Edgar Santos

The continuum of spreading depolarizations in acute cortical lesion development: Examining Leão's legacy.

A modern understanding of how cerebral cortical lesions develop after acute brain injury is based on Aristides Leão’s historic discoveries of spreading depression and asphyxial/anoxic depolarization. Treated as separate entities for decades, we now appreciate that these events define a continuum of spreading mass depolarizations, a concept that is central to understanding their pathologic effects. Within minutes of acute severe ischemia, the onset of persistent depolarization triggers the breakdown of ion homeostasis and development of cytotoxic edema. These persistent changes are diagnosed as diffusion restriction in magnetic resonance imaging and define the ischemic core. In delayed lesion growth, transient spreading depolarizations arise spontaneously in the ischemic penumbra and induce further persistent depolarization and excitotoxic damage, progressively expanding the ischemic core. The causal role of these waves in lesion development has been proven by real-time monitoring of electrophysiology, blood flow, and cytotoxic edema. The spreading depolarization continuum further applies to other models of acute cortical lesions, suggesting that it is a universal principle of cortical lesion development. These pathophysiologic concepts establish a working hypothesis for translation to human disease, where complex patterns of depolarizations are observed in acute brain injury and appear to mediate and signal ongoing secondary damage.

Clusters of Spreading Depolarizations Are Associated With Disturbed Cerebral Metabolism in Patients With Aneurysmal Subarachnoid Hemorrhage

Background and Purpose— We studied the dynamics of extracellular brain tissue concentrations of glucose, lactate, pyruvate, and glutamate during the occurrence of spreading depolarizations (SDs) in patients with aneurysmal subarachnoid hemorrhage. Methods— In this prospective observational study, patients with aneurysmal subarachnoid hemorrhage received multimodal cerebral monitoring, including intracranial pressure, cerebral microdialysis, and subdural electrocorticography. Results— Seven of the 17 recruited patients had intracerebral hemorrhage, acute ischemia and severe brain oedema leading to acute ischemic neurological deficits associated with early disturbance of metabolism at the recording site. They displayed a total of 130 SDs. The remaining 10 patients without acute ischemic neurological deficits exhibited 138 single SDs and 68 SDs in clusters. In patients without acute ischemic neurological deficits, clustered SDs were associated with a significant transient decrease in glucose and increase in lactate compared with baseline during the first 140 minutes after SDs. Moreover, the number of clustered SDs correlated with the outcome (R=−0.659; P<0.01). Conclusion— SDs can propagate in nonischemic human brain tissue. Clusters of SDs are related to metabolic changes suggestive of ongoing secondary damage in primarily nonischemic brain tissue.

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.

Radial, spiral and reverberating waves of spreading depolarization occur in the gyrencephalic brain

OBJECTIVES The detection of the hemodynamic and propagation patterns of spreading depolarizations (SDs) in the gyrencephalic brain using intrinsic optical signal imaging (IOS). METHODS The convexity of the brain surface was surgically exposed in fourteen male swine. Within the boundaries of this window, brains were immersed and preconditioned with an elevated K(+) concentration (7 mmol/l) in the standard Ringer lactate solution for 30-40 min. SDs were triggered using 3-5 μl of 1 mol/l KCl solution. Changes in tissue absorbency or reflection were registered with a CCD camera at a wavelength of 564 nm (14 nm FWHM), which was mounted 25 cm above the exposed cortex. Additional monitoring by electrocorticography and laser-Doppler was used in a subset of animals (n=7) to validate the detection of SD. RESULTS Of 198 SDs quantified in all of the experiments, 187 SDs appeared as radial waves that developed semi-planar fronts. The morphology was affected by the surface of the gyri, the sulci and the pial vessels. Other SD patterns such as spirals and reverberating waves, which have not been described before in gyrencephalic brains, were also observed. Diffusion gradients created in the cortex surface (i.e., KCl concentrations), sulci, vessels and SD-SD interactions make the gyrencephalic brain prone to the appearance of irregular SD waves. CONCLUSION The gyrencephalic brain is capable of irregular SD propagation patterns. The irregularities of the gyrencephalic brain cortex may promote the presence of re-entrance waves, such as spirals and reverberating waves.

The role of spreading depolarization in subarachnoid hemorrhage

Subarachnoid hemorrhage (SAH) is a devastating disease associated with death and poor functional outcome. Despite decades of intense research and improvements in clinical management, delayed cerebral ischaemia (DCI) remains the most important cause of morbidity and mortality after SAH. The key role of angiographic cerebral vasospasm, thought to be the main cause of DCI, has been questioned. Emerging evidence suggests that DCI is likely to have a multifactorial etiology. Over the last few years, spreading depolarization (SD) has been identified as a potential pathophysiological mechanism contributing to DCI. The presence of cortical spreading ischaemia, due to an inverse hemodynamic response to SD, offers a possible explanation for DCI and requires more intensive research. Understanding the role of SD as another mechanism inducing DCI and its relationship with other pathological factors could instigate the development of new approaches to the diagnosis and treatment of DCI in order to improve the clinical outcome.

Decompressive Craniectomy in Patients with Aneurysmal Subarachnoid Hemorrhage: A Single-Center Matched-Pair Analysis

Background: The role of decompressive craniectomy (DC) in aneurysmal subarachnoid hemorrhage (aSAH) patients is still controversial. In this study we evaluated the effect of DC for aSAH patients. Methods: A matched-pair analysis was performed to compare the outcomes of patients with DC to those of patients without DC. Among 295 consecutive aSAH patients, 56 required DC. Of the remaining group, 56 matched controls were found. The match was conducted on the basis of epidemiological and potential prognostic factors, such as age, gender, World Federation of Neurosurgical Societies (WFNS) grade, Fisher group and occurrence of vasospasm. Results: Fifty-four of 56 (96.4%) patients with DC were dependent or dead at 1 month, compared with 49 of 56 (87.5%) without DC. There was no significant difference between the groups (p = 0.16). One-year outcomes were available for 108 patients (96.4%). Thirty-nine of 54 (72.2%) patients treated with DC were dependent or dead at 1 year, compared with 30 of 54 (55.6%) patients in the control group. There was no significant difference between the groups (p = 0.11). This result was unaffected by age, sex and WFNS grade. Subgroup analyses whether DC was performed primarily or delayed, and whether DC was performed due to spasm, hematoma or vessel occlusion failed to detect any significant difference. Conclusion: There was no significant advantage for patients treated with DC, but more than 25% achieved a good long-term outcome. While the value of DC is deemed uncertain, it may be effective for a very specific subset of aSAH patients. Further comparative studies are needed to resolve this matter.

Short pressure reactivity index versus long pressure reactivity index in the management of traumatic brain injury.

OBJECT The pressure reactivity index (PRx) correlates with outcome after traumatic brain injury (TBI) and is used to calculate optimal cerebral perfusion pressure (CPPopt). The PRx is a correlation coefficient between slow, spontaneous changes (0.003-0.05 Hz) in intracranial pressure (ICP) and arterial blood pressure (ABP). A novel index-the so-called long PRx (L-PRx)-that considers ABP and ICP changes (0.0008-0.008 Hz) was proposed. METHODS The authors compared PRx and L-PRx for 6-month outcome prediction and CPPopt calculation in 307 patients with TBI. The PRx- and L-PRx-based CPPopt were determined and the predictive power and discriminant abilities were compared. RESULTS The PRx and L-PRx correlation was good (R = 0.7, p < 0.00001; Spearman test). The PRx, age, CPP, and Glasgow Coma Scale score but not L-PRx were significant fatal outcome predictors (death and persistent vegetative state). There was a significant difference between the areas under the receiver operating characteristic curves calculated for PRx and L-PRx (0.61 ± 0.04 vs 0.51 ± 0.04; z-statistic = -3.26, p = 0.011), which indicates a better ability by PRx than L-PRx to predict fatal outcome. The CPPopt was higher for L-PRx than for PRx, without a statistical difference (median CPPopt for L-PRx: 76.9 mm Hg, interquartile range [IQR] ± 10.1 mm Hg; median CPPopt for PRx: 74.7 mm Hg, IQR ± 8.2 mm Hg). Death was associated with CPP below CPPopt for PRx (χ(2) = 30.6, p < 0.00001), and severe disability was associated with CPP above CPPopt for PRx (χ(2) = 7.8, p = 0.005). These relationships were not statistically significant for CPPopt for L-PRx. CONCLUSIONS The PRx is superior to the L-PRx for TBI outcome prediction. Individual CPPopt for L-PRx and PRx are not statistically different. Deviations between CPP and CPPopt for PRx are relevant for outcome prediction; those between CPP and CPPopt for L-PRx are not. The PRx uses the entire B-wave spectrum for index calculation, whereas the L-PRX covers only one-third of it. This may explain the performance discrepancy.

Spreading depolarizations in a case of migraine-related stroke

Background: Cortical spreading depolarization (CSD) has been implicated in the pathophysiology of migraine with aura. Patients that suffer from this type of migraine have shown a higher risk of developing an ischaemic stroke. Case: A 42-year-old female exhibited reoccurring migraine attacks for the first time 1 month before suffering an ischaemic infarction. Imaging studies revealed an occlusion in the right middle cerebral artery. Other possible disorders were excluded. It was possible to register 20 CSDs, of which 12 coincided with high levels of glutamate and lactate/pyruvate ratio. Loss of electrocorticographic activity was observed for 89 hours after the 8th depolarization. Conclusions: Migraine with aura symptoms may be induced by CSDs triggered by hypoperfusion states. Our case supports the idea of the migraine with aura–stroke continuum.

Cerebral Glucose and Spreading Depolarization in Patients with Aneurysmal Subarachnoid Hemorrhage

The pathogenesis of delayed cerebral ischemia (DCI) is multifactorial and not completely elucidated. Our objective was to determine if episodes of spreading depolarization (SD) are reflected in compromised levels of extracellular glucose monitored by bedside microdialysis (MD) in aneurysmal subarachnoid hemorrhage (aSAH) patients. Patients with aSAH, prospectively included in the COSBID (CoOperative Study on Brain Injury Depolarisations) protocol (Berlin, Heidelberg), had hourly monitoring of cerebral glucose by MD and in parallel electrocorticographic (ECoG) monitoring for SD detection on day of admission until days 10-14 after aSAH. Cerebral MD probes were placed in the vascular territory at risk for DCI. Twenty-one aSAH patients (53.3 ± 9.1 years; mean ± standard deviation), classified according to the World Federation of Neurosurgical Societies (WFNS) in low (I-III, 11) and high (IV-V, 10) grades, were studied. Of these, 13 patients (62%) presented with DCI. Median glucose was 1.48 (0.00-8.79). Median occurrence of SD was 7 (0-66)/patients. High WFNS grade (WFNS grades IV-V) patients had more SDs (p = 0.027), while the overall glucose level did not differ. In high-grade SAH patients, SDs were more frequent. Individually, the occurrence of SD was not linked to local deviations (neither high nor low) from the LOWESS (locally weighted scatterplot smoothing) trend curve for extracellular glucose concentrations. Rapid-sampling MD techniques and analyses of SD clusters may elucidate more detail of the relationship between SD and brain energy metabolism.

Cerebral Microdialysis in Acutely Brain-Injured Patients with Spreading Depolarizations

Multimodal cerebral monitoring was utilized to examine the relationship between pathological changes in microdialysis parameters and the occurrence of spreading depolarizations (SD) in brain-injured patients. SD are a relatively newly discovered phenomenon in man found to be linked to secondary insults and infarct growth and they can be detected via electrocorticography (ECoG). A total of 24 brain-injured patients (mean age: 52±11 years) requiring craniotomy took part in this prospective observational study. Each patient was monitored with a linear strip electrode for ECoG data and a cerebral microdialysis probe. SD were detected in 13 of the 24 patients. Pathological concentrations of glucose and lactate in brain parenchyma were significantly correlated with various time points prior to and/or immediately following the SD. Severe systemic hyperglycemia and systemic hypoglycemia were also found to be correlated with the occurrence of SD. The present study shows a clear relationship between SD and pathological changes in cerebral metabolism; further studies are needed to elucidate these complex interactions with the ultimate goal of developing therapeutic strategies for improving outcome in brain-injured patients.