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.