Antonio Arauz

Effect of a Novel Free Radical Scavenger, Edaravone (MCI-186), on Acute Brain Infarction

Edaravone, a novel free radical scavenger, demonstrates neuroprotective effects by inhibiting vascular endothelial cell injury and ameliorating neuronal damage in ischemic brain models. The present study was undertaken to verify its therapeutic efficacy following acute ischemic stroke. We performed a multicenter, randomized, placebo-controlled, double-blind study on acute ischemic stroke patients commencing within 72 h of onset. Edaravone was infused at a dose of 30 mg, twice a day, for 14 days. At discharge within 3 months or at 3 months after onset, the functional outcome was evaluated using the modified Rankin Scale. Two hundred and fifty-two patients were initially enrolled. Of these, 125 were allocated to the edaravone group and 125 to the placebo group for analysis. Two patients were excluded because of subarachnoid hemorrhage and disseminated intravascular coagulation. A significant improvement in functional outcome was observed in the edaravone group as evaluated by the modified Rankin Scale (p = 0.0382). Edaravone represents a neuroprotective agent which is potentially useful for treating acute ischemic stroke, since it can exert significant effects on functional outcome as compared with placebo.

Stroke Associated With Sympathomimetics Contained in Over-the-Counter Cough and Cold Drugs

Background and Purpose— Phenylpropanolamine (PPA) and pseudoephedrine are sympathomimetics contained in over-the-counter cold preparations. A case-control study linked PPA use with hemorrhagic stroke in women. Twenty-two patients with stroke associated with use of these drugs are described. Methods— In a consecutive stroke registry since 1988, 22 patients had stroke associated with over-the-counter sympathomimetics. Sympathomimetic dosage and type, time interval until stroke onset, and neuroimaging findings are described. Results— Ten male and 12 female patients were included. Intracerebral hemorrhage occurred in 17 patients, subarachnoid hemorrhage in 4, and ischemic stroke in 1. Stroke was associated with PPA use in 16 patients (dose 75 to 675 mg), with pseudoephedrine in 4 (dose 60 to 300 mg), and with others administered by the nasal route in 2 (oxymetazoline and phenylephrine). Stroke occurred after a single dose in 17 patients and after daily use during several days in 5. The interval between drug exposure and clinical onset varied from 30 minutes to 24 hours. Stroke occurred after recommended doses of PPA (50 to 75 mg) in 32% and pseudoephedrine (60 mg) in 50% of patients. Eight patients had acute hypertension at stroke onset. Cerebral angiography was normal in 8 cases and showed diffuse vasospasm or beading in 10 patients. Conclusions— Stroke related to over-the-counter sympathomimetics was associated with acute hypertension and/or vasospasm or angiitis mechanisms, most related to the use of PPA; however, stroke also occurred with the use of other sympathomimetics, particularly pseudoephedrine. Although stroke complications occurred when doses were used that were higher than recommended doses, apparently there is also a stroke risk when these agents are taken properly.

Prospective Study of Single and Multiple Lacunar Infarcts Using Magnetic Resonance Imaging: Risk Factors, Recurrence, and Outcome in 175 Consecutive Cases

Background and Purpose— We investigated whether lacunar infarct (LI) patients with >1 lacune have different vascular risk factors, a different prognosis, and poorer functional outcome than those with a single lacune. Methods— The study included 175 first-ever LI patients. The group was divided according to the presence of multiple (n=136) or single (n=39) LI. The association of single or multiple LI with the principal vascular risk factors, leukoaraiosis, outcome, and recurrence was investigated with logistic regression models that included age, sex, and cardiac disease. Results— No significant differences were found between single and multiple LI with respect to age, hypertension, hyperlipidemia, smoking, and heavy alcohol drinking. Diabetes mellitus (odds ratio [OR], 2.43; 95% CI, 1.09 to 5.4), high levels of hematocrit (>0.47) (OR, 1.09; 95% CI, 1.04 to 1.21), and leukoaraiosis (OR, 3.58; 95% CI, 1.77 to 7.51) were significantly related to multiple but not to single LI. Stroke recurrence rate was 7.7% in patients with single LI and 24.3% in the multiple LI group (OR, 3.84; 95% CI, 1.1 to 13.3). During a median follow-up of 12 months (range, 6 to 156 months), 94% of the single LI patients and 77.2% of the multiple LI patients had favorable outcomes (Rankin Scale score 0 to 2) (OR, 5.4; 95% CI, 1.25 to 23.9). Conclusions— Diabetes mellitus, leukoaraiosis, and high levels of hematocrit are important risk factors in patients with >1 LI. The presence of multiple LI may be an important prognostic indicator not only for functional recovery but also for a higher rate of recurrence.

Dissection of Cervical Arteries: Long-Term Follow-Up Study of 130 Consecutive Cases

Background and Purpose: We describe the natural history, functional prognosis and long-term recurrences of patients with dissection of cervical arteries (DCA) in a sequential observational study. Methods: We describe 130 patients with angiographically-proven DCA admitted to the Neurology Institute in Mexico City (Mexico), and analyzed clinical and neuroimaging data, treatment and outcome. Treatment with either anticoagulation or aspirin was decided by the primary physician. Primary outcome measures were recurrence (stroke and death) and clinical outcome at 6 months. Follow-up studies were performed to determine recanalization. Results: Mean age was 35.4 years; 4 patients died (3%) and 126 were followed for 3,906 person/years; 17 patients (13%) had a heralding ischemic cerebral event (6 strokes, 11 TIAS) about 8 days before the diagnosis of DCA. After diagnosis, recurrent ischemic stroke occurred in 6 patients (4.8%) within the 2 first weeks (1.5 persons/1,000 follow-up years). No significant differences were found between aspirin and anticoagulation. Recanalization was more frequent in vertebral dissections. Complete recanalization of vertebral dissections was associated with a favorable prognosis [OR 3.2 (95% CI 1.1–8.8; p = 0.02)]. Conclusions: In Mexico, DCA affects young adults and may present with a heralding stroke or TIA. We found rare, early ischemic recurrences. Vertebral territory dissections had better prognosis than carotid ones, particularly in patients with demonstrated complete recanalization.

Carotid plaque inflammation detected by 18F -fluorodeoxyglucose -positron emission tomography pilot study

OBJECTIVES Inflammation is important in both the pathogenesis and outcome of atherosclerosis. Current imaging techniques provide anatomic data but no indication of plaque inflammation. We tested the hypothesis that plaque inflammation could be assessed in vivo by (18)FDG-PET and that plaque inflammation could increase the risk of recurrent vascular events and poor response to treatment in a pilot study. PATIENTS AND METHODS Thirteen patients (median age 66.1 years [55-82 years]) with recent carotid territory TIA or ischemic stroke and internal carotid artery (ICA) stenosis > or =50% were studied. Angiography and (18)F-fluorodeoxyglucose-positron emission tomography ((18)FDG-PET) imaging were carried out in all patients. Treatment for carotid stenosis in each patient was selected by the attending physician and consisted in medical treatment, endarterectomy or stent placement. During 6 months of follow-up, the specific end points assessed were the occurrence of any stroke, death, or re-stenosis. RESULTS Patients with symptomatic carotid atherosclerosis were imaged using (18)FDG-PET. Strong (18)FDG uptake (SUV> or =2.7) was seen in 11 of 13 (85%) carotid lesions. Among these patients two died during follow-up, 3 had recurrent non-fatal ipsilateral ischemic stroke and 1 patient who had undergone stenting had non-symptomatic re-stenosis in control studies. There was a significant correlation between the (18)FDG uptake and degree of ICA stenosis detected by angiography. CONCLUSION Carotid atherosclerotic plaques contain a variable degree of inflammation which can be assessed in vivo by means of FDG and PET. The prognostic value of this marker is, however, still unclear and needs further study.

Predictive Factors for Intracerebral Hemorrhage in Patients with Cavernous Angiomas

Abstract Objectives: Prediction of intracerebral hemorrhage (ICH) in patients with cavernous angiomas is not totally elucidated. The aims of our study were to determine the rate of cerebral hemorrhage, its associated factors, and the clinical outcome in patients with cavernous angiomas in a Hispanic population. Methods: We studied 133 patients with cavernous angiomas. The patients were classified into two groups depending on whether they presented an ICH. A comparative analysis of demographics and clinical data, neuroimaging characteristics, and prognosis was carried out in patients with and without hemorrhage. The hemorrhage rate (expressed as the percentage per patient per year) was also estimated. Results: Seventy–eight patients (59%) had hemorrhage. Non–lobar location of angiomas was associated with hemorrhage [OR 4.82 (CI 95% 2.17–10.73; p=<0.001)]. In contrast, factors associated with a decreased risk of hemorrhage were a family history of epilepsy [OR 0.30 (CI 95% 0.10–0.79; p=0.016)] and lobar location of the angiomas [OR 0.21 (CI 95% 0.09–0.46; p=<0.001)]. The hemorrhagic rate of 1.71% per patient per year was influenced by the location. It was only 1.22% per patient per year in lobar angiomas and 2.33, 2.39, and 2.82% per patient per year for brainstem, cerebellum, and deep hemispheric angiomas, respectively. Conclusions: The non–lobar location of cavernous angiomas gives a higher risk of hemorrhage in our Mexican mestizo population, without the hemorrhage being related to either age or sex.

Mild Hyperhomocysteinemia and Low Folate Concentrations as Risk Factors for Cervical Arterial Dissection

Background and Purpose: Elevated homocysteine (Hcy) plasma levels are associated with an increased risk of spontaneous cervical artery dissection (sCAD). We examined the potential association between Hcy, folate, vitamin B12 levels and 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms in patients with cerebral infarct caused by sCAD. Patients and Methods: 39 patients who survived a cerebral infarct caused by sCAD [20 (51%) women; 24 (61.5%) vertebral and 15 (38.5%) internal carotid arteries], and 76 healthy control subjects were included. Hcy plasma levels (fasting and after methionine load), folate and vitamin B12 levels were measured. We also performed polymorphisms of MTHFR. Hcy, vitamin B12, folates and polymorphisms of MTHFR were assessed and any associations were analyzed using multivariate statistics. Results: Mean plasma fasting Hcy level was 9.81 µmol/l for cases and 6.38 for controls (p = 0.001). The occurrence of sCAD was associated with elevated fasting Hcy levels (>95th percentile over the control group) with an adjusted odds ratio of 7.9 (95% CI 1.66–35). The association between low plasma folate values (<5th percentile) and the presence of CAD was 7.9 (95% CI 1.6–31) after adjusting for confounding variables. The distribution of the MTHFR genotype showed a higher TT mutant frequency among CAD patients (p = 0.034). Conclusions: High plasma concentrations of Hcy and low plasma levels of folate were associated with an increased risk of sCAD in the sample studied. We conclude that deficiencies in nutritional status may contribute to the relatively high incidence of CAD in Mexico.

Serum Uric Acid and Outcome after Acute Ischemic Stroke: PREMIER Study

Background: Current evidence shows that uric acid is a potent antioxidant whose serum concentration increases rapidly after acute ischemic stroke (AIS). Nevertheless, the re-lationship between serum uric acid (SUA) levels and AIS outcome remains debatable. We aimed to describe the prognostic significance of SUA in AIS. Methods: We studied 463 patients (52% men, mean age 68 years, 13% with glomerular filtration rate <60 ml/min at hospital arrival) with AIS pertaining to the multicenter registry PREMIER, who had SUA measurements at hospital presentation. Multivariate models were constructed to analyze the association of SUA with functional outcome as assessed by the modified Rankin scale (mRS) at 30-day, 3-, 6- and 12-month follow-up. A mRS 0-1 was regarded as a very good outcome. Results: Mean SUA concentration at hospital arrival was 6.1 ± 3.7 mg/dl (362.8 ± 220.0 μmol/l). Compared with cases with higher SUA levels at hospital admission, patients with ≤4.5 mg/dl (≤267.7 μmol/l; the lowest tertile of the sample) had more cases of a very good 30-day outcome (30.5 vs. 18.9%, respectively; p = 0.004). SUA was not associated with mortality or functional dependence (mRS >2) at 30 days, or with any outcome measure at 3, 6 or 12 months poststroke. After adjustment for age, gender, stroke type and severity (NIHSS <9), time since event onset, serum creatinine, hypertension, diabetes and smoking, a SUA ≤4.5 mg/dl (≤267.7 μmol/l) was positively associated with a very good short-term outcome (odds ratio: 1.76, 95% confidence interval: 1.05-2.95; negative predictive value: 81.1%), but not at 3, 6 or 12 months of follow-up. When NIHSS was entered in the multivariate model as a continuous variable, the independent association of SUA with outcome was lost. Compared with cases with higher levels, patients with SUA ≤4.5 mg/dl (≤267.7 μmol/l) were more frequently younger than 55 years, women, with mild strokes, with normal serum creatinine and fewer had hypertension. The time since event onset to hospital arrival was not significantly associated with AIS severity or SUA levels; nevertheless, a nonsignificant tendency was observed for patients with severe strokes and high SUA levels arriving in <24 h. Conclusions: A low SUA concentration is modestly associated with a very good short-term outcome. Our findings support the hypothesis that SUA is more a marker of the magnitude of the cerebral infarction than an independent predictor of stroke outcome.

Cerebral venous thrombosis in a Mexican multicenter registry of acute cerebrovascular disease: the RENAMEVASC study.

BACKGROUND Cerebral venous thrombosis (CVT) is a rare form of cerebrovascular disease that is usually not mentioned in multicenter registries on all-type acute stroke. We aimed to describe the experience on hospitalized patients with CVT in a Mexican multicenter registry on acute cerebrovascular disease. METHODS CVT patients were selected from the RENAMEVASC registry, which was conducted between 2002 and 2004 in 25 Mexican hospitals. Risk factors, neuroimaging, and 30-day outcome as assessed by the modified Rankin scale (mRS) were analyzed. RESULTS Among 2000 all-type acute stroke patients, 59 (3%; 95% CI, 2.3-3.8%) had CVT (50 women; female:male ratio, 5:1; median age, 31 years). Puerperium (42%), contraceptive use (18%), and pregnancy (12%) were the main risk factors in women. In 67% of men, CVT was registered as idiopathic, but thrombophilia assessment was suboptimal. Longitudinal superior sinus was the most frequent thrombosis location (78%). Extensive (>5 cm) venous infarction occurred in 36% of patients. Only 81% of patients received anticoagulation since the acute phase, and 3% needed decompressive craniectomy. Mechanical ventilation (13.6%), pneumonia (10.2%) and systemic thromboembolism (8.5%) were the main in-hospital complications. The 30-day case fatality rate was 3% (2 patients; 95% CI, 0.23-12.2%). In a Cox proportional hazards model, only age <40 years was associated with a mRS score of 0 to 2 (functional independence; rate ratio, 3.46; 95% CI, 1.34-8.92). CONCLUSIONS The relative frequency of CVT and the associated in-hospital complications were higher than in other registries. Thrombophilia assessment and acute treatment was suboptimal. Young age is the main determinant of a good short-term outcome.

Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source: Design of the NAVIGATE ESUS randomized trial

Background Embolic strokes of undetermined source comprise up to 20% of ischemic strokes. The stroke recurrence rate is substantial with aspirin, widely used for secondary prevention. The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source international trial will compare the efficacy and safety of rivaroxaban, an oral factor Xa inhibitor, versus aspirin for secondary prevention in patients with recent embolic strokes of undetermined source. Main hypothesis In patients with recent embolic strokes of undetermined source, rivaroxaban 15 mg once daily will reduce the risk of recurrent stroke (both ischemic and hemorrhagic) and systemic embolism (primary efficacy outcome) compared with aspirin 100 mg once daily. Design Double-blind, randomized trial in patients with embolic strokes of undetermined source, defined as nonlacunar cryptogenic ischemic stroke, enrolled between seven days and six months from the qualifying stroke. The planned sample size of 7000 participants will be recruited from approximately 480 sites in 31 countries between 2014 and 2017 and followed for a mean of about two years until at least 450 primary efficacy outcome events have occurred. The primary safety outcome is major bleeding. Two substudies assess (1) the relative effect of treatments on MRI-determined covert brain infarcts and (2) the biological underpinnings of embolic strokes of undetermined source using genomic and biomarker approaches. Summary The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source trial is evaluating the benefits and risks of rivaroxaban for secondary stroke prevention in embolic strokes of undetermined source patients. Main results are anticipated in 2018.