J.M. Pumar

Plasma Metalloproteinase-9 Concentration Predicts Hemorrhagic Transformation in Acute Ischemic Stroke

Background and Purpose— Matrix metalloproteinase-9 (MMP-9) activity has been associated with hemorrhagic transformation (HT) in experimental models of cerebral ischemia. Our aim was to investigate the relationship between MMP-9 concentrations in blood within 24 hours of stroke onset and subsequent HT of cerebral infarction. Methods— We studied 250 patients with a hemispheric ischemic stroke of 7.8±4.5 hours’ duration. Early CT signs of cerebral infarction were evaluated on admission. The HT and infarct volume were analyzed from the CT performed on days 4 through 7. MMP-9 levels were determined by enzyme-linked immunosorbent assay in blood samples obtained on admission. Results— HT was observed in 38 patients (15.2%): 24 (63.2%) had a hemorrhagic infarction, and 14 (36.8%) had a parenchymal hematoma. A total of 108 patients (43%) received anticoagulants before the second CT scan. Systolic and diastolic blood pressures, body temperature, frequency of early CT signs of ischemia (92% versus 22%), and treatment with anticoagulants (79% versus 37%) were significantly higher in the group with HT (P <0.001). Mean infarct volume was 126±60 cm3 in the HT group and 90±68 cm3 in the group without HT (P =0.003). Median (quartiles) plasma MMP-9 concentrations were higher in the HT group (193 [163, 213] versus 62 [40, 93] ng/mL, P <0.001), even in the 24 patients seen within 3 hours of symptom onset (P =0.014). MMP-9 levels ≥140 ng/mL had a positive and negative predictive value of HT of 61% and 97%, respectively. MMP-9 ≥140 ng/mL was associated with HT (odds ratio, 12; 95% confidence interval, 3 to 51;P <0.001) after adjustment for potential confounders and final infarct volume. Conclusions— High plasma MMP-9 concentration in the acute phase of a cerebral infarct is an independent biochemical predictor of HT in all stroke subtypes.

Molecular signatures of brain injury after intracerebral hemorrhage.

BackgroundThe mechanisms of cellular death in the tissue surrounding an intracerebral hemorrhage (ICH) are not defined. ObjectiveTo investigate the relationship of markers of excitotoxicity and inflammation to brain injury after ICH. MethodsA total of 124 consecutive patients with spontaneous ICH admitted within 24 hours of stroke onset were prospectively investigated. The volumes of the initial ICH, peripheral edema on days 3 to 4, and the residual cavity at 3 months were measured on CT scan. Glutamate, cytokines, and adhesion molecules were measured in blood samples obtained on admission. Stroke severity and neurologic outcome were evaluated with the Canadian Stroke Scale. ResultsPoor neurologic outcome at 3 months (Canadian Stroke Scale < 7) was observed in 53 patients (43%). Stroke severity and glutamate concentrations (by each increment of 10 &mgr;mol/L, odds ratio 1.23; 95% CI 1.09 to 1.41), but not the initial volume of ICH, were independent predictors of poor outcome. In the multiple linear regression analyses, tumor necrosis factor-&agr; concentration was correlated (r = 0.83, p < 0.0001) with the volume of perihematoma edema, and glutamate concentrations were correlated (r = 0.78, p < 0.0001) with the volume of the residual cavity. These same results were observed when lobar (n = 58) and deep (n = 66) ICH were analyzed separately. ConclusionsHigh plasma levels of proinflammatory molecules within 24 hours of intracerebral hemorrhage onset are correlated with the magnitude of the subsequent perihematoma brain edema, whereas poor neurologic outcome and the volume of the residual cavity are related to increased plasma glutamate concentrations.

The clinical-DWI mismatch: a new diagnostic approach to the brain tissue at risk of infarction.

Objective: To evaluate the usefulness of a mismatch between the severity of acute clinical manifestations and the diffusion-weighted imaging (DWI) lesion in predicting early stroke outcome and infarct volume. Methods: One hundred sixty-six patients with a hemispheric ischemic stroke of <12 hours’ duration were studied. The NIH Stroke Scale (NIHSS) score and the volume of DWI lesion were measured on admission and at 72 ± 12 hours. Infarct volume was measured on T2-weighted or fluid-attenuated inversion recovery images at day 30. Early neurologic deterioration (END) was defined as an increase of ≥4 points between the two NIHSS evaluations. Thirty-eight patients received IV thrombolysis or abciximab. Clinical–DWI mismatch (CDM) was defined as NIHSS score of ≥8 and ischemic volume on DWI of ≤25 mL on admission. The adjusted influence of CDM on END, DWI lesion enlargement at 72 hours, and infarct growth at day 30 was evaluated by logistic regression analysis and generalized linear models. Results: CDM was found in 87 patients (52.4%). Patients with CDM had a higher risk of END than patients without CDM because NIHSS < 8 (odds ratio [OR], 9.0; 95% CI,1.9 to 42) or DWI lesion > 25 mL (OR, 2.0; 95% CI, 0.8 to 4.9). CDM was associated with an increase of 46 to 68 mL in the mean volume of DWI lesion enlargement and infarct growth in comparison with non-CDM. All the effects were even greater and significant in patients not treated with reperfusion therapies. Conclusions: Acute stroke patients with an NIHSS score of ≥8 and DWI volume of ≤25 mL have a higher probability of infarct growth and early neurologic deterioration. The new concept of CDM may identify patients with tissue at risk of infarction for thrombolytic or neuroprotective drugs.

Neurological Deterioration in Acute Lacunar Infarctions The Role of Excitatory and Inhibitory Neurotransmitters

Background and Purpose The mechanisms involved in the neurological deterioration of acute lacunar strokes are unknown. Although accumulating evidence suggests that glutamate release plays a role in the progression of territorial infarctions, it remains to be established whether excitotoxicity also participates in lacunar stroke progression. We investigated whether excitatory and inhibitory amino acid concentrations in blood predict subsequent progressive motor deficits in lacunar infarctions. Methods We studied 113 consecutive patients with lacunar infarct, defined by clinical and computed tomography/magnetic resonance imaging criteria, within the first 24 hours after stroke onset. Neurological deterioration was defined as a decrease of ≥1 points in the motor items of the Canadian Stroke Scale in the first 48 hours after admission. Glutamate, glycine, and GABA were determined by high-performance liquid chromatography in plasma samples obtained on admission. Predictive values, sensitivity, specificity, and accuracy of specific glutamate and GABA concentrations and glutamate×glycine/GABA index for progression of lacunar stroke were calculated. Results Twenty-seven patients (23.9%) had neurological worsening. Plasma concentrations of glutamate (253±70 versus 123±73 &mgr;mol/L, mean±SD) were higher and those of GABA (140±63 versus 411±97 nmol/L) were lower in the progressing group than in the nonprogressing group (both P <0.001). Glutamate concentrations >200 &mgr;mol/L and GABA levels <240 nmol/L had a positive predictive value for neurological deterioration of 67% and 84%, respectively. A excitotoxic index >106 had a positive predictive value of 85%. Conclusions These findings suggest that an imbalance between the glutamate and GABA concentrations may play a role in the pathophysiology of progressing lacunar infarctions.

Body Temperature and Fibrinogen Are Related to Early Neurological Deterioration in Acute Ischemic Stroke

In a prospective study of 128 patients with acute ischemic stroke less than 24 h from onset, we explored new predictive factors for early neurological deterioration (a decrease in Canadian Stroke Scal

High plasma glutamate concentrations are associated with infarct growth in acute ischemic stroke

Background: Excitotoxic and inflammatory mechanisms have been demonstrated as mediating early neurologic deterioration (END) in patients with cerebral infarction. Here we investigate whether molecular markers associated with END are related to the volume and outcome of the diffusion weighted image (DWI) lesion in acute ischemic stroke. Methods: MRI was performed on admission and at 72 hours in 197 patients with acute hemispheric infarction of <12 hours’ duration. DWI lesion enlargement was calculated as the absolute difference between volumes on admission and day 3 of evolution. NIH Stroke Scale was scored at the same intervals. END was defined as an increase ≥4 points within the 3 days. Glutamate, l-arginine, interleukin-6 (IL-6), and tumor necrosis factor-α levels were analyzed in blood samples obtained on admission. Results: DWI lesion growth was found in 144 (73%) patients (median increase 38 [6.5, 83.4] cm3) and END occurred in 58 (29.4%) patients. Baseline glutamate (r = 0.71), l-arginine (r = −0.35), and IL-6 levels (r = 0.50) showed a high and significant correlation with the DWI lesion enlargement (all p < 0.001). After adjustment for potential confounders, glutamate levels were the only molecular marker associated with DWI lesion enlargement at 72 hours (β = 0.21; SD = 0.07; p = 0.004). Conclusions: Molecular markers of early neurologic deterioration may play a role as mediators of lesion growth in cerebral ischemia. Plasma glutamate concentration is the most powerful and independent predictor biomarker of lesion enlargement in the acute phase of ischemic stroke, and so may well be useful as a signature of tissue at risk of infarction. GLOSSARY: CBF = cerebral blood flow; CBV = cerebral blood volume; DWI = diffusion-weighted imaging; END = early neurologic deterioration; FLAIR = fluid-attenuated inversion recovery; IL-6 = interleukin-6; MTT = mean transient time; NIHSS = NIH Stroke Scale; NO = nitric oxide; PWI = perfusion-weighted imaging; rt-PA = recombinant tissue plasminogen activator; T2-WI = T2-weighted imaging; TNFα = tumor necrosis factor-α.

The Feasibility of a Collaborative Double-Blind Study Using an Anticoagulant

We present the methodology and data indicating the feasibility of a five-study collaborative stroke trial. The core study, the Warfarin-Aspirin Recurrent Stroke Study (WARSS), is a prospective, random

LEO Stent Monotherapy for the Endovascular Reconstruction of Fusiform Aneurysms of the Middle Cerebral Artery

SUMMARY: We present the case of a patient with a fusiform aneurysm of the M1 segment of the middle cerebral artery (MCA) in which endovascular stent placement without coiling was performed. A 3.5-mm × 25-mm LEO self-expanding stent was deployed along the fusiform aneurysm of the horizontal MCA M1 segment. Digital subtraction angiography showed progressive thrombosis at 6 months and complete thrombosis of the fusiform MCA aneurysm at 12 months.

Optimizing Intensive Care in Stroke: A European Perspective

The concept of critical care in stroke is a controversial issue. The question of whether full-scale critical care management of stroke improves patient outcome is still open and probably depends on th

Headache as A Surrogate Marker of the Molecular Mechanisms Implicated in Progressing Stroke

The mechanism for headache in patients with acute ischaemic stroke are not completely understood. We analysed the relationship between headache and the early worsening of neurological symptoms in patients with acute ischaemic stroke, and we studied the possible biochemical mechanisms implicated. Headache at the onset of ischaemic stroke predicted progression with a sensitivity, specificity, and positive predictive value of 56%, 99%, and 98%, respectively. CSF concentrations of glutamate, Interleukin-6, and NO-m were significantly greater in patients with progressing stroke than in patients with nonprogressing stroke, and these biochemical markers were also significantly higher in patients with headache than in those without headache. Results of this study suggest that headache at the onset of ischaemic stroke is an independent predictor of neurological worsening and we hypothesize that headache might be a surrogate marker of the molecular mechanisms involved in neurological worsening after acute stroke.