Unterschiede in der Anfälligkeit von akut verletztem und chronisch epileptischem Gehirn gegenüber Auslösung von Cortical Spreading Depolarization und epileptischer Aktivität

Epileptic seizures and cortical spreading depolarization (CSD) are two patterns of electrophysiological activity that can be studied in the healthy and in the injured brain. They can be triggered by the same pathologies, such as stroke, traumatic brain injury and fever, with disruption of the blood brain barrier as a common hallmark. The latter is associated with entry of serum components into the brain interstitial space, such as albumin and immune factors, and a shift of extracellular ion concentrations towards serum values. While CSD can acutely deteriorate patients’ outcome, hyperexcitability of the tissue is potentially indicative for the development of chronic seizures. Chronic epilepsy is usually preceded by an initial silent period, during which reorganization processes take place. In my thesis, I have examined the relationship between CSD, acute and chronic tissue excitability and blood brain barrier disruption, using electrophysiological recordings from acute temporo-hippocampal slices and immunocytochemistry stains of the temporo- hippocampal formation. The main findings of the work are that CSD and epileptic seizures can coexist in both acute brain injury and chronic epilepsy. However chronic epileptic tissue is more resistant to agents, which have proven to be potent inducers of epileptic seizures and/or CSDs in the healthy brain. Moreover, agents, which are harmless or even play a physiological function in the healthy brain, can become ictogenic in the chronically epileptic brain, as is the case with the neurotransmitter acetylcholine. These results provide evidence that hyperexcitability in acute brain injury and chronic epilepsy are driven by different mechanisms and therefore distinct treatment strategies should be considered.Epileptische Entladungen und kortikale „spreading depolarizations“ (CSDs) sind zwei Muster elektrophysiologischer Aktivität, die sowohl im gesunden als auch im verletzten Gehirngewebe untersucht werden können. Beide können von denselben pathogenen Zuständen ausgelöst werden, u.a. Schlaganfall, Trauma oder Fieber. All diese Zustände sind charakterisiert durch eine Beeinträchtigung der Blut-Hirn Schranke und daher durch Austreten von Serum Proteinen wie Albumin und Immunfaktoren ins Interstitium. Zudem werden die Ionenkonzentrationen im Liquor an Serumwerte angepasst. Während Auftreten von CSDs die Akutprognose nach Gehirnschaden verschlechtert, deuten epileptische Entladungen auf eine mögliche spätere Entwicklung einer chronischen Epilepsie nach einer Latenzphase, während der Anpassungs- und Reorganisationsprozesse stattfinden. In meiner Doktorarbeit, habe ich den Zusammenhang zwischen CSD, akuter und chronischer Iktogenese und Blut-Hirn –Schrankenstörung untersucht. Anhand von elektrophysiologischen Messungen und immunohistochemischen Färbungen in temporo-hippokampalen Schnittpräparaten, konnte ich zeigen, dass CSDs und epileptische Entladungen sowohl im akut beschädigten als auch im chronisch epileptischen Gewebe zusammen auftreten können. Allerdings ist chronisch epileptisches Gewebe widerstandsfähiger gegen Mittel, die als potente Induktoren epileptischer Anfällen und/ oder CSDs im gesunden Gehirn gelten. Darüber hinaus können Stoffe, die im naiven Gewebe harmlos sind oder sogar eine physiologische Funktion ausüben (wie z.B. der Neurotransmitter Acetylcholin), in chronisch epileptischem Gewebe iktogen wirken. Demzufolge ist Übererregbarkeit nach akuter Verletzung und in chronisch epileptischem Gewebe durch unterschiedliche Mechanismen verursacht und sollte dementsprechend spezifisch therapiert werden

Status epilepticus induces chronic silencing of burster and dominance of regular firing neurons during sharp wave-ripples in the mouse subiculum

Summary: Sharp wave-ripples (SWRs) are hippocampal oscillations associated with memory consolidation. The subiculum, as the hippocampal output structure, ensures that hippocampal memory representations are transferred correctly to the consolidating neocortical regions. Because patients with temporal lobe epilepsy often develop memory deficits, we hypothesized that epileptic networks may disrupt subicular SWRs. We therefore investigated the impact of experimentally induced status epilepticus (SE) on subicular SWRs and contributing pyramidal neurons using electrophysiological recordings in mouse hippocampal slices. Subicular SWRs expressed hyperexcitable features post-SE, including increased ripple and unit activity. While regular firing neurons normally remain silent during SWRs, selective disinhibition recruited more regular firing neurons for action potential generation during SWRs post-SE. By contrast, burster neurons generated fewer action potential bursts during SWRs post-SE. Furthermore, altered timing of postsynaptic and action potentials suggested distorted neuronal recruitment during SWRs. Distorted subicular SWRs may therefore impair information processing and memory consolidation in epilepsy

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. 0.60 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. Focal damage after subarachnoid haemorrhage results from intracerebral haemorrhage and cerebral ischaemia. In a prospective, observational, multicentre, diagnostic phase III trial, DISCHARGE-1, Dreier et al. examine whether monitoring cortical spreading depolarizations can predict delayed infarction-and thus poor outcomes

Recording, analysis, and interpretation of spreading depolarizations in neurointensive care : Review and recommendations of the COSBID research group

Spreading depolarizations (SD) are waves of abrupt, near-complete breakdown of neuronal transmembrane ion gradients, are the largest possible pathophysiologic disruption of viable cerebral gray matter, and are a crucial mechanism of lesion development. Spreading depolarizations are increasingly recorded during multimodal neuromonitoring in neurocritical care as a causal biomarker providing a diagnostic summary measure of metabolic failure and excitotoxic injury. Focal ischemia causes spreading depolarization within minutes. Further spreading depolarizations arise for hours to days due to energy supply-demand mismatch in viable tissue. Spreading depolarizations exacerbate neuronal injury through prolonged ionic breakdown and spreading depolarization-related hypoperfusion (spreading ischemia). Local duration of the depolarization indicates local tissue energy status and risk of injury. Regional electrocorticographic monitoring affords even remote detection of injury because spreading depolarizations propagate widely from ischemic or metabolically stressed zones; characteristic patterns, including temporal clusters of spreading depolarizations and persistent depression of spontaneous cortical activity, can be recognized and quantified. Here, we describe the experimental basis for interpreting these patterns and illustrate their translation to human disease. We further provide consensus recommendations for electrocorticographic methods to record, classify, and score spreading depolarizations and associated spreading depressions. These methods offer distinct advantages over other neuromonitoring modalities and allow for future refinement through less invasive and more automated approaches

Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: Review and recommendations of the COSBID research group

Spreading depolarizations (SD) are waves of abrupt, near-complete breakdown of neuronal transmembrane ion gradients, are the largest possible pathophysiologic disruption of viable cerebral gray matter, and are a crucial mechanism of lesion development. Spreading depolarizations are increasingly recorded during multimodal neuromonitoring in neuro-critical care as a causal biomarker providing a diagnostic summary measure of metabolic failure and excitotoxic injury. Focal ischemia causes spreading depolarization within minutes. Further spreading depolarizations arise for hours to days due to energy supply-demand mismatch in viable tissue. Spreading depolarizations exacerbate neuronal injury through prolonged ionic breakdown and spreading depolarization-related hypoperfusion (spreading ischemia). Local duration of the depolarization indicates local tissue energy status and risk of injury. Regional electrocorticographic monitoring affords even remote detection of injury because spreading depolarizations propagate widely from ischemic or metabolically stressed zones; characteristic patterns, including temporal clusters of spreading depolarizations and persistent depression of spontaneous cortical activity, can be recognized and quantified. Here, we describe the experimental basis for interpreting these patterns and illustrate their translation to human disease. We further provide consensus recommendations for electrocorticographic methods to record, classify, and score spreading depolarizations and associated spreading depressions. These methods offer distinct advantages over other neuromonitoring modalities and allow for future refinement through less invasive and more automated approaches