Dr Baptiste BALANCA

Delayed cerebral ischemia (DCI) is a devastating complication of aneurysmal subarachnoid hemorrhage (ASAH) causing brain infarction and disability. Cerebral microdialysis (CMD) monitoring is a focal technique that may detect DCI-related neurochemical changes as an advance warning. We conducted retrospective analyses from 44 poor-grade ASAH patients and analyzed glucose, lactate, pyruvate, and glutamate concentrations in control patients without DCI (n = 19), and in patients with DCI whose CMD probe was located within (n = 17) or outside (n = 8) a new infarct. When monitored from within a lesion, DCI was preceded by a decrease in glucose and a surge in glutamate, accompanied by increases in lactate/pyruvate and lactate/glucose ratios whereas these parameters remained stable in control patients. When CMD monitoring was performed outside the lesion, the glutamate surge was absent, but glucose and L/G ratio were still significantly altered. Overall, glucose and L/G ratio were significant biomarkers of DCI (se96.0, spe73.7-68.4). Glucose and L/G predicted DCI 67 h before CT detection of a new infarct. The pathogenesis of DCI therefore induces early metabolic disturbances that can be detected by CMD as an advance warning. Glucose and L/G could provide a trigger for initiating further examination or therapy, earlier than when guided by other monitoring techniques.

Early or primary injury due to brain aggression, such as mechanical trauma, hemorrhage or is-chemia, triggers the release of damage-associated molecular patterns (DAMPs) in the extracellular space. Some DAMPs, such as S100B, participate in the regulation of cell growth and survival but may also trigger cellular damage as their concentration increases in the extracellular space. When DAMPs bind to pattern-recognition receptors, such as the receptor of advanced glycation end-products (RAGE), they lead to non-infectious inflammation that will contribute to necrotic cell clearance but may also worsen brain injury. In this narrative review, we describe the role and ki-netics of DAMPs and RAGE at the acute phase of brain injury. We searched the MEDLINE database for « DAMPs » or « RAGE » or « S100B » and « traumatic brain injury » or « subarachnoid hemorrhage » or « stroke ». We selected original articles reporting data on acute brain injury pathophysiology, from which we describe DAMPs release and clearance upon acute brain injury, and the implication of RAGE in the development of brain injury. We will also discuss the clinical strategies that emerge from this overview in terms of biomarkers and therapeutic perspectives.

Background: Early brain injuries (EBI) are one of the most important causes of morbidity and mortality after subarachnoid hemorrhage. At admission, a third of patients are unconscious (spontaneously or sedated) and EBI consequences are not evaluable. To date, it is unclear who will still be comatose (with severe EBI) and who will recover (with less severe EBI) once the aneurysm is treated and sedation withdrawn. The objective of the present study was to determine the diagnostic accuracy of S100B levels at hospital admission to identify patients with severe neurological consequences of EBI.

Methods: Patients were consecutively included in this prospective blinded observational study. A motor component of the Glasgow coma score under 6 on day 3 was used to define patients with severe neurological consequences of EBI.

Results: A total of 81 patients were included: 25 patients were unconscious at admission, 68 were treated by coiling. On day 3, 12 patients had severe consequences of EBI. A maximal S100B value between admission and day 1 had an area under the receiver operating characteristic curve (AUC) of 86.7% to predict severe EBI consequences. In patients with impaired consciousness at admission, the AUC was 88.2%.

Conclusion: Early S100B seems to have a good diagnostic value to predict severe EBI. Before claiming the usefulness of S100B as a surrogate marker of EBI severity to start earlier multimodal monitoring, these results must be confirmed in an independent validation cohort.

Methods: We used EEG with a montage matching vascular territories (right and left anterior central and posterior) and compared them to follow-up brain imaging.

Results: 15 SAH patients (Fischer ≥ 3, World Federation of Neurological Surgeons scale ≥4, 9 DCI) were monitored during 6.4 [4-8] days (min = 2d, max = 13d). AT/D changes could follow three different patterns: (1) prolonged or (2) transient decrease and (3) no decrease or progressive increase. A regional 30% decrease outlasting 3.7 h reached 100% sensitivity and 88.9% specificity to detect DCI. Only 22.6% were in a zone of uncertain diagnosis (3.7-8.04 h). These prolonged decreases, with a loss of transient changes, started in cortical areas evolving toward DCI, and preceded intracranial changes when available.

Conclusion: Although this study has a small sample size, prolonged AT/D decrease seems to be a reliable biomarker of DCI.

Significance: cEEG changes are likely to precede cerebral infarction and could be useful at the bedside to detect DCI before irreversible damage.

Spreading depolarizations are waves of near-complete breakdown of neuronal transmembrane ion gradients, free energy starving, and mass depolarization. Spreading depolarizations in electrically inactive tissue are associated with poor outcome in patients with traumatic brain injury. Here, we studied changes in regional cerebral blood flow and brain oxygen (PbtO₂), glucose ([Glc]b), and lactate ([Lac]b) concentrations in rats, using minimally invasive real-time sensors. Rats underwent either spreading depolarizations chemically triggered by KCl in naïve cortex in absence of traumatic brain injury or spontaneous spreading depolarizations in the traumatic penumbra after traumatic brain injury, or a cluster of spreading depolarizations triggered chemically by KCl in a remote window from which spreading depolarizations invaded penumbral tissue. Spreading depolarizations in noninjured cortex induced a hypermetabolic response characterized by a decline in [Glc]b and monophasic increases in regional cerebral blood flow, PbtO₂, and [Lac]b, indicating transient hyperglycolysis. Following traumatic brain injury, spontaneous spreading depolarizations occurred, causing further decline in [Glc]b and reducing the increase in regional cerebral blood flow and biphasic responses of PbtO₂ and [Lac]b, followed by prolonged decline. Recovery of PbtO₂ and [Lac]b was significantly delayed in traumatized animals. Prespreading depolarization [Glc]b levels determined the metabolic response to clusters. The results suggest a compromised hypermetabolic response to spreading depolarizations and slower return to physiological conditions following traumatic brain injury-induced spreading depolarizations.

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.