Exuperio Díez-Tejedor

Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II)

Summary Background Thrombolysis for acute ischaemic stroke has been investigated in several clinical trials, with variable results. We have assessed the safety and efficacy of intravenous thrombolysis with alteplase (0·9 mg/kg bodyweight) within 6 h of stroke onset. Methods This non-angiographic, randomised, double-blind, trial enrolled 800 patients in Europe, Australia, and New Zealand. Computed tomography was used to exclude patients with signs of major infarction. Alteplase (n=409) and placebo (n=391) were randomly assigned with stratification for time since symptom onset (0–3 h or 3–6 h). The primary endpoint was the modified Rankin scale (mRS) at 90 days, dichotomised for favourable (score 0–1) and unfavourable (score 2–6) outcome. Analyses were by intention to treat. Findings 165 (40·3%) alteplase-group patients and 143 (36·6%) placebo-group patients had favourable mRS outcomes (absolute difference 3·7%, p=0·277). In a post-hoc analysis of mRS scores dichotomised for death or dependency, 222 (54·3%) alteplase-group and 180 (46·0%) placebo-group patients had favourable outcomes (score 0–2; absolute difference 8·3%, p=0·024). Treatment differences were similar whether patients were treated within 3 h or 3–6 h. 85 (10·6%) patients died, with no difference between treatment groups at day 90·14 days (43 alteplase, 42 placebo). Symptomatic intracranial haemorrhage occurred in 36 (8·8%) alteplase-group patients and 13 (3·4%) placebo-group patients. Interpretation The results do not confirm a statistical benefit for alteplase. However, we believe the trend towards efficacy should be interpreted in the light of evidence from previous trials. Despite the increased risk of intracranial haemorrhage, thrombolysis with alteplase at a dose of 0·9 mg/kg in selected patients may lead to a clinically relevant improvement in outcome.

Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial)

BACKGROUND Citicoline is approved in some countries for the treatment of acute ischaemic stroke. The drug has shown some evidence of efficacy in a pooled analysis. We sought to confirm the efficacy of citicoline in a larger trial. METHODS We undertook a randomised, placebo-controlled, sequential trial in patients with moderate-to-severe acute ischaemic stroke admitted at university hospitals in Germany, Portugal, and Spain. Using a centralised minimisation process, patients were randomly assigned in a 1:1 ratio to receive citicoline or placebo within 24 h after the onset of symptoms (1000 mg every 12 h intravenously during the first 3 days and orally thereafter for a total of 6 weeks [2×500 mg oral tablets given every 12 h]). All study participants were masked. The primary outcome was recovery at 90 days measured by a global test combining three measures of success: National Institutes of Health Stroke Scale ≤1, modified Rankin score ≤1, and Barthel Index ≥95. Safety endpoints included symptomatic intracranial haemorrhage in patients treated with recombinant tissue plasminogen activator, neurological deterioration, and mortality. This trial is registered, NCT00331890. RESULTS 2298 patients were enrolled into the study from Nov 26, 2006, to Oct 27, 2011. 37 centres in Spain, 11 in Portugal, and 11 in Germany recruited patients. Of the 2298 patients who gave informed consent and underwent randomisation, 1148 were assigned to citicoline and 1150 to placebo. The trial was stopped for futility at the third interim analysis on the basis of complete data from 2078 patients. The final randomised analysis was based on data for 2298 patients: 1148 in citicoline group and 1150 in placebo group. Global recovery was similar in both groups (odds ratio 1·03, 95% CI 0·86-1·25; p=0·364). No significant differences were reported in the safety variables nor in the rate of adverse events. INTERPRETATION Under the circumstances of the ICTUS trial, citicoline is not efficacious in the treatment of moderate-to-severe acute ischaemic stroke. FUNDING Ferrer Grupo.

The Prognostic Value of Capillary Glucose Levels in Acute Stroke The GLycemia in Acute Stroke (GLIAS) Study

Background and Purpose— Evidence is accumulating regarding the prognostic influence of hyperglycemia in patients with acute ischemic stroke. However, the level associated with poor outcome is unknown. Our objectives were to establish the capillary glucose threshold with the highest predictive accuracy of poor outcome and to evaluate its hypothetical value in influencing functional outcome by adjusting for other well-known prognostic factors in acute stroke. Methods— The authors conducted a multicenter, prospective, and observational cohort study of 476 patients with ischemic stroke within less than 24 hours from stroke onset. Capillary finger-prick glucose and stroke severity were determined on admission and 3 times a day during the first 48 hours. Poor outcome (modified Rankin Scale >2) was evaluated at 3 months. Results— The receiver operating characteristic curves showed the predictive value of maximum capillary glucose at any time within the first 48 hours with an area under the curve of 0.656 (95% CI, 0.592 to 0.720; P<0.01) and pointed to 155 mg/dL as the optimal cutoff level for poor outcome at 3 months (53% sensitivity; 73% specificity). This point was associated with a 2.7-fold increase (95% CI, 1.42 to 5.24) in the odds of poor outcome after adjustment for age, diabetes, capillary glucose on admission, infarct volume, and baseline stroke severity and with a 3-fold increase in the risk of death at 3 months (hazard ratio, 3.80; 95% CI, 1.79 to 8.10). Conclusions— Hyperglycemia ≥155 mg/dL at any time within the first 48 hours from stroke onset, and not only the isolated value of admission glycemia, is associated with poor outcome independently of stroke severity, infarct volume, diabetes, or age.

Statin Therapy and Outcome After Ischemic Stroke Systematic Review and Meta-Analysis of Observational Studies and Randomized Trials

Background and Purpose— Although experimental data suggest that statin therapy may improve neurological outcome after acute cerebral ischemia, the results from clinical studies are conflicting. We performed a systematic review and meta-analysis investigating the relationship between statin therapy and outcome after ischemic stroke. Methods— The primary analysis investigated statin therapy at stroke onset (prestroke statin use) and good functional outcome (modified Rankin score 0 to 2) and death. Secondary analyses included the following: (1) acute poststroke statin therapy (⩽72 hours after stroke), and (2) thrombolysis-treated patients. Results— The primary analysis included 113 148 subjects (27 studies). Among observational studies, statin treatment at stroke onset was associated with good functional outcome at 90 days (pooled odds ratio [OR], 1.41; 95% confidence interval [CI], 1.29–1.56; P<0.001), but not 1 year (OR, 1.12; 95% CI, 0.9–1.4; P=0.31), and with reduced fatality at 90 days (pooled OR, 0.71; 95% CI, 0.62–0.82; P<0.001) and 1 year (OR, 0.80; 95% CI, 0.67–0.95; P=0.01). In the single randomized controlled trial reporting 90-day functional outcome, statin treatment was associated with good outcome (OR, 1.5; 95% CI, 1.0–2.24; P=0.05). No reduction in fatality was observed on meta-analysis of data from 3 randomized controlled trials (P=0.9). In studies restricted to of thrombolysis-treated patients, an association between statins and increased fatality at 90 days was observed (pooled OR, 1.25; 95% CI, 1.02–1.52; P=0.03, 3 studies, 4339 patients). However, this association was no longer present after adjusting for age and stroke severity in the largest study (adjusted OR, 1.14; 95% CI, 0.90–1.44; 4012 patients). Conclusion— In the largest meta-analysis to date, statin therapy at stroke onset was associated with improved outcome, a finding not observed in studies restricted to thrombolysis-treated patients. Randomized trials of statin therapy in acute ischemic stroke are needed.

Effects of intravenous administration of allogenic bone marrow- and adipose tissue-derived mesenchymal stem cells on functional recovery and brain repair markers in experimental ischemic stroke

IntroductionStem cell therapy can promote good recovery from stroke. Several studies have demonstrated that mesenchymal stem cells (MSC) are safe and effective. However, more information regarding appropriate cell type is needed from animal model. This study was targeted at analyzing the effects in ischemic stroke of acute intravenous (i.v.) administration of allogenic bone marrow- (BM-MSC) and adipose-derived-stem cells (AD-MSC) on functional evaluation results and brain repair markers.MethodsAllogenic MSC (2 × 106 cells) were administered intravenously 30 minutes after permanent middle cerebral artery occlusion (pMCAO) to rats. Infarct volume and cell migration and implantation were analyzed by magnetic resonance imaging (MRI) and immunohistochemistry. Function was evaluated by the Rogers and rotarod tests, and cell proliferation and cell-death were also determined. Brain repair markers were analyzed by confocal microscopy and confirmed by western blot.ResultsCompared to infarct group, function had significantly improved at 24 h and continued at 14 d after i.v. administration of either BM-MSC or AD-MSC. No reduction in infarct volume or any migration/implantation of cells into the damaged brain were observed. Nevertheless, cell death was reduced and cellular proliferation significantly increased in both treatment groups with respect to the infarct group. At 14 d after MSC administration vascular endothelial growth factor (VEGF), synaptophysin (SYP), oligodendrocyte (Olig-2) and neurofilament (NF) levels were significantly increased while those of glial fiibrillary acid protein (GFAP) were decreased.Conclusionsi.v. administration of allogenic MSC - whether BM-MSC or AD-MSC, in pMCAO infarct was associated with good functional recovery, and reductions in cell death as well as increases in cellular proliferation, neurogenesis, oligodendrogenesis, synaptogenesis and angiogenesis markers at 14 days post-infarct.

TH1/TH2 Cytokine profile in relapsing-remitting multiple sclerosis patients treated with Glatiramer acetate or Natalizumab

BackgroundThe balance between T helper cells Th2- and Th1-related cytokines plays a key role in multiple sclerosis (MS). A shift from a Th1 towards a Th2 cytokine profile could have a beneficial effect on the clinical course of the disease. The objective of this study was to assess Th2/Th1 cytokine profile in relapsing-remitting MS (RRMS) patients receiving an immunosuppressive treatment with natalizumab (NAT), or an immunomodulatory treatment with glatiramer acetate (GA) after one year of treatment.MethodsThis was an observational cross-sectional study. All consecutive patients diagnosed with RRMS who had received GA or NAT for 12 months were included in the study. We determined serum levels of Th1 and Th2 cytokines (interleukin [IL]-1a, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, monocyte chemotactic protein [MCP]-1, tumor-necrosis factor [TNF]-α, interferon [IFN]-γ and granulocyte macrophage colony stimulating factor [GM-CSF]) by flow cytometry. Th2/Th1 bias was defined based on the ratio of IL-4, IL-5, IL-6 or IL-10 Th2 cytokines and proinflammatory INF-γ or TNF-α Th1 cytokines.ResultsEleven patients under treatment with NAT and 12 patients treated with GA were evaluated. RRMS patients treated with NAT showed significantly higher levels of IL-6 (p < 0.05), MCP-1 (p < 0.01), and GM-CSF (p < 0.05) compared to GA patients after one year of treatment. A trend for increasing of IL-12p70, IL-1b, TNF- α and IFN- γ levels was also found in patients receiving NAT compared to GA patients. IL-4/IFN-γ, IFN-γ/TNF-α and IL-10/IFN-γ ratios as markers of Th2/Th1 ratio were significantly elevated in GA patients compared to those receiving NAT (p < 0.05).ConclusionIn conclusion, our findings suggest that GA promotes a superior Th2-biased anti-inflammatory response as compared with NAT in the systemic circulation of RRMS patients. Future studies with larger cohorts will determine whether this immune Th2 shift in GA patients is associated with a beneficial effect on disease outcome.

Does a Relationship Exist Between Carotid Stenosis and Lacunar Infarction

Background and Purpose— The presence of carotid stenosis (CS) in a patient with lacunar stroke is usually considered an indication of atherosclerosis and not directly related to the development of this infarction subtype. This study was designed to determine the relationship between CS and lacunar infarction (LI) and to assess the differences between single and multiple LIs. Methods— We classified 330 patients with a first-ever cerebral infarction in the carotid territory into LI and non-LI (NLI) groups. In the LI group, patients with a single LI and those with multiple LIs were identified. In this last subgroup, 2 patterns were identified: 1 subtype with lacunar lesions distributed in both cerebral hemispheres, and another with lesions predominantly in 1 hemisphere. Results— In the LI group, isolated CS was significantly more frequent on the homolateral side than on the contralateral side (odds ratio [OR], 5.5; 95% CI, 1.2 to 23;P =0.03). A significant relationship between the pattern of distribution of the infarctions in only 1 hemisphere and homolateral CS >70% was observed (OR, 4.4; 95% CI, 0.9 to 19;P =0.03). In a multivariate analysis, the following variables were found to predict unilateral multiple LI: left ventricular hypertrophy (OR, 9.1; 95% CI, 2.5 to 33.6) and homolateral CS >75% (OR, 14.4; 95% CI, 2.0 to 99.6). Conclusions— The significant incidence of isolated ipsilateral CS in patients with LI located in the carotid territory and the relationship of CS to ipsilateral multiple LI suggest that CS has a very important role in the development of LI.

Acute Care in Stroke: Do Stroke Units Make the Difference?

The consideration of stroke as a medical emergency and the development of new specific treatments to be applied in a narrow therapeutic window have shown the need to establish an adequate organization system for the management of stroke. It should be considered as an integral process both outside and inside the hospital. General care is essential and must already start outside the hospital, and comprises respiratory and cardiac care, fluid and metabolic management, especially blood glucose control, avoiding the administration of glucose solutions, blood pressure control, early treatment of hyperthermia and prevention and treatment of neurologic and systemic complications. In the early 70s, the first stroke units (SU) were established as intensive-care SU, but failed to show improvement in terms of reduction of mortality-morbidity. Nowadays, the concept has changed to a non-intensive-care SU. The benefit of these SU has been amply demonstrated in terms of reduction in mortality and in long institutionalization, as well as better functional outcome compared with general wards, and the efficacy of a neurology ward compared to a general medicine department has also been shown, but at the moment there are no studies analyzing the differences between a stroke team (ST) in a department of neurology and a SU. In this regard, we have performed a sequential analysis comparing both SU and ST and demonstrated a reduction in length of stay, complications and acute care costs with an improvement in functional state at hospital discharge, a reduction in the discharge to nursing homes with an increase in patients translated into rehabilitation wards. With these data, we can conclude that SU, not ST are the most effective organizational model for acute stroke management. Definitely, the SU make the difference.

Cerebral ischemia: from animal studies to clinical practice. Should the methods be reviewed?

The development of experimental models of focal cerebral ischemia has allowed for a better knowledge of its pathophysiology and for testing therapeutic strategies. However, most neuroprotective substances giving favorable results in these models have later not been shown to be clinically effective. This could be explained by several reasons. First, the homogeneity obtained in animal models in order to achieve results is not seen in clinical practice in humans, in whom a given pathological condition may show a high variability depending on several parameters. This makes it difficult to achieve groups of patients sufficiently large and homogeneous to obtain valid conclusions in the clinical trials. The lack of agreement between the experimental studies and the clinical practice can also be explained by other reasons, such as the methods of the experimental model itself; by the fact that the methods to assess results in these models are not comparable to those used in clinical practice; by pathophysiological differences between experimental animals and man, and even by the fact that the substances tested have different pharmacological properties in the different species. These disadvantages must not invalidate preclinical neuroprotection studies. Rather, the knowledge of the reasons for divergences with the clinical situation can help to optimize experimental models so that both become actually comparable, and the laboratory results can be confirmed by clinical studies.

Poststroke Depression: Importance of Its Detection and Treatment

Background: Poststroke depression (PSD) is a complication that occurs in up to 30% of the patients who have had a stroke. Its development is associated with a poor functional prognosis and a negative impact on the patient’s quality of life. Methods: In the present review, we summarize the diagnostic criteria, prevalence, predisposing factors, the lesion site, the impact of PSD on the clinical evolution of the patient, the current therapeutic approaches and even the relationship between depression and cerebrovascular disease. Results: There are differences in relation to prevalence, essentially due to the use of different diagnostic criteria. Also, there have been few studies focusing on the search for factors that are predictive of PSD (age, female sex, single vascular lesion independent of site) and the reluctance to initiate preventive treatments to minimize the effects on the clinical evolution of the patients. There have been several advances with respect to the treatment of PSD. It seems that treatments show improvement trends, but today there is not enough evidence to recommend a preventive therapy for depression in any stroke patient. Conclusions: We consider that the prevalence of PSD is relevant and that the risk factors as well as the early diagnosis are important for the best management and prognosis of stroke patients. Further studies are needed in this field in order to reduce PSD.