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IntroductionDespite the significant stroke burden in the region, the RESILIENT trial remains the only randomized controlled trial (RCT) for stroke treatment in Latin America. Imbalances in baseline factors typically hamper comparisons between stroke populations. The Latin American Stroke Registry (LASE) is a registry of patients receiving tPA and thrombectomy from 17 centers across 9 countries. We compared the outcomes of LASE and RESILIENT at each cohort’s baseline characteristics against models derived from other RCTs.MethodsA systematic search identified RCTs that provided median NIHSS, mean age, percentage of patients receiving tPA, time-to-randomization, 90-day mRS0-2, and mortality. Akaike Information Criterion (AIC) was used to select the best model amongst 31 combinations of 5 variables. 90-day outcomes of LASE and RESILIENT were compared at their baseline values against the selected model.Results35 RCTs encompassing 8376 subjects were identified. Models based on baseline NIHSS and the percentage of intravenous thrombolysis (IVT) were considered the most optimum in terms of AIC. The LASE registry included 950 patients receiving IVT alone, 127 that received IVT and mechanical thrombectomy (MT), and 101 receiving only MT. LASE & RESILIENT outcomes were plotted onto the models at their baseline values. LASE IVT alone group outcomes were in line with the RCT-informed model. LASE MT alone and MT + IVT, and the RESILIENT MT arm (68.5% IVT) demonstrated superior efficacy compared to no-MT. The RESILIENT control arm (71.8% tPA) had higher-than-expected mortality, while mortality of all other arms was within the predicted range.ConclusionFunctional outcomes and mortality of patients from the LASE and RESILIENT trial receiving MT and MT+IVT compared favorably to the 90-day functional and mortality outcomes predicted in a model derived from no-MT data from other stroke RCTs, indicating Latin American MT systems of care are comparable to those of more resourceful regions. Higher mortality from IVT in the RESILIENT trial requires further investigation.

IMPORTANCE Cryptogenic strokes constitute approximately 40% of ischemic strokes in young adults, and most meet criteria for the embolic stroke of undetermined source (ESUS). Two randomized clinical trials, NAVIGATE ESUS and RESPECT ESUS, showed a high rate of stroke recurrence in older adults with ESUS but the prognosis and prognostic factors among younger individuals with ESUS is uncertain. OBJECTIVE To determine rates of and factors associated with recurrent ischemic stroke and death and new-onset atrial fibrillation (AF) among young adults. DESIGN, SETTING, AND PARTICIPANTS This multicenter longitudinal cohort study with enrollment from October 2017 to October 2019 and a mean follow-up period of 12 months ending in October 2020 included 41 stroke research centers in 13 countries. Consecutive patients 50 years and younger with a diagnosis of ESUS were included. Of 576 screened, 535 participants were enrolled after 1 withdrew consent, 41 were found to be ineligible, and 2 were excluded for other reasons. The final follow-up visit was completed by 520 patients. MAIN OUTCOMES AND MEASURES Recurrent ischemic stroke and/or death, recurrent ischemic stroke, and prevalence of patent foramen ovale (PFO). RESULTS The mean (SD) age of participants was 40.4 (7.3) years, and 297 (56%) participants were male. The most frequent vascular risk factors were tobacco use (240 patients [45%]), hypertension (118 patients [22%]), and dyslipidemia (109 patients [20%]). PFO was detected in 177 participants (50%) who had transthoracic echocardiograms with bubble studies. Following initial ESUS, 468 participants (88%) were receiving antiplatelet therapy, and 52 (10%) received anticoagulation. The recurrent ischemic stroke and death rate was 2.19 per 100 patient-years, and the ischemic stroke recurrence rate was 1.9 per 100 patient-years. Of the recurrent strokes, 9 (64%) were ESUS, 2 (14%) were cardioembolic, and 3 (21%) were of other determined cause. AF was detected in 15 participants (2.8%; 95% CI, 1.6-4.6). In multivariate analysis, the following were associated with recurrent ischemic stroke: history of stroke or transient ischemic attack (hazard ratio, 5.3; 95% CI, 1.8-15), presence of diabetes (hazard ratio, 4.4; 95% CI, 1.5-13), and history of coronary artery disease (hazard ratio, 10; 95% CI, 4.8-22). CONCLUSIONS AND RELEVANCE In this large cohort of young adult patients with ESUS, there was a relatively low rate of subsequent ischemic stroke and a low frequency of new-onset AF. Most recurrent strokes also met the criteria for ESUS, suggesting the need for future studies to improve our understanding of the underlying stroke mechanism in this population.

Background and Purpose: The spectrum of brain infarction in patients with embolic stroke of undetermined source (ESUS) has not been well characterized. Our objective was to define the frequency and pattern of brain infarcts detected by magnetic resonance imaging (MRI) among patients with recent ESUS participating in a clinical trial. Methods: In the NAVIGATE ESUS trial (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source), an MRI substudy was carried out at 87 sites in 15 countries. Participants underwent an MRI using a specified protocol near randomization. Images were interpreted centrally by those unaware of clinical characteristics. Results: Among the 918 substudy cohort participants, the mean age was 67 years and 60% were men with a median (interquartile range) of 64 (26–115) days between the qualifying ischemic stroke and MRI. On MRI, 855 (93%) had recent or chronic brain infarcts that were multiple in 646 (70%) and involved multiple arterial territories in 62% (401/646). Multiple brain infarcts were present in 68% (510/755) of those without a history of stroke or transient ischemic attack before the qualifying ESUS. Prior stroke/transient ischemic attack ( P 0 ( P P =0.01) were associated with multiple infarcts. Topographically, large and/or cortical infarcts were present in 89% (757/855) of patients with infarcts, while in 11% (98/855) infarcts were exclusively small and subcortical. Among those with multiple large and/or cortical infarcts, 57% (251/437) had one or more involving a different vascular territory from the qualifying ESUS. Conclusions: Most patients with ESUS, including those without prior clinical stroke or transient ischemic attack, had multiple large and/or cortical brain infarcts detected by MRI, reflecting a substantial burden of clinical stroke and covert brain infarction. Infarcts most frequently involved multiple vascular territories. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02313909.

Introduction: As acute stroke therapies expand to less well-resourced regions, it is imperative to study real-world data to assess outcomes and the quality of stroke care. The present study analyzes clinical, and imaging outcomes after acute IV thrombolysis (IV-tPA) compared to mechanical thrombectomy (MT) or combined therapy in the LASE. Methods: A retrospective analysis of consecutive acute ischemic stroke cases in 17 centers from 9 Latin American (LA) countries since 2012 was performed using weighted Euclidean matching of nearest neighbors in 3-D space of baseline NIHSS, age, and glucose. Results: 950 patients receiving only IV-tPA were matched to 127 treated with MT+IV-tPA. Matching resulted in 97 pairs well balanced for age (69.1 vs. 69.3), baseline NIHSS (17 vs. 17), and glucose (124.3 vs. 124.5), all p>0.2. 3-month mRS 0-1 (38.3% vs 29.8%, p=0.23) and mRS 0-2 (46.8% vs 41.5%, p=0.54) were non-significantly higher in the MT+IV-tPA group, with higher hemorrhage (26.6% vs 15.5%, p=0.05) and trends for higher death (15.1% vs 9.5%, p=0.40) and symptomatic hemorrhage (7.4% vs 6.2%, p=1.0). One hundred one patients receiving only MT were matched to 127 patients with MT+IV-tPA, resulting in 61 pairs; MT+IV-tPA showed trends for higher rates of 3-month mRS 0-1 (45.0% vs 35.6%, p=0.31), mRS 0-2 (48.3% vs 42.4%, p=0.54); with trends for lower rates of death (16.9% vs 20.0%, p=1.0) and symptomatic hemorrhage (8.3% vs 11.1%, p=0.75). Conclusions: In this real-world LA sample, trends for better functional outcomes were demonstrated with MT+IV-tPA compared to either treatment alone, as in non-LA populations. A trend for higher adverse events in the combined group requires further investigation.

It is estimated that two thirds of people who have suffered a stroke have sequels that condition their quality of life. The rehabilitation of the stroke is a complex process, which requires the multidisciplinary approach of specialized professionals (doctors, kinesiologists, nurses, occupational therapists, phonoaudiologists, neuropsychologists and nutritionists). Currently, the practices carried out are a consequence of the combination of evidence and consensus, most of them through international stroke rehabilitation guides. The objective of this review is to adjust the international recommendations on stroke rehabilitation to what is applied to daily practice, in order to unify the criteria of the recommendations and to reduce the variability of the practices carried out. This work is a review of the literature on stroke rehabilitation guides developed in the last 10 years. Each section was supervised by different professionals specialized in these areas. We analyze the time and organization necessary to develop rehabilitation, recommendations for motor, cognitive and visual rehabilitation, the management of dysphagia and nutrition, the approach of comorbidities (venous thrombosis, skin ulcers, pain, psychiatric disorders and osteoporosis) and the necessary tasks to favor the return to the activities of daily life.

To assess clinical and/or imaging features useful to distinguish between Susac syndrome (SuS) and primary angiitis of central nervous system (PACNS).Multicenter retrospective analysis of two cohorts of Argentine patients diagnosed with SuS and PACNS.13 patients diagnosed with SuS (6 women and 7 men, mean age 35 ± 10 years) and 15 with PACNS (10 women and 5 men, mean age 44 ± 18 years) were analyzed. Cognitive impairment (11 out of 13 patients vs. 5 out of 15, p = .006), ataxia (7 out of 13 vs. 2 out of 15, p = .042) and auditory disturbances (7 out of 13 vs. 0 out of 15, p = .003) were more frequent in SuS patients; whereas seizures were more frequent in PACNS patients (8 out of 15 vs. 1 out of 13, p = .035). On MRI, corpus callosum (CC) involvement was observed more often in SuS, with abnormalities in CC genu, in 13 out of 13 SuS patients vs. only 2 out of 15 PACNS patients (p .001); in CC body these were present in 13 out of 13 SuS patients vs. 1 out of 15 PACNS patients, (p .001); and in CC splenium in 12 out of 13 Sus patients vs. 1 of 15 PACNS, p .001). Cortical lesions were more frequent in PACNS patients (10 out of 15 vs. 3 out of 13 SuS patients, p = .02), as were hemorrhages (5 out of 15 vs. 0 out of 13 SuS, p = .04) and multiple basal ganglia infarcts (7 out of 15 vs. 1 out of 13 Sus, p = .037).Specific clinical and/or MRI findings may help distinguish SuS from PACNS with potential therapeutic implications.

Background: \ud Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial.\ud \ud Methods: \ud NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy.\ud \ud Findings: \ud Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22–1·36), and the risk was similar for those without known PFO (1·06; 0·84–1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51–8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69–4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24–0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity.\ud \ud Interpretation: \ud Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted.\ud \ud Funding: \ud Bayer and Janssen.

Atrial fibrillation is the most common cause of embolic stroke associated to heart disease. Oral anticoagulation with vitamin K antagonists substantially reduces this risk.We assessed a group of patients with prior diagnosis of atrial fibrillation who sustained an ischemic stroke while receiving an adequate regime of oral anticoagulation.We evaluated consecutive patients with ischemic stroke and prior diagnosis of atrial fibrillation. We determined demographics, clinical characteristics, TOAST stroke subtypes, CHADS2 scores, and prior or concomitant use of oral anticoagulants.We studied 112 patients. Thirty nine of them (35%) had received an adequate dose of a vitamin K antagonist during the 24-hour period preceding the stroke. There were no differences in demographics, vascular risk factors, CHADS2 scores, nor medications use between patients who were or were not receiving anticoagulation. Other potential etiologies for stroke occurrence were found in 8 (21%) anticoagulated patients, and in 3 (4%) non-anticoagulated subjects (p0.01). Anticoagulated patients had a mean international normalized ratio (INR) of 2.3 ± 1.3 (median 2.05), and INR was within therapeutic ranges (i.e., ≥ 2) in 54% of these subjects.A substantial proportion of patients with atrial fibrillation who have an ischemic stroke are already receiving oral anticoagulation. Sub-optimal levels of anticoagulation and additional etiologies explain, only in part, this failure. Further research is needed to help find adequate therapeutic strategies in atrial fibrillation patients who sustain an ischemic stroke while receiving oral anticoagulation.

The aim of this study was to investigate everyday executive functioning abilities in patients with focal cerebellar lesions using an executive battery sensitive for the detection of damage to the prefrontal cortex, including a "real life" situation task. Eleven patients with focal cerebellar infarcts were studied prospectively after their injury. All subjects underwent a complete neurological, neuropsychiatric, and neuropsychological examination, as well as a specific computerized battery (Test of Attentional Performance), and an "ecological" test: the Multiple Errands Task-hospital version (MET-hv, adapted version). Significant differences were found between patients and normal controls in language and executive functions tasks. Significant differences were observed in the flexibility subscale of the Test of Attentional Performance and several subscales of the MET-hv (total amount of failures, interpretation failures, task completion score, and inefficiencies subscale). This study supports previous reports showing a pattern of cognitive abnormalities following focal cerebellar damage that includes impairments of executive function. Moreover, it suggests that the ecological test used in this investigation might be useful for the detection of deficits in real-life executive functioning among this patient population.

Background and Purpose— Although prior studies have demonstrated that 25% to 35% of stroke patients have had a recent infection, the role of infection as a risk factor remains unclear. Our aim was to characterize the effect of infectious/inflammatory syndromes on stroke risk. Methods— Case-control and crossover analyses of 233 cases and 363 controls aged 21 to 89 years were performed. Cases were patients hospitalized with a first ischemic stroke at a Los Angeles, California, medical center. Controls were outpatients in the hypertension, diabetes, and general medical clinics. All subjects were administered a neurological examination, an infection/inflammation (I/I) examination, and an interview to elicit recent I/I history at baseline (within several days of stroke onset) and again approximately 2 months later. Three physicians classified subjects by the presence or absence of I/I within 1 month of the index dates, based on findings of the I/I examination, the interview report, and laboratory results. Results— Infections, either total or specific, were not found more frequently in cases than controls. However, patients with a recent respiratory tract infection suffered more often from large-vessel atherothromboembolic or cardioembolic stroke than did patients without infection (48% vs 24%, P =0.07). The age- and sex-adjusted relative risk estimate for these subtypes was 1.75 (95% CI, 0.86 to 3.55). The risk was notably high for those without stroke risk factors: 4.15 (95% CI, 1.22 to 14.1) for normotensives, 2.71 (95% CI, 1.04 to 7.06) for nondiabetics, and 1.74 (95% CI, 0.74 to 4.07) for nonsmokers. Patients with a recent respiratory infection also had a more severe neurological deficit on admission than those without infection ( P =0.05). Conclusions— Our results suggest that respiratory tract infection may act as a trigger and increase the risk of large-vessel and/or cardioembolic ischemic stroke, especially in those without vascular risk factors.

Background and Purpose —Several lines of evidence point toward a relationship between infection and atherosclerotic vascular disease. Thus, infection and inflammation often precede ischemic neurological events. Transient alterations in coagulation and direct arterial invasion by certain microorganisms have been reported. Helicobacter pylori infection is the major cause of peptic ulcer disease and appears to be a risk factor for ischemic cerebrovascular disease. However, in contrast to other chronic infectious agents, H pylori has not been consistently isolated from atherosclerotic lesions. Methods —We investigated the presence of H pylori in 38 atherosclerotic plaques obtained at carotid endarterectomy by using morphological and immunohistochemical techniques and a highly sensitive polymerase chain reaction method. We performed immunohistochemical detection of intercellular adhesion molecule-1, a marker related to inflammatory cell response. We also examined 7 carotid arteries obtained at autopsy from subjects without carotid atherosclerosis. Results — H pylori DNA was found in 20 of 38 atherosclerotic plaques. Ten of the H pylori DNA–positive plaques also showed morphological and immunohistochemical evidence of H pylori infection. None of 7 normal carotid arteries was positive for H pylori . Intercellular adhesion molecule-1 was expressed in 75% of H pylori –positive plaques and in 22% of H pylori –negative plaques. The presence of the microorganism was associated with male sex but was independent of age, vascular risk factor profile, and prior neurological symptoms. Conclusions — H pylori is present in a substantial number of carotid atherosclerotic lesions and is associated with features of inflammatory cell response. This study provides additional evidence of the relationship between H pylori infection and atherosclerotic disease.

Rapid lowering of blood pressure can precipitate or worsen ischemic strokes. This usually has been observed in the setting of profoundly lowered pressure and hypotension. We report on six patients in whom ischemic neurologic injury ensued or worsened after moderate reduction of blood pressure by pharmacological treatment. The 6 patients suffered new or worsened ischemic neurologic deficits after receiving oral or intravenous antihypertensive medications, mostly after relatively small doses. Mean arterial blood pressure in these patients was decreased by 25 ± 7.7%, or 37 ± 16 mm Hg (mean ± SD) without resultant hypotension. These cases emphasize the potential hazards of moderate blood pressure reduction by antihypertensive medications in the setting of an acute ischemic stroke or transient ischemic attack (TIA), as well as rapidly treated hypertension even in those who have not yet manifested ischemic symptoms.

Temporal arteritis is a form of systemic vasculitis that involves branches of the carotid artery. Clinical features are headache, visual loss, ophthalmoplegia, jaw claudication, temporal headache, with tenderness and thickening on the affected temporal artery. We present 3 cases of tongue necrosis due to this granulomatous arteritis. Ischemic necrosis of the tongue is unusual and appears to be an association between its occurrence and high dose steroid tapering.

Background and Purpose Infection/inflammation appears to be an important predisposing risk factor for brain infarction, but little is known regarding underlying molecular mechanisms. We examined the hypothesis that patients with brain infarction preceded by infection/inflammation within 1 week could be identified by a distinctive procoagulant laboratory profile characterized by abnormalities in the protein C system and endogenous fibrinolysis. Methods We performed a case-control study examining the relationship between preceding systemic infectious/inflammatory syndromes and selected immunohematologic variables in 36 patients with acute brain infarction and 81 control subjects (community control subjects [n=47] and hospitalized nonstroke neurological patient controls [n=34]). Results The stroke group had a lower mean level of the circulating antithrombotic enzyme activated protein C (APC) (4.33±0.34% [log-transformed percentage of control value, mean±SD]) than community control subjects (4.51±0.27%, P P r =−.55, P P P P Conclusions Impairments in the protein C pathway and endogenous fibrinolysis may contribute to the increased risk for brain infarction after recent (≤1 week) infection/inflammation. A decrease in the circulating anticoagulant APC may be related to elevated antiphospholipid antibody titers.

Background and Purpose Antecedent febrile infection and psychological stress are described as predisposing risk factors for brain infarction. We examined the temporal relationship between preceding infection/inflammation and stroke onset as well as the role of recent psychological stress as a potential precipitant for brain infarction. Methods In this case-control study, a standardized evaluation including a signs/symptoms-based questionnaire was used to characterize the prevalence and timing of recent prior ( Results The prevalence of infection/inflammation was significantly higher in the stroke group only within the preceding 1 week compared with either community control subjects (13/37 versus 6/47, P P Conclusions Our data suggest that both febrile and nonfebrile infectious/inflammatory syndromes may be a common predisposing risk factor for brain infarction and that the period of increased risk is confined within a brief temporal window of less than 1 week. Results of this study argue against a role for recent psychological stress as a precipitant for cerebral infarction.

Risk factors for ischemic stroke broadly overlap with predictors of atherosclerotic vascular disease. Few studies have examined this risk in patients with different types of symptomatic atherosclerotic disease. Methods: TRA 2°P-TIMI 50 was a multinational, randomized, trial of 26449 patients with atherothrombosis randomized to vorapaxar or placebo added to standard therapy. Patients qualified with a history of myocardial infarction (MI), symptomatic peripheral arterial disease (PAD), or recent ischemic stroke (CVD, 2 wks to 12 mo.). Stroke was adjudicated by an independent CEC. Correlates of stroke were determined in placebo patients (N=13,169) Results: A total of 294 ischemic strokes occurred during follow up. Overall age, hypertension, diabetes mellitus, PAD, prior ischemic stroke, renal dysfunction, atrial fibrillation/flutter, and carotid stenosis ≥ 50% were associated with new ischemic stroke during follow up (Figure A). After adjustment age, hypertension, diabetes, prior ischemic stroke, and atrial fibrillation/flutter remained significantly associated with ischemic stroke with a history of ischemic stroke associated with the greatest hazard (adj HR 5.15, 95% CI 4.02 - 6.61, p Conclusions: Predictors of ischemic stroke in patients with atherosclerotic vascular disease vary by the primary symptomatic bed. In patients with recent MI or PAD, prior stroke is the strongest predictor while traditional risk factors are also associated with recurrent events. In patients with recent stroke only prior MI and diabetes predict recurrent stroke.

Intracranial hemorrhage (ICH) is a serious complication of antithrombotic therapy and is associated with high mortality (>50% at 30 days). The frequency of ICH subtypes and their outcomes in the era of contemporary oral antiplatelet therapy have not been well described. Methods: TRA 2°P-TIMI 50 was a randomized trial of 26449 pts with history of atherothrombosis randomized to vorapaxar or placebo plus standard antiplatelet therapy. Patients qualified with myocardial infarction (MI), peripheral artery disease (PAD) (N=21,492 combined), or recent ischemic stroke (CVD, 2 wks to 12 mo. N=4860). ICH was adjudicated by an independent CEC and analyzed in the safety cohort (N=26,352) Results: A total of 155 ICH events occurred. Traumatic/Provoked ICH was most frequent (Figure A). ICH occurred more frequently in patients qualified with CVD compared to those qualified with MI/PAD (1.4% vs 0.4%, p= 4 (p=NS) after stroke associated ICH in patients receiving vorapaxar compared with placebo. Conclusions: The frequency and subtypes of ICH vary based on patient history. Case-fatality rates vary based on subtype. These findings suggest that events traditionally categorized broadly as ICH are heterogeneous in specific types and outcomes. These subtypes should be considered discretely both clinically and in research.

Intracranial hemorrhage (ICH) is a rare event that is difficult to predict and often has devastating consequences. Clinical predictors of ICH in stable patients with atherosclerosis are not well described. Methods: We evaluated the clinical correlates of ICH risk in patients randomized to placebo (N=13,166) in the TRA 2°P-TIMI 50 trial, a multinational trial of patients with atherothrombosis randomized to vorapaxar or placebo added to standard therapy. Eligible patients had a history of myocardial infarction, peripheral arterial disease, or recent ischemic stroke (2 wks to 12 mo.). ICH was adjudicated by an independent CEC. Results: A total of 53 ICH events (0.5% at 3 years) occurred during follow up in the placebo group. 94% of patients were receiving aspirin, 5% a thienopyridine alone, and 57% dual antiplatelet therapy. Overall, age, sex, prior ischemic stroke, and renal dysfunction were significantly associated with ICH (Table 1). After adjustment age, male gender, and prior ischemic stroke remained significantly associated with an increased hazard of ICH (Figure 1). Notably, the predictors differed between qualifying groups. After adjustment renal dysfunction (p=0.018) and diabetes (p=0.073) were associated with ICH in the MI/PAD group. In contrast, only male gender was associated with ICH in the CVD group (p=0.048). Conclusions: Advanced age, male gender, and history of ischemic stroke are associated with an increased hazard of ICH in patients with a history of atherothrombosis. Predictors of ICH vary depending on background vascular disease. In patients with MI/PAD and no recent stroke, traditional risk factors including diabetes and renal dysfunction are associated with ICH.

The widespread use of aspirin-driven vascular prevention strategies does not impede the occurrence of first and recurrent ischemic strokes in numerous subjects. It is not clear what factors are associated with aspirin failure beyond the functional diagnosis of aspirin resistance in selected subjects. Current management guidelines provide little or no recommendations on the proper strategy for subjects who had a stroke while receiving aspirin. We assessed clinical features of subjects who had a first or recurrent stroke while taking aspirin.We studied demographic characteristics, vascular risk factors, stroke subtypes, and concomitant medication use in subjects with first or recurrent ischemic strokes. Patients receiving antiplatelet medications other than aspirin and/or oral anticoagulants were excluded from this analysis.Seven hundred and nine patients with first (n = 552) or recurrent (n = 157) ischemic stroke were evaluated. Aspirin was being taken by 29% of first and 48% of recurrent stroke subjects. There was a higher prevalence of hypertension, hypercholesterolemia, and smoking in aspirin users with first and recurrent stroke (P.05). Diabetes and coronary artery disease were more frequent in aspirin users with first ischemic strokes (P.003), but not in those who had recurrent ischemic strokes. Aspirin users were more likely to be also receiving statins and antihypertensive drugs (P.001).Aspirin failure in ischemic stroke prevention may exceed functional resistance to aspirin and could be associated with a higher prevalence of lacunar stroke, comorbidities, and/or adverse interactions with other drugs. These patients may require a different approach regarding prevention strategies.

Magnetic resonance imaging (MRI) findings in a group of 60 ambulatory elderly individuals (average age, 75.8 yr) were characterized as normal (grade 0), periventricular changes only (grade 1 ). small punctate lesions (grade 2), and confluent or large (> 2 mm) punctate lesions (grade 3). Patients were characterized by stroke risk factors, cardiolipin antibodies, coagulation factors (fibrinogen and plasminogen activator inhibitor-1 ). and Doppler ultrasound findings in the carotid and middle cerebral arteries. Subcortical signal abnormalities were present in 62% (37 /60), relatively evenly distributed between grade 1 (18%), grade 2 (25%), and grade 3 (18%). There was no significant association between variables and MRI grade. These findings suggest that ischemia is not a major cause of MRI signal abnormalities in neurologically asymptomatic elderly individuals.

We studied the effects of the calcium channel antagonist nimodipine on the evolution of hemorheological variables during the first 3 weeks following ischemic stroke. We studied 13 patients and found that, compared to baseline levels, plasma fibrinogen concentration and low-shear whole-blood viscosity rose significantly in patients receiving placebo but not in those receiving nimodipine. Red blood cell aggregation rose in both groups but less so in nimodipine-treated patients. Hematocrit, high-shear whole-blood viscosity, and red blood cell deformability did not change significantly in either group. In conclusion, the use of nimodipine appears to alter the evolution of some hemorheological variables following acute ischemic stroke.

We analyzed the association between hematologic factors and blood velocity of the middle cerebral artery in 42 healthy ambulatory subjects aged 63-86 years. We found a significant inverse association between mean velocity and both hematocrit (r = -0.37, p less than 0.02) and fibrinogen concentration (r = -0.42, p less than 0.005). These two variables are independently associated with velocity and together explain 29% of the variance in mean velocity. Both hematocrit and fibrinogen concentration should be considered in the interpretation of transcranial Doppler findings in this population.

A polymerase chain reaction (PCR) method for the detection of the glmM gene, selected as Helicobacter pylori target sequence, was improved. While performing pathogenicity island cagA gene detection to discriminate pathogenic strains in atherosclerotic carotid samples, several cagA-positive but glmM-negative samples were found. Polymorphisms present in the region amplified in the nested PCR reaction could explain this result; primers were therefore designed to perform a seminested reaction; this modification optimized sensitivity while maintaining specificity. A real-time PCR for Helicobacter DNA detection was also setup. The combination of all 4 PCR reactions detected 83% of H. pylori DNA-positive samples in atherosclerotic carotid tissue, 64% of which were cagA gene positive.

Background and Purpose— It is not well established what are the features, if any, that distinguish symptomatic from asymptomatic carotid atherosclerotic plaques. Inducible heme oxygenase-1 (HO-1) is a component of cellular defense mechanisms against oxidative stress. We aimed to assess the presence of Helicobacter pylori (H pylori ) and the expression of HO-1 in carotid atherosclerotic plaques of patients with and without prior neurologic symptoms attributable to the operated artery. Methods— We examined 25 symptomatic and 23 asymptomatic carotid atherosclerotic plaques removed during endarterectomy and 7 normal carotid arteries obtained at autopsy. We investigated the presence of H pylori DNA in the vessel wall and performed immunohistochemical detection of HO-1. Results— H pylori DNA was present in 28 plaques and HO-1 was expressed in 30 plaques. HO-1 was found in 27 H pylori- positive specimens but in only 3 H pylori- negative specimens ( P H pylori and HO-1. Although 82% of asymptomatic specimens were positive for H pylori and 87% for HO-1, only 36% of symptomatic specimens were positive for both H pylori and HO-1 ( P Conclusions— This study suggests a strong association between H pylori infection and expression of HO-1 in carotid atherosclerotic plaques. There was a substantial prevalence of these features in specimens obtained from asymptomatic subjects.

Analysis of the effect of hemorheologic factors on middle cerebral artery (MCA) blood flow velocity in 55 healthy individuals aged 18 to 30 years demonstrated an inverse association between mean MCA blood flow velocity and hematocrit (r = -0.27, p < 0.05). This association was largely explained by the effect of whole-blood viscosity. Neither fibrinogen concentration nor plasma viscosity were significantly associated with MCA blood flow velocity in this group; this lack of a fibrinogen association is in contrast to results previously obtained in elderly individuals where an inverse association was observed. These findings thus demonstrate age-dependent differences in the relationship between fibrinogen and MCA blood flow velocity.

The relationship between sinusitis and ischemic stroke is unexplored. The anatomic proximity between the paranasal sinuses and the internal carotid artery suggests that inflammation of the sinuses could easily extend to the intracranial vasculature. We report 4 patients with acute ischemic stroke and extensive disease of the paranasal sinuses. All patients had large vessel stroke involving the internal carotid artery territory. All patients had extensive disease of the sphenoid and other sinuses. The sinus disease was demonstrated by magnetic resonance imaging. These case report observations suggest a relationship between inflammation of the paranasal sinuses, particularly sphenoid sinusitis, and ischemic stroke.

This chapter describes the mechanisms of ischemia in in situ vascular occlusive disease. Cerebral blood flow below critical levels is the most important factor responsible for brain damage in patients with ischemic stroke. In patients with in situ vascular occlusive disease, stroke is most commonly caused by atherosclerosis. Two basic mechanisms can explain the vast majority of episodes of focal cerebral ischemia due to in situ vascular disease: vascular thrombosis or other condition resulting in narrowed vessel lumen and limitation of flow, and thrombus fragmentation at a vessel resulting in embolic occlusion of a distal vessel. In most patients, a thorough general physical and neurological exam can determine the presence of vascular risk factors, evidence of atherosclerosis in other organs, the vascular territory involved, and the nature of the occlusion. Lacunar syndromes reflect ischemia caused by occlusion of small vessels secondary to lipohyalinosis. Diagnostic studies demonstrate the presence of narrowing of the vessel lumen. Tests used for this purpose are ultrasound studies, magnetic resonance angiography, and catheter-requiring arteriography.

Background and Purpose Resistance to activated protein C (APC), a natural plasma anticoagulant, is the most common identifiable risk factor for venous thromboembolic disease. One point mutation in coagulation factor V that renders it APC-resistant is found in >90% of APC-resistant venous thrombosis patients. To determine the prevalence of APC resistance and of this factor V mutation in stroke, we screened a group of ischemic stroke patients. Methods Hispanic ischemic stroke patients were screened using two different activated partial thromboplastin time-based assays. One assay using neat patient plasma determined APC resistance, and the other assay using patient plasma diluted into factor V-deficient plasma determined APC-resistant factor V, including the Arg 506 →Gln mutation. Results were compared with those in 31 Hispanic control subjects of similar ages. Results Six of 63 (9.5%) stroke patients had APC resistance compared with none of 31 (0%) control subjects. No patient or control subject had APC-resistant factor V, ie, the factor V Arg 506 →Gln mutation. Conclusions In Hispanic patients with ischemic stroke, the incidence (approximately 10%) of APC resistance is not caused by the factor V Arg 506 →Gln mutation. APC resistance not caused by this factor V mutation may be a risk factor for ischemic stroke in this population.

Transcranial Doppler blood flow velocities are inversely related to age and hematocrit, but the relative importance of age, oxygenation, and hemorheological factors has not previously been examined. We evaluated the relative contributions of these factors to middle cerebral artery blood flow velocity in adults with chronic renal failure, a population subject to significant fluctuations in hematologic profile. Twenty-six subjects were studied, with arterial shunt blood sampled at the time of transcranial Doppler before dialysis. Twenty subjects from the original cohort were studied twice to examine the effects of intraindividual changes in blood oxygenation and rheology on Doppler velocities. Age (r = -.61, P < .001), high-shear viscosity (r = -.46, P < .02), and arterial oxygen content (r = -.44, P < .05) were all inversely related to middle cerebral artery blood flow velocity. Age was the strongest velocity predictor, accounting for 37% of variance by simple regression analysis. Intraindividual change in arterial oxygen content explained most (54%) of the middle cerebral artery blood flow velocity variation between studies (r = -.74, P < .001). Multiple regression analysis showed that inclusion of additional variables could not account for more velocity variation than change in arterial oxygen content alone. In this population, age and arterial oxygen content were the most important determinants of interindividual middle cerebral artery blood flow velocity variance and intraindividual middle cerebral artery blood flow velocity variation, respectively.

Delayed ischemic deficits contribute to the high morbidity and mortality rates associated with subarachnoid hemorrhage. We evaluated the potential usefulness of measuring coagulation and hemorheological variables and cardiolipin antibodies for prediction of delayed ischemic deficit after subarachnoid hemorrhage. Consecutive patients with subarachnoid hemorrhage were studied. Coagulation and hemorheological variables and cardiolipin antibodies were measured on admission, within 7 days of subarachnoid hemorrhage. A subset of patients was studied on admission and at two subsequent occasions. Sixty-nine patients were studied. Sixty-one of these were without clinical manifestations of vasospasm at admission, and 16 developed delayed ischemic deficit during their hospitalization. None of the laboratory variables measured were significantly different between patients with or without later development of delayed ischemic deficit. Elevation of the fibrin fragment D-dimer was found in the group of eight patients admitted with ischemic symptoms and in 49% (34 of 69) of all patients, but this was not associated with delayed ischemic deficit. Sixteen patients were studied on three occasions; this group showed a significant decrease in hematocrit, an increased white blood cell count, and no change in fibrinogen concentration. Fibrin D-dimer levels rose significantly after surgery (from 5.01 +/- 0.69 to 5.53 +/- 0.58 ln-ng/ml, p less than 0.025) and after onset of delayed ischemic deficit (from 4.71 +/- 0.64 to 5.84 +/- 0.34 ln-ng/ml, p less than 0.01). Hemostatic measurements, hemorheological variables, and cardiolipin immunoreactivity did not predict delayed ischemic deficit in this population.

We evaluated 50 consecutive patients with acute ischemic stroke to assess the prevalence of systemic infection preceding the neurological event. We analyzed the immunohematologic characteristics of patients with and without signs and/or symptoms of a preceding infectious process. Patients were examined less than or equal to 7 days after cerebral infarction and evaluated for fibrinogen, anticardiolipin antibodies, fibrin D-dimer (a fragment of cross-linked fibrin), plasminogen activator inhibitor-1, and protein S. Of the 50 patients, 17 had symptoms of infection beginning less than or equal to 1 month before the stroke (11 had upper respiratory tract infections, three urinary tract infections, two subacute bacterial endocarditis, and one pneumonia). Compared with patients without infection, patients with infection had significant increases in fibrin D-dimer concentration (5.3 +/- 1.1 versus 4.7 +/- 0.9 log-transformed ng/ml, p less than 0.05) and cardiolipin immunoreactivity, IgG isotype (1.8 +/- 1.3 versus 1.1 +/- 0.9 log-transformed phospholipid units, p less than 0.04), and, when studied less than or equal to 2 days after the stroke, increased fibrinogen levels (459 +/- 126 versus 360 +/- 94 mg/dl, p less than 0.05). In conclusion, infection-associated cerebral infarction is common and is associated with substantial immunohematologic abnormalities.

Atrial fibrillation and congestive heart failure are risk factors for ischemic stroke usually attributed to cardiac embolism. To define potential alternative mechanisms, patients with atrial fibrillation and congestive heart failure were investigated by transcranial Doppler. Middle cerebral artery (MCA) blood flow velocities were analyzed in neurologically asymptomatic patients with nonvalvular (n = 10) and valvular (n = 13) atrial fibrillation, patients in normal sinus rhythm with congestive heart failure (n = 13), and control subjects (n = 11). Compared to patients in sinus rhythm with congestive heart failure and to control subjects, patients in both atrial fibrillation groups had significantly greater beat-to-beat variation in peak, mean, and diastolic velocities and in pulsatility index. Peak, mean, and diastolic MCA velocities in patients with atrial fibrillation and those with congestive heart failure were significantly less than those in control subjects. Patients with nonvalvular atrial fibrillation had a higher pulsatility index compared to each of the other three groups. These findings demonstrate substantial nonemboligenic alterations of the intracranial circulation associated with atrial fibrillation and congestive heart failure, and also provide an intracranial hemodynamic profile that may distinguish valvular from nonvalvular atrial fibrillation.

The effect of premature ventricular contractions on blood flow velocity in the middle cerebral artery was studied by transcranial Doppler ultrasonography in 1 0 patients. Velocity during three ectopic beats for each patient was lower than that during the preceding and the following beat in every recording. The decrease in peak velocity was 30.7 ± 12.4% and 37.1 ± 13.3% (mean ± standard deviation) compared to the preceding and following beat, respectively. This variation was significantly larger (p < 0.0001) than the spontaneous change observed during sinus rhythm, 2. 7 ± 2.2% in patients with premature ventricular contractions and 3.5 ± 3.2% in control subjects. Similar results were obtained for both mean and diastolic blood flow velocities. Systolic-diastolic ratios were similar for premature ventricular contractions, beats preceding or following premature ventricular contractions, and sinus rhythm beats. Transcranial Doppler ultrasound appears to be an excellent technique for analyzing the effects of cardiac arrhythmias on the cerebral circulation.

INTRODUCTION: Fibrinolytic agents are effective in the treatment of acute ischemic stroke. However, logistic and clinical factors limit their use. Neuroprotective drugs pose less risks and can be used even before performance of computed tomography of the brain as they are not detrimental in hemorrhagic stroke. These aspects, in theory, will allow the use of neuroprotective drugs in larger number of patients. OBJECTIVE: To evaluate the feasibility of a neuroprotection protocol and the potential usefulness of citicoline in acute ischemic stroke. PATIENTS AND METHODS: Thirty seven patients admitted with a clinical diagnosis of acute ischemic stroke (later confirmed with computed tomography) received, within 12 hours of onset of symptoms, citicoline 500 mg intravenously in a single bolus daily for 7 days. Neurological outcome in this group was compared with a group of 37 patients admitted during the 6 month period before the initiation of the trial and not treated with citicoline. Groups were matched by National Institute of Health Stroke Scale (NIHSS) on admission. RESULTS: Patients treated with citicoline (aged 69+/-14 years) improved on their NIHSS from admission (5.7+/-4.2) to discharge (4.7+/-4.5), p= 0.015. The control group (aged 60+/-17 years) did not change between admission (5.7+/-4.3) and discharge (5.2+/-3.5), ns. Patients treated within 6 hours of admission (n= 12) had more substantial improvement, from 5.4+/-2.3 on admission to 3.9+/-2.9 at discharge, p= 0.008. There were no differences in vascular risk factor profile between the groups. Citicoline was well tolerated in every subject. CONCLUSIONS: A protocol of acute stroke management using neuroprotective agents presents clear logistic advantages allowing the inclusion of larger number of patients. Citicoline appears as a safe and potentially effective option.

P118 Stroke risk is increased in the presence of some infections. We studied potential mechanisms linking infections and stroke risk. We used endotoxin, a component of gram negative bacteria, as a standardized inflammatory stimulus. We infused low-dose endotoxin (1ng/kg) as a bolus in four healthy men, and analyzed cerebrovascular and hemostatic effects over 24 hours. We measured cerebral vasomotor reactivity, using transcranial Doppler ultrasonography to calculate breath-holding index (BHI); the latter consists of the percent change of middle cerebral artery blood flow velocity over time during breath holding. We also measured thrombin-antithrombin complexes (TAT, an index of thrombin generation), and soluble e-selectin (a marker of endothelial activation). Following infusion of endotoxin, there were substantial physiological changes primarily at three to six hours post-infusion. Temperature peaked at 100 °F (p

We measured cerebral vasomotor reactivity during normoventilation, hyperventilation (hypocapnia), and breathing of 6% CO2 (hypercapnia) in 20 normal subjects during the hours of 6 to 8 AM, 1 to 3 PM, and 7 to 9 PM. Cerebral vasomotor reactivity was calculated, using transcranial Doppler, as percent change in the mean blood flow velocity of the middle cerebral artery per mm Hg change in end-tidal CO2 during hypocapnia and hypercapnia. Vasomotor reactivity during hypercapnia was lower in the morning (1.72 +/- 0.66 %/mm Hg) than in the afternoon (2.34 +/- 0.74 %/mm Hg, p < 0.01) and evening (2.31 +/- 0.56 %/mm Hg, p < 0.001). Vasomotor reactivity during hypocapnia did not vary significantly during the three periods (2.34 +/- 0.59 %/mm Hg in the morning, 2.43 +/- 0.51 %/mm Hg in the afternoon, and 2.26 +/- 0.52 %/mm Hg in the evening). This reduced morning response to hypercapnia suggests diminished vasodilator reserve during this period, and may be related to the increased stroke risk during the morning hours.

We report 2 patients with transient, focal, repetitive, stereotyped episodes of neurologic deficits during treatment with interleukin-2. One patient had recurrent monocular blindness, while the 2nd had recurrent homonymous quadrantanopia. We suggest that these attacks are provoked by endothelial cell activation induced by interleukin-2.