Nasal exudate for diagnosis of stroke: fundamental studies through iron fractionation, total iron, and targeted protein determinations.

During the last years, there has been an increasing research interest in the analysis of biological fluids requiring non-invasive sampling for biomedical and clinical applications. In this work, we have focused on the nasal exudate with the aim of investigating the potential use of this fluid to know the role of iron in stroke and also for diagnosis. Potential differences in the nasal exudate, collected in swabs, from diagnosed hemorrhagic stroke, ischemic stroke, and control groups were investigated with regard to total iron by inductively coupled plasma-mass spectrometry, iron fractionation studies by size exclusion chromatography together with post-column isotope dilution analysis, and four proteins containing iron (ferritin, transferrin, lactoferrin, and ferroportin) with ELISA kits. All these analyses represent an analytical challenge, considering the rather limited amount of sample (10-40 mg) available, being the nasal exudate extracted from the swab with 300 µL 10 mM Tris/HCl, pH = 7.4. Studies to obtain reliable analytical information, such as the blank contribution of the sampling step, evaluation of the extraction efficiency of the nasal exudate from the swab, and normalization strategies for data treatment, have been carried out. Results showed that despite the limited number of investigated samples, fractionation studies as well as the concentrations of ferritin and ferroportin obtained with ELISA kits showed a differential behavior between the different cohorts.

Measurement of GFAP in nasal exudate in the differential diagnosis between ischemic and hemorrhagic stroke.

INTRODUCTION: Differential diagnosis between ischemic stroke (IS) and intracerebral hemorrhage (ICH) is a great challenge. Recently, the discovery of cerebral lymphatic drainage towards the nostrils suggested nasal exudate (NE) as a new source for measure biomarkers from neural damage. We sought to confirm whether glial fibrillary acidic protein (GFAP) levels in NE could identify ICH. METHODS: GFAP in nasal exudate (nGFAP) was studied in 5 IS and 5 ICH patients. All patients underwent neurological examination, brain computed tomography, laboratory tests and measurement of nGFAP and serum GFAP. RESULTS: We found higher concentrations in ICH patients (p=0.02). The area under the ROC curve for IS/ICH discrimination was 0.840, with a cut-off point of 0.06 pg/mg for 100% sensitivity and 80% specificity Conclusions: These findings suggest that nGFAP could be a useful biomarker for differential diagnosis between IS and ICH and opens a potential field of study for other biomarkers in NE in neurological disorders.

Impact of Mediterranean Diet prior to Stroke on the Prognosis of Patients Undergoing Endovascular Treatment.

INTRODUCTION: Mediterranean diet (MeDiet) has been associated with lower risk of stroke. Additionally, animal models suggested that some components of MeDiet are associated with better outcomes after ischemic stroke (IS). We aimed to evaluate the association between global adherence to the MeDiet and the consumption of particular components of the MeDiet with stroke outcomes. MATERIAL AND METHODS: Multicenter observational study of consecutive IS patients treated with endovascular therapy. Inclusion criteria were large anterior circulation vessel occlusion and pre-stroke modified Rankin scale (mRS) <2. Adherence to MeDiet prior to stroke was evaluated using MEDAS 14-item scale. We evaluated the total score and also individual components of the scale. Clinical, radiological, and prognostic variables were collected. Good functional prognosis was considered as mRS ≤2 and complete recanalization as thrombolysis in cerebral infarction 3. RESULTS: From January 1 to October 30, 2018, 239 patients were included (mean age 71 years, 48% women, median baseline NIHSS 16). Median MEDAS scale was 8 points (7-10). Patients with a higher adherence to MeDiet had significantly lower total and LDL-cholesterol levels. Total adherence score was not associated with stroke outcomes. In multivariate analyses, consumption of olive oil as the principal source of fat was independently associated with good functional outcome at 3 months, OR 3.2 (1.1-10.1) and daily consumption of wine was independently associated with complete recanalization, OR 2.0 (1.1-3.8). CONCLUSIONS: Our study suggests that some components of MeDiet, such as olive oil and wine consumption, are related to better prognosis after stroke. More studies are needed to confirm these findings.

Time Trends in Intracerebral Hemorrhage Associated with Oral Anticoagulation and Its Risks Factors in Spain from 2008 to 2015.

BACKGROUND: Intracerebral hemorrhage (ICH) is 7- to 10-fold higher in anticoagulated patients. Given the more extended use of oral anticoagulants, an increase in the prevalence of ICH associated with oral anticoagulation (ICH-OAC) could be expected. However, there is no previous study that assesses the time trends of ICH-OAC in Spain. METHODS: We conducted a combined data analysis after creating a joint database of the 3 most important epidemiological studies on ICH-OAC of our country: the EPICES study (2008-2009), the TAC Registry (TR) study (2012-2013) and the TAC Registry 2 (TR2) study (2015). We finally included 65, 235, and 366 patients from the EPICES, TR, and TR2 studies, respectively. RESULTS: We have observed a 3.73-fold increase in the crude annual incidence of ICH-OAC throughout the period of study, with proportion of ICH-OAC out of total ICH increasing from 8.4% in 2008 to 18.2% in 2015. Age, dyslipidemia, and prior antiplatelet treatment increased during the study, but we found no statistically significant differences in other risk factors for ICH-OAC. CONCLUSIONS: The incidence of ICH-OAC is increasing in our country. It might at least be partly explained by aging of the population, with mean age at presentation being higher in the last years.

Iron Measured in Nasal Exudate Samples as a New and Useful Biomarker in the Differential Diagnosis of Patients with Acute Stroke.

INTRODUCTION: Differential diagnosis between ischemic and hemorrhagic strokes in the acute stage is one of the major challenges of neurovascular research. Several biomarkers have been studied, but attempts to date have focused on determining their blood levels. Recently, cerebral lymphatic drainage toward the nostrils has been discovered, giving us the chance to study nasal exudate looking for biomarkers of neural damage. We sought to confirm whether iron levels in nasal exudate could identify the hemorrhagic nature of acute stroke. METHODS: We studied iron nasal exudate levels in 32 ischemic and 43 hemorrhagic stroke patients. All patients underwent neurological examination assessed by the National Institutes of Health Stroke Scale (NIHSS), brain computed tomography to the differential diagnosis of stroke subtype, laboratory tests, and measurement of iron levels in nasal exudate. RESULTS: The iron levels in nasal exudate were higher in hemorrhagic stroke patients. The area under the receiver operating characteristic curve for ischemic/hemorrhagic stroke discrimination was 0.896 (95% confidence interval 0.823-0.970) and cutoff point of 0.078 nmol/mg (sensitivity 93%, specificity 73%). CONCLUSIONS: Our findings suggest that iron levels in nasal exudate may be useful in the acute stage for the differential diagnosis between ischemic and hemorrhagic damage in acute stroke patients. They also open a potential field to study other biomarkers in nasal exudate in several neurological disorders. Clinical studies must be performed to confirm our results.

Obtaining information from the brain in a non-invasive way: determination of iron in nasal exudate to differentiate hemorrhagic and ischemic strokes.

Background Differentiation between hemorrhagic and ischemic stroke is currently made by brain imaging or analyzing blood and cerebrospinal fluid (CSF) samples. After describing a new drainage route from brain to nasal mucosa, nasal exudate samples can be considered a new and promising source of biomarkers. Saliva can also be evaluated. Methods We determined iron in nasal exudate and saliva samples from patients of acute stroke during the first 48 h from onset. A simple, non-invasive sampling procedure was employed to obtain information from the brain. Samples were taken with a pre-weighed swab, solved in a 2% nitric acid solution and iron was measured by inductively coupled plasma-tandem mass spectrometry (ICP-MS/MS). Results A significant difference in the dispersion of results of iron concentration for both stroke subtypes was observed in nasal exudate samples. The interquartile range was 0.608 nmol mg-1 of iron for hemorrhagic strokes and only 0.044 nmol mg-1 for ischemic strokes. In saliva samples, however, the values were 0.236 vs. 0.157 nmol mg-1. A cut-off limit of 0.102 nmol of iron per mg of nasal exudate provides a methodology with a 90% of sensitivity and a 90% of specificity. The value of the area under (AUC) the receiver operating characteristic curve (ROC) for nasal exudate samples is 0.960, considered as very good in which regards to its predictive value. Conclusions Non-invasive samples of nasal secretion have allowed obtaining, for the first time, information from the brain. Determination of iron in nasal exudate by ICP-MS allowed differentiation between ischemic and hemorrhagic strokes.

Vitamin K antagonist-associated intracerebral hemorrhage: lessons from a devastating disease in the dawn of the new oral anticoagulants.

BACKGROUND: Intracerebral hemorrhage (ICH) is the most feared complication associated with vitamin K antagonists (VKAs). We performed a retrospective study on the clinicoradiologic characteristics that influence its outcome. METHODS: We reviewed the clinical histories and neuroimaging studies of all patients attended at the Hospital Universitario Central de Asturias in 2010-2011 who had an ICH while being on VKA and analyzed the differential characteristics between patients with acceptable versus poor outcomes attending to 3 end points: death, poor outcome (modified Rankin Scale [mRS] score ≥ 4) at discharge, and poor outcome 3 months later. Additionally, CHA2DS2-VASc and HAS-BLED scores (validated tools for prediction of the risk of stroke and major hemorrhage, respectively, in patients with atrial fibrillation) were calculated to assess a priori risk-benefit balance for anticoagulant therapy. RESULTS: Eighty patients entered the sample (median age of 79 years). A priori annual risk of major bleeding surpassed ischemic stroke risk-without anticoagulation-only in 4. Fifty percent of the patients had an initial Glasgow Coma Scale (GCS) score lower than 13; in 51.3%, initial international normalized ratio was above their therapeutic range. Median hematoma size was 24.75 cc(3); relevant growth (≥33%) occurred in 29.4% of patients with a second computed tomography scan. On multivariable analysis, overall in-hospital mortality (47.5%) was related to prior antiplatelet therapy (P = .008), GCS (P = .001), and perilesional edema size (P = .036). Baseline mRS (P = .058) and National Institutes of Health Stroke Scale (NIHSS) scores (P = .008) were associated with poor outcome at discharge (77.5%). Initial NIHSS (P = .005) and glycemia (P = .038) predicted 3-month poor outcome (68.3%). VKA reversal was performed in almost all patients, which prevented assessment of its therapeutic value. CONCLUSIONS: VKA-associated ICH presents in a particularly vulnerable population and has a poor prognosis that may be reliably predicted by several clinicoradiologic features.

Serum Prealbumin Levels on Admission as a Prognostic Marker in Stroke Patients Treated with Mechanical Thrombectomy.

INTRODUCTION: Prealbumin is a marker of malnutrition and inflammation. It has been associated with poor prognosis in cardiovascular disease, but less is known in stroke patients. Our objective was to evaluate the association of prealbumin levels at admission with prognosis in patients with stroke treated with mechanical thrombectomy. METHODS: Retrospective study of a prospective database of consecutive patients treated with mechanical thrombectomy. Clinical, radiological, and blood parameters including serum prealbumin, and prognostic variables such as respiratory infection, in-hospital mortality, and the modified Rankin scale at 3 months were collected. RESULTS: We included 319 patients between 2018 and 2019. Prealbumin levels were significantly lower in patients older than 80 years, women, patients with a prestroke Rankin score >2, a glomerular filtrate rate <60 mL/min, and in those with atrial fibrillation. Regarding prognostic variables, prealbumin levels were not associated with respiratory infection. Low prealbumin levels were associated with poor functional prognosis (Rankin score >2), in-hospital mortality, and 3-month mortality. In multivariate analysis, prealbumin was an independent risk factor associated with mortality at 3 months, OR 0.92 [0.86-0.98], p = 0.019. CONCLUSION: Lower prealbumin levels at admission behaved as an independent predictor of long-term mortality in patients treated with mechanical thrombectomy. These results should be replicated in other cohorts.

Efficacy and Safety of Endovascular Treatment in Acute Tandem Carotid Occlusions: Analysis of a Single-Center Cohort.

INTRODUCTION: Acute ischemic strokes with tandem occlusions, which represent 10-20% of all ischemic strokes, have a particularly poor prognosis. Since emergent treatment of tandem lesions has not been specifically addressed in randomized trials, there is an absence of standardized management. OBJECTIVE: We sought to assess the efficacy and safety of acute endovascular treatment in stroke due to tandem occlusions in our center and compare the results with previous reports. METHODS: From a prospective registry we analyzed data of 99 consecutive patients (males: 77.7%, mean age ± SD: 67.5 ± 9.5 years) with stroke due to tandem occlusions who underwent treatment with emergent carotid stenting and intracranial mechanical thrombectomy. Successful recanalization was defined as a TICI score of 2b-3 and a good functional outcome was defined as a modified Rankin scale score ≤2 at 90 days. Symptomatic intracranial hemorrhage (sICH) was considered when associated with worsening on the National Institutes of Health Stroke Scale (≥4 points). RESULTS: A successful recanalization rate was achieved in 87.8 and 48.5% of the patients had a good functional outcome. sICH and mortality rates were 12.1 and 20.2%, respectively, and 21.2% of the patients received combined treatment with intravenous thrombolysis, which did not affect neither the prognosis nor the recanalization or sICH rates. The time from symptom onset to recanalization and the degree of recanalization were the main factors associated with prognosis and the occurrence of sICH. CONCLUSIONS: Our results suggest that endovascular treatment with emergent carotid stenting and intracranial thrombectomy in patients with acute stroke due to tandem occlusions is an effective and safe procedure.

Epidemiology of Intracranial Hemorrhage Associated with Oral Anticoagulants in Spain: Trends in Anticoagulation Complications Registry - The TAC 2 Study.

OBJECTIVE: Patients receiving treatment with oral anticoagulants (OACs) are at risk of intracranial hemorrhage (ICH). In this study, we describe the epidemiological and clinical characteristics of patients receiving OACs who experience ICH and compare those receiving vitamin K antagonists (ICH-VKAs) with those receiving direct OACs (ICH-DOACs). METHODS: We performed a national, multicenter, descriptive, observational, retrospective study of all adult patients receiving OACs who were admitted to the neurology department with ICH over a 1-year period. The study population was divided into 2 groups (ICH-VKAs and ICH-DOACs). Epidemiological, clinical, radiological, and therapy-related variables, as well as functional outcome, were compared at 3 months. A total of 366 cases were included (331 ICH-VKAs, 35 ICH- DOACs). RESULTS: The crude annual incidence of OAC-induced ICH was 3.8 (95% CI, 2.78-3.41) per 100,000 inhabitants/year. The mean (± SD) age was greater for ICH-DOACs (81.5 ± 8.3 vs. 77.7 ± 8.3 years; p = 0.012). The median (IQR) volume of the hemorrhage was lower for ICH-DOACs (11 [30.8] vs. 25 [50.7] mL; p = 0.03). The functional independence rate at 3 months (modified Rankin Scale, mRS < 3) was similar in both groups, although stroke-related mortality was greater in ICH-VKAs (40 vs. 72.7%; p = 0.02). The most frequently indicated poststroke antithrombotic therapy was DOACs (38.7%). CONCLUSION: We found that the incidence of OAC-induced ICH was greater than in previous studies. Hemorrhage volume and mortality were lower in ICH-DOACs than in ICH-VKAs. After stroke, DOACs were the most frequently indicated antithrombotic treatment.

Endovascular reconstruction of internal carotid artery dissection in patients with acute ischemic stroke using the Wingspan stent.

OBJECTIVE: The purpose of this study is to demonstrate our experience in endovascular reconstruction of carotid dissections using the Wingspan Stent System™ (Boston Scientific, Natick, MA, USA), a device we use because of its high radial force and its navigation in extreme curves. METHODS: We treated 11 consecutive patients with acute ischemic stroke due to carotid dissection with the Wingspan stent, in the cervical carotid artery. RESULTS: Functional evaluation revealed that 10 of the 11 patients were independent at 3 months post surgery and that the 11 stents used were found to be patent at the 6-month follow-up digital subtraction angiography (DSA). CONCLUSIONS: The Wingspan stent is an alternative to classic carotid stents and flow diverters for the treatment of cervical internal carotid artery (ICA) dissection associated with ectasias or large loops. The device remains patent over the long term and it is not associated with arterial wall complications.

Epidemiology of Intracranial Haemorrhages Associated with Vitamin K Antagonist Oral Anticoagulants in Spain: TAC Registry.

BACKGROUND: Vitamin K antagonist oral anticoagulants (VKA-OACs) are effective for primary and secondary prevention of embolic events. The rate of haemorrhagic neurological complications in patients admitted to neurology departments in Spain is not yet known. AIMS: We aimed to determine the clinical and epidemiological characteristics of patients with intracranial haemorrhage secondary to VKA-OACs as well as the incidence of this severe complication. METHODS: We conducted a retrospective, descriptive, multi-centre study using information from the medical records of all patients admitted to neurology departments, diagnosed with spontaneous intracranial haemorrhage, and treated with VKA-OACs within a 1-year period. We collected demographic and care data from centres, patients' medical records [demographic data, medical history, haemorrhage origin, vascular risk factors, concomitant treatment, and National Institutes of Health Stroke Scale (NIHSS) scores], and patients' outcome at 3 months [independence (modified Rankin Scale score <3) and mortality rate]. RESULTS: Twenty-one hospitals serving a population of 8,155,628 inhabitants participated in the study. The total number of cases was 235, the mean age was 78.2 (SD 9.4) years, and the baseline NIHSS score was 11.6 (SD 9.5; median 9; interquartile range 14). The VKA-OACs used were acenocoumarol in 95.3% (224 patients) and warfarin in 4.7% (11 patients). The haemorrhage origin was deep in 29.8%, lobar in 25.5%, intraventricular in 11.5%, extensive in 17.4% (>100 ml), cerebellar in 12.3%, and in the brainstem in 3.4%. The international normalised ratio was within therapeutic ranges at admission (according to indication) in 29.4% (69 patients). The global incidence (cases per 100,000 inhabitants per year) is 2.88. The in-hospital mortality rate was 40%, and 24.3% of the patients were independent at 3 months, while the mortality at 3 months was 42.6%. CONCLUSION: VKA-OAC treatment is associated with a large percentage of all cases of spontaneous intracranial haemorrhage, an event leading to high dependence and mortality rates.

[Endovascular treatment of carotid stenosis: an experience in the Hospital Universitario Central de Asturias]. / Tratamiento endovascular de la estenosis carotídea: experiencia en el Hospital Universitario Central de Asturias.

INTRODUCTION: Carotid stenosis accounts for about 25% of all ischaemic cerebrovascular events. Carotid angioplasty and stenting (CAS) is a minimally invasive procedure used as an alternative to carotid endarterectomy, especially in high surgical risk patients. AIM: To analyse the effectiveness and safety of the endovascular treatment of carotid stenosis in the Hospital Universitario Central de Asturias. PATIENTS AND METHODS: The study consisted in a retrospective analysis of the carotid stenoses treated by means of CAS between February 2005 and April 2010, and the following information was recorded: demographic data, clinical diagnosis, indication of treatment, time between the onset of symptoms and beginning of treatment, angiographic findings, complications and long-term follow-up (including the rate of restenosis). RESULTS: Altogether 121 patients were treated (77.8% males and 22.2% females), with a mean age of 70.8 ± 10.7 years. The main vascular risk factors were arterial hypertension (65.3%), smoking (61.2%) and dyslipidaemia (42.1%). In 86% of cases the stenoses were symptomatic and in the remaining 14% they were asymptomatic. In 60.3% of cases they were stenoses > 70%, in 30.6% they were preocclusive stenoses and in 9.1% they were recanalisations of unstable carotid occlusions. The mean treatment time was 17.0 ± 8.3 days after the ischaemic event. The residual stenosis was less than 30% in all cases. The morbidity and mortality rate at 30 days was 4.1% and the rate of restenosis throughout a mean follow-up of 31.2 ± 10.8 months was 2.4%. CONCLUSIONS: In our hospital CAS is considered an effective and safe technique, with a rate of complications that is within the parameters that justify its indication.