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.

SUMMARY Peri-infarct depolarizations (PIDs) are seemingly spontaneous spreading depression-like waves that negatively impact tissue outcome in both experimental and human stroke. Factors triggering PIDs are unknown. Here, we show that somatosensory activation of peri-infarct cortex triggers PIDs when the activated cortex is within a critical range of ischemia. We show that the mechanism involves increased oxygen utilization within the activated cortex, worsening the supply-demand mismatch. We support the concept by clinical data showing that mismatch predisposes to PIDs in human stroke as well. Conversely, transient worsening of mismatch by episodic hypoxemia or hypotension also reproducibly triggers PIDs. Therefore, PIDs are triggered upon supply-demand mismatch transients in metastable peri-infarct hot zones due to increased demand or reduced supply. Based on the data, we propose that minimizing sensory stimulation and hypoxic or hypotensive transients in stroke and brain injury would reduce PID incidence and their adverse impact on outcome.

It has been hypothesized that vasospasm is the prime mechanism of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). Recently, it was found that clusters of spreading depolarizations (SDs) are associated with DCI. Surgical placement of nicardipine prolonged-release implants (NPRIs) was shown to strongly attenuate vasospasm. In the present study, we tested whether SDs and DCI are abolished when vasospasm is reduced or abolished by NPRIs. After aneurysm clipping, 10 NPRIs were placed next to the proximal intracranial vessels. The SDs were recorded using a subdural electrode strip. Proximal vasospasm was assessed by digital subtraction angiography (DSA). 534 SDs were recorded in 10 of 13 patients (77%). Digital subtraction angiography revealed no vasospasm in 8 of 13 patients (62%) and only mild or moderate vasospasm in the remaining. Five patients developed DCI associated with clusters of SD despite the absence of angiographic vasospasm in three of those patients. The number of SDs correlated significantly with the development of DCI. This may explain why reduction of angiographic vasospasm alone has not been sufficient to improve outcome in some clinical studies.

Despite treatment, initial mortality and severe disability remain high. Nevertheless, a favourable outcome was achieved in 26 % of aggressively treated patients, rendering the withdrawal of maximal therapy for WFNS grade V SAH patients unacceptable today. In cases of old patients with IVH, the indication for aggressive therapy should be put in place more carefully due to a very poor prognosis.

SUMMARY 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.

No abstract

Currently, a reliable method for real-time prediction of ischemia in the human brain is not available. Here, we took a first step towards validating non-invasive intraoperative laser speckle imaging (iLSI) for prediction of infarction in 22 patients undergoing decompressive surgery for treatment of malignant hemispheric stroke. During surgery, cortical perfusion was visualized and recorded in real-time with iLSI. The true morphological infarct extension within the iLSI imaging field was superimposed onto the iLSI blood flow maps according to a postoperative MRI (16 h [95% CI: 13, 19] after surgery) with three-dimensional magnetization-prepared rapid gradient-echo and diffusion-weighted imaging reconstruction. Based on the frequency distribution of iLSI perfusion values within the infarcted and non-infarcted territories, probability curves and perfusion thresholds of normalized cerebral blood flow predictive of eventual infarction or non-infarction were calculated. Intraoperative LSI predicted and excluded cortical ischemia with 95% probability at normalized perfusion levels below 40% and above 110%, respectively, which represented 73% of the entire cortical surface area. Together, our results suggest that iLSI is valid for (pseudo-) quantitative assessment of blood flow in the human brain and may be used to identify tissue at risk for infarction at a given time-point in the course of ischemic stroke.

Our results show that dose reduction or discontinuation of nimodipine due to changes in MAP occur frequently in clinical routine and may be associated with unfavorable clinical outcome.