Subarachnoid blood acutely induces spreading depolarizations and early cortical infarction.
Jed A. Hartings,Jonathan York,Christopher P. Carroll,Jason M. Hinzman,Eric Mahoney,Bryan M Krueger,Maren K.L. Winkler,Sebastian Major,Viktor Horst,Paul Jahnke,Johannes Woitzik,Vasilis Kola,Yifeng Du,Matthew C. Hagen,Jianxiong Jiang,Jens P. Dreier +15 more
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TLDR
The results suggest that subarachnoid clots in sulci/fissures are sufficient to induce spreading depolarizations and acute infarction in adjacent cortex, and hypothesize that the cellular toxicity and vasoconstrictive effects of depolarization act in synergy with direct ischaemic effects of haemorrhage as mechanisms of infarct development.Abstract:
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 1–2 ml of fresh blood at 200 µl/min over cortical sulci caused clusters of spreading depolarizations (count range: 12–34) 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: 4–20 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 0–3 after initial haemorrhage and magnetic resonance imaging studies were performed at ∼ 24–48 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.read more
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Cerebrospinal fluid influx drives acute ischemic tissue swelling
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Initial and recurrent bleeding are the major causes of death following subarachnoid hemorrhage
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Spreading depolarization is not an epiphenomenon but the principal mechanism of the cytotoxic edema in various gray matter structures of the brain during stroke.
TL;DR: It is summarized that spreading depolarization is the electrophysiological correlate of the cytotoxic edema in various gray matter structures of the brain and vasogenic edema is the other major type of cerebral edema with relevance to ischemic stroke.
Journal ArticleDOI
Early Brain Injury After Poor-Grade Subarachnoid Hemorrhage.
Verena Rass,Raimund Helbok +1 more
TL;DR: A large heterogeneity is found in the definition used for EBI comprising clinical symptoms, neuroimaging parameters, and advanced neuromonitoring techniques and future research integrating brain-derived biomarkers is warranted to improve pathophysiologic understanding of EBI.
Journal ArticleDOI
The negative ultraslow potential, electrophysiological correlate of infarction in the human cortex
Janos Luckl,Coline L. Lemale,Vasilis Kola,Viktor Horst,Uldus Khojasteh,Ana I Oliveira-Ferreira,Sebastian Major,Maren K.L. Winkler,Eun-Jeung Kang,Karl Schoknecht,Peter Martus,Jed A. Hartings,Johannes Woitzik,Jens P. Dreier +13 more
TL;DR: The data suggest that the negative ultraslow potential is the electrophysiological correlate of infarction in human cerebral cortex and a neuromonitoring-detected medical emergency in patients with aneurysmal subarachnoid haemorrhage.
References
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Relation of Cerebral Vasospasm to Subarachnoid Hemorrhage Visualized by Computerized Tomographic Scanning
TL;DR: The results indicate that blood localized in the subarachnoid space in sufficient amount at specific sites is the only important etiological factor in vasospasm and it should be possible to identify patients in jeopardy from vasospasms and institute early preventive measures.
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The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease
TL;DR: Therapies that target spreading depolarization or the inverse hemodynamic response may potentially treat neurological conditions such as aneurismal subarachnoid hemorrhage or traumatic brain injury.
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Initial and recurrent bleeding are the major causes of death following subarachnoid hemorrhage.
TL;DR: Most deaths after subarachnoid hemorrhage occur very rapidly and are due to the initial hemorrhage, and rebleeding is the most important preventable cause of death in hospitalized patients.
Journal ArticleDOI
Clinical Relevance of Cortical Spreading Depression in Neurological Disorders: Migraine, Malignant Stroke, Subarachnoid and Intracranial Hemorrhage, and Traumatic Brain Injury:
Martin Lauritzen,Jens P. Dreier,Martin Fabricius,Jed A. Hartings,Rudolf Graf,Anthony J. Strong +5 more
TL;DR: Treatment strategies are suggested which may be used to prevent or attenuate secondary neuronal damage in acutely injured human brain cortex caused by depolarization waves, which implicates CSD as a pathophysiological mechanism for this group of acute neurological disorders.
Journal ArticleDOI
Delayed ischaemic neurological deficits after subarachnoid haemorrhage are associated with clusters of spreading depolarizations
Jens P. Dreier,Johannes Woitzik,Martin Fabricius,Robin Bhatia,Sebastian Major,Chistoph Drenckhahn,Thomas-Nicolas Lehmann,Asita S. Sarrafzadeh,Lisette Willumsen,Jed A. Hartings,Oliver W. Sakowitz,Jörg H. Seemann,Anja Thieme,Martin Lauritzen,Anthony J. Strong +14 more
TL;DR: It is suggested that spreading depolarizations with prolonged depressions are a promising target for treatment development in SAH and ischaemic stroke.
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