Irene Klærke Mikkelsen

The role of the cerebral capillaries in acute ischemic stroke: the extended penumbra model

The pathophysiology of cerebral ischemia is traditionally understood in relation to reductions in cerebral blood flow (CBF). However, a recent reanalysis of the flow-diffusion equation shows that increased capillary transit time heterogeneity (CTTH) can reduce the oxygen extraction efficacy in brain tissue for a given CBF. Changes in capillary morphology are typical of conditions predisposing to stroke and of experimental ischemia. Changes in capillary flow patterns have been observed by direct microscopy in animal models of ischemia and by indirect methods in humans stroke, but their metabolic significance remain unclear. We modeled the effects of progressive increases in CTTH on the way in which brain tissue can secure sufficient oxygen to meet its metabolic needs. Our analysis predicts that as CTTH increases, CBF responses to functional activation and to vasodilators must be suppressed to maintain sufficient tissue oxygenation. Reductions in CBF, increases in CTTH, and combinations thereof can seemingly trigger a critical lack of oxygen in brain tissue, and the restoration of capillary perfusion patterns therefore appears to be crucial for the restoration of the tissue oxygenation after ischemic episodes. In this review, we discuss the possible implications of these findings for the prevention, diagnosis, and treatment of acute stroke.

The role of the microcirculation in delayed cerebral ischemia and chronic degenerative changes after subarachnoid hemorrhage.

The mortality after aneurysmal subarachnoid hemorrhage (SAH) is 50%, and most survivors suffer severe functional and cognitive deficits. Half of SAH patients deteriorate 5 to 14 days after the initial bleeding, so-called delayed cerebral ischemia (DCI). Although often attributed to vasospasms, DCI may develop in the absence of angiographic vasospasms, and therapeutic reversal of angiographic vasospasms fails to improve patient outcome. The etiology of chronic neurodegenerative changes after SAH remains poorly understood. Brain oxygenation depends on both cerebral blood flow (CBF) and its microscopic distribution, the so-called capillary transit time heterogeneity (CTH). In theory, increased CTH can therefore lead to tissue hypoxia in the absence of severe CBF reductions, whereas reductions in CBF, paradoxically, improve brain oxygenation if CTH is critically elevated. We review potential sources of elevated CTH after SAH. Pericyte constrictions in relation to the initial ischemic episode and subsequent oxidative stress, nitric oxide depletion during the pericapillary clearance of oxyhemoglobin, vasogenic edema, leukocytosis, and astrocytic endfeet swelling are identified as potential sources of elevated CTH, and hence of metabolic derangement, after SAH. Irreversible changes in capillary morphology and function are predicted to contribute to long-term relative tissue hypoxia, inflammation, and neurodegeneration. We discuss diagnostic and therapeutic implications of these predictions.

Analysis of partial volume effects on arterial input functions using gradient echo: a simulation study.

Absolute blood flow and blood volume measurements using perfusion weighted MRI require an accurately measured arterial input function (AIF). Because of limited spatial resolution of MR images, AIF voxels cannot be placed completely within a feeding artery. We present a two‐compartment model of an AIF voxel including the relaxation properties of blood and tissue. Artery orientations parallel and perpendicular to the main magnetic field were investigated and AIF voxels were modeled to either include or be situated close to a large artery. The impact of partial volume effects on quantitative perfusion metrics was investigated for the gradient echo pulse sequence at 1.5 T and 3.0 T. It is shown that the tissue contribution broadens and introduces fluctuations in the AIF. Furthermore, partial volume effects bias perfusion metrics in a nonlinear fashion, compromising quantitative perfusion estimates and profoundly effecting local AIF selection. Magn Reson Med, 2009.

Capillary Transit Time Heterogeneity and Flow-Metabolism Coupling after Traumatic Brain Injury

Most patients who die after traumatic brain injury (TBI) show evidence of ischemic brain damage. Nevertheless, it has proven difficult to demonstrate cerebral ischemia in TBI patients. After TBI, both global and localized changes in cerebral blood flow (CBF) are observed, depending on the extent of diffuse brain swelling and the size and location of contusions and hematoma. These changes vary considerably over time, with most TBI patients showing reduced CBF during the first 12hours after injury, then hyperperfusion, and in some patients vasospasms before CBF eventually normalizes. This apparent neurovascular uncoupling has been ascribed to mitochondrial dysfunction, hindered oxygen diffusion into tissue, or microthrombosis. Capillary compression by astrocytic endfeet swelling is observed in biopsies acquired from TBI patients. In animal models, elevated intracranial pressure compresses capillaries, causing redistribution of capillary flows into patterns argued to cause functional shunting of oxygenated blood through the capillary bed. We used a biophysical model of oxygen transport in tissue to examine how capillary flow disturbances may contribute to the profound changes in CBF after TBI. The analysis suggests that elevated capillary transit time heterogeneity can cause critical reductions in oxygen availability in the absence of ‘classic’ ischemia. We discuss diagnostic and therapeutic consequences of these predictions.

Reperfusion Within 6 Hours Outperforms Recanalization in Predicting Penumbra Salvage, Lesion Growth, Final Infarct, and Clinical Outcome

Background and Purpose— The relative merits of reperfusion versus recanalization to predict tissue and clinical outcomes in anterior circulation stroke have been previously assessed using data acquired >12 hours postonset. To avoid late-occurring confounders such as non-nutritional reperfusion, futile recanalization and no-reflow phenomenon, we performed ultraearly assessment of reperfusion and recanalization. Methods— From a multicenter prospective database, 46 patients with acute magnetic resonance angiography–visible occlusion and in whom both reperfusion and recanalization were assessed on follow-up magnetic resonance imaging ⩽6 hours of symptom onset were identified. Multiple linear regressions modeled salvaged penumbra, diffusion-weighted imaging lesion growth, and final infarct at 1 month using baseline clinical and imaging parameters and acute reperfusion or recanalization. Best predictors were determined with the Akaike information criterion. Univariate and multivariate logistic regressions identified the clinical and imaging predictors of clinical outcome. Results— Admission magnetic resonance imaging showed M1 occlusion in 15 (33%) patients; median penumbra volume was 13.4 mL. Acute reperfusion was observed in 27 (59%) patients; 42% of nonrecanalized patients demonstrated reperfusion. The dichotomized classification of reperfusion and recanalization was discordant (P=0.0002). Reperfusion ⩽6 hours was a significant (P<0.05) predictor of increased penumbra salvage, reduced lesion growth, and final infarct size. Recanalization did not improve model accuracy. Reperfusion, but not recanalization, was significantly associated with good clinical outcome in logistic regressions. Conclusions— Reperfusion ⩽6 hours was consistently superior to recanalization in predicting tissue and clinical outcome. Reperfusion without recanalization was frequent and probably related to retrograde reperfusion through leptomeningeal collaterals. Acute reperfusion was the strongest predictor of, and may therefore, represent a reliable surrogate for, clinical outcome.

Predicting Infarction Within the Diffusion-Weighted Imaging Lesion: Does the Mean Transit Time Have Added Value?

Background and Purpose— There is ample evidence that in anterior circulation stroke, the diffusion-weighted imaging (DWI) lesion may escape infarction and thus is not a reliable infarct predictor. In this study, we assessed the predictive value of the mean transit time (MTT) for final infarction within the DWI lesion, first in patients scanned back-to-back with 15O-positron emission tomography and MR (DWI and perfusion-weighted imaging; “Cambridge sample”) within 7 to 21 hours of clinical onset, then in a large sample of patients with anterior circulation stroke receiving DWI and perfusion-weighted imaging within 12 hours (85% within 6 hours; “I-KNOW sample”). Methods— Both samples underwent structural MRI at approximately 1 month to map final infarcts. For both imaging modalities, MTT was calculated as cerebral blood volume/cerebral blood flow. After image coregistration and matrix resampling, the MTT values between voxels of interest that later infarcted or not were compared separately within and outside DWI lesions (DWI+ and DWI−, respectively) both within and across patients. In the I-KNOW sample, receiver operating characteristic curves were calculated for these voxel of interest populations and areas under the curve and optimal thresholds calculated. Results— In the Cambridge data set (n=4), there was good concordance between predictive values of MTTpositron emission tomography and MTTperfusion-weighted imaging for both DWI+ and DWI− voxels of interest indicating adequate reliability of MTTperfusion-weighted imaging for this purpose. In the I-KNOW data set (N=42), the MTT significantly added to the DWI lesion to predict infarction in both DWI− and DWI+ voxels of interest with areas under the curve approximately 0.78 and 0.64 (both P<0.001) and optimal thresholds approximately 8 seconds and 11 seconds, respectively. Conclusions— Despite the relatively small samples, this study suggests that adding MTTperfusion-weighted imaging may improve infarct prediction not only as already known outside, but also within, DWI lesions.

Very Low Cerebral Blood Volume Predicts Parenchymal Hematoma in Acute Ischemic Stroke

Background and Purpose— Parenchymal hematoma (PH) may worsen the outcome of patients with stroke. The aim of our study was to confirm the relationship between the volume of very low cerebral blood volume (CBV) and PH using a European multicenter database (I-KNOW). A secondary objective was to explore the impact of early reperfusion and recanalization. Methods— The volume of cerebral tissue with CBV ⩽2.5th percentile of the normal hemisphere was calculated within the acute diffusion-weighted imaging lesion. Hemorrhagic transformation was assessed on day 2 MRI according to the European Cooperative Acute Stroke Study II criteria. Recanalization and reperfusion were assessed on 3-hour follow-up MRI. Results— Of the 110 patients, hemorrhagic transformation occurred in 59 patients, including 7 PH. In univariate analysis, the acute National Institutes of Health Stroke Scale score (P=0.002), acute diffusion-weighted imaging lesion volume (P=0.02), and thrombolysis (P=0.03), but not very low CBV (P=0.52), were associated with hemorrhagic transformation. The volume of very low CBV was the only predictor of PH (P=0.007). Early reperfusion and recanalization had no influence on either hemorrhagic transformation or PH. Conclusion— Very low CBV was the only independent predictor of PH in patients with acute stroke.

Sensitivity of Diffusion- and Perfusion-Weighted Imaging for Diagnosing Acute Ischemic Stroke Is 97.5%

Background and Purpose— MRI using diffusion-weighted imaging (DWI) is the most sensitive diagnostic imaging modality for early detection of ischemia, but how accurate is it and how much does perfusion-weighted imaging (PWI) add to the sensitivity have to be known. Methods— In this single-center study, we collected epidemiological, imaging, and outcome data on all patients with stroke undergoing MRI-based treatment with intravenous tissue-type plasminogen activator at our center from 2004 to 2010. The DWI negative patients were identified, and we calculated the sensitivity and specificity of DWI and additional PWI for diagnosing acute ischemic stroke. We compared DWI positive and negative patients to identify characteristics associated with DWI negativity. Results— Five hundred sixty-nine consecutive patients were treated with intravenous tissue-type plasminogen activator on the basis of an acute MRI. A DWI lesion was evident in 518 patients. Forty-seven patients were DWI negative; however, a relevant PWI lesion was found in 33 of these patients. Four stroke mimics were treated with intravenous tissue-type plasminogen activator and 1 of these patients had a DWI lesion. Thus, 8% of all patients with stroke were DWI negative. The combination of DWI and PWI resulted in a sensitivity of 97.5% for the ischemic stroke diagnosis. DWI negativity was associated with less severe strokes, location in the posterior circulation, a longer time from onset to scan, and an improved 90-day outcome. The cause of small-vessel disease was more likely to be DWI negative. Conclusions— The combination of DWI and PWI before intravenous tissue-type plasminogen activator confirms the diagnosis in 97.5% of all ischemic strokes.

Absolute quantification of cerebral blood flow in neurologically normal volunteers: Dynamic‐susceptibility contrast MRI‐perfusion compared with computed tomography (CT)‐perfusion

To improve the reproducibility of arterial input function (AIF) registration and absolute cerebral blood flow (CBF) quantification in dynamic‐susceptibility MRI‐perfusion (MRP) at 1.5T, we rescaled the AIF by use of a venous output function (VOF). We compared CBF estimates of 20 healthy, elderly volunteers, obtained by computed tomography (CT)‐perfusion (CTP) and MRP on two consecutive days. MRP, calculated without the AIF correction, did not result in any significant correlation with CTP. The rescaled MRP showed fair to moderate correlation with CTP for the central gray matter (GM) and the whole brain. Our results indicate that the method used for correction of partial volume effects (PVEs) improves MRP experiments by reducing AIF‐introduced variance at 1.5T. Magn Reson Med, 2009.

Cerebral perfusion measured by dynamic susceptibility contrast MRI is reduced in patients with idiopathic normal pressure hydrocephalus

To demonstrate in idiopathic normal pressure hydrocephalus (iNPH) patients by dynamic susceptibility contrast MRI a reduced preoperative cerebral blood flow (CBF) which correlates with the severity of clinical symptoms and predicts shunt outcome.