulcal blood clots after tSAH in the absence of proximal vasospasm, similar to results found previously for aSAH. As for aSAH, this case suggests that assessment of angiographic vasospasm is not sufficient to screen for risk of delayed infarcts after tSAH. Electrocorticography is suggested as a complementary method to monitor the hypothesized mechanism of spreading depolarizations.

Subarachnoid blood acutely induces spreading depolarizations and early cortical infarction.

See Ghoshal and Claassen (doi:10.1093/brain/awx226) for a scientific commentary on this article. Early cortical infarcts are common in poor-grade patients after aneurysmal subarachnoid haemorrhage. There are no animal models of these lesions and mechanisms are unknown, although mass cortical spreading depolarizations are hypothesized as a requisite mechanism and clinical marker of infarct development. Here we studied acute sequelae of subarachnoid haemorrhage in the gyrencephalic brain of propofol-anaesthetized juvenile swine using subdural electrode strips (electrocorticography) and intraparenchymal neuromonitoring probes. Subarachnoid infusion of 1­2 ml of fresh blood at 200 µl/min over cortical sulci caused clusters of spreading depolarizations (count range: 12­34) in 7/17 animals in the ipsilateral but not contralateral hemisphere in 6 h of monitoring, without meaningful changes in other variables. Spreading depolarization clusters were associated with formation of sulcal clots (P < 0.01), a high likelihood of adjacent cortical infarcts (5/7 versus 2/10, P < 0.06), and upregulation of cyclooxygenase-2 in ipsilateral cortex remote from clots/infarcts. In a second cohort, infusion of 1 ml of clotted blood into a sulcus caused spreading depolarizations in 5/6 animals (count range: 4­20 in 6 h) and persistent thick clots with patchy or extensive infarction of circumscribed cortex in all animals. Infarcts were significantly larger after blood clot infusion compared to mass effect controls using fibrin clots of equal volume. Haematoxylin and eosin staining of infarcts showed well demarcated zones of oedema and hypoxic-ischaemic neuronal injury, consistent with acute infarction. The association of spreading depolarizations with early brain injury was then investigated in 23 patients [14 female; age (median, quartiles): 57 years (47, 63)] after repair of ruptured anterior communicating artery aneurysms by clip ligation (n = 14) or coiling (n = 9). Frontal electrocorticography [duration: 54 h (34, 66)] from subdural electrode strips was analysed over Days 0­3 after initial haemorrhage and magnetic resonance imaging studies were performed at ∼ 24­48 h after aneurysm treatment. Patients with frontal infarcts only and those with frontal infarcts and/or intracerebral haemorrhage were both significantly more likely to have spreading depolarizations (6/7 and 10/12, respectively) than those without frontal brain lesions (1/11, P's < 0.05). These results suggest that subarachnoid clots in sulci/fissures are sufficient to induce spreading depolarizations and acute infarction in adjacent cortex. We hypothesize that the cellular toxicity and vasoconstrictive effects of depolarizations act in synergy with direct ischaemic effects of haemorrhage as mechanisms of infarct development. Results further validate spreading depolarizations as a clinical marker of early brain injury and establish a clinically relevant model to investigate causal pathologic sequences and potential therapeutic interventions.