Patent foramen ovale closure in stroke patients with migraine in the CLOSE trial. The CLOSE-MIG study.

BACKGROUND AND PURPOSE: The efficacy of patent foramen ovale (PFO) closure to reduce the frequency of migraine attacks remains controversial. METHODS: This was a planned sub-study in migraine patients enrolled in a randomized, clinical trial designed to assess the superiority of PFO closure plus antiplatelet therapy over antiplatelet therapy alone to prevent stroke recurrence in patients younger than 60 years with a PFO-associated cryptogenic ischaemic stroke. The main outcome was the mean annual number of migraine attacks in migraine patients with aura and in those without aura, as recorded at each follow-up visit by study neurologists. RESULTS: Of 473 patients randomized to PFO closure or antiplatelet therapy, 145 (mean age 41.9 years; women 58.6%) had migraine (75 with aura and 70 without aura). Sixty-seven patients were randomized to PFO closure and 78 to antiplatelet therapy. During a mean follow-up of about 5 years, there were no differences between antiplatelet-only and PFO closure groups in the mean annual number of migraine attacks, both in migraine patients with aura (9.2 [11.9] vs. 12.0 [19.1], p = 0.81) and in those without aura (12.1 [16.1] vs. 11.8 [18.4], p > 0.999). There were no differences between treatment groups regarding cessation of migraine attacks, migraine-related disability at 2 years and use of migraine-preventive drugs during follow-up. CONCLUSIONS: In young and middle-aged adults with PFO-associated cryptogenic stroke and migraine, PFO closure plus antiplatelet therapy did not reduce the mean annual number of migraine attacks compared to antiplatelet therapy alone, in migraine patients both with and without aura.

Patent Foramen Ovale Closure or Anticoagulation vs. Antiplatelets after Stroke.

BACKGROUND: Trials of patent foramen ovale (PFO) closure to prevent recurrent stroke have been inconclusive. We investigated whether patients with cryptogenic stroke and echocardiographic features representing risk of stroke would benefit from PFO closure or anticoagulation, as compared with antiplatelet therapy. METHODS: In a multicenter, randomized, open-label trial, we assigned, in a 1:1:1 ratio, patients 16 to 60 years of age who had had a recent stroke attributed to PFO, with an associated atrial septal aneurysm or large interatrial shunt, to transcatheter PFO closure plus long-term antiplatelet therapy (PFO closure group), antiplatelet therapy alone (antiplatelet-only group), or oral anticoagulation (anticoagulation group) (randomization group 1). Patients with contraindications to anticoagulants or to PFO closure were randomly assigned to the alternative noncontraindicated treatment or to antiplatelet therapy (randomization groups 2 and 3). The primary outcome was occurrence of stroke. The comparison of PFO closure plus antiplatelet therapy with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 2, and the comparison of oral anticoagulation with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 3. RESULTS: A total of 663 patients underwent randomization and were followed for a mean (±SD) of 5.3±2.0 years. In the analysis of randomization groups 1 and 2, no stroke occurred among the 238 patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the antiplatelet-only group (hazard ratio, 0.03; 95% confidence interval, 0 to 0.26; P<0.001). Procedural complications from PFO closure occurred in 14 patients (5.9%). The rate of atrial fibrillation was higher in the PFO closure group than in the antiplatelet-only group (4.6% vs. 0.9%, P=0.02). The number of serious adverse events did not differ significantly between the treatment groups (P=0.56). In the analysis of randomization groups 1 and 3, stroke occurred in 3 of 187 patients assigned to oral anticoagulants and in 7 of 174 patients assigned to antiplatelet therapy alone. CONCLUSIONS: Among patients who had had a recent cryptogenic stroke attributed to PFO with an associated atrial septal aneurysm or large interatrial shunt, the rate of stroke recurrence was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone. PFO closure was associated with an increased risk of atrial fibrillation. (Funded by the French Ministry of Health; CLOSE ClinicalTrials.gov number, NCT00562289 .).

Use of MRI to predict symptomatic haemorrhagic transformation after thrombolysis for cerebral ischaemia.

BACKGROUND AND OBJECTIVE: Predictors of symptomatic haemorrhagic transformation (s-HT) of cerebral ischaemia after intravenous recombinant tissue-plasminogen activator (rt-PA) were identified in studies using CT scans. We evaluated whether MRI can identify other predictors. METHOD: We analysed predictors of s-HT in a cohort of consecutive patients who received intravenous rt-PA for cerebral ischaemia after MRI at baseline. We used receiver operating characteristic curves considering an area under the curve (AUC) of 0.70 or higher as indicating acceptable discrimination. RESULTS: Of 944 patients, 49 patients (5.2%) developed s-HT. Clinical factors independently associated with s-HT were age (adjusted OR (adjOR) 1.03 for 1 year increase; 95% CI 1.01 to 1.05), excessive alcohol consumption (adjOR 3.13; 95% CI 1.32 to 7.42), recent transient ischaemic attack (adjOR 2.88; 95% CI 1.04 to 7.95) and baseline national institutes of health stroke scale score (adjOR 1.06 for 1 point increase; 95% CI 1.02 to 1.10). MRI predictors were vascular hyperintensities (adjOR 3.89; 95% CI 1.50 to 10.08), old infarcts (adjOR 2.01; 95% CI 1.11 to 3.66) and volume of diffusion-weighted imaging (DWI) abnormality (adjOR 1.02 for 1 cm3 increase; 95% CI 1.01 to 1.03). The only variable with an acceptable discrimination was volume of DWI abnormality (AUC 0.72; 95% CI 0.64 to 0.79), a value of 4 cm3 predicting s-HT with a 78% sensitivity and 58% specificity. Variables that can be assessed only with MRI did not predict s-HT. CONCLUSION: Although the volume of DWI abnormality predicts s-HT, other imaging characteristics that can only be assessed with MRI were not significantly associated with s-HT. Trial registration number NCT01614080.

Recanalization therapies in acute ischemic stroke patients: impact of prior treatment with novel oral anticoagulants on bleeding complications and outcome.

BACKGROUND: We explored the safety of intravenous thrombolysis (IVT) or intra-arterial treatment (IAT) in patients with ischemic stroke on non-vitamin K antagonist oral anticoagulants (NOACs, last intake <48 hours) in comparison with patients (1) taking vitamin K antagonists (VKAs) or (2) without previous anticoagulation (no-OAC). METHODS AND RESULTS: This is a multicenter cohort pilot study. Primary outcome measures were (1) occurrence of intracranial hemorrhage (ICH) in 3 categories: any ICH (ICHany), symptomatic ICH according to the criteria of the European Cooperative Acute Stroke Study II (ECASS-II) (sICHECASS-II) and the National Institute of Neurological Disorders and Stroke (NINDS) thrombolysis trial (sICHNINDS); and (2) death (at 3 months). Cohorts were compared by using propensity score matching. Our NOAC cohort comprised 78 patients treated with IVT/IAT and the comparison groups of 441 VKA patients and 8938 no-OAC patients. The median time from last NOAC intake to IVT/IAT was 13 hours (interquartile range, 8-22 hours). In VKA patients, median pre-IVT/IAT international normalized ratio was 1.3 (interquartile range, 1.1-1.6). ICHany was observed in 18.4% NOAC patients versus 26.8% in VKA patients and 17.4% in no-OAC patients. sICHECASS-II and sICHNINDS occurred in 2.6%/3.9% NOAC patients, in comparison with 6.5%/9.3% of VKA patients and 5.0%/7.2% of no-OAC patients, respectively. At 3 months, 23.0% of NOAC patients in comparison with 26.9% of VKA patients and 13.9% of no-OAC patients had died. Propensity score matching revealed no statistically significant differences. CONCLUSIONS: IVT/IAT in selected patients with ischemic stroke under NOAC treatment has a safety profile similar to both IVT/IAT in patients on subtherapeutic VKA treatment or in those without previous anticoagulation. However, further prospective studies are needed, including the impact of specific coagulation tests.

Incident Cerebral Microbleeds in a Cohort of Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: We aimed to identify prognostic and associated factors of incident cerebral microbleeds (CMBs) in intracerebral hemorrhage (ICH) survivors. METHODS: Observational prospective cohort of 168 ICH survivors who underwent 1.5T magnetic resonance imaging at ICH onset and during follow-up (median scan interval, 3.4; interquartile range, 1.4-4.7) years. We used logistic regression adjusted for age, sex, and scan interval. Analyses were stratified according to the index ICH location (58 lobar ICH, 103 nonlobar ICH, excluding patients with multiple or unclassifiable ICH). RESULTS: Eighty-nine (53%) patients had CMBs at ICH onset, and 80 (48%) exhibited incident CMBs during follow-up. Predictors of incident CMBs at ICH onset were ≥1 CMBs (adjusted odds ratio [aOR], 2.27; 95% confidence interval [CI], 1.18-4.35), old radiological macrohemorrhage (aOR, 6.78; 95% CI, 2.76-16.68), and CMBs in mixed location (aOR, 3.73; 95% CI, 1.67-8.31). When stratifying by ICH location, incident CMBs were associated in nonlobar ICH with incident lacunes (aOR, 2.86; 95% CI, 1.04-7.85) and with the use of antiplatelet agents (aOR, 2.89; 95% CI, 1.14-7.32). In lobar ICH, incident CMBs were associated with incident radiological macrohemorrhage (aOR, 9.76; 95% CI, 1.07-88.77). CONCLUSIONS: Prognostic and associated factors of incident CMBs differed according to the index ICH location. Whereas in lobar ICH, incident CMBs were associated with hemorrhagic biomarkers, in nonlobar ICH, ischemic burden also increased. CMBs may be interesting biomarkers to monitor in randomized trials on restarting antithrombotic drugs after ICH.

Orolingual Angioedema During or After Thrombolysis for Cerebral Ischemia.

BACKGROUND AND PURPOSE: Orolingual angioedema (OLAE) is a life-threatening complication of intravenous thrombolysis. Our objective was to compare outcomes of patients with and without OLAE. METHODS: We prospectively included consecutive patients who received intravenous thrombolysis for cerebral ischemia at Lille University Hospital. We examined tongue and lips every 15 minutes during thrombolysis and ≤30 minutes after. We evaluated the 3-month outcome with the modified Rankin scale (mRS) and compared outcomes of patients with and without OLAE. RESULTS: Of 923 consecutive patients, 20 (2.2%) developed OLAE. None of them needed oro-tracheal intubation. They were more likely to be under angiotensin-converting enzyme inhibitors (adjusted odds ratio [adjOR], 3.9; 95% confidence interval [CI], 1.6-9.7; P=0.005) to have total insular infarcts (OR, 5.0; 95% CI, 1.5-16.5; P=0.004) and tended to develop more symptomatic intracerebral hemorrhages. Results concerning angiotensin-converting enzyme inhibitors were not modified after adjustment for propensity scores (OR, 4.4; 95% CI, 1.6-11.9; P=0.004) or matched analysis based on propensity scores (OR, 3.4; 95% CI, 1.3-8.1; P=0.010). Patients with OLAE did not significantly differ at 3 months for the proportion of patients with mRS score of 0 to 1 (adjOR, 0.9; 95% CI, 0.3-2.1), mRS score of 0 to 2 (adjOR, 0.8; 95% CI, 0.1-1.8), and death (adjOR, 1.1; 95% CI, 0.3-3.8). CONCLUSIONS: OLAE occurs in 1 of 50 patients who receive intravenous thrombolysis, 1 of 10 in case of total insular infarct, and 1 of 6 if they are under angiotensin-converting enzyme inhibitors. Their long-term outcome does not differ from that of other patients.

Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage.

OBJECTIVE: There is little evidence to guide treatment strategies for intracerebral hemorrhage on vitamin K antagonists (VKA-ICH). Treatments utilized in clinical practice include fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC). Our aim was to compare case fatality with different reversal strategies. METHODS: We pooled individual ICH patient data from 16 stroke registries in 9 countries (n = 10 282), of whom 1,797 (17%) were on VKA. After excluding 250 patients with international normalized ratio < 1.3 and/or missing data required for analysis, we compared all-cause 30-day case fatality using Cox regression. RESULTS: We included 1,547 patients treated with FFP (n = 377, 24%), PCC (n = 585, 38%), both (n = 131, 9%), or neither (n = 454, 29%). The crude case fatality and adjusted hazard ratio (HR) were highest with no reversal (61.7%, HR = 2.540, 95% confidence interval [CI] = 1.784-3.616, p < 0.001), followed by FFP alone (45.6%, HR = 1.344, 95% CI = 0.934-1.934, p = 0.112), then PCC alone (37.3%, HR = 1.445, 95% CI = 1.014-2.058, p = 0.041), compared to reversal with both FFP and PCC (27.8%, reference). Outcomes with PCC versus FFP were similar (HR = 1.075, 95% CI = 0.874-1.323, p = 0.492); 4-factor PCC (n = 441) was associated with higher case fatality compared to 3-factor PCC (n = 144, HR = 1.441, 95% CI = 1.041-1.995, p = 0.027). INTERPRETATION: The combination of FFP and PCC might be associated with the lowest case fatality in reversal of VKA-ICH, and FFP may be equivalent to PCC. Randomized controlled trials with functional outcomes are needed to establish the most effective treatment.

Cerebral venous thrombosis causing posterior fossa lesions: description of a case series and assessment of safety of anticoagulation.

BACKGROUND: Isolated posterior fossa parenchymal lesions associated with cerebral venous thrombosis (CVT) are rare. Posterior fossa lesions are an independent predictor of death in CVT. We aim to describe the characteristics and outcome of patients with CVT and isolated posterior fossa lesions and assess the safety of anticoagulation in patients with posterior fossa lesions associated with CVT. METHODS: We retrieved data from all patients with posterior fossa parenchymal lesions in the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) cohort related to clinical features, therapy and outcome. Fisher's exact test was used to evaluate associations. To assess the safety of anticoagulation in CVT patients with posterior fossa lesions we considered all patients with a lesion in this topography, either isolated or with concomitant supratentorial lesions, and compared the rate of new intracranial haemorrhages on repeated imaging with the remaining cohort. RESULTS: Out of 624 patients, 12 had isolated posterior fossa lesions and 14 had posterior fossa lesion with accompanying supratentorial lesions. The lateral sinus was most frequently occluded (n = 11). Involvement of the superior sagittal sinus was significantly less frequent compared to the remaining patients of the cohort (p = 0.013). None of the patients with isolated posterior fossa lesion died but 3 remained dependent on follow-up. Poor outcome (modified Rankin Scale ≥3) was more frequent in patients with any posterior fossa lesion, even when on anticoagulation (29.2% vs. 11.9%; OR 3.04; 95% CI 1.2-7.6; p = 0.018). Of the 24 anticoagulated patients with a posterior fossa lesion, 3 (12.5%) had new haemorrhages on repeated imaging, compared with 30 out of 495 anticoagulated patients (6.1%) without posterior fossa lesions (p = 0.19). CONCLUSIONS: We describe the largest series of CVT patients with associated posterior fossa lesions. When compared to anticoagulated CVT patients without posterior fossa lesions, CVT patients with posterior fossa lesions on full anticoagulation did not have a significant increase in the rate of new intracranial haemorrhages.

Vitamin K antagonists-associated cerebral hemorrhages: what are their characteristics?

BACKGROUND AND PURPOSE: The high prevalence of atrial fibrillation in aging populations leads to an increasing incidence of vitamin K antagonists-associated intracerebral hemorrhages (VKAs-ICH). It remains unclear whether VKAs are causes or risk factors for ICH. We aimed at identifying the specificities of VKAs-ICH. METHODS: We compared baseline characteristics of 545 consecutive patients receiving or not receiving VKAs before admission for spontaneous ICH. To determine whether the influence of VKAs depends on the underlying vasculopathy, that is, cerebral amyloid angiopathy in lobar, and deep perforating arteries vasculopathy in deep ICH, we compared characteristics of ICH (including volume) according to the anatomic distribution of ICH in multiple linear regression. RESULTS: VKAs-ICH accounted for 83 patients, that is, 15% (95% confidence intervals, 12-18) of ICH in our cohort. The use of VKAs did not influence anatomic distribution of ICH. The impact of VKAs on ICH volume differed according to ICH location: in nonlobar ICH, VKAs use was associated with significant larger ICH volumes (median volume 25 mL vs 12 mL; P=0.002). In lobar ICH, VKAs use did not influence the volume (median 26 mL vs 30 mL; P=0.507). CONCLUSIONS: A similar anatomic distribution of ICH in patients with or without VKAs suggests that VKAs should not be considered as a cause of ICH because both locations are usually due to different vasculopathies (deep perforating arteries vasculopathy in deep and cerebral amyloid angiopathy in lobar). The different impact of VKAs on ICH volumes according to location suggests a different susceptibility of these vasculopathies to VKAs. This finding may lead to specific therapeutic strategies.

Incidence and predictors of late seizures in intracerebral hemorrhages.

BACKGROUND AND PURPOSE: To identify incidence and predictors of late seizures (LS, occurring >1 week of stroke) in a cohort of patients with intracerebral hemorrhage (ICH). METHODS: Prospective cohort of consecutive adults with spontaneous ICH. Incidence and predictors were identified with Cox regression. We included multivariate analyses on MRI biomarkers (global cortical atrophy, leukoaraiosis, brain microbleeds). RESULTS: Our study population consisted of 325 patients: 54% men, median age 70 years (interquartile range, 58-79). During 778 person-years of follow-up, the incidence rate was 4 new cases/100 person-years (95% confidence interval, 3-6). The median delay between ICH and LS was 9 months (interquartile range, 3-23). The only factor independently associated with the occurrence of LS was a cortical involvement of the ICH (hazard ratio, 2.8; 95% confidence interval, 1.3-6.1). Concerning MRI biomarkers, multivariate analyses found lobar brain microbleeds to be associated with LS (hazard ratio, 2.4; 95% confidence interval, 1.1-5.4), especially if ≥ 3 (hazard ratio, 2.7; 95% confidence interval, 1.1-6.8). LS were associated with a worse functional outcome after 3 years of follow-up (P=0.009). CONCLUSIONS: LS frequently occur >9 months after ICH onset, imposing a long-term follow-up. The association of lobar brain microbleeds with the risk of LS might suggest a link with the underlying vasculopathy (cerebral amyloid angiopathy).

Geographical Requirements for the Applicability of the Results of the RACECAT Study to Other Stroke Networks.

Background The RACECAT (Transfer to the Closest Local Stroke Center vs Direct Transfer to Endovascular Stroke Center of Acute Stroke Patients With Suspected Large Vessel Occlusion in the Catalan Territory) trial was the first randomized trial addressing the prehospital triage of acute stroke patients based on the distribution of thrombolysis centers and intervention centers in Catalonia, Spain. The study compared the drip-and-ship with the mothership paradigm in regions where a local thrombolysis center can be reached faster than the nearest intervention center (equipoise region). The present study aims to determine the population-based applicability of the results of the RACECAT study to 4 stroke networks with a different degree of clustering of the intervention centers (clustered, dispersed). Methods and Results Stroke networks were compared with regard to transport time saved for thrombolysis (under the drip-and-ship approach) and transport time saved for endovascular therapy (under the mothership approach). Population-based transport times were modeled with a local instance of an openrouteservice server using open data from OpenStreetMap.The fraction of the population in the equipoise region differed substantially between clustered networks (Catalonia, 63.4%; France North, 87.7%) and dispersed networks (Southwest Bavaria, 40.1%; Switzerland, 40.0%). Transport time savings for thrombolysis under the drip-and-ship approach were more marked in clustered networks (Catalonia, 29 minutes; France North, 27 minutes) than in dispersed networks (Southwest Bavaria and Switzerland, both 18 minutes). Conclusions Infrastructure differences between stroke networks may hamper the applicability of the results of the RACECAT study to other stroke networks with a different distribution of intervention centers. Stroke networks should assess the population densities and hospital type/distribution in the temporal domain before applying prehospital triage algorithms to their specific setting.

Early epileptic seizures in ischaemic stroke treated by mechanical thrombectomy: influence of rt-PA.

BACKGROUND: The epileptogenicity of recombinant tissue-plasminogen activator (rt-PA) has been suggested, but seizures were not evaluated in randomised controlled trials. OBJECTIVE: To evaluate whether rt-PA was associated with early seizures in a cohort of consecutive patients with cerebral ischaemia. METHOD: We included consecutive adults with ischaemic stroke due to large-vessel occlusion from the North-of-France stroke network selected for a mechanical thrombectomy (MT). Patients without contraindication received i.v. rt-PA. We evaluated stroke severity with the National Institutes of Health Stroke Scale (NIHSS), and functional status with the modified Rankin scale (mRS), and recorded epileptic seizures occurring between the end of imaging and day 7. We performed statistics using propensity analyses. RESULTS: We included 1638 patients (783 men, 47.8%; median age 71 years; median NIHSS score 16; 1007 treated by rt-PA, 61.5%), in whom 60 (3.7%) developed early epileptic seizures. After adjustment on propensity scores, early seizures were associated with infections [adjusted odds ratio (adjOR) 2.86; 95% confidence interval (CI) 1.37-5.95] and delay between stroke recognition and end of MT (adjOR 1.04 for 10 min more; 95% CI 1.01-1.08), but not with rt-PA (adjOR 1.35; 95% CI 0.55-3.33). The propensity-matched analysis of 343 pairs of patients found no difference in the occurrence of early seizures between those with and without rt-PA (p = 0.386). CONCLUSION: We found no significant association between rt-PA and early epileptic seizures. If rt-PA has the potential for epileptogenicity, the magnitude of the effect should be modest compared to its favourable effect on functional outcome.

Remote brain hemorrhage after IV thrombolysis: Role of preexisting lesions.

OBJECTIVE: To test the hypothesis that remote intracerebral hemorrhages (r-ICHs) after IV thrombolysis occur in preexisting brain lesions. METHOD: We prospectively collected baseline data from consecutive patients treated with IV thrombolysis for cerebral ischemia and reviewed their baseline MRI scans to identify preexisting lesions in those who developed r-ICH. We evaluated outcomes with the modified Rankin Scale (mRS) and defined good outcomes as scores of 0 to 2 or similar to the preexisting mRS score. RESULTS: Of 944 patients, 24 (2.5%) had r-ICH: lobar in 14, deep in 7, and both in 3. Sixteen of them (1.7% of all patients, 66.7% of those with r-ICH) were asymptomatic. Of the 41 r-ICHs found in these patients, 17 (41%) occurred within a lesion present before thrombolysis: 6 cerebral microbleeds (CMBs), 6 old and 1 recent infarct, and 4 areas of white matter hyperintensity. Patients with r-ICH were more likely to have strictly lobar CMBs (p = 0.049). They were 10 years older (p = 0.007), had a 16-mm Hg higher systolic blood pressure (p = 0.035) at baseline, and had more CMBs (p = 0.007). r-ICHs were better predicted by clinical (age, baseline systolic blood pressure) than imaging (purely lobar CMBs and having >5 CMBs) variables. r-ICHs tended to be associated with worse outcomes. CONCLUSION: We identified preexisting brain lesions in nearly half of the patients with r-ICH. All were of vascular origin, supporting the hypothesis that r-ICHs occur in preexisting brain lesions. Higher-field machines could help identifying preexisting lesions in those who developed r-ICH in an apparently normal area.

Mechanical thrombectomy for ischaemic stroke in the anterior circulation: off-hours effect.

BACKGROUND: Patients treated at off-hours for acute conditions have increased mortality rates. This effect has been poorly evaluated in patients treated by mechanical thrombectomy (MT). OBJECTIVE: This study aimed at comparing outcomes between patients treated at off-hours and at working hours by MT for acute stroke due to large-vessel occlusion in the anterior circulation, in a well-organised network. METHOD: We included consecutive adults who underwent MT for large-vessel occlusion in the anterior circulation over a 51-month period, in the network of 16 hospitals from the North-of-France area, sharing similar protocols. Patients underwent magnetic resonance imaging-scans at admission and then 22-36 h later. We compared 3-month outcomes of patients treated at off-hours and at working time, the primary outcome being a modified Rankin scale (mRS) 0 to 2. RESULTS: The study population consisted of 1,179 patients (631 women, 53.5%; mean age 72 years; median baseline National Institutes of Stroke Scale 17; 639 at off-hours, 54.2%; 734 treated with rt-PA, 62.3%; median delay stroke recognition to end of MT 281 min). No patient was lost to follow-up. The outcomes did not differ between the two groups: adjusted odds ratio (adjOR) for mRS 0-2: 0.89; 95% confidence interval (CI) 0.67-1.18; adjOR for mRS 0-1: 0.91; 95% CI 0.68-1.21; adjOR for death 1.12; 95% CI 0.81-1.55). CONCLUSION: Our study did not show worse outcomes in patients treated at off-hours. This result suggests that the off-hours effect reported in other studies can be minimized by a coordinated organisation of stroke care providing similar levels of care at off-hours.

Hematoma location and morphology of anticoagulation-associated intracerebral hemorrhage.

OBJECTIVE: To study hematoma location and morphology of intracerebral hemorrhage (ICH) associated with oral anticoagulants (OAC) and delineate causes and mechanism. METHODS: We performed a systematic literature research and meta-analysis of studies comparing neuroimaging findings in patients with OAC-ICH compared to those with ICH not associated with OAC (non-OAC ICH). We calculated pooled risk ratios (RRs) for ICH location using the Mantel-Haenszel random-effects method and corresponding 95% confidence intervals (95% CI). RESULTS: We identified 8 studies including 6,259 patients (OAC-ICH n = 1,107, pooled OAC-ICH population 17.7%). There was some evidence for deep ICH location (defined as ICH in the thalamus, basal ganglia, internal capsule, or brainstem) being less frequent in patients with OAC-ICH (OAC-ICH: 450 of 1,102/40.8% vs non-OAC ICH: 2,656 of 4,819/55.1%; RR 0.94, 95% CI 0.88-1.00, p = 0.05, I 2 = 0%) while cerebellar ICH location was significantly more common in OAC-ICH (OAC-ICH: 111 of 1,069/10.4% vs non-OAC ICH: 326 of 4,787/6.8%; RR 1.45, 95% CI 1.12-1.89, p = 0.005, I 2 = 21%) compared to non-OAC ICH. There was no statistically significant relationship to OAC use for lobar (OAC-ICH: 423 of 1,107/38.2% vs non-OAC ICH: 1,884 of 5,152/36.6%; RR 1.02, 95% CI 0.89-1.17, p = 0.75, I 2 = 53%, p for heterogeneity = 0.04) or brainstem ICH (OAC-ICH: 36 of 546/6.6% vs non-OAC ICH: 172 of 2,626/6.5%; RR 1.04, 95% CI 0.58-1.87, p = 0.89, I 2 = 59%, p for heterogeneity = 0.04). The risk for intraventricular extension (OAC-ICH: 436 of 840/51.9% vs non-OAC ICH: 1,429 of 3,508/40.7%; RR 1.26, 95% CI 1.16-1.36, p < 0.001, I 2 = 0%) was significantly increased in patients with OAC-ICH. We found few data on ICH morphology in OAC-ICH vs non-OAC ICH. CONCLUSION: The overrepresentation of cerebellar ICH location and intraventricular extension in OAC-ICH might have mechanistic relevance for the underlying arteriopathy, pathophysiology, or bleeding pattern of OAC-ICH, and should be investigated further.

Cerebral Microbleeds, Vascular Risk Factors, and Magnetic Resonance Imaging Markers: The Northern Manhattan Study.

BACKGROUND: Cerebral microbleeds (CMBs) represent intracerebral hemorrhages due to amyloid angiopathy or exposure to modifiable risk factors. Few community-based stroke-free studies including blacks and Hispanics have been done. METHODS AND RESULTS: The Northern Manhattan Study (NOMAS) is a stroke-free, racially and ethnically diverse cohort study. Brain MRI was performed in 1290 participants, 925 of whom had available T2* gradient-recall echo data. We used multivariable logistic regression to examine the association of sociodemographics, vascular risk factors, apolipoprotein E (APOE) genotype, and brain MRI markers with CMB presence and location. The prevalence of CMBs in our cohort was 5%. Of the 46 participants with CMBs, 37% had only deep CMBs, 48% had only lobar CMBs, and 15% had CMBs in both locations. The difference in CMB distribution was not statistically significant across race/ethnic group or APOE genotype. In multivariable analyses, age (OR [95% CI]: 1.09 [1.04, 1.15]) and SBIs (2.58 [1.01, 6.59]) were positively associated with CMB presence, and diabetes medication use was negatively associated (0.25 [0.07, 0.86]). CONCLUSIONS: CMBs may represent the severity of vascular disease in this racially and ethnically diverse cohort. Larger studies are needed to elucidate the association between diabetes medication use and CMB presence.

Proportion of single-chain recombinant tissue plasminogen activator and outcome after stroke.

OBJECTIVE: To determine whether the ratio single chain (sc)/(sc + 2 chain [tc]) recombinant tissue plasminogen activator (rtPA) influences outcomes in patients with cerebral ischemia. METHODS: We prospectively included consecutive patients treated with IV rtPA for cerebral ischemia in 13 stroke centers and determined the sc/(sc + tc) ratio in the treatment administered to each patient. We evaluated the outcome with the modified Rankin Scale (mRS) at 3 months (prespecified analysis) and occurrence of epileptic seizures (post hoc analysis). We registered Outcome of Patients Treated by IV Rt-PA for Cerebral Ischaemia According to the Ratio Sc-tPA/Tc-tPA (OPHELIE) under ClinicalTrials.gov identifier no. NCT01614080. RESULTS: We recruited 1,004 patients (515 men, median age 75 years, median onset-to-needle time 170 minutes, median NIH Stroke Scale score 10). We found no statistical association between sc/(sc + tc) ratios and handicap (mRS > 1), dependency (mRS > 2), or death at 3 months. Patients with symptomatic intracerebral hemorrhages had lower ratios (median 69% vs 72%, adjusted p = 0.003). The sc/(sc + tc) rtPA ratio did not differ between patients with and without seizures, but patients with early seizures were more likely to have received a sc/(sc + tc) rtPA ratio >80.5% (odds ratio 3.61; 95% confidence interval 1.26-10.34). CONCLUSIONS: The sc/(sc + tc) rtPA ratio does not influence outcomes in patients with cerebral ischemia. The capacity of rtPA to modulate NMDA receptor signaling might be associated with early seizures, but we observed this effect only in patients with a ratio of sc/(sc + tc) rtPA >80.5% in a post hoc analysis.

Influence of neurologists' experience on the outcome of patients treated by intravenous thrombolysis for cerebral ischaemia.

Intravenous (i.v.) recombinant tissue plasminogen activator (rt-PA) should be available on a 24/7 basis in hospitals admitting patients with stroke. We aimed at evaluating the influence of the number of patients previously treated with i.v. rt-PA by neurologists on patients' outcome. For each patient consecutively treated with i.v. rt-PA for cerebral ischaemia at the Lille University Hospital, we determined the number of previous treatments with rt-PA administered by the neurologist. We performed logistic regression analyses to determine the influence of the experience on the outcome evaluated by the modified Rankin scale (mRS) after 3 months, 0-1 meaning independence, and 0-2 meaning absence of handicap. We compared outcomes of patients treated by the 25% less experienced neurologists with those of trials. Forty-four neurologists treated 800 patients. The experience of the treating neurologist was independently associated with independence (adjusted odds ratio [(adj)OR] 1.062 for 10 patients more; 95% confidence interval [CI] 1.008-1.120), and absence of handicap ((adj)OR 1.076 for 10 patients more; 95%CI 1.016-1.140) at 3 months, but not with symptomatic intracerebral haemorrhage and death. The proportions of patients from the 1st quartile who were independent and without handicap at 3 months were 37.9 and 51.1%. Patients treated by less experienced neurologists, have similar outcomes than expected from trials, suggesting they benefit from thrombolysis. However, the outcome of patients treated by more experienced neurologists was slightly better. Less experienced neurologists should not be excluded from rt-PA programmes, but their practices should be evaluated and educational programmes organised.

Higher neutrophil counts before thrombolysis for cerebral ischemia predict worse outcomes.

OBJECTIVE: To determine whether higher neutrophil counts before IV recombinant tissue plasminogen activator (rtPA) administration in ischemic stroke (IS) patients are associated with symptomatic intracerebral hemorrhages (sICH) and worse outcomes at 3 months. METHODS: Blood samples for leukocyte, neutrophil, and lymphocyte counts were drawn before IV rtPA administration in IS patients included in the cohorts of Lille and Helsinki. The primary endpoint was sICH (European Cooperative Acute Stroke-II definition). Secondary endpoints were death and excellent (modified Rankin Scale [mRS] score 0-1 or equal to prestroke mRS) and good (mRS score 0-2 or equal to prestroke mRS) outcomes at 3 months. RESULTS: We included 846 patients (median age 71 years; 50.8% men). The neutrophil count and neutrophil to lymphocyte ratio (NLR) were independently associated with the 4 endpoints: sICH (adjusted odds ratio [adjOR] for an increase of 1,000 neutrophils = 1.21 and adjOR 1.11, respectively), death (adjOR 1.16 and adjOR 1.08), and excellent (adjOR 0.87 and adjOR 0.85) and good (adjOR 0.86 and adjOR 0.91) outcomes. The total leukocyte count was not associated with any of the 4 endpoints. The best discriminating factor for sICH was NLR ≥4.80 (sensitivity 66.7%, specificity 71.3%, likelihood ratio 2.32). Patients with NLR ≥4.80 had a 3.71-fold increased risk for sICH (95% confidence interval adjOR: 1.97-6.98) compared to patients with NLR <4.80. CONCLUSIONS: Higher neutrophil counts and NLR are independently associated with sICH and worse outcome at 3 months. The identification of mediators of this effect could provide new targets for neuroprotection in patients treated by rtPA.

Heavy alcohol intake and intracerebral hemorrhage: characteristics and effect on outcome.

OBJECTIVES: To identify associated factors and influence on long-term outcome of heavy alcohol intake in a large prospective cohort of consecutive patients with a spontaneous intracerebral hemorrhage (ICH). METHODS: Between November 2004 and March 2009, we prospectively recruited 562 consecutive adults with a spontaneous ICH. We excluded patients without information on drinking habit (n = 22). Heavy alcohol intake was defined as a regular consumption of more than 300 g alcohol/week. We performed bivariate and multivariate analyses (logistic regression) based on demographic and radiologic models. Survival analyses were performed using Kaplan-Meier statistics. RESULTS: Among 540 patients with ICH, 137 (25) were heavy alcohol drinkers (median age 60 vs 74 years in nonabusers; p < 0.0001). In the multivariate demographic model, heavy alcohol drinkers were less likely to be older (odds ratio [OR] 0.97 per 1-year increase, 95% confidence interval [CI] 0.95-0.98) and to have a history of ischemic heart disease (OR 0.34, 95% CI 0.15-0.77) and more likely to be smokers (OR 3.96, 95% CI 2.43-6.46). In the radiologic model, independent factors were nonlobar location of ICH (OR 1.71, 95% CI 1.05-2.77) and less severe leukoaraiosis (OR 0.76 per 1-step increase, 95%CI 0.62-0.73). Platelet counts and prothrombin ratio were significantly lower among heavy alcohol drinkers (respectively, p = 0.01 and p = 0.017). Heavy alcohol intake was predictive of 2 years mortality only among patients younger than 60 years with nonlobar ICH (hazard ratio 1.96, 95% CI 1.06-3.63). CONCLUSION: Heavy alcohol intake is associated with the occurrence of ICH at a young age. However, the underlying vasculopathy remains unexplored in these patients. Indirect markers suggest small-vessel disease at an early stage that might be enhanced by moderate hemostatic disorders.