R. J. van Oostenbrugge

Virchow-Robin spaces relate to cerebral small vessel disease severity

Background and purposeVirchow-Robin spaces (VRs) are perivascular spaces surrounding the deep perforating brain arteries. VRs dilatation is pathologic, and it could be a manifestation of cerebral small vessel disease. In the present study we assessed the relation between VRs and silent ischemic lesions in a cohort of patients with cerebral small vessel disease.MethodsWe divided dilated VRs on MRI (1.5 Tesla) into three semi-quantitative categories in 165 first ever lacunar stroke patients. We counted asymptomatic lacunar infarcts and graded white matter lesions, and compared the prevalence of vascular risk factors in different categories of VRs. We also determined independent predictors of silent ischemic lesions.ResultsVRs at basal ganglia level related to age, hypertension, asymptomatic lacunar infarcts, and white matter lesions. VRs at basal ganglia level predicted silent ischemic lesions (odds ratio 10.58 per higher VRs category; 95 %- confidence interval 3.40 – 32.92).ConclusionDilated VRs in the basal ganglia relate to the severity of cerebral small vessel disease and might be a manifestation of the same small vessel abnormality that causes silent ischemic lesions. This adds a role for VRs as a potential marker for small vessel disease.

Presenting features and value of diagnostic procedures in leptomeningeal metastases

Objective: To study the presenting features and value of routine diagnostic procedures in patients with leptomeningeal metastases (LMM) related to the primary malignancy to improve diagnostic assessment. Methods: The authors studied the presenting features and value of routine diagnostic procedures in relation to the histology of primary malignant disease in 45 patients with LMM of solid (n = 30) or hematologic (n = 15) malignancies. Results: Patients with solid LMM present mostly with spinal or radicular symptoms (53%), whereas patients with hematologic LMM more often show cranial nerve dysfunction at presentation (53%). Multifocal neurologic symptoms were seen in 67% of patients. The first CSF cytology demonstrated malignant cells more frequently in solid LMM compared with hematologic LMM (73% versus 53%). Extralumbar punctures increased the sensitivity of cytology to a greater extent in hematologic LMM than in solid LMM (34% versus 10%). Abnormal neuroimaging findings were found more often in solid LMM than in hematologic LMM (67% versus 40%). Increased total CSF protein in combination with either multifocal neurologic symptoms or abnormal neuroimaging findings was found in 73% of patients with a negative first CSF cytology. Conclusions: Patients with LMM presented differently depending on the histology of the primary tumor. In patients with a negative first CSF cytologic examination, multiple lumbar punctures increased the diagnostic accuracy, especially in hematologic LMM. LMM could also be diagnosed in patients with known cancer if total CSF protein was increased in combination with either multifocal neurologic symptoms or abnormal neuroimaging findings, preferably MRI.

Plaque at RISK (PARISK): Prospective Multicenter Study to Improve Diagnosis of High-Risk Carotid Plaques

Background Patients with symptomatic carotid artery stenosis are at high risk for recurrent stroke. To date, the decision to perform carotid endarterectomy in patients with a recent cerebrovascular event is mainly based on degree of stenosis of the ipsilateral carotid artery. However, additional atherosclerotic plaque characteristics might be better predictors of stroke, allowing for more precise selection of patients for carotid endarterectomy. Aims and hypothesis We investigate the hypothesis that the assessment of carotid plaque characteristics with magnetic resonance imaging, multidetector-row computed tomography angiography, ultrasonography, and transcranial Doppler, either alone or in combination, may improve identification of a subgroup of patients with <70% carotid artery stenosis with an increased risk of recurrent stroke. Methods The Plaque At RISK (PARISK) study is a prospective multicenter cohort study of patients with recent (<3 months) neurological symptoms due to ischemia in the territory of the carotid artery and < 70% ipsilateral carotid artery stenosis who are not scheduled for carotid endarterectomy or stenting. At baseline, 300 patients will undergo magnetic resonance imaging, multidetector-row computed tomography angiography, and ultrasonography examination of the carotid arteries. In addition, magnetic resonance imaging of the brain, ambulatory transcranial Doppler recording of the middle cerebral artery and blood withdrawal will be performed. After two-years, imaging will be repeated in 150 patients. All patients undergo a follow-up brain magnetic resonance imaging, and there will be regular clinical follow-up until the end of the study. Study outcomes The combined primary end-point contains ipsilateral recurrent ischemic stroke or transient ischemic attack or new ipsilateral ischemic brain lesions on follow-up brain magnetic resonance imaging.

Potential of integrated [18F] fluorodeoxyglucose positron-emission tomography/CT in identifying vulnerable carotid plaques.

It is known that risk of cerebrovascular accident is not only associated with degree of carotid artery stenosis but probably more importantly with type of plaque: vulnerable vs stable. Myriad studies have looked at this issue with high-resolution MR imaging but the present one used FDG-PET and CT. Fifty patients with transient ischemic attack/stroke who had ipsilateral stenosis and plaque along with contralateral asymptomatic plaque were imaged. High uptake was seen in ipsilateral plaques when compared with contralateral asymptomatic ones but these differences were not significant. CT also showed larger lipid-rich necrotic cores and thicker arterial walls in symptomatic plaques, but again these differences were not significant. Thus, it remains to be determined if the combination of FDG-PET/CT is valuable. BACKGROUND AND PURPOSE: There is a need for improved risk stratification of patients with TIA/stroke and carotid atherosclerosis. The purpose of this study was to prospectively investigate the potential of integrated 18F-FDG PET/MDCT in identifying vulnerable carotid plaques. MATERIALS AND METHODS: Fifty patients with TIA/stroke with an ipsilateral carotid plaque causing <70% stenosis and a plaque on the contralateral asymptomatic side underwent integrated 18F-FDG PET/MDCT within 36.1 ± 20.0 days (range, 9–95 days) of the last symptoms. Carotid plaque 18F-FDG uptake was measured as both the mean and maximum blood-normalized SUV, known as the TBR. Using MDCT, we assessed volumes of vessel wall and individual plaque components. RESULTS: Mean TBR was only significantly larger in the ipsilateral plaques of patients who were imaged within 38 days (1.24 ± 0.04 [SE] versus 1.17 ± 0.05, P = .014). This also accounted for maximum TBR (1.53 ± 0.06 versus 1.42 ± 0.06, P = .015). MDCT-assessed vessel wall and LRNC volumes were larger in ipsilateral plaques of all patients (982.3 ± 121.3 versus 811.3 ± 106.6 mm3, P = .016; 164.7 ± 26.1 versus 134.3 ± 35.2 mm3, P = .026, respectively). CONCLUSIONS: In the present study, 18F-FDG PET only detected significant differences between ipsilateral and contralateral asymptomatic plaques in patients with TIA/stroke who were imaged within 38 days, whereas MDCT detected larger vessel wall and LRNC volumes, regardless of time after symptoms. In view of the substantial overlap in measurements of both sides, it remains to be determined whether the differences we found will be clinically meaningful.

Haptoglobin Phenotype May Alter Endothelial Progenitor Cell Cluster Formation in Cerebral Small Vessel Disease

Cerebral small vessel disease results in silent ischemic lesions (SIL) among which is leukoaraiosis. In this process, endothelial damage is probably involved. Endothelial progenitor cells (EPC), are involved in endothelial repair. By restoring the damaged endothelium, EPC could mitigate SIL and cerebral small vessel disease. Haptoglobin 1-1, one of three phenotypes of haptoglobin, relates to SIL and may therefore attenuate the endothelial repair by EPC. Our aim was to quantify EPC number and function and to assess haptoglobin phenotype and its effect on EPC function in patients with a high prevalence of SIL: lacunar stroke patients. We assessed EPC In 42 lacunar stroke patients and 18 controls by flow cytometry and culture with fetal calf serum, patient and control serum. We determined haptoglobin phenotype and cultured EPC with the three different haptoglobin phenotypes. We found that EPC cluster counts were lower in patients (96.9 clusters/well +/- 83.4 (mean +/- SD)), especially in those with SIL (85.0 +/- 64.3), than in controls (174.4 +/- 112.2). Cluster formation was inhibited by patient serum, especially by SIL patient serum, but not by control serum. Patients with haptoglobin 1-1 had less clusters in culture, and when haptoglobin 1-1 was added to EPC cultures, cluster numbers were lower than with the other haptoglobin phenotypes. We conclude that lacunar stroke patients, especially those with SIL, have impaired EPC cluster formation, which may point at decreased endothelial repair potential. The haptoglobin 1-1 phenotype is likely a causative factor in this impairment.

The value of interphase cytogenetics in cytology for the diagnosis of leptomeningeal metastases

We studied the use of fluorescence in situ hybridization (FISH) in CSF to enhance the diagnostic yield for the detection of malignancy on the first lumbar puncture in patients clinically suspected of having leptomeningeal metastases (LMM). Although repeated lumbar punctures were still needed in some patients, the use of FISH did speed up the diagnosis in approximately one-third of the patients clinically suspected of having LMM with atypical cells at first cytology. This eliminates the need for repeated lumbar punctures in these patients and enables an earlier start of treatment.

Baseline Blood Pressure Effect on the Benefit and Safety of Intra-Arterial Treatment in MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands).

Background and Purpose— High blood pressure (BP) is associated with poor outcome and the occurrence of symptomatic intracranial hemorrhage in acute ischemic stroke. Whether BP influences the benefit or safety of intra-arterial treatment (IAT) is not known. We aimed to assess the relation of BP with functional outcome, occurrence of symptomatic intracranial hemorrhage and effect of IAT. Methods— This is a post hoc analysis of the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands). BP was measured at baseline, before IAT or stroke unit admission. We estimated the association of baseline BP with the score on the modified Rankin Scale at 90 days and safety parameters with ordinal and logistic regression analysis. Effect of BP on the effect of IAT was tested with multiplicative interaction terms. Results— Systolic BP (SBP) had the best correlation with functional outcome. This correlation was U-shaped; both low and high baseline SBP were associated with poor functional outcome. Higher SBP was associated with symptomatic intracranial hemorrhage (adjusted odds ratio, 1.25 for every 10 mm Hg higher SBP [95% confidence interval, 1.09–1.44]). Between SBP and IAT, there was no interaction for functional outcome, symptomatic intracranial hemorrhage, or other safety parameters; the absolute benefit of IAT was evident for the whole SBP range. The same was found for diastolic BP. Conclusions— BP does not affect the benefit or safety of IAT in patients with acute ischemic stroke caused by proximal intracranial vessel occlusion. Our data provide no arguments to withhold or delay IAT based on BP. Clinical Trial Registration— URL: http://www.isrctn.com. Unique identifier: ISRCTN10888758.

Disappearing Hyperdense Middle Cerebral Artery Sign Is Associated with Striatocapsular Infarcts on Follow-Up CT in Ischemic Stroke Patients Treated with Intravenous Thrombolysis

Background: A striatocapsular infarct (SCI) is a subcortical infarct in the territory of the lenticulostriate arteries, most likely due to transient occlusion of the main stem of the middle cerebral artery (MCA). Presence of the hyperdense middle cerebral artery sign (HMCAS) is a reliable marker of occlusion of the MCA. We hypothesized that SCIs are related to HMCAS at baseline, which subsequently disappears (HMCAS-D) on follow-up CT in stroke patients treated with intravenous rtPA. Methods: Baseline and 24-hour follow-up CTs were evaluated for HMCAS in acute ischemic stroke patients treated with intravenous rtPA and follow-up scans were also reviewed for the presence of isolated cortical (CIn), SCI, cortical and striatocapsular (CI-SCI) or lacunar infarct. We determined the incidence of SCI and the association between SCI and HMCAS on baseline and follow-up CT. Results: Of the 247 patients, 43 had an SCI (17.4%; 95% CI: 13.1–22.5). The presence of HMCAS at baseline was related to the occurrence of infarction with involvement of the striatocapsular region (SCI or CI-SCI) on follow-up CT (OR: 11.6; 95% CI: 5.9–22.8). HMCAS-D on follow-up scans was significantly related to SCI on follow-up CT compared to CI-SCI (OR: 4.9; 95% CI: 3.7–6.1). Conclusions: Occurrence of SCI and CI-SCI is associated with the presence of HMCAS on CT before thrombolysis, whereas HMCAS-D on follow-up CT is strongly related to the occurrence of SCI. Our findings support the causative role of transient occlusion of the MCA main stem in the pathogenesis of SCI.

Plaque Components in Symptomatic Moderately Stenosed Carotid Arteries Related to Cerebral Infarcts The Plaque At RISK Study

Background and Purpose— Carotid plaque composition is a major determinant of cerebrovascular events. In the present analysis, we evaluated the relationship between intraplaque hemorrhage (IPH) and a thin/ruptured fibrous cap (TRFC) in moderately stenosed carotid arteries and cerebral infarcts on MRI in the ipsilateral hemisphere. Methods— A total of 101 patients with a symptomatic 30% to 69% carotid artery stenosis underwent MRI of the carotid arteries and the brain, within a median time of 45 days from onset of symptoms. The presence of ipsilateral infarcts in patients with and without IPH and TRFC was evaluated. Results— IPH was seen in 40 of 101 plaques. TRFC was seen in 49 of 86 plaques (postcontrast series were not obtained in 15 patients). In total, 51 infarcts in the flow territory of the symptomatic carotid artery were found in 47 patients. Twenty nine of these infarcts, found in 24 patients, were cortical infarcts. No significant relationship was found between IPH or TRFC and the presence of ipsilateral infarcts. Conclusions— MRI detected IPH and TRFC are not related to the presence of old and recent cortical and subcortical infarcts ipsilateral to a symptomatic carotid artery stenosis of 30% to 69%. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01208025.

Increased admission and fasting glucose are associated with unfavorable short-term outcome after intra-arterial treatment of ischemic stroke in the MR CLEAN pretrial cohort

BACKGROUND Limited data are available on the impact of fasting glucose on outcome after intra-arterial treatment (IAT). We studied whether hyperglycemia on admission and impaired fasting glucose (IFG) are associated with unfavorable outcome after IAT in acute ischemic stroke. METHODS Patients were derived from the pretrial registry of the MR CLEAN-trial. Hyperglycemia on admission was defined as glucose>7.8mmol/L, IFG as fasting glucose>5.5mmol/L in the first week of admission. Primary effect measure was the adjusted common odds ratio (acOR) for a shift in the direction of worse outcome on the modified Rankin Scale at discharge, estimated with ordinal logistic regression, adjusted for common prognostic factors. RESULTS Of the 335 patients in which glucose on admission was available, 86 (26%) were hyperglycemic, 148 of the 240 patients with available fasting glucose levels (62%) had IFG. Median admission glucose was 6.8mmol/L (IQR 6-8). Increased admission glucose (acOR 1.2, 95%CI 1.1-1.3), hyperglycemia on admission (acOR 2.6, 95%CI 1.5-4.6) and IFG (acOR 2.8, 95%CI 1.4-5.6) were associated with worse functional outcome at discharge. CONCLUSION Increased glucose on admission and IFG in the first week after stroke onset are associated with unfavorable short-term outcome after IAT of acute ischemic stroke.