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Observational Study
. 2025 Sep;56(9):2627-2632.
doi: 10.1161/STROKEAHA.124.050317. Epub 2025 Jun 25.

Hypodensity Beyond the Ischemic Core: Penumbral Changes Detected With Relative Noncontrast Computed Tomography

Lieselotte Vandewalle  1   2 , Praneeta R Konduri  3 , Soren Christensen  3 , Pierre Seners  4   5 , Anke Wouters  2 , Nicole Yuen  3 , Michael Mlynash  3 , Stephanie Kemp  3 , Jeremy J Heit  3 , Gregory W Albers  3 , Jelle Demeestere  1   2 , Maarten G Lansberg  3 , Robin Lemmens  1
Affiliations
Observational Study

Hypodensity Beyond the Ischemic Core: Penumbral Changes Detected With Relative Noncontrast Computed Tomography

Lieselotte Vandewalle et al. Stroke. 2025 Sep.

Abstract

Background: In acute ischemic stroke, infarcted tissue gradually becomes detectable on noncontrast computed tomography (NCCT) as a hypodensity representing vasogenic edema. We studied whether subtle NCCT density changes are also present in penumbral tissue.

Methods: This observational cohort study included patients with stroke with anterior circulation occlusions from the CRISP2 study (CT Perfusion to Predict Response to Recanalization in Ischemic Stroke Project 2) who were transferred from a primary to a comprehensive stroke center for consideration of endovascular thrombectomy. Patients received baseline NCCT and computed tomography perfusion at the referring hospital and magnetic resonance imaging at the receiving hospital. We created baseline relative NCCT images, which compare voxel density to the corresponding area in the contralateral hemisphere. We analyzed the relative density of rNCCT in the core and penumbra (based on computed tomography perfusion in referring hospitals). We also assessed the correlation between relative density and the degree of hypoperfusion in the penumbra, defined as the time-to-maximum of the tissue residue function. We studied the association between penumbral changes and functional outcomes on the full distribution of the modified Rankin Scale score at 90 days.

Results: From the 314 patients, 162 met inclusion criteria with a median (interquartile range) age of 73 (61-83) years, penumbra volume of 78 (52-113) mL, and core volume of 0.6 (0-13.0) mL; 54% were men. The relative density was reduced by a median of 1.8% (P<0.0001) in the penumbra and 3.3% in the core (P<0.0001). Relative hypodensity in the penumbra was more profound with increasing hypoperfusion: 1.5% in regions with time-to-maximum of 6- to 8-second region, 1.8% in time-to-maximum of 8- to 10-seconds, and 2.2% in time-to-maximum >10-second region (P<0.0001). We identified a trend toward worse outcomes with more hypodense penumbra (odds ratio, 1.193 [95% CI, 0.996-1.430]).

Conclusions: In patients with anterior circulation acute ischemic stroke, we identified relative hypodensity in penumbral tissue on NCCT with potential clinical relevance on 90-day functional outcomes. The hypodensity was more pronounced with increasing hypoperfusion severity.

Keywords: brain infarction; cerebrovascular circulation; edema; infarction; ischemic stroke.

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Conflict of interest statement

Dr Konduri is also a co-founder and a shareholder of inSteps B.V. Dr Christensen reports employment by Cercare Medical and stock holdings in Ischemaview. Dr Seners reports compensation from Acticor for consultant services. Dr Heit reports consulting fees from Medtronic and MicroVention, is a member of the medical and scientific advisory board for iSchemaView, and reports stock holdings in Dragon Vascular. Dr Albers reports stock holdings in iSchemaView and compensation from Biogen, iSchemaView, and Genentech for consultant services. Dr Lemmens reports institutional fees paid to KU Leuven for consultancy by iSchemaview. The other authors report no conflicts.

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