Cortical spreading ischaemia is a novel process involved in ischaemic damage in patients with aneurysmal subarachnoid haemorrhage.

The term cortical spreading depolarization (CSD) describes a wave of mass neuronal depolarization associated with net influx of cations and water. Clusters of prolonged CSDs were measured time-locked to progressive ischaemic damage in human cortex. CSD induces tone alterations in resistance vessels, causing either transient hyperperfusion (physiological haemodynamic response) in healthy tissue; or hypoperfusion [inverse haemodynamic response = cortical spreading ischaemia (CSI)] in tissue at risk for progressive damage, which has so far only been shown experimentally. Here, we performed a prospective, multicentre study in 13 patients with aneurysmal subarachnoid haemorrhage, using novel subdural opto-electrode technology for simultaneous laser-Doppler flowmetry (LDF) and direct current-electrocorticography, combined with measurements of tissue partial pressure of oxygen (ptiO(2)). Regional cerebral blood flow and electrocorticography were simultaneously recorded in 417 CSDs. Isolated CSDs occurred in 12 patients and were associated with either physiological, absent or inverse haemodynamic responses. Whereas the physiological haemodynamic response caused tissue hyperoxia, the inverse response led to tissue hypoxia. Clusters of prolonged CSDs were measured in five patients in close proximity to structural brain damage as assessed by neuroimaging. Clusters were associated with CSD-induced spreading hypoperfusions, which were significantly longer in duration (up to 144 min) than those of isolated CSDs. Thus, oxygen depletion caused by the inverse haemodynamic response may contribute to the establishment of clusters of prolonged CSDs and lesion progression. Combined electrocorticography and perfusion monitoring also revealed a characteristic vascular signature that might be used for non-invasive detection of CSD. Low-frequency vascular fluctuations (LF-VF) (f < 0.1 Hz), detectable by functional imaging methods, are determined by the brain's resting neuronal activity. CSD provides a depolarization block of the resting activity, recorded electrophysiologically as spreading depression of high-frequency-electrocorticography activity. Accordingly, we observed a spreading suppression of LF-VF, which accompanied spreading depression of high-frequency-electrocorticography activity, independently of whether CSD was associated with a physiological, absent or inverse haemodynamic response. Spreading suppressions of LF-VF thus allow the differentiation of progressive ischaemia and repair phases in a fashion similar to that shown previously for spreading depressions of high-frequency-electrocorticography activity. In conclusion, it is suggested that (i) CSI is a novel human disease mechanism associated with lesion development and a potential target for therapeutic intervention in stroke; and that (ii) prolonged spreading suppressions of LF-VF are a novel 'functional marker' for progressive ischaemia.

Delayed ischaemic neurological deficits after subarachnoid haemorrhage are associated with clusters of spreading depolarizations.

Progressive ischaemic damage in animals is associated with spreading mass depolarizations of neurons and astrocytes, detected as spreading negative slow voltage variations. Speculation on whether spreading depolarizations occur in human ischaemic stroke has continued for the past 60 years. Therefore, we performed a prospective multicentre study assessing incidence and timing of spreading depolarizations and delayed ischaemic neurological deficit (DIND) in patients with major subarachnoid haemorrhage (SAH) requiring aneurysm surgery. Spreading depolarizations were recorded by electrocorticography with a subdural electrode strip placed on cerebral cortex for up to 10 days. A total of 2110 h recording time was analysed. The clinical state was monitored every 6 h. Delayed infarcts after SAH were verified by serial CT scans and/or MRI. Electrocorticography revealed 298 spreading depolarizations in 13 of the 18 patients (72%). A clinical DIND was observed in seven patients 7.8 days (7.3, 8.2) after SAH. DIND was time-locked to a sequence of recurrent spreading depolarizations in every single case (positive and negative predictive values: 86 and 100%, respectively). In four patients delayed infarcts developed in the recording area. As in the ischaemic penumbra of animals, delayed infarction was preceded by progressive prolongation of the electrocorticographic depression periods associated with spreading depolarizations to >60 min in each case. This study demonstrates that spreading depolarizations have a high incidence in major SAH and occur in ischaemic stroke. Repeated spreading depolarizations with prolonged depression periods are an early indicator of delayed ischaemic brain damage after SAH. In view of experimental evidence and the present clinical results, we suggest that spreading depolarizations with prolonged depressions are a promising target for treatment development in SAH and ischaemic stroke.