Alejandro Martínez-Domeño

Pretreatment hemostatic markers of symptomatic intracerebral hemorrhage in patients treated with tissue plasminogen activator.

Background and Purpose— Symptomatic intracerebral hemorrhage (ICH) is a major complication of thrombolysis in patients with acute ischemic stroke. We analyzed whether baseline hemostatic markers could predict symptomatic ICH (SICH). Methods— In a multicenter study of patients treated with intravenous tissue plasminogen activator (t-PA) within 3 hours of stroke onset, we analyzed the following variables: demographic data, vascular risk factors, blood glucose at admission, time from the onset of symptoms to t-PA infusion, blood pressure, neurological deficit measured by the National Institutes of Health Stroke Scale (NIHSS) score, early signs of ischemia on the baseline computed tomography (CT) scan, and protocol deviations. In blood samples, the following markers of coagulation/fibrinolysis were measured before treatment: fibrinogen, prothrombin fragments 1+2, Factor XIII, Factor VII, &agr;2 antiplasmin, plasminogen activator inhibitor-1 (PAI-1), and thrombin-activatable fibrinolysis inhibitor. ICH was classified according to the European Cooperative Acute Stroke Study (ECASS) II criteria. SICH was defined as a parenchymal hematoma-1 (PH1) or PH2 type, associated with an increase in ≥4 points on the NIHSS score appearing within 36 hours after infusion. Results— We studied 114 patients. Mean age was 68.4±12.7 years, and 61% were men. The median baseline NIHSS score was 14. Mean time to treatment was 153±33 minutes. Eight patients had SICH (7%), and 18 patients (15.7%) had asymptomatic ICH. None of the baseline markers of coagulation/fibrinolysis were associated with SICH. In the multivariate analysis, only NIHSS on admission was an independent risk factor for SICH. Conclusions— None of the hemostatic markers analyzed in our study predicted symptomatic cerebral hemorrhage in patients with ischemic stroke treated with t-PA.

Effect of levetiracetam on cognitive functions and quality of life: a one-year follow-up study

PURPOSE The purpose of the study was to assess changes in cognitive functions and quality of life in patients with epilepsy over one year of treatment with levetiracetam (LEV) as add-on therapy. METHODS Thirty-two patients (16 women; 16 men) who received LEV as an add-on treatment were included, and 27 completed the one-year follow-up period. Extensive neuropsychological assessments, together with a quality-of-life questionnaire were administered at baseline and at one, three, six and twelve months after beginning the add-on treatment. Patients received LEV starting with 500 mg/day in the first week, increasing by a further 500 mg/day per week until a target dose of 2 000 mg/day was reached by the end of the first month. RESULTS At the one-year follow-up, a significant improvement was observed in measurements of prospective memory, working memory, motor functions, verbal fluency, attention and quality of life. Performance for neuropsychological and quality-of-life tests was not affected by external variables such as seizure reduction or changes in previous anti-epileptic treatment. Slight changes between patients were observed, but these were not clinically significant.The limited sample size and the lack of a control group should be mentioned as limitations of the study. No control group was evaluated as in our clinical practice it was difficult to establish a comparable group of patients. Changes in the different variables were assessed by comparing baseline information with follow-up results.Despite the study limitations, we consider that the one-year treatment period provides valuable information regarding the drugs long-term effects in this setting. CONCLUSIONS Results of the present study suggest that long-term LEV treatment as add-on therapy does not interfere with cognitive function and improves quality of life.

Circulating Endothelial Progenitor Cells and the Risk of Vascular Events after Ischemic Stroke

Background and Purpose We evaluated the hypothesis that the number of circulating EPC could be associated with the risk of stroke recurrence (SR) or vascular events (VE) after an ischemic stroke. Methods We studied prospectively consecutive patients with cerebral infarction within the first 48 hours after the onset. We recorded demographic factors, vascular risk factors, previous Rankin scale (RS) score, and etiology. We analyzed EPC counts by flow cytometry in blood collected at day 7 and defined EPC as CD34+/CD133+/KDR+ cells. Mean follow-up was 29.3 ± 16 months. We evaluated SR as well as VE. Patients were classified as to the presence or absence of EPC in the circulation (either EPC+ or EPC-). Bivariate analyses, Kaplan-Meier survival curves and Cox regression models were used. Results We included 121 patients (mean age 70.1±12.6 years; 65% were men). The percentage of EPC+ patients was 47.1%. SR occurred in 12 (9.9%) and VE in 18 (14.9%) patients. SR was associated significantly with a worse prior RS score, previous stroke and etiology, but not with EPC count. VE were associated significantly with EPC-, worse prior RS score, previous stroke, high age, peripheral artery disease and etiology. Cox regression model showed that EPC- (HR 7.07, p=0.003), age (HR 1.08, p=0.004) and a worse prior RS score (HR 5.8, p=0.004) were associated significantly with an increased risk of VE. Conclusions The absence of circulating EPC is not associated with the risk of stroke recurrence, but is associated with an increased risk of future vascular events.

Remote Intracerebral Hemorrhage After Intravenous Thrombolysis: Results From a Multicenter Study

Background and Purpose— Remote parenchymal hemorrhage (rPH) after intravenous thrombolysis with recombinant tissue-type plasminogen activator may be associated with cerebral amyloid angiopathy, although supportive data are limited. We aimed to investigate risk factors of rPH after intravenous thrombolysis with recombinant tissue-type plasminogen activator. Methods— This is an observational study of patients with ischemic stroke who were treated with intravenous thrombolysis with recombinant tissue-type plasminogen activator and were included in a multicenter prospective registry. rPH was defined as any extraischemic hemorrhage detected in the follow-up computed tomography. We collected demographic, clinical, laboratory, radiological, and outcome variables. In the subset of patients who underwent a magnetic resonance imaging examination, we evaluated the distribution and burden of cerebral microbleeds, cortical superficial siderosis, leukoaraiosis, and recent silent ischemia in regions anatomically unrelated to the ischemic lesion that caused the initial symptoms. We compared patients with rPH with those without rPH or parenchymal hemorrhage. Independent risk factors for rPH were obtained by multivariable logistic regression analyses. Results— We evaluated 992 patients (mean age, 74.0±12.6 years; 52.9% were men), and 408 (41%) of them underwent a magnetic resonance imaging. Twenty-six patients (2.6%) had a rPH, 8 (0.8%) had both rPH and PH, 58 (5.8%) had PH, and 900 (90.7%) had no bleeding complication. Lobar cerebral microbleeds (odds ratio, 8.0; 95% confidence interval, 2.3–27.2) and recent silent ischemia (odds ratio, 4.8; 95% confidence interval, 1.6–14.1) increased the risk of rPH. Conclusions— The occurrence of rPH after intravenous thrombolysis with recombinant tissue-type plasminogen activator in patients with ischemic stroke is associated with lobar cerebral microbleeds and multiple ischemic lesions in different regions.

The H-ATOMIC Criteria for the Etiologic Classification of Patients with Intracerebral Hemorrhage.

Background and Purpose There are no generally accepted criteria for the etiologic classification of intracerebral hemorrhage (ICH). For this reason, we have developed a set of etiologic criteria and have applied them to a large number of patients to determine their utility. Methods The H-ATOMIC classification includes 7 etiologic categories: Hypertension, cerebral Amyloid angiopathy, Tumour, Oral anticoagulants, vascular Malformation, Infrequent causes and Cryptogenic. For each category, the etiology is scored with three degrees of certainty: Possible(3), Probable(2) and Definite(1). Our aim was to perform a basic study consisting of neuroimaging, blood tests, and CT-angio when a numerical score (SICH) suggested an underlying structural abnormality. Combinations of >1 etiologic category for an individual patient were acceptable. The criteria were evaluated in a multicenter and prospective study of consecutive patients with spontaneous ICH. Results Our study included 439 patients (age 70.8 ± 14.5 years; 61.3% were men). A definite etiology was achieved in 176 (40.1% of the patients: Hypertension 28.2%, cerebral Amyloid angiopathy 0.2%, Tumour 0.2%, Oral anticoagulants 2.2%, vascular Malformation 4.5%, Infrequent causes 4.5%). A total of 7 patients (1.6%) were cryptogenic. In the remaining 58.3% of the patients, ICH was attributable to a single (n = 56, 12.7%) or the combination of ≥2 (n = 200, 45.5%) possible/probable etiologies. The most frequent combinations of etiologies involved possible hypertension with possible CAA (H3A3, n = 38) or with probable CAA (H3A2, n = 29), and probable hypertension with probable OA (H2O2, n = 27). The most frequent category with any degree of certainty was hypertension (H1+2+3 = 80.6%) followed by cerebral amyloid angiopathy (A1+2+3 = 30.9%). Conclusions According to our etiologic criteria, only about 40% patients received a definite diagnosis, while in the remaining patients ICH was attributable to a single possible/probable etiology or to more than one possible/probable etiology. The use of these criteria would likely help in the management of patients with ICH.

Clinical characteristics and outcome of the capsular warning syndrome: a multicenter study.

Background The capsular warning syndrome is defined as recurrent transient lacunar syndromes that usually precede a capsular infarction. Several aspects regarding the clinical management are controversial. We report the clinical and radiological characteristics of a multicenter series of patients with capsular warning syndrome, as well as their functional outcome during the follow-up. Aims We sought to describe the clinico-radiological spectrum of the capsular warning syndrome and to report the functional outcomes and recurrences of these patients during the follow-up. Methods We conducted a multicenter study that collected clinical and radiological data from patients with capsular warning syndrome during 2003–2013. Capsular warning syndrome was defined as the succession of three or more motor or sensory-motor lacunar syndromes within a period of 72 h, with complete recovery between them. We recorded the functional outcome (favorable when Rankin scale score ≤2) and recurrences during follow-up. Results Our study included 42 patients whose mean age was 66·4 ± 10 years; 71·4% of them were men. The mean number of episodes before a permanent neurological impairment occurred or before a complete recovery of symptoms was 5·1 ± 2·3. Up to 30 patients (71·2%) had an acute infarct visible on the neuroimaging (computed tomography/magnetic resonance imaging). The internal capsule was the most frequent infarct location (50%), but other locations were noted. Twelve patients (28·6%) received thrombolysis in the acute phase. A favorable outcome was observed in 39 patients (92·9%). After a mean follow-up of 35 ± 29 months, only one patient suffered a recurrent ischemic stroke. Conclusions Capsular warning syndrome preceded an ischemic infarction in 71·2% of patients. In addition to the internal capsule, other locations were noted. The most effective treatment remains unclear. The functional prognosis is favorable in most patients and recurrences are rare.

Statins do not increase Markers of Cerebral Angiopathies in patients with Cardioembolic Stroke

We investigated whether pre-treatment with statins is associated with surrogate markers of amyloid and hypertensive angiopathies in patients who need to start long-term oral anticoagulation therapy. A prospective multicenter study of patients naive for oral anticoagulants, who had an acute cardioembolic stroke. MRI was performed at admission to evaluate microbleeds, leukoaraiosis and superficial siderosis. We collected data on the specific statin compound, the dose and the statin intensity. We performed bivariate analyses and a logistic regression to investigate variables associated with microbleeds. We studied 470 patients (age 77.5 ± 6.4 years, 43.7% were men), and 193 (41.1%) of them received prior treatment with a statin. Microbleeds were detected in 140 (29.8%), leukoaraiosis in 388 (82.5%) and superficial siderosis in 20 (4.3%) patients. The presence of microbleeds, leukoaraiosis or superficial siderosis was not related to pre-treatment with statins. Microbleeds were more frequent in patients with prior intracerebral hemorrhage (OR 9.7, 95% CI 1.06–90.9) and in those pre-treated antiplatelets (OR 1.66, 95% CI 1.09–2.53). Prior treatment with statins was not associated with markers of bleeding-prone cerebral angiopathies in patients with cardioembolic stroke. Therefore, previous statin treatment should not influence the decision to initiate or withhold oral anticoagulation if these neuroimaging markers are detected.

SMASH-U versus H-ATOMIC: A Head-to-Head Comparison for the Etiologic Classification of Intracerebral Hemorrhage

BACKGROUND There is no agreement for the etiologic classification of patients with intracerebral hemorrhage (ICH). In a series of patients with ICH, we performed a randomized head-to-head comparison between the two recently proposed etiologic classification systems. METHODS We evaluated patients registered in a prospective database of consecutive patients. A simplified H-ATOMIC classification defines 8 categories: hypertension, amyloid, tumor, oral anticoagulants, malformation, infrequent, cryptogenic, and combination. SMASH-U also defines 8 categories: structural, medication, amyloid, systemic, hypertension, and undetermined, and nonstroke and stroke-non-ICH. Experienced stroke neurologists applied both classification systems to a randomly assigned list of patients. The concordances between the 2 systems were analyzed. In a subset of patients, the percent of agreement and the inter-rater reliability (kappa coefficient) were calculated. RESULTS A total of 156 patients (age 72.3 ± 13.5 years) were evaluated, and 54 of these patients were evaluated by 2 neurologists. Concordance (a patient classified in equivalent categories for both systems) was 63%. The percentage of interobserver agreement was 85.5% for SMASH-U and 87.6% for H-ATOMIC. Inter-rater reliability was similar for SMASH-U (kappa .82) and H-ATOMIC (kappa .76). The range of reliability among neurologists was .66-.93 for SMASH-U and .66-.94 for H-ATOMIC. CONCLUSIONS The percentage agreement among investigators is remarkably high for both classification systems, and the inter-rater reliability is substantial to almost perfect for both systems. However, discrepancies between the 2 systems are frequent (in about one third of the patients) due to different categories and definitions.

Risk factors are different for deep and lobar remote hemorrhages after intravenous thrombolysis

Background and purpose Remote parenchymal haemorrhage (rPH) after intravenous thrombolysis is defined as hemorrhages that appear in brain regions without visible ischemic damage, remote from the area of ischemia causing the initial stroke symptom. The pathophysiology of rPH is not clear and may be explained by different underlying mechanisms. We hypothesized that rPH may have different risk factors according to the bleeding location. We report the variables that we found associated with deep and lobar rPH after intravenous thrombolysis. Methods This is a descriptive study of patients with ischemic stroke who were treated with intravenous thrombolysis. These patients were included in a multicenter prospective registry. We collected demographic, clinical and radiological data. We evaluated the number and distribution of cerebral microbleeds (CMB) from Magnetic Resonance Imaging. We excluded patients treated endovascularly, patients with parenchymal hemorrhage without concomitant rPH and stroke mimics. We compared the variables from patients with deep or lobar rPH with those with no intracranial hemorrhage. Results We studied 934 patients (mean age 73.9±12.6 years) and 52.8% were men. We observed rPH in 34 patients (3.6%); 9 (0.9%) were deep and 25 (2.7%) lobar. No hemorrhage was observed in 900 (96.6%) patients. Deep rPH were associated with hypertensive episodes within first 24 hours after intravenous thrombolysis (77.7% vs 23.3%, p<0.001). Lobar rPH were associated with the presence of CMB (53.8% vs 7.9%, p<0.001), multiple (>1) CMB (30.7% vs 4.4%, p = 0.003), lobar CMB (53.8% vs 3.0%, p<0.001) and severe leukoaraiosis (76.9% vs 42%, p = 0.02). Conclusions A high blood pressure within the first 24 hours after intravenous thrombolysis is associated with deep rPH, whereas lobar rPH are associated with imaging markers of amyloid deposition. Thus, our results suggest that deep and lobar rPH after intravenous thrombolysis may have different mechanisms.