Catharina J.M. Frijns

Soluble Adhesion Molecules Reflect Endothelial Cell Activation in Ischemic Stroke and in Carotid Atherosclerosis

BACKGROUND AND PURPOSE Activation of endothelial cells and platelets plays an important role in the development of atherosclerosis and thrombotic disorders. Soluble adhesion molecules originating from these cells can be demonstrated in plasma. We hypothesized that elevated plasma concentrations of soluble P-selectin (sP-selectin), soluble intercellular adhesion mole-cule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and soluble E-selectin (sE-selectin) can reflect activation of endothelial cells and/or platelets in acute ischemic stroke and in previously symptomatic internal carotid artery stenosis. METHODS Plasma was sampled from patients within 2 days of acute ischemic stroke (n = 28), from patients with a previous (> 1 week) transient or persistent ischemic neurological deficit associated with stenosis of the internal carotid artery (n = 34), and from control patients without a history of vascular disease (n = 34). Concentrations of sP-selectin, sICAM-1, sVCAM-1, and sE-selectin were measured by means of an enzyme-linked immunosorbent assay. RESULTS Compared with control subjects, sP-selectin and sE-selectin were significantly elevated in the acute stage of ischemic stroke (P < .0001 and P = .001, respectively) as well as in previously symptomatic carotid stenosis (P < .0001 and P = .0007). sICAM-1 and sVCAM-1 were not increased. CONCLUSIONS The elevated levels of sE-selectin indicate that endothelial cell activation occurs both in the acute stage of ischemic stroke and in previously symptomatic carotid atherosclerosis. Increased sP-selectin concentrations reflect endothelial cell activation as well but may also be caused by platelet activation.

Diagnosing Delayed Cerebral Ischemia With Different CT Modalities in Patients With Subarachnoid Hemorrhage With Clinical Deterioration

Background and Purpose— Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage worsens the prognosis and is difficult to diagnose. We investigated the diagnostic value of noncontrast CT (NCT), CT perfusion (CTP), and CT angiography (CTA) for DCI after clinical deterioration in patients with subarachnoid hemorrhage. Methods— We prospectively enrolled 42 patients with subarachnoid hemorrhage with clinical deterioration suspect for DCI (new focal deficit or Glasgow Coma Scale decrease ≥2 points) within 21 days after hemorrhage. All patients underwent NCT, CTP, and CTA scans on admission and directly after clinical deterioration. The gold standard was the clinical diagnosis DCI made retrospectively by 2 neurologists who interpreted all clinical data, except CTP and CTA, to rule out other causes for the deterioration. Radiologists interpreted NCT and CTP images for signs of ischemia (NCT) or hypoperfusion (CTP) not localized in the neurosurgical trajectory or around intracerebral hematomas, and CTA images for presence of vasospasm. Diagnostic values for DCI of NCT, CTP, and CTA were assessed by calculating sensitivities, specificities, positive predictive values, and negative predictive values with 95% CIs. Results— In 3 patients with clinical deterioration, imaging failed due to motion artifacts. Of the remaining 39 patients, 25 had DCI and 14 did not. NCT had a sensitivity of 0.56 (95% CI, 0.37 to 0.73), specificity=0.71 (0.57 to 0.77), positive predictive value=0.78 (0.55 to 0.91), negative predictive value=0.48 (0.28 to 0.68); CTP: sensitivity=0.84 (0.65 to 0.94), specificity=0.79 (0.52 to 0.92), positive predictive value=0.88 (0.69 to 0.96), negative predictive value=0.73 (0.48 to 0.89); CTA: sensitivity=0.64 (0.45 to 0.80), specificity=0.50 (0.27 to 0.73), positive predictive value=0.70 (0.49 to 0.84), negative predictive value=0.44 (0.23 to 0.67). Conclusion— As a diagnostic tool for DCI, qualitative assessment of CTP is overall superior to NCT and CTA and could be useful for fast decision-making and guiding treatment.

Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: A Systematic Review of Clinical, Laboratory, and Radiological Predictors

Background and Purpose— Established predictors of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage are large amounts of extravasated blood and poor clinical condition on admission. The predictive value of other factors is uncertain. Methods— We searched MEDLINE (1960–2012) for clinical, laboratory, and radiological predictors routinely available within 72 hours after subarachnoid hemorrhage. The studies were categorized according to methodological quality. Crude data and effect estimates (odds ratio [OR], hazard ratios, and risk ratio) with 95% CI were extracted, (re-)calculated and pooled if possible. For every potential predictor we assessed all effect estimates on consistency (point estimates in equal direction) and clinical relevance (size and 95% CI). Results— Fifty-two studies on 33 potential predictors were included. There was strong evidence (≥3 high-quality studies) for a higher risk of delayed cerebral ischemia in smokers (pooled OR, 1.2; 95% CI, 1.1–1.4), and moderate evidence (2 high-quality studies) for an increased risk in patients with hyperglycemia (OR, 3.2; 1.8–5.8 and hazard ratios, 1.7; 1.1–2.5), hydrocephalus (OR, 1.3; 1.1–1.5 and OR, 2.6; 1.2–5.5), history of diabetes mellitus (pooled OR, 6.7; 1.7–26), and early systemic inflammatory response syndrome (pooled OR, 2.1; 1.4–3.3). Evidence was limited for increased risk in women (pooled OR, 1.3; 1.1–1.6) and in patients with history of hypertension (pooled OR, 1.5; 1.3–1.7). The evidence on initial loss of consciousness, history of migraine, previous use of selective serotonin reuptake inhibitors, hypomagnesemia, low hemoglobin, or high blood flow on early transcranial Doppler was also limited. Conclusions— There is strong evidence that smoking is a predictor of delayed cerebral ischemia. For several other potential predictions the evidence is moderate, limited, or inconsistent.

Plasminogen Activator Inhibitor-1 4G Allele in the 4G/5G Promoter Polymorphism Increases the Occurrence of Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage

Background and Purpose— In several acute life-threatening diseases, the 4G-allele in the 4G/5G-promotor polymorphism in the plasminogen activator inhibitor-1 (PAI-1) gene is associated with higher PAI-1 levels and increased poor outcome, probably by promoting the formation of microthrombi. The aim of the present study was to investigate whether the PAI-1 4G/5G polymorphism is associated with the occurrence of cerebral ischemia, rebleeding, and other events, and clinical outcome after aneurysmal subarachnoid hemorrhage. Methods— DNA was collected and analyzed in 126 patients with aneurysmal subarachnoid hemorrhage admitted to the Academic Medical Centre Amsterdam and University Medical Centre Utrecht in the Netherlands. All episodes of deterioration were classified according to predefined criteria. Causes of poor outcome and functional outcome were assessed 3 months after the initial bleeding according to the 5-point Glasgow Outcome Scale (GOS). Results— Secondary ischemia occurred more often in patients with the 4G genotype than in patients homozygous for the 5G allele (RR: 3.3; 95% CI: 1.1 to 10.0). No significant differences were found between the groups for rebleeding or other events. Patients with the 4G genotype tended to have a higher risk for poor outcome than patients with the 5G/5G genotype (RR 1.2; 95% CI 0.7 to 2.2). Conclusion— The 4G allele in the PAI-1 gene increases the risk for cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH) and probably also the risk for poor outcome. After early aneurysm occlusion, treatment aimed at enhancing fibrinolysis might be effective to prevent and treat cerebral ischemia in patients with aneurysmal SAH.

Early Prediction of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: Development and Validation of a Practical Risk Chart

Background and Purpose— To develop and validate a risk chart for prediction of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage based on admission characteristics. Methods— For derivation of the risk chart, we studied data from 371 prospectively collected consecutive subarachnoid hemorrhage patients with a confirmed aneurysm admitted between 1999 and 2007. For its validation we similarly studied 255 patients admitted between 2007 and 2009. The predictive value of admission characteristics was tested in logistic regression models with delayed cerebral ischemia–related infarction as primary outcome. Procedure-related infarctions were not included. Performance of the models was tested by discrimination and calibration. On the basis of these models, a risk chart was developed for application in clinical practice. Results— The strongest predictors were clinical condition on admission, amount of blood on computed tomography (both cisternal and intraventricular) and age. A model that combined these 4 predictors had an area under the receiver operating characteristic curve of 0.63 (95% confidence interval, 0.57–0.69). This model improved little by including current smoking and hyperglycemia on admission (area under the receiver operating characteristic curve, 0.65; 95% confidence interval, 0.59–0.71). The risk chart predicted risks of delayed cerebral ischemia–related infarction varying from 12% to 61%. Both low risk (<20% risk) and high risk (>40% risk) were predicted in ≈20% of the patients. Validation confirmed that the discriminative ability was adequate (area under the receiver operating characteristic curve, 0.69; 95% confidence interval, 0.61–0.77). Conclusions— Absolute risks of delayed cerebral ischemia–related infarction can be reliably estimated by a simple risk chart that includes clinical condition on admission, amount of blood on computed tomography (both cisternal and intraventricular), and age.

Endothelial cell activation markers and delayed cerebral ischaemia in patients with subarachnoid haemorrhage

Background: Endothelial cell activation may be connected with the pathogenesis of delayed cerebral ischaemia (DCI) after subarachnoid haemorrhage (SAH). Aim: To assess the relationship between serial concentrations of circulating markers of endothelial cell activation (soluble intercellular adhesion molecule-1, soluble platelet selectin (sP-selectin), soluble endothelial selectin, ED1-fibronectin, Von Willebrand Factor (VWF) and VWF propeptide) and development of DCI. Methods: 687 blood samples were collected from 106 consecutive patients admitted within 72 h after onset of SAH. Changes in levels were analysed in the last sample before and in the first sample after the onset of DCI (n = 30), and in subgroups with DCI occurring within 24 h after treatment of the aneurysm (n = 12) or unrelated to treatment of the aneurysm (n = 18). Patients without DCI (n = 56) served as controls. Results: Concentrations of sP-selectin, but not of the other markers, were found to increase considerably after DCI unrelated to treatment of the aneurysm (increase 25 ng/ml, 95% CI 8 to 43), whereas they tended to decrease in the control patients without DCI (decrease 13 ng/ml, 95% CI −28 to 2.4). Surgery was found to profoundly influence the levels of the markers irrespective of the occurrence of DCI. Conclusion: The rise in sP-selectin level during DCI is suggested to be the result of platelet activation, as levels of the other markers of endothelial cell activation were not increased after DCI unrelated to treatment. Whether a causal role of platelet activation is implicated in the development of DCI should be determined in further studies in which the relationship between concentrations of markers and treatment is taken into account.

Neural correlates of human wayfinding in stroke patients.

Wayfinding is a complex cognitive function involving different types of information, such as knowledge about landmarks and direction information. This variety of processes suggest that multiple neural mechanisms are involved, e.g., the hippocampal system, the posterior parietal and temporal cortical areas. Although patient studies and imaging studies have given important insights in the exact neural circuitry underlying wayfinding, many controversies remain. Therefore, the current study sets out to further examine the neuroanatomical correlates of wayfinding in a sample of 31 stroke patients with unilateral lesions, tested with a series of different wayfinding tasks, including landmark recognition, landmark ordering, route reversal and route drawing. For all patients, the exact location of their lesion was determined using CT or MRI scans. Based on existing literature, a number of relevant brain areas were demarcated, after which the extent of damage to these areas was determined for each patient separately. Performance on the landmark recognition task was impaired by damage to the right hippocampal formation, whereas a weak correlation was found between damage to the dorsolateral prefrontal cortex and processing the order of the landmarks. Several brain areas were found to be involved in retracing a route from the end to the beginning, including the right hippocampal formation, the right posterior parietal cortex, the right dorsolateral prefrontal cortex and the right temporal lobe. Finally, damage to the right temporal lobe impaired the ability to draw the route.

Genes and outcome after aneurysmal subarachnoid haemorrhage

ObjectivesInitial and secondary ischaemia are important determinants of outcome after subarachnoid haemorrhage (SAH). Cerebral ischaemia is a potent stimulus for expression of genes that may influence recovery.We investigated whether functional polymorphisms in the apolipoprotein E (APOE), insulin–like growth factor-1 (IGF–1), tumor necrosis factor-A (TNF–A), interleukin-1A (IL–1A), interleukin-1B (IL–1B), and interleukin-6 (IL–6) genes are related with outcome after aneurysmal SAH.MethodsGenotyping of the polymorphisms was performed in a consecutive series of 167 patients with aneurysmal SAH. The risk of a poor outcome was analysed with logistic regression with adjustment for prognostic factors for outcome after SAH, using the homozygotes for the wild type alleles as a reference.ResultsPatients carrying any IGF–1 non–wild type allele had a lower risk of a poor outcome (OR 0.4, 95% CI 0.2–1.0), while carriers of the TNF–A non–wild type allele had a higher risk (OR 2.3, 95% CI 1.0–5.4). We could not demonstrate an association with outcome for APOE (APOEε4 OR 0.4, 95% CI 0.1–1.2; APOE ε2 OR 0.7, 95% CI 0.2–2.4), IL–1A (OR 1.8, 95% CI 0.8–4.0), IL–1B (OR 0.7, 95% CI 0.3–1.5) and IL–6 (OR 0.7, 95% CI 0.3–1.8) polymorphisms.ConclusionsVariation in some genes that are expressed after cerebral ischaemia may partly explain the large differences in outcome between patients with aneurysmal SAH. SAH patients homozygote for the IGF–1 wild type allele or carriers of the TNF–A non–wild type allele have a higher risk of poor outcome. Additional studies in other populations are needed to assess the generalisability of our results.

Endothelial Cell Activation after Subarachnoid Hemorrhage

OBJECTIVE Evidence from animal experiments suggests that endothelial cell activation plays a pathogenetic role in the development of cerebral ischemia after subarachnoid hemorrhage (SAH). We measured plasma concentrations of two markers of endothelial cell activation, i.e., ED1-fibronectin (ED1-fn) and von Willebrand factor (vWf), among patients with aneurysmal SAH. We analyzed the relationships of concentrations to initial clinical conditions, treatment modalities, and the occurrence of delayed cerebral ischemia. METHODS We collected 123 blood samples from 27 patients with aneurysmal SAH. Aneurysms were treated surgically in 19 cases, were treated endovascularly in 7 cases, and remained untreated in 1 case. Twelve patients developed symptomatic delayed cerebral ischemia. RESULTS Initial concentrations of ED1-fn (4.3 ± 3.7 &mgr;g/ml) and vWf (17.8 ± 8.2 &mgr;g/ml) were higher than the reference values (ED1-fn, 1.7 ± 0.9 &mgr;g/ml, P < 0.001; vWf, 11.5 ± 5.2 &mgr;g/ml, P = 0.003). Concentrations were higher among patients in poor clinical condition at admission, compared with patients in good clinical condition (mean difference, ED1-fn, 5.7 &mgr;g/ml, P = 0.04; vWf, 10.4 &mgr;g/ml, P = 0.02). Levels of both markers increased significantly after surgery (mean increase, ED1-fn, 7.5 &mgr;g/ml, P = 0.01; vWf, 13.2 &mgr;g/ml, P = 0.05) and after ischemic episodes (mean increase, ED1-fn, 8.3 &mgr;g/ml, P = 0.02; vWf, 5.0 &mgr;g/ml, P = 0.04). CONCLUSION Plasma concentrations of markers of endothelial cell activation were increased early after SAH and were significantly associated with the clinical condition at admission. We also observed a significant increase in concentrations after surgery and after ischemic episodes. Whether endothelial cell activation is a causal or indirectly related factor in the pathogenesis of delayed cerebral ischemia after SAH is still uncertain.

Diagnostic criteria for Susac syndrome.

Background Susac syndrome is characterised by the triad of encephalopathy with or without focal neurological signs, branch retinal artery occlusions and hearing loss. Establishment of the diagnosis is often delayed because the triad is complete only in a minority of patients at disease onset. This leads to a critical delay in the initiation of appropriate treatment. Our objective was to establish criteria for diagnosis of either definite or probable Susac syndrome. Method The establishment of diagnostic criteria was based on the following three steps: (1) Definition of a reference group of 32 patients with an unambiguous diagnosis of Susac syndrome as assessed by all interdisciplinary experts of the European Susac Consortium (EuSaC) team (EuSaC cohort); (2) selection of diagnostic criteria, based on common clinical and paraclinical findings in the EuSaC cohort and on a review of the literature; and (3) validation of the proposed criteria in the previously published cohort of all Susac cases reported until 2012. Results Integrating the clinical presentation and paraclinical findings, we propose formal criteria and recommend a diagnostic workup to facilitate the diagnosis of Susac syndrome. More than 90% of the cases in the literature fulfilled the proposed criteria for probable or definite Susac syndrome. We surmise that more patients could have been diagnosed with the recommended diagnostic workup. Conclusions We propose diagnostic criteria for Susac syndrome that may help both experts and physicians not familiar with Susac syndrome to make a correct diagnosis and to prevent delayed treatment initiation.