Brain lesion volume and capacity for consent in stroke trials: potential regulatory barriers to the use of surrogate markers

<p><b>Background and Purpose:</b> European directives and legislation in some countries forbid inclusion of subjects incapable of consent in research if recruitment of patients capable of consent will yield similar results. We compared brain lesion volumes in stroke patients deemed to have capacity to consent with those defined as incapacitated.</p> <p><b>Methods:</b> Data were obtained from 3 trials recruiting patients primarily with cortical stroke syndromes. Patients were recruited within 24 hours of onset and used MRI based selection or outcome criteria. Method of recruitment was recorded with stroke severity, age, and brain lesion volumes on Diffusion Weighted Imaging.</p> <p><b>Results:</b> Of the 56 subjects included, 38 (68%) were recruited by assent and 18 (32%) by consent. The assent group had a median lesion volume of 18.35 cubic centimetres (cc) (interquartile range [IQR] 8.27–110.31 cc), compared to 2.79 cc (IQR 1.31–12.33 cc) when patients consented (P=0.0004). Lesions were smaller than 5 cc in 7/38 (18%) in the assent group and 11/18 (61%) in the consent group (P=0.0024). There was good correlation between neurological deficit by NIH stroke scale score and lesion volume (r=0.584, P<0.0001). Logistic regression demonstrated NIHSS or lesion volume predicted capacity to consent.</p> <p><b>Conclusions:</b> Patients with acute stroke who retain capacity to consent have significantly smaller infarct volumes than those incapable of consent, and these are frequently below the limits where measurement error significantly compromises valid use of volumetric end points. Only a small proportion of patients with capacity to consent would be eligible for, and contribute usefully to, most acute stroke trial protocols.</p&gt

Hyperintense vessel sign on fluid-attenuated inversion recovery MR imaging is reduced by gadolinium

The HVS on FLAIR imaging is a useful marker of acute ischemic stroke. We investigated whether prior administration of gadolinium-based contrast hindered detection of this sign on images from subjects with acute nonlacunar ischemic stroke <4.5 hours after onset. Both blinded and comparative unblinded analyses showed significantly reduced HVS detection on postcontrast images. We suggest that assessment for this sign should be performed on images acquired prior to contrast administration

Metabolic imaging of ischemic stroke: the present and future

Measures of cerebral metabolism may be useful in the selection of patients for reperfusion therapies and as end points in clinical trials. However, there are currently no clinically routine techniques that provide such data directly. We review how imaging modalities in current clinical use may provide surrogate markers of metabolic activity. Promising techniques for metabolic imaging that are currently in the pipeline are reviewed

Do iodinated contrast agents impair fibrinolysis in acute stroke? A systematic review

Background and purpose: In vitro and nonhuman in vivo studies demonstrating impaired fibrinolysis of thrombus by thrombolytic agents in the presence of iodinated contrast media (Icm) Have prompted concern regarding the clinical use of icm. A systematic review and meta-analysis were performed to investigate the proportion of patients with acute stroke experiencing recanalization after thrombolytic therapy in whom icm were administered compared with those in whom they were not. Materials and methods: Embase and medline searches identified studies reporting recanalization rates in acute ischemic anterior circulation stroke. Pooled proportions of patients who recanalized were calculated with a random-effects model, and studies involving contrast (Cs) Were compared with those without (Ncs). Results: Six studies were found in which icm were administered, and 1 2 studies, in which they were not. Studies were statistically heterogeneous. Combined pooled proportions and 95% confidence intervals (Ci) For recanalization in unselected cs and ncs were 53% (36%-70%) And 61% (52%-71%), Respectively. In a subgroup analysis in which only middle cerebral artery occlusions were considered, the pooled proportions in cs (N = 3 studies) And ncs (N = 9 studies) Were 66% (95% Cl, 49%-82%; I-2, 0%) And 63% (Ci, 52%-74%; I-2, 82.5%). Conclusions: Recanalization rates were not significantly different inpatients who received iodinated contrast agents in clinical studies. A randomized trial to test whether icm affect recanalization would require a prohibitively large number of subject

Pilot results of in vivo brain glutathione measurements in stroke patients

Measurement of glutathione concentration for the study of redox status in subjects with neurological disease has been limited to peripheral markers. We recruited 19 subjects with large strokes. Using magnetic resonance spectroscopy we measured brain glutathione concentration in the stroke region and in healthy tissue to calculate a glutathione-ratio. Elevated glutathione-ratio was observed in subacute (<72 hours) subjects without hemorrhagic transformation (mean=1.19, P=0.03, n=6). No trend was seen when all subjects were considered (n=19, 3 to 754 hours, range=0.45 to 1.41). This technique can detect glutathione changes because of disease, and may be valuable in clinical trials of stroke and other neurological diseases

Multivoxel MR spectroscopy in acute ischemic stroke: comparison to the stroke protocol MRI

<p>Background and Purpose — Few patients with stroke have been imaged with MR spectroscopy (MRS) within the first few hours after onset. We compared data from current MRI protocols to MRS in subjects with ischemic stroke.</p> <p>Methods — MRS was incorporated into the standard clinical MRI stroke protocol for subjects <24 hours after onset. MRI and clinical correlates for the metabolic data from MRS were sought.</p> <p>Results — One hundred thirty-six MRS voxels from 32 subjects were analyzed. Lactate preceded the appearance of the lesion on diffusion-weighted imaging in some voxels but in others lagged behind it. Current protocols may predict up to 41% of the variance of MRS metabolites. Serum glucose concentration and time to maximum partially predicted the concentration of all major metabolites.</p> <p>Conclusion — MRS may be helpful in acute stroke, especially for lactate detection when perfusion-weighted imaging is unavailable. Current MRI protocols do provide surrogate markers for some indices of metabolic activity.</p&gt

Crossed cerebellar diaschisis: insights into oxygen challenge MRI

Hyperoxia during T2*-weighted magnetic resonance imaging (oxygen challenge imaging (OCI)) causes T2*-weighted signal change that is dependent on cerebral blood volume (CBV) and oxygen extraction fraction (OEF). Crossed cerebellar diaschisis (CCD), where CBV is reduced but OEF is maintained, may be used to understand the relative contributions of OEF and CBV to OCI results. In subjects with large hemispheric strokes, OCI showed reduced signal change in the contralesional cerebellum (P=0.027, n=12). This was associated with reduced CBV in contralesional cerebellum (P=0.039, n=9). CCD may be a useful model to determine the relative contribution of CBV to signal change measured by OCI

Systematic review of perfusion imaging with computed tomography and magnetic resonance in acute ischemic stroke: heterogeneity of acquisition and postprocessing parameters: a translational medicine research collaboration multicentre acute stroke imaging study

<b>Background and Purpose</b>-Heterogeneity of acquisition and postprocessing parameters for magnetic resonance– and computed tomography–based perfusion imaging in acute stroke may limit comparisons between studies, but the current degree of heterogeneity in the literature has not been precisely defined.<p></p> <b>Methods</b>-We examined articles published before August 30, 2009 that reported perfusion thresholds, average lesion perfusion values, or correlations of perfusion deficit volumes from acute stroke patients <24 hours postictus. We compared acquisition parameters from published studies with guidance from the Acute Stroke Imaging Research Roadmap1. In addition, we assessed the consistency of postprocessing parameters.<p></p> <b>Results</b>-Twenty computed tomography perfusion and 49 perfusion-weighted imaging studies were included from 7152 articles. Although certain parameters were reported frequently, consistently, and in line with the Roadmap proposals, we found substantial heterogeneity in other parameters, and there was considerable variation and underreporting of postprocessing methodology.<p></p> <b>Conclusions</b>-There is substantial scope to increase homogeneity in future studies, eg, through reporting standards