Spreading depolarization and angiographic spasm are separate mediators of delayed infarcts.

In DISCHARGE-1, a recent Phase III diagnostic trial in aneurysmal subarachnoid haemorrhage patients, spreading depolarization variables were found to be an independent real-time biomarker of delayed cerebral ischaemia. We here investigated based on prospectively collected data from DISCHARGE-1 whether delayed infarcts in the anterior, middle, or posterior cerebral artery territories correlate with (i) extravascular blood volumes; (ii) predefined spreading depolarization variables, or proximal vasospasm assessed by either (iii) digital subtraction angiography or (iv) transcranial Doppler-sonography; and whether spreading depolarizations and/or vasospasm are mediators between extravascular blood and delayed infarcts. Relationships between variable groups were analysed using Spearman correlations in 136 patients. Thereafter, principal component analyses were performed for each variable group. Obtained components were included in path models with a priori defined structure. In the first path model, we only included spreading depolarization variables, as our primary interest was to investigate spreading depolarizations. Standardised path coefficients were 0.22 for the path from extravascular bloodcomponent to depolarizationcomponent (P = 0.010); and 0.44 for the path from depolarizationcomponent to the first principal component of delayed infarct volume (P < 0.001); but only 0.07 for the direct path from bloodcomponent to delayed infarctcomponent (P = 0.36). Thus, the role of spreading depolarizations as a mediator between blood and delayed infarcts was confirmed. In the principal component analysis of extravascular blood volume, intraventricular haemorrhage was not represented in the first component. Therefore, based on the correlation analyses, we also constructed another path model with bloodcomponent without intraventricular haemorrhage as first and intraventricular haemorrhage as second extrinsic variable. We found two paths, one from (subarachnoid) bloodcomponent to delayed infarctcomponent with depolarizationcomponent as mediator (path coefficients from bloodcomponent to depolarizationcomponent = 0.23, P = 0.03; path coefficients from depolarizationcomponent to delayed infarctcomponent = 0.29, P = 0.002), and one from intraventricular haemorrhage to delayed infarctcomponent with angiographic vasospasmcomponent as mediator variable (path coefficients from intraventricular haemorrhage to vasospasmcomponent = 0.24, P = 0.03; path coefficients from vasospasmcomponent to delayed infarctcomponent = 0.35, P < 0.001). Human autopsy studies shaped the hypothesis that blood clots on the cortex surface suffice to cause delayed infarcts beneath the clots. Experimentally, clot-released factors induce cortical spreading depolarizations that trigger (i) neuronal cytotoxic oedema and (ii) spreading ischaemia. The statistical mediator role of spreading depolarization variables between subarachnoid blood volume and delayed infarct volume supports this pathogenetic concept. We did not find that angiographic vasospasm triggers spreading depolarizations, but angiographic vasospasm contributed to delayed infarct volume. This could possibly result from enhancement of spreading depolarization-induced spreading ischaemia by reduced upstream blood supply.

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.

Early focal brain injury after subarachnoid hemorrhage correlates with spreading depolarizations.

OBJECTIVE: To investigate whether spreading depolarization (SD)-related variables at 2 different time windows (days 1-4 and 5-8) after aneurysmal subarachnoid hemorrhage (aSAH) correlate with the stereologically determined volume of early focal brain injury on the preinterventional CT scan. METHODS: In this observational multicenter study of 54 patients, volumes of unaffected brain tissue, ventricles, cerebellum, aSAH, intracerebral hemorrhage, and focal parenchymal hypodensity were stereologically estimated. Patients were electrocorticographically monitored using subdural electrodes for 81.8 hours (median) (interquartile range: 70.6-90.5) during days 1-4 (n = 54) and for 75.9 (59.5-88.7) hours during days 5-8 (n = 51). Peak total SD-induced depression duration of a recording day (PTDDD) and peak numbers of (1) SDs, (2) isoelectric SDs, and (3) spreading depressions of a recording day were determined following the recommendations of the Co-Operative Studies on Brain Injury Depolarizations. RESULTS: Thirty-three of 37 patients with early focal brain injury (intracerebral hemorrhage and/or hypodensity) in contrast to 7 of 17 without displayed SDs during days 1-4 (sensitivity: 89% [95% confidence interval, CI: 75%-97%], specificity: 59% [CI: 33%-82%], positive predictive value: 83% [CI: 67%-93%], negative predictive value: 71% [CI: 42%-92%], Fisher exact test, p < 0.001). All 4 SD-related variables during days 1-4 significantly correlated with the volume of early focal brain injury (Spearman rank order correlations). A multiple ordinal regression analysis identified the PTDDD as the most important predictor. CONCLUSIONS: Our findings suggest that early focal brain injury after aSAH is associated with early SDs and further support the notion that SDs are a biomarker of focal brain lesions.

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.

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.

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.

Simulation of spreading depolarization trajectories in cerebral cortex: Correlation of velocity and susceptibility in patients with aneurysmal subarachnoid hemorrhage.

In many cerebral grey matter structures including the neocortex, spreading depolarization (SD) is the principal mechanism of the near-complete breakdown of the transcellular ion gradients with abrupt water influx into neurons. Accordingly, SDs are abundantly recorded in patients with traumatic brain injury, spontaneous intracerebral hemorrhage, aneurysmal subarachnoid hemorrhage (aSAH) and malignant hemispheric stroke using subdural electrode strips. SD is observed as a large slow potential change, spreading in the cortex at velocities between 2 and 9 mm/min. Velocity and SD susceptibility typically correlate positively in various animal models. In patients monitored in neurocritical care, the Co-Operative Studies on Brain Injury Depolarizations (COSBID) recommends several variables to quantify SD occurrence and susceptibility, although accurate measures of SD velocity have not been possible. Therefore, we developed an algorithm to estimate SD velocities based on reconstructing SD trajectories of the wave-front's curvature center from magnetic resonance imaging scans and time-of-SD-arrival-differences between subdural electrode pairs. We then correlated variables indicating SD susceptibility with algorithm-estimated SD velocities in twelve aSAH patients. Highly significant correlations supported the algorithm's validity. The trajectory search failed significantly more often for SDs recorded directly over emerging focal brain lesions suggesting in humans similar to animals that the complexity of SD propagation paths increase in tissue undergoing injury.

The Hijdra scale has significant prognostic value for the functional outcome of Fisher grade 3 patients with subarachnoid hemorrhage.

PURPOSE: Despite its high prevalence among patients with aneurysmal subarachnoid hemorrhage (aSAH) and high risk of delayed cerebral ischemia (DCI), the Fisher grade 3 category remains a poorly studied subgroup. The aim of this cohort study has been to investigate the prognostic value of the Hijdra sum scoring system for the functional outcome in patients with Fisher grade 3 aSAH, in order to improve the risk stratification within this Fisher category. METHODS: Initial CT scans of 72 prospectively enrolled patients with Fisher grade 3 aSAH were analyzed, and cisternal, ventricular, and total amount of blood were graded according to the Hijdra scale. Additionally, space-occupying subarachnoid blood clots were assessed. Outcome was evaluated after 6 months. RESULTS: Within the subgroup of Fisher grade 3, aSAH patients with an unfavorable outcome showed a significantly larger cisternal Hijdra sum score (HSS: 21.1 ± 5.2) than patients with a favorable outcome (HSS: 17.6 ± 5.9; p = 0.009). However, both the amount of ventricular blood (p = 0.165) and space-occupying blood clots (p = 0.206) appeared to have no prognostic relevance. After adjusting for the patient's age, gender, tobacco use, clinical status at admission, and presence of intracerebral hemorrhage, the cisternal and total HSS remained the only independent parameters included in multivariate logistic regression models to predict functional outcome (p < 0.01). CONCLUSION: The cisternal Hijdra score is fairly easy to perform and the present study indicates that it has an additional predictive value for the functional outcome within the Fisher 3 category. We suggest that the Hijdra scale is a practically useful prognostic instrument for the risk evaluation after aSAH and should be applied more often in the clinical setting.

Propagation of cortical spreading depolarization in the human cortex after malignant stroke.

OBJECTIVE: To investigate hemodynamic response pattern and spatiotemporal propagation of cortical spreading depolarization in the peri-infarct region of malignant hemispheric stroke. METHODS: In this prospective observational case study we used intraoperative laser speckle technology to measure cerebral blood flow in patients with malignant hemispheric stroke. Additionally, postoperative occurrence of cortical spreading depolarization was monitored using a subdural recording strip for electrocorticography and infarct progression was assessed by serial MRI. RESULTS: In 7 of 20 patients, 19 blood flow changes typical of cortical spreading depolarizations occurred during a 20-minute period. Thirteen events were characterized by increase, 2 by biphasic response, and 4 by decrease of blood flow. Propagation velocity ranged from 1.7 to 9.2 mm/min and propagation area from 0.1 to 4.8 cm(2). Intrinsic optical signal alterations preceded and low-frequency vascular fluctuations were suppressed during the hemodynamic responses. A mean number of 56 ± 82 cortical spreading depolarizations per patient was recorded and a mean infarct progression of 30 ± 13 cm(3) was detected in 5 of 7 patients. CONCLUSIONS: We visualize the spatiotemporal propagation of spreading depolarizations in the human cerebral cortex intraoperatively. In patients with focal ischemia, multiple cortical spreading depolarizations with either hyperemic or hypoemic flow responses occurred. Our data suggest that, in patients with focal ischemia, cortical spreading depolarizations are associated with both unfavorable and protective hemodynamic responses.

Impaired neurovascular coupling to ictal epileptic activity and spreading depolarization in a patient with subarachnoid hemorrhage: possible link to blood-brain barrier dysfunction.

Spreading depolarization describes a sustained neuronal and astroglial depolarization with abrupt ion translocation between intraneuronal and extracellular space leading to a cytotoxic edema and silencing of spontaneous activity. Spreading depolarizations occur abundantly in acutely injured human brain and are assumed to facilitate neuronal death through toxic effects, increased metabolic demand, and inverse neurovascular coupling. Inverse coupling describes severe hypoperfusion in response to spreading depolarization. Ictal epileptic events are less frequent than spreading depolarizations in acutely injured human brain but may also contribute to lesion progression through increased metabolic demand. Whether abnormal neurovascular coupling can occur with ictal epileptic events is unknown. Herein we describe a patient with aneurysmal subarachnoid hemorrhage in whom spreading depolarizations and ictal epileptic events were measured using subdural opto-electrodes for direct current electrocorticography and regional cerebral blood flow recordings with laser-Doppler flowmetry. Simultaneously, changes in tissue partial pressure of oxygen were recorded with an intraparenchymal oxygen sensor. Isolated spreading depolarizations and clusters of recurrent spreading depolarizations with persistent depression of spontaneous activity were recorded over several days followed by a status epilepticus. Both spreading depolarizations and ictal epileptic events where accompanied by hyperemic blood flow responses at one optode but mildly hypoemic blood flow responses at another. Of note, quantitative analysis of Gadolinium-diethylene-triamine-pentaacetic acid (DTPA)-enhanced magnetic resonance imaging detected impaired blood-brain barrier integrity in the region where the optode had recorded the mildly hypoemic flow responses. The data suggest that abnormal flow responses to spreading depolarizations and ictal epileptic events, respectively, may be associated with blood-brain barrier dysfunction.

Correlates of spreading depolarization in human scalp electroencephalography.

It has been known for decades that suppression of spontaneous scalp electroencephalographic activity occurs during ischaemia. Trend analysis for such suppression was found useful for intraoperative monitoring during carotid endarterectomy, or as a screening tool to detect delayed cerebral ischaemia after aneurismal subarachnoid haemorrhage. Nevertheless, pathogenesis of such suppression of activity has remained unclear. In five patients with aneurismal subarachnoid haemorrhage and four patients with decompressive hemicraniectomy after malignant hemispheric stroke due to middle cerebral artery occlusion, we here performed simultaneously full-band direct and alternating current electroencephalography at the scalp and direct and alternating current electrocorticography at the cortical surface. After subarachnoid haemorrhage, 275 slow potential changes, identifying spreading depolarizations, were recorded electrocorticographically over 694 h. Visual inspection of time-compressed scalp electroencephalography identified 193 (70.2%) slow potential changes [amplitude: -272 (-174, -375) µV (median quartiles), duration: 5.4 (4.0, 7.1) min, electrocorticography-electroencephalography delay: 1.8 (0.8, 3.5) min]. Intervals between successive spreading depolarizations were significantly shorter for depolarizations with electroencephalographically identified slow potential change [33.0 (27.0, 76.5) versus 53.0 (28.0, 130.5) min, P = 0.009]. Electroencephalography was thus more likely to display slow potential changes of clustered than isolated spreading depolarizations. In contrast to electrocorticography, no spread of electroencephalographic slow potential changes was seen, presumably due to superposition of volume-conducted electroencephalographic signals from widespread cortical generators. In two of five patients with subarachnoid haemorrhage, serial magnetic resonance imaging revealed large delayed infarcts at the recording site, while electrocorticography showed clusters of spreading depolarizations with persistent depression of spontaneous activity. Alternating current electroencephalography similarly displayed persistent depression of spontaneous activity, and direct current electroencephalography slow potential changes riding on a shallow negative ultraslow potential. Isolated spreading depolarizations with depression of both spontaneous electrocorticographic and electroencephalographic activity displayed significantly longer intervals between successive spreading depolarizations than isolated depolarizations with only depression of electrocorticographic activity [44.0 (28.0, 132.0) min, n = 96, versus 30.0 (26.5, 51.5) min, n = 109, P = 0.001]. This suggests fusion of electroencephalographic depression periods at high depolarization frequency. No propagation of electroencephalographic depression was seen between scalp electrodes. Durations/magnitudes of isolated electroencephalographic and corresponding electrocorticographic depression periods correlated significantly. Fewer spreading depolarizations were recorded in patients with malignant hemispheric stroke but characteristics were similar to those after subarachnoid haemorrhage. In conclusion, spreading depolarizations and depressions of spontaneous activity display correlates in time-compressed human scalp direct and alternating current electroencephalography that may serve for their non-invasive detection.

Spreading convulsions, spreading depolarization and epileptogenesis in human cerebral cortex.

Spreading depolarization of cells in cerebral grey matter is characterized by massive ion translocation, neuronal swelling and large changes in direct current-coupled voltage recording. The near-complete sustained depolarization above the inactivation threshold for action potential generating channels initiates spreading depression of brain activity. In contrast, epileptic seizures show modest ion translocation and sustained depolarization below the inactivation threshold for action potential generating channels. Such modest sustained depolarization allows synchronous, highly frequent neuronal firing; ictal epileptic field potentials being its electrocorticographic and epileptic seizure its clinical correlate. Nevertheless, Leão in 1944 and Van Harreveld and Stamm in 1953 described in animals that silencing of brain activity induced by spreading depolarization changed during minimal electrical stimulations. Eventually, epileptic field potentials were recorded during the period that had originally seen spreading depression of activity. Such spreading convulsions are characterized by epileptic field potentials on the final shoulder of the large slow potential change of spreading depolarization. We here report on such spreading convulsions in monopolar subdural recordings in 2 of 25 consecutive aneurismal subarachnoid haemorrhage patients in vivo and neocortical slices from 12 patients with intractable temporal lobe epilepsy in vitro. The in vitro results suggest that γ-aminobutyric acid-mediated inhibition protects from spreading convulsions. Moreover, we describe arterial pulse artefacts mimicking epileptic field potentials in three patients with subarachnoid haemorrhage that ride on the slow potential peak. Twenty-one of the 25 subarachnoid haemorrhage patients (84%) had 656 spreading depolarizations in contrast to only three patients (12%) with 55 ictal epileptic events isolated from spreading depolarizations. Spreading depolarization frequency and depression periods per 24 h recording episodes showed an early and a delayed peak on Day 7. Patients surviving subarachnoid haemorrhage with poor outcome at 6 months showed significantly higher total and peak numbers of spreading depolarizations and significantly longer total and peak depression periods during the electrocorticographic monitoring than patients with good outcome. In a semi-structured telephone interview 3 years after the initial haemorrhage, 44% of the subarachnoid haemorrhage survivors had developed late post-haemorrhagic seizures requiring anti-convulsant medication. In those patients, peak spreading depolarization number had been significantly higher [15.1 (11.4-30.8) versus 7.0 (0.8-11.2) events per day, P = 0.045]. In summary, monopolar recordings here provided unequivocal evidence of spreading convulsions in patients. Hence, practically all major pathological cortical network events in animals have now been observed in people. Early spreading depolarizations may indicate a risk for late post-haemorrhagic seizures.