Spreading depolarizations in ischaemia after subarachnoid haemorrhage, a diagnostic phase III study

Abstract

Focal brain damage after aneurysmal subarachnoid haemorrhage predominantly results from intracerebral haemorrhage, and early and delayed cerebral ischaemia. The prospective, observational, multicentre, cohort, diagnostic phase III trial, DISCHARGE-1, primarily investigated whether the peak total spreading depolarization-induced depression duration of a recording day during delayed neuromonitoring (delayed depression duration) indicates delayed ipsilateral infarction. Consecutive patients (n = 205) who required neurosurgery were enrolled in six university hospitals from September 2009 to April 2018. Subdural electrodes for electrocorticography were implanted. Participants were excluded on the basis of exclusion criteria, technical problems in data quality, missing neuroimages or patient withdrawal (n = 25). Evaluators were blinded to other measures. Longitudinal MRI, and CT studies if clinically indicated, revealed that 162/180 patients developed focal brain damage during the first 2 weeks. During 4.5 years of cumulative recording, 6777 spreading depolarizations occurred in 161/180 patients and 238 electrographic seizures in 14/180. Ten patients died early; 90/170 developed delayed infarction ipsilateral to the electrodes. Primary objective was to investigate whether a 60-min delayed depression duration cut-off in a 24-h window predicts delayed infarction with >0.60 sensitivity and >0.80 specificity, and to estimate a new cut-off. The 60-min cut-off was too short. Sensitivity was sufficient [= 0.76 (95% confidence interval: 0.65–0.84), P = 0.0014] but specificity was 0.59 (0.47–0.70), i.e. <0.80 (P < 0.0001). Nevertheless, the area under the receiver operating characteristic (AUROC) curve of delayed depression duration was 0.76 (0.69–0.83, P < 0.0001) for delayed infarction and 0.88 (0.81–0.94, P < 0.0001) for delayed ischaemia (reversible delayed neurological deficit or infarction). In secondary analysis, a new 180-min cut-off indicated delayed infarction with a targeted 0.62 sensitivity and 0.83 specificity. In awake patients, the AUROC curve of delayed depression duration was 0.84 (0.70–0.97, P = 0.001) and the prespecified 60-min cut-off showed 0.71 sensitivity and 0.82 specificity for reversible neurological deficits. In multivariate analysis, delayed depression duration (β = 0.474, P < 0.001), delayed median Glasgow Coma Score (β = −0.201, P = 0.005) and peak transcranial Doppler (β = 0.169, P = 0.016) explained 35% of variance in delayed infarction. Another key finding was that spreading depolarization-variables were included in every multiple regression model of early, delayed and total brain damage, patient outcome and death, strongly suggesting that they are an independent biomarker of progressive brain injury. While the 60-min cut-off of cumulative depression in a 24-h window indicated reversible delayed neurological deficit, only a 180-min cut-off indicated new infarction with >0.60 sensitivity and >0.80 specificity. Although spontaneous resolution of the neurological deficit is still possible, we recommend initiating rescue treatment at the 60-min rather than the 180-min cut-off if progression of injury to infarction is to be prevented.

Depth-profile of impairments in endothelin-1 – induced focal cortical ischemia

“…Morphologically, they resemble bell-shaped brain lesions secondary to aSAH due to ruptured aneurysms described in the autopsy study by Stoltenburg-Didinger and Schwarz. 23 Supplementary Figure 4 provides an example of an MRI-proven early wedge-shaped infarct seen in an aSAH patient of the DISCHARGE-1 population (Dreier et al, 2022). Wedge-shaped infarcts with a triangular infarct rim with its base pointing toward the cortical surface were also reported in the primate clot model of cerebral ischemia after aSAH.…”

“…Neuromonitoring and longitudinal neuroimaging were performed in the patient as part of the. 6 On day 7 after the initial hemorrhage, a cluster of 10 SDs developed. The first SD resulted in spreading depression of spontaneous activity at all electrodes.…”

“…The patient was enrolled at Charité – Universitätsmedizin Berlin in the prospective, observational, multicenter, cohort, diagnostic phase III trial ‘DISCHARGE-1’. 6 Traces 1 to 6 from top to bottom give the direct current (DC)/alternating current (AC)-electrocorticography (ECoG) recordings (bandpass: 0–45 Hz) at electrodes 1–6. SDs are observed as a negative DC shift (marked in red, negative voltage changes are shown as upward deflections following the EEG polarity convention).…”

“…In this regard, early electrographic changes in cortical activity during ischemia are of particular interest because they can serve as predictors of the onset of ischemic stroke and its severity, and may also be used as an alarm to initiate treatment during ongoing electrophysiological monitoring in patients at risk for ischemic complications. 6,[14][15][16][17][18] In the present study, we explored alterations in electrical activity across layers of a cortical barrel column during transient (1 hour) focal ischemia produced by topical epipial ET1 application, followed by 3 hours of ET1 washout. Functional impairments were then compared with histological lesion size, and retrospective analysis was used to estimate the predictive value of early neurophysiological changes at the onset of ischemia for predicting the severity of ischemic impairments.…”

“…(a) This 64-year-old woman with aneurysmal subarachnoid hemorrhage (aSAH) showed a cluster of ten spreading depolarizations (SDs) that occurred during six hours on the seventh day after the initial hemorrhage. The patient was enrolled at Charit e -Universit€ atsmedizin Berlin in the prospective, observational, multicenter, cohort, diagnostic phase III trial 'DISCHARGE-1' 6. Traces 1 to 6 from top to bottom give the direct current (DC)/alternating current (AC)-electrocorticography (ECoG) recordings (bandpass: 0-45 Hz) at electrodes 1-6.…”