Hyperglycaemia, insulin therapy and critical penumbral regions for prognosis in acute stroke: further insights from the INSULINFARCT trial

Abstract

Background: Recently, the concept of 'clinically relevant penumbra' was defined as an area saved by arterial recanalization and correlated with stroke outcome. This clinically relevant penumbra was located in the subcortical structures, especially the periventricular white matter. Our aims were to confirm this hypothesis, to investigate the impact of admission hyperglycemia and of insulin treatment on the severity of ischemic damages in this area and to study the respective contributions of infarct volume and ischemic damage severity of the clinically relevant penumbra on 3-month outcome.

Methods: We included 99 patients from the INSULINFARCT trial. Voxel-Based Analysis was carried on the Apparent Diffusion Coefficient (ADC) maps obtained at day one to localize the regions, which were more damaged in patients i) with poor clinical outcomes at three months and ii) without arterial recanalization. We determined the intersection of the detected areas, which represents the clinically relevant penumbra and investigated whether hyperglycemic status and insulin regimen affected the severity of ischemic damages in this area. We performed logistic regression to examine the contribution of infarct volume or early ADC decrease in this strategic area on 3-month outcome.

Findings: Lower ADC values were found in the corona radiata in patients with poor prognosis (p< 0.0001) and in those without arterial recanalization (p< 0.0001). The tracking analysis showed that lesions in this area interrupted many important pathways. ADC values in this area were lower in hyperglycemic than in normoglycemic patients (average decrease of 41.6 ± 20.8 x10(-6) mm2/s) and unaffected by the insulin regimen (p: 0.10). ADC values in the clinically relevant penumbra, but not infarct volumes, were significant predictors of 3-month outcome.

Conclusion: These results confirm that the deep hemispheric white matter is part of the clinically relevant penumbra and show that hyperglycaemia exacerbates the apparition of irreversible ischemic damage within 24 hours in this area. However, early intensive insulin therapy fails to protect this area from infarction.

Trial registration: ClinicalTrials.gov NCT00472381.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Flow chart of the study.

CGT means Capillary glucose test. As pre-specified in the main protocol, patients for whom ore than 3 CGTs were missing during the treatment had to be excluded. VBA means voxel-based analysis and the VBA study refers to the study presented in this paper.

Fig 2. Region with lower ADC values at day one in non-recanalized patients and in poor outcome patients.

A. Superposition of the area of day-one ADC decrease associated with 90-day poor outcome (in red) on ADC images (MNI space, z-coordinates). B. Superposition of the area of day-one ADC decrease associated with non-recanalized (vs. recanalized) patients (in blue) on ADC images (MNI space, z-coordinates). Images are shown using neuroradiological conventions (right hemisphere on the left side).

Fig 3. Tracking analysis from the strategic area.

Color code is directional (blue for z-axis, green for y-axis and red for x-axis). A. Superposition of the strategic area (in yellow) on a normalized ADC map. B Association and Projection tracts passing through the strategic area on a coronal view (left image) and on a sagittal view of a normalized ADC map. The color code is directional (pink for the x-axis, blue for z-axis and pink for y-axis). C. Association and Projection tracts travelling though the strategic area (in yellow). Left: The projections tract projections at the top in the following areas: primary motor, premotor, and parietal cortices (blue); Middle: The association tract passing through the yellow region contains part of the superior longitudinal fasciculus (green); Right: The fibers of the corpus callosum passing through the strategic area (pink).