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Objective: To update the Spanish Society of Neurology's guidelines for subarachnoid haemorrhage diagnosis and treatment. Materials and methods: A review and analysis of the existing literature. Recommendations are given based on the level of evidence for each study reviewed. Results: The most common cause of spontaneous subarachnoid haemorrhage (SAH) is cerebral aneurysm rupture. Its estimated incidence in Spain is 9/100, 000 inhabitants/year with a relative frequency of approximately 5% of all strokes. Hypertension and smoking are the main risk factors. Stroke patients require treatment in a specialised centre. Admission to a stroke unit should be considered for SAH patients whose initial clinical condition is good (Grades I or II on the Hunt and Hess scale). We recommend early exclusion of aneurysms from the circulation. The diagnostic study of choice for SAH is brain CT (computed tomography) without contrast. If the test is negative and SAH is still suspected, a lumbar puncture should then be performed. The diagnostic tests recommended in order to determine the source of the haemorrhage are MRI (magnetic resonance imaging) and angiography. Doppler ultrasonography studies are very useful for diagnosing and monitoring vasospasm. Nimodipine is recommended for preventing delayed cerebral ischaemia. Blood pressure treatment and neurovascular intervention may be considered in treating refractory vasospasm. Conclusions: SAH is a severe and complex disease which must be managed in specialised centres by professionals with ample experience in relevant diagnostic and therapeutic processes. Resumen: Objetivo: Actualización de la guía para el diagnóstico y tratamiento de la hemorragia subaracnoidea de la Sociedad Española de Neurología. Material y métodos: Revisión y análisis de la bibliografía existente. Se establecen recomendaciones en función del nivel de evidencia que ofrecen los estudios revisados. Resultados: La causa más frecuente de hemorragia subaracnoidea espontánea (HSA) es la rotura de un aneurisma cerebral. Su incidencia se sitúa en torno 9 casos por 100.000 habitantes/año y supone un 5% de todos los ictus. La hipertensión arterial y el tabaquismo son sus principales factores de riesgo. Se ha de realizar el tratamiento en centros especializados. Se debe considerar el ingreso en unidades de ictus de aquellos pacientes con HSA y buena situación clínica inicial (grados I y II en la escala de Hunt y Hess). Se recomienda la exclusión precoz de la circulación del aneurisma. El estudio diagnóstico de elección es la tomografía computarizada (TC) craneal sin contraste. Si esta es negativa y persiste la sospecha clínica se aconseja realizar una punción lumbar. Los estudios de elección para identificar la fuente de sangrado son la resonancia magnética (RM) y la angiografía. Los estudios ultrasonográficos son útiles para el diagnóstico y seguimiento del vasoespasmo. Se recomienda el nimodipino para la prevención de la isquemia cerebral diferida. La terapia hipertensiva y el intervencionismo neurovascular pueden plantearse para tratar el vasoespasmo establecido. Conclusiones: La HSA es una enfermedad grave y compleja que debe ser atendida en centros especializados, con suficiente experiencia para abordar el proceso diagnóstico y terapéutico. Keywords: Subarachnoid haemorrhage, Cerebral aneurysm, Diagnosis, Vasospasm, Delayed cerebral ischaemia, Rebleeding, Medical treatment, Palabras clave: Hemorragia subaracnoidea, Aneurisma cerebral, Diagnóstico, Vasoespasmo, Isquemia cerebral diferida, Resangrado, Tratamiento médico

Background and objective: To update the ad hoc Committee of the Cerebrovascular Diseases Study Group of The Spanish Neurological Society guidelines on prevention of ischemic stroke (IS) and Transient Ischaemic Attack (TIA). Methods: We reviewed the available evidence on ischaemic stroke and TIA prevention according to aetiological subtype. Levels of evidence and recommendation levels are based on the classification of the Centre for Evidence-Based Medicine. Results: In atherothrombotic IS, antiplatelet therapy and revascularization procedures in selected cases of ipsilateral carotid stenosis (70–99%) reduce the risk of recurrences. In cardioembolic IS (atrial fibrillation, valvular diseases, prosthetic valves and myocardial infarction with mural thrombus) prevention is based on the use of oral anticoagulants. Preventive therapies for uncommon causes of IS will depend on the aetiology. In the case of cerebral venous thrombosis oral anticoagulation is effective. Conclusions: We conclude with recommendations for clinical practice in prevention of IS according to the aetiological subtype presented by the patient. Resumen: Fundamento y objetivo: Actualizar las guías terapéuticas del Comité ad hoc del Grupo de Estudio de Enfermedades Cerebrovasculares de la SEN en el tratamiento preventivo de ictus isquémico (II) y ataque isquémico transitorio (AIT). Métodos: Revisión de evidencias disponibles sobre la prevención del ictus isquémico y AIT en función del subtipo etiológico. Los niveles de evidencia y grados de recomendación se han basado en la clasificación del Centro de Medicina Basada en la Evidencia. Resultados: En el II de origen aterotrombótico reducen el riesgo de recurrencias el tratamiento antiagregante y los procedimientos revascularizadores en casos seleccionados de estenosis carotidea ipsilateral (70-99%). La prevención de II de origen cardioembólico (fibrilación auricular, valulopatías, prótesis valvulares y en infarto de miocardio con trombo mural) se basa en el uso de anticoagulantes orales. En el II de origen inhabitual, las terapias preventivas dependerán dela etiología; en la trombosis venosa cerebral la anticoagulación oral es eficaz. Conclusiones: Se concluye con recomendaciones de práctica clínica en prevención de ictus isquémico y AIT adaptadas al subtipo etiológico de II que ha presentado el paciente. Keywords: Guidelines, Ischaemic stroke, Transient ischemic attack, Prevention, Palabras clave: Guía de práctica clínica, Ictus isquémico, Ataque isquémico transitorio, Prevención

Introduction: Update of Acute Ischaemic Stroke Treatment Guidelines of the Spanish Neurological Society based on a critical review of the literature. Recommendations are made based on levels of evidence from published data and studies. Development: Organised systems of care should be implemented to ensure access to the optimal management of all acute stroke patients in stroke units. Standard of care should include treatment of blood pressure (should only be treated if values are over 185/105 mmHg), treatment of hyperglycaemia over 155 mg/dl, and treatment of body temperature with antipyretic drugs if it rises above 37.5 °C. Neurological and systemic complications must be prevented and promptly treated. Decompressive hemicraniectomy should be considered in cases of malignant cerebral oedema. Intravenous thrombolysis with rtPA should be administered within 4.5 hours from symptom onset, except when there are contraindications. Intra-arterial pharmacological thrombolysis can be considered within 6 hours, and mechanical thrombectomy within 8 hours from onset, for anterior circulation strokes, while a wider window of opportunity up to 12–24 hours is feasible for posterior strokes. There is not enough evidence to recommend routine use of the so-called neuroprotective drugs. Anticoagulation should be administered to patients with cerebral vein thrombosis. Rehabilitation should be started as early as possible. Conclusion: Treatment of acute ischaemic stroke includes management of patients in stroke units. Systemic thrombolysis should be considered within 4.5 hours from symptom onset. Intra-arterial approaches with a wider window of opportunity can be an option in certain cases. Protective and restorative therapies are being investigated. Resumen: Introducción: Actualización de la guía para el tratamiento del infarto cerebral agudo de la Sociedad Española de Neurología basada en la revisión y análisis de la bibliografía existente sobre el tema. Se establecen recomendaciones en base al nivel de evidencia que ofrecen los estudios revisados. Desarrollo: Los sistemas de asistencia urgente extrahospitalaria se organizarán para asegurar la atención especializada de los pacientes y el ingreso en unidades de ictus (UI). Deben aplicarse cuidados generales para mantener la homeostasis (tratar la tensión arterial sistólica > 185 mmHg o diastólica > 105 mmHg, evitar hiperglucemia > 155 mg/dl y controlar la temperatura, tratando con antitérmicos cifras > 37,5 °C), y prevenir y tratar las complicaciones. La craniectomía descompresiva debe ser considerada en casos seleccionados de oedema cerebral maligno. La trombólisis intravenosa con rtPA se administrará en las primeras 4,5 horas en pacientes sin contraindicación. La trombólisis intraarterial farmacológica puede indicarse en las primeras 6 horas de evolución y la trombectomía mecánica hasta las 8 horas. En el territorio posterior la ventana puede ampliarse hasta 12–24 horas. No hay evidencias para recomendar el uso rutinario de los fármacos denominados neuroprotectores. Se recomienda la anticoagulación en pacientes con trombosis de senos venosos. Se aconseja el inicio precoz de rehabilitación. Conclusiones: El tratamiento del infarto cerebral se basa en la atención especializada en UI, la aplicación urgente de cuidados generales y el tratamiento trombolítico intravenoso en las primeras 4,5 horas. La recanalización intraarterial farmacológica o mecánica pueden ser útiles en casos seleccionados. Terapias de protección y reparación cerebral están en desarrollo. Keywords: Cerebral infarct, Ischaemic stroke, Thrombolysis, Brain protection, Stroke units, Cerebral venous thrombosis, Palabras clave: Infarto cerebral, Ictus isquémico, Trombólisis, Cerebroprotección, Unidades de ictus, Trombosis venosa cerebral

Objective: To update the ad hoc Committee of the Cerebrovascular Diseases Study Group of The Spanish Neurological Society guidelines on prevention of ischaemic stroke (IS) and transient ischaemic attack (TIA). Methods: We reviewed available evidence on risk factors and means of modifying them to prevent IS and TIA. Levels of evidence and recommendation grades are based on the classification of the Centre for Evidence-Based Medicine. Results: This first section summarises the recommendations for action on the following factors: blood pressure, diabetes, lipids, tobacco and alcohol consumption, diet and physical activity, cardio-embolic diseases, asymptomatic carotid stenosis, hormone replacement therapy (HRT) and contraceptives, hyperhomocysteinemia, prothrombotic states and sleep apnea syndrome. Conclusions: Changes in lifestyle and pharmacological treatment for hypertension, diabetes mellitus and dyslipidemia, according to criteria of primary and secondary prevention, are recommended for preventing IS. Resumen: Objetivo: Actualizar las guías terapéuticas del Comité ad hoc del Grupo de Estudio de Enfermedades Cerebrovasculares de la SEN en el tratamiento preventivo de ictus isquémico (II) y ataque isquémico transitorio (AIT). Métodos: Revisión de evidencias disponibles sobre los factores de riesgo y la oportunidad de su modificación para prevenir el ictus isquémico y AIT. Los niveles de evidencia y grados de recomendación se han basado en la clasificación del Centro de Medicina Basada en la Evidencia. Resultados: En esta primera parte se resumen las recomendaciones sobre la actuación sobre los siguientes factores: presión arterial, DM, lípidos plasmáticos, consumo de tabaco y alcohol, dieta y actividad física, cardiopatías embolígenas, estenosis carotídea asintomática, terapia hormonal sustitutiva y anticonceptivos, hiperhomocisteinemía, estados protrombóticos y síndrome de apnea del sueño. Conclusiones: La modificación de los estilos de vida y el tratamiento farmacológico de la hipertensión arterial, diabetes méllitus y dislipemia según criterios de prevención primaria y secundaria se recomiendan en la prevención de ictus isquémico. Keywords: Guidelines, Ischaemic stroke, Transient ischaemic attack, Prevention, Palabras clave: Guías de práctica clínica, Prevención de ictus, Ictus, Ataque isquémico transitorio

Background: Speed of administration conditions the effectiveness of intravenous fibrinolysis in treating acute ischaemic stroke. To reduce the risk of haemorrhagic complications, the intervention is contraindicated in certain cases, such as where the International Normalised Ratio (INR) is ≥1.7. This study aimed to determine the reliability of point-of-care INR readings (POC-INR) taken using the CoaguChek® XS portable coagulometer compared to laboratory results (L-INR). Methods: We conducted a retrospective observational study of consecutive patients admitted to our centre with acute ischaemic stroke and who were treated with intravenous fibrinolysis, over a period of 4 years. Patients’ INR was measured with a portable coagulometer and in the laboratory. Results were compared using the paired-sample t test; using L-INR results as a reference value, ROC analysis was performed to determine POC-INR with greater predictive value. Results: The study included 210 patients with a mean age of 74.3 ± 11.5 years old; 18 (8.6%) were taking vitamin K antagonist oral anticoagulants (OAC). There were no significant differences between the 2 INR measurements in the population as a whole (POC-INR–L-INR difference: 0.001 ± 0.085; P = .82). In subgroup analysis, the results coincided for patients taking OACs (0.001 ± 0.081; P = .42) and those with L-INR ≤ 1.2 (0.008 ± 0.081; P = .16). For L-INR > 1.2, however, the portable coagulometer underestimated INR (0.058 ± 0.095; P = .01). Through ROC analysis, POC-INR 1,2, CPINR infraestimó la INR (diferencia LINR-CPINR 0,058 ± 0,095; p = 0,01). Mediante análisis ROC una CPINR < 1,6 fue el punto de corte más sensible y específico para seleccionar pacientes tratables con fibrinólisis intravenosa (LINR < 1,7). Conclusiones: El CP en el código ictus tiene una buena concordancia con el laboratorio. Este estudio indica que en nuestro centro una CPINR < 1,6 es el mejor umbral para predecir una LINR< 1,7. La validación de la CPINR en cada centro es recomendable para su uso protocolizado.

Introduction: The use of oral anticoagulants in patients with a history of atrial fibrillation (AF) and intracranial haemorrhage (ICH) is controversial on account of the risk of haemorrhagic stroke recurrence. This study presents our experience regarding the safety and efficacy of percutaneous left atrial appendage closure (LAAC), an alternative to anticoagulation in these patients. Methods: We conducted a retrospective, single-centre, observational study. LAAC was performed in patients with a history of ICH and non-valvular AF. Risk of ischaemic and haemorrhagic events was estimated using the CHA2DS2-VASc and HAS-BLED scales. We recorded periprocedural complications, IHC recurrence, cerebral/systemic embolism, mortality and use of antithrombotic drugs following the procedure. Results: LAAC was performed in 9 patients (7 men, 2 women) using the AMPLATZER Amulet device in 7 cases and the AMPLATZER Cardiac Plug device in 2. Mean age was 72.7 ± 8.2 years. Time between ICH and LAAC was less than one month in 5 patients and more than one month in 4 patients. Median CHA2DS2-VASc score was 4 (interquartile range of 2.5). Median HAS-BLED score was 3 (interquartile range of 0). No periprocedural complications were recorded. All patients received single anti-platelet therapy (clopidogrel in 5 patients, aspirin in 4) after the procedure; 5 patients received this treatment for 6 months and 4 received it indefinitely. No ischaemic or haemorrhagic events were recorded during follow-up (mean duration of 15 months). Conclusions: In our series, LAAC was found to be safe and effective in patients with a history of ICH who required anticoagulation due to AF. Resumen: Introducción: El uso de anticoagulantes orales es controvertido en pacientes con antecedentes de fibrilación auricular (FA) y hemorragia intracraneal (HIC), por riesgo de recurrencia de ictus hemorrágico. Presentamos la experiencia de nuestro centro en relación con la seguridad y la eficacia del cierre percutáneo de orejuela (CPO), una alternativa a la anticoagulación en dicho contexto. Métodos: Estudio observacional, retrospectivo y unicéntrico. El CPO se realizó en pacientes con antecedentes de HIC y FA no valvular. El riesgo de eventos isquémicos y hemorrágicos se estimó usando las escalas CHA2DS2Vasc y HAS-BLED. Se registraron: complicaciones periprocedimiento, recurrencia de HIC, embolismo cerebral/sistémico, mortalidad tras el cierre y al seguimiento y uso de antitrombóticos tras el procedimiento. Resultados: El CPO se realizó en 9 pacientes (7 hombres, 2 mujeres). Se utilizó en 7 casos el dispositivo Amplatzer Amulet y en 2 el Amplatzer Cardiac Plug. La media de edad fue 72,7 ± 8,2 años. El tiempo entre la HIC y el CPO fue menor de un mes en 5 pacientes y mayor en 4. La mediana y el rango intercuartil para la escala CHA2DS2Vasc fueron de 4 y 2,5, respectivamente, siendo de 3 y 0 para la escala HAS-BLED. No hubo complicaciones periprocedimiento. Todos recibieron antiagregación simple tras el procedimiento (5 clopidogrel y 4 aspirina); en 5 se mantuvo 6 meses, en 4 indefinidamente. Durante el seguimiento (15 meses de promedio) no se registraron eventos isquémicos ni hemorrágicos. Conclusiones: En nuestra serie, el CPO supone una alternativa segura y eficaz en pacientes que han presentado HIC y que precisan ser anticoagulados por FA. Keywords: Left atrial appendage closure, Atrial fibrillation, Intracranial haemorrhage, Oral anticoagulation, Palabras clave: Cierre percutáneo de orejuela, Fibrilación auricular, Hemorragia intracraneal, Anticoagulación oral

Intracerebral haemorrhage accounts for 10% to 15% of all strokes, however it has a poor prognosis with higher rates of morbidity and mortality. Neurological deterioration is often observed during the first hours from onset, and determines the poor prognosis. Intracerebral haemorrhage, therefore, is a neurological emergency which must be diagnosed and treated properly as soon as possible. In this guide we review the diagnostic procedures and factors that influence the prognosis of patients with intracerebral haemorrhage and we establish recommendations for the therapeutic strategy, systematic diagnosis, acute treatment and secondary prevention for this condition. Resumen: La hemorragia intracerebral sólo representa entre el 10 y el 15% de todos los ictus, sin embargo condiciona un peor pronóstico, con unas tasas más elevadas de morbilidad y mortalidad. Es frecuente que durante las primeras horas tras el inicio de los síntomas se produzca un empeoramiento clínico, lo cual condiciona un peor pronóstico, por lo que la hemorragia intracerebral constituye una emergencia neurológica en la que debe realizarse un diagnóstico y tratamiento adecuado de manera precoz. En esta guía realizamos una revisión de los procedimientos diagnósticos y los factores que influyen en el pronóstico de los pacientes con hemorragia intracerebral y establecemos unas recomendaciones para la estrategia asistencial, sistemática diagnóstica, tratamiento en fase aguda y prevención secundaria en la hemorragia intracerebral. Keywords: Intracerebral haemorrhage, Guidelines, Stroke, Palabras clave: Hemorragia intracerebral, Guías, Ictus

Introduction: The management of antithrombotic therapy after intracerebral haemorrhage (ICH) in anticoagulated patients is not well defined. We analysed the risks and benefits of antiplatelet therapy (AG) against the resumption of anticoagulation with vitamin K antagonists (AVK) in a series of patients. Material and methods: Retrospective study of ICH in anticoagulated patients was done. We registered demographic data, history of hypertension (HT), time of follow-up and new cerebral vascular events (ICH, stroke [IC]). Results: We evaluated 88 patients, mean age 69 ± 9 years, 50% men, 73% hypertensive. During the acute phase 18 patients died and the follow-up was lost in 31. Of the remaining (n = 39), AVKs were resumed in 25 and changed to AG in 14. Comparing the characteristics of both groups, the anticoagulated group was younger (P = .005) and the embolic sources were more often of higher risk (P = .003). After an average follow-up of 54 ± 31 months, the distribution of events was: IC (AVKs 8%, AG 14.3%, P = .6), ICH (AVKs 24%, AG 7.1%, P = .38), IC or ICH (AVKs 32%, AG 21.4%, P = .48) and death (AVKs 29%, AG 7.1%, P = .21). This trend of increased risk of new events in patients with AVKs was confirmed by Kaplan–Meier curves, although without statistical differences. Conclusions: Restarting AVK treatment after ICH in anticoagulated patients could increase the risk of new bleeding events and mortality. Prospective studies are needed to define a better and appropriate antithrombotic therapy after ICH related with anticoagulation. Resumen: Introducción: El manejo del tratamiento antitrombótico tras una hemorragia intracerebral (HIC) en pacientes anticoagulados no está bien definido. Analizamos los riesgos y beneficios de la antiagregación (AG) frente al reinicio de la anticoagulación con antagonistas de la vitamina K (AVK) en una serie de pacientes. Material-métodos: Estudio retrospectivo de HIC en pacientes anticoagulados. Se registraron datos demográficos, antecedentes de hipertensión arterial, tiempo de seguimiento y nuevo evento vascular cerebral (HIC, infarto cerebral [IC]). Resultados: Se evaluó a 88 pacientes, de edad media 69 ± 9 años, 50% varones, 73% hipertensos. Durante la fase aguda fallecieron 18 pacientes y el seguimiento se perdió en 31. De los restantes (n = 39), se reinició AVK en 25 y se cambió a AG en 14. Comparando las características de ambos grupos, el grupo anticoagulado era de menor edad (p = 0,005) y las fuentes cardioembólicas eran con mayor frecuencia de alto riesgo (p = 0,003). Tras un seguimiento promedio de 54 ± 31 meses, la distribución de eventos fue: IC (grupo AVK 8%, grupo AG 14,3%, p = 0,6); HIC (AVK 24%, AG 7.1%, p = 0,38); IC o HIC (AVK 32%, AG 21,4%, p = 0,48); muerte (AVK 29%, AG 7,1%, p = 0,21). Esta tendencia de mayor riesgo de nuevos eventos en pacientes con AVK se confirmó mediante curvas de Kaplan-Meier, aunque sin significación estadística. Conclusiones: El reinicio del tratamiento con AVK tras una HIC en pacientes anticoagulados podría aumentar el riesgo de nuevos eventos hemorrágicos y la mortalidad. Son necesarios estudios prospectivos, para definir mejor el tratamiento antitrombótico idóneo tras una HIC relacionada con la anticoagulación. Keywords: Cerebral haemorrhage, Anticoagulation, Vitamin K antagonists, Antiplatelet treatment, Palabras clave: Hemorragia cerebral, Anticoagulación, Antagonistas de la vitamina K

Background: CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is characterized by recurrent cerebral ischemic episodes of the lacunar subtype usually without traditional vascular risk factors. We investigated the frequency of CADASIL among selected patients with cerebral ischemia of the lacunar subtype. Methods: We studied patients under 65 years old who presented cerebral ischemia of the lacunar subtype without hypertension, diabetes mellitus or other causes that explained the cerebral ischemia. On the skin biopsies, we performed immunostaining analysis on 5μm frozen sections with monoclonal antibody anti-Notch 3 (1E4). We also performed a genetic analysis of the Notch 3 gene (exons 3,4,5,6,11 and 19). Results: Of 1.519 patients analyzed, only 57 (3.7%) fulfilled the selection criteria, and 30 of them accepted to participated in the study. We studied 30 patients, mean age was 53 years (range 34 to 65), 50% were men and all patients suffered a lacunar stroke. Immunostaining analysis was positive in two patients (6.6%) and the genetic analysis confirmed a mutation characteristic of CADASIL in exon 4 nt 622C/T (Arg 182 Cys) and 694 T/C (Cys206Arg) respectively. Conclusions: CADASIL disease was present in 6.6% of patients younger than 65 years with a lacunar stroke and without hypertension or diabetes mellitus. Screening for CADASIL should be considered in these patients. Resumen: Introducción: La enfermedad de CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) se caracteriza por isquemias cerebrales recurrentes de tipo lacunar, habitualmente en pacientes sin factores de riesgo vascular. Analizamos la frecuencia de enfermedad de CADASIL en pacientes con infarto lacunar sin factores de riesgo vascular clásicos. Métodos: Estudiamos pacientes con un primer infarto lacunar menores de 65 años sin hipertensión, diabetes mellitus u otra causa que justificara la isquemia cerebral. Realizamos estudio inmunohistoquímico de 5μm de espesor sobre biopsia cutánea usando el anticuerpo monoclonal anti-Notch 3 (1E4). Además del estudio inmunohistoquímico se realizó en todos los casos el estudio genético del gen Notch 3 de los exones 3, 4, 5, 6, 11 y 19. Resultados: De 1.519 pacientes con infarto lacunar, sólo 57 (3,7%) cumplieron los criterios de selección, y 30 de ellos aceptaron participar en el estudio. Analizamos 30 pacientes con edad media de 53 años; el 50% fueron hombres y todos presentaron un primer infarto cerebral tipo lacunar. El estudio inmunohistoquímico y genético confirmó la enfermedad de CADASIL en dos pacientes (6,6%) en el exón 4 nt 622C/T(Arg 182 Cys) y 694 T/C(Cys206Arg) respectivamente. Conclusiones: Detectamos la enfermedad de CADASIL en un 6,6% de los pacientes menores de 65 años con un primer infarto lacunar sin hipertensión ni diabetes mellitus. El despistaje de esta enfermedad debería de ser considerado en estos casos. Keywords: CADASIL, Lacunar infarct, Stroke, Notch 3 gen, Scheltens scale, Cerebral infarct, Palabras clave: CADASIL, Infarto lacunar, Rictus, Gen Notch 3, Escala de Scheltens, Infarto cerebral

Background: Cerebral edema (CED) is associated with poorer outcome in patients with acute ischemic stroke (AIS). The aim of the study was to investigate the factors contributing to greater early CED formation in patients with AIS who underwent endovascular therapy (EVT) and its association with functional outcome., Methods: We conducted a multicenter cohort study of patients with an anterior circulation AIS undergoing EVT. The volume of cerebrospinal fluid (CSF) was extracted from baseline and 24-hour follow-up CT using an automated algorithm. The severity of CED was quantified by the percentage reduction in CSF volume between CT scans (∆CSF). The primary endpoint was a shift towards an unfavorable outcome, assessed by modified Rankin Scale (mRS) score at 3 months. Multivariable ordinal logistic regression analyses were performed. The ∆CSF threshold that predicted unfavorable outcome was selected using receiver operating characteristic curve analysis., Results: We analyzed 201 patients (mean age 72.7 years, 47.8% women) in whom CED was assessable for 85.6%. Higher systolic blood pressure during EVT and failure to achieve modified Thrombolysis In Cerebral Infarction (mTICI) 3 were found to be independent predictors of greater CED. ∆CSF was independently associated with the probability of a one-point worsening in the mRS score (common odds ratio (cOR) 1.05, 95% CI 1.03 to 1.08) after adjusting for age, baseline mRS, National Institutes of Health Stroke Scale (NIHSS), and number of passes. Displacement of more than 25% of CSF was associated with an unfavorable outcome (OR 6.09, 95% CI 3.01 to 12.33) and mortality (OR 6.72, 95% CI 2.94 to 15.32)., Conclusions: Early CED formation in patients undergoing EVT was affected by higher blood pressure and incomplete reperfusion. The extent of early CED, measured by automated ∆CSF, was associated with worse outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Ischemic stroke (IS) risk heritability is partly explained by genetics. Other heritable factors, such as epigenetics, could explain an unknown proportion of the IS risk. The objective of this study is to evaluate DNA methylation association with IS using epigenome-wide association studies (EWAS)., Methods:  We performed a two-stage EWAS comprising 1,156 subjects. Differentially methylated positions (DMPs) and differentially methylated regions (DMRs) were assessed using the Infinium 450K and EPIC BeadChip in the discovery cohort (252 IS and 43 controls). Significant DMPs were replicated in an independent cohort (618 IS and 243 controls). Stroke subtype associations were also evaluated. Differentially methylated cell-type (DMCT) was analyzed in the replicated CpG sites using EpiDISH. We additionally performed pathway enrichment analysis and causality analysis with Mendelian randomization for the replicated CpG sites., Results:  A total of 957 CpG sites were epigenome-wide-significant ( p ≤ 10 -7 ) in the discovery cohort, being CpG sites in the top signals (logFC = 0.058, p  = 2.35 × 10 -22 ; logFC = 0.035, p  = 3.22 × 10 -22 , respectively). ZFHX3 and MAP3K1 were among the most significant DMRs. In addition, 697 CpG sites were replicated considering Bonferroni-corrected p -values ( p  < 5.22 × 10 -5 ). All the replicated DMPs were associated with risk of cardioembolic, atherothrombotic, and undetermined stroke. The DMCT analysis demonstrated that the significant associations were driven by natural killer cells. The pathway enrichment analysis showed overrepresentation of genes belonging to certain pathways including oxidative stress. ZFHX3 and MAP3K1 methylation was causally associated with specific stroke-subtype risk., Conclusion:  Specific DNA methylation pattern is causally associated with IS risk. These results could be useful for specifically predicting stroke occurrence and could potentially be evaluated as therapeutic targets., Competing Interests: None declared., (Thieme. All rights reserved.)

Background and Purpose: The neurological course after stroke is highly variable and is determined by demographic, clinical and genetic factors. However, other heritable factors such as epigenetic DNA methylation could play a role in neurological changes after stroke., Methods: We performed a three-stage epigenome-wide association study to evaluate DNA methylation associated with the difference between the National Institutes of Health Stroke Scale (NIHSS) at baseline and at discharge (ΔNIHSS) in ischaemic stroke patients. DNA methylation data in the Discovery (n = 643) and Replication (n = 62) Cohorts were interrogated with the 450 K and EPIC BeadChip. Nominal CpG sites from the Discovery (p value < 10 -06 ) were also evaluated in a meta-analysis of the Discovery and Replication cohorts, using a random-fixed effect model. Metabolic pathway enrichment was calculated with methylGSA. We integrated the methylation data with 1305 plasma protein expression levels measured by SOMAscan in 46 subjects and measured RNA expression with RT-PCR in a subgroup of 13 subjects. Specific cell-type methylation was assessed using EpiDISH., Results: The meta-analysis revealed an epigenome-wide significant association in EXOC4 (p value = 8.4 × 10 -08 ) and in MERTK (p value = 1.56 × 10 -07 ). Only the methylation in EXOC4 was also associated in the Discovery and in the Replication Cohorts (p value = 1.14 × 10 -06 and p value = 1.3 × 10 -02 , respectively). EXOC4 methylation negatively correlated with the long-term outcome (coefficient = - 4.91) and showed a tendency towards a decrease in EXOC4 expression (rho = - 0.469, p value = 0.091). Pathway enrichment from the meta-analysis revealed significant associations related to the endocytosis and deubiquitination processes. Seventy-nine plasma proteins were differentially expressed in association with EXOC4 methylation. Pathway analysis of these proteins showed an enrichment in natural killer (NK) cell activation. The cell-type methylation analysis in blood also revealed a differential methylation in NK cells., Conclusions: DNA methylation of EXOC4 is associated with a worse neurological course after stroke. The results indicate a potential modulation of pathways involving endocytosis and NK cells regulation., (© 2022. The Author(s).)

Background and Purpose: The minor stroke concept has not been analyzed in intracerebral hemorrhage (ICH) patients. Our purpose was to determine the optimal cut point on the NIH Stroke Scale (NIHSS) for defining a minor ICH (mICH) in patients with primary ICH., Methods: An ICH was considered minor if associated with a favorable 3-month outcome (modified Rankin Scale score ≤2). For supratentorial ICH, the discovery cohort consisted of 478 patients prospectively admitted at University Hospital del Mar. Association between NIHSS at admission and 3-month outcome was evaluated with area under the curve-receiver operating characteristics (AUC-ROC) and Youden's index to identify the optimal NIHSS cutoff point to define mICH. External validation was performed in a cohort of 242 supratentorial ICH patients from University Hospital Sant Pau. For infratentorial location, patients from both hospitals (n = 85) were analyzed together., Results: The best -NIHSS cutoff point defining supratentorial-mICH was 6 (AUC-ROC = 0.815 [0.774-0.857] in the discovery cohort and AUC-ROC = 0.819 [0.756-0.882] in the external validation cohort). For infratentorial ICH, the best cutoff point was 4 (AUC-ROC = 0.771 [0.664-0.877]). Using these cutoff points, 40.5% of all primary ICH cases were mICH. Of these, 70.2% were living independently at 3-month follow-up (72% for supratentorial ICH and 56.1% for infratentorial ICH) and 6.5% had died (5.3% for supratentorial ICH, and 14.6% for infratentorial ICH). For patients identified as non-mICH, good 3-month outcome was observed in 11.3% of cases; mortality was 51%., Conclusions: The definition of mICH using the NIHSS cutoff point of 6 for supratentorial ICH and 4 for infratentorial ICH is useful to identify good outcome in ICH patients., (© 2021 S. Karger AG, Basel.)

The main objective of this research work was to study the association of serum levels of growth factors (GF) and SDF-1α with the functional outcome and reduction of lesion volume in ischemic stroke patients. In this multicenter study, 552 patients with non-lacunar stroke (male, 62.1%; mean age, 68.2 ± 11.4) were included within 24 h from symptom onset. The main outcome variable was good functional outcome (modified Rankin Scale [mRS] ≤ 2) at 12 months. Secondary outcome variable was infarct volume (in mL) after 6 ± 3 months. Serum levels of VEGF, Ang-1, G-CSF, BDNF, and SDF-1α were measured by ELISA at admission, 7 ± 1 days, at 3 ± 1 months, and 12 ± 3 months. Except for BDNF, all GF and SDF-1α serum levels showed a peak value at day 7 and remained elevated during the first 3 months (all p < 0.01). High serum levels at day 7 of VEGF (OR, 19.3), Ang-1 (OR, 14.7), G-CSF (OR, 9.6), and SDF-1α (OR, 28.5) were independently associated with good outcome at 12 months (all p < 0.0001). On the other hand, serum levels of VEGF (B, - 21.4), G-CSF (B, - 14.0), Ang-1 (B, - 13.3), and SDF-1α (B, - 44.6) measured at day 7 were independently associated with lesion volume at 6 months (p < 0.01). In summary, high serum levels of VEGF, Ang-1, G-CSF, and SDF-1α at day 7 and 3 months after ischemic stroke are associated with good functional outcome and smaller residual lesion at 1 year of follow-up.

Background and Purpose- Stroke Risk Analysis (SRA) comprises an algorithm for automated analysis of ECG monitoring, enabling the detection of paroxysmal atrial fibrillation (pxAF) and identifying patterns indicating a high risk of atrial fibrillation (R&#95;AF). We compared Holter-enabled continuous ECG monitoring in combination with SRA (hSRA) with standard continuous ECG monitoring for pxAF detection in patients with acute ischemic stroke. Also, we sought to identify whether the detection of R&#95;AF patterns during the first cycle (first 2 hours) of hSRA recording was associated with the detection of pxAF during the Stroke Unit stay. Methods- We enrolled 524 consecutive patients admitted in the Stroke Unit with acute ischemic stroke or transient ischemic attack with neither history of AF nor AF at admission into a prospective multicentric observational analytic clinical study with intrapatient comparison, who received both continuous ECG monitoring as well as hSRA up to 7 days. Investigators were blinded to hSRA results unless pxAF was detected on SRA. Results- Of the 524 consecutive acute stroke patients (median age, 70.0 years; 60% male; acute ischemic stroke 93%, transient ischemic attack 7%), 462 were eligible and included in the study. Among 462 patients with hSRA available for 66 hours, AF was documented by hSRA in 79 patients (17.1%). From this group, 45 AF cases (9.7%) were confirmed after review by an independent and blinded cardiologist. continuous ECG monitoring detected 21 AF cases (4.3%; P <0.0001). hSRA detected R&#95;AF patterns in 92 patients. 35 out of the 92 R&#95;AF patients showed an episode of AF during the Stroke Unit stay. Predictive values of R&#95;AF patterns within the first cycle of hSRA were: sensitivity 71%, specificity 86%, positive predictive value 38%, and negative predictive value 96%. Conclusions- Automated analysis using SRA technology strongly improves pxAF detection in acute ischemic stroke patients compared with continuous ECG monitoring. The predictive value of a R&#95;AF pattern, as detected by hSRA during the first few hours after admission, deserves further investigation.

Background: In-hospital stroke death rate is an important sanitary issue. Despite advances in the acute phase management of stroke patients, mortality and disability rates remain high. In aging populations and with different mortality between the sexes in general, the study of sex- and age-related differences becomes increasingly relevant for optimization of post-acute clinical care of stroke patients., Methods: We designed a cohort follow-up study with 13,932 consecutive ischemic stroke (IS) patients from 19 Spanish hospitals. Data was obtained from the Spanish Stroke Registry; transient ischemic attacks and ages <18 years were excluded. Patients were organised by age group and sex. We compared female and male patient cohorts within and across age groups univariately and used multivariable logistic regression to adjust for confounders in differential in-hospital mortality., Results: The median (percentiles 2.5 and 97.5%) age was 78 (41-92) years old for women and 71 (41-92) for men. IS women were more likely to be older, to exhibit cardio-embolic aetiology, and less likely to have been admitted to a stroke unit or to have had a stroke code activated. Both pre-stroke modified Rankin Scale and National Institute of Health Stroke Scale (NIHSS) scores at admission increased significantly with age and were higher in women than those in men. Differences in distributions of common risk factors for IS and of in-hospital outcomes between women and men actually changed with patient's age. It is to be noted here that although there were no statistically significant differences (p > 0.05) between the sexes within any age group, in-hospital mortality appeared significantly higher in women than that in men when analysed overall, due to confounding. Death was more closely related to stroke in women than in men and occurred earlier. Although there were some age-specific sex differences between the predictors for in-hospital mortality, stroke severity measured by NIHSS was the main predictor of in-hospital mortality for both sexes. Topographic classifications - partial anterior circulatory infarct and total anterior circulatory infarct - were significant prognostic factors for men aged <60 years and for those in the 60-69 years range respectively., Conclusion: Although most of our findings were consistent with previous studies, it is important to take into account and highlight differences in in-hospital mortality between the sex and age group. Not to account for age-related differences between the sexes can give false results that may mislead management decisions. As most deaths in women were related to stroke, it is important to improve their early management, stroke code activation, access to stroke units and/or revascularisation therapies, especially in the older age groups., (© 2019 S. Karger AG, Basel.)

Objective: To identify factors associated with poor anticoagulation control with vitaminK antagonists (VKA) among outpatients with nonvalvular atrial fibrillation (NVAF) attended in Neurology and Internal Medicine in Spain., Methods: Cross-sectional and multicenter study, from the ALADIN database, of outpatients with NVAF treated with VKA and attended in Internal Medicine and Neurology in Spain. Rates of anticoagulation control were determined with the direct and Rosendaal methods, considering data from the 6months before the inclusion., Results: Out of 1,337 patients included in the ALADIN study, 750 were taking VKA, and complete information about INR values in the last 6months was available in 383 patients. Mean scores of Charlson Index, CHADS 2 , CHA 2 DS 2 -VASc and HAS-BLED were 1.94±1.54; 3.10±1.26; 4.63±1.54, and 2.20±0.90, respectively. 46.2% and 47.0% of patients had an adequate anticoagulation control according to the direct and Rosendaal methods, respectively. Inadequate anticoagulation control according to the direct method was associated with diabetes (OR: 2.511; 95%CI: 1.144-5.659), prior labile INR (OR: 35.371; 95%CI: 15.058-83.083) and the determination of >6INR controls in the last 6months (OR: 4.747; 95%CI: 2.094-10.759), and according to the Rosendaal method, with prior labile INR (P<.001) and HAS-BLED score (OR: 3.991; 95%CI: 2.520-6.319)., Conclusions: Despite the high thromboembolic risk, only a little more than a half of patients were well controlled. Factors associated with poor anticoagulation control were diabetes, labile INR, >6INR controls and HAS-BLED., (Copyright © 2018 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.)

Background and Purpose: Vascular recurrence occurs in 11% of patients during the first year after ischemic stroke (IS) or transient ischemic attack. Clinical scores do not predict the whole vascular recurrence risk; therefore, we aimed to find genetic variants associated with recurrence that might improve the clinical predictive models in IS., Methods: We analyzed 256 polymorphisms from 115 candidate genes in 3 patient cohorts comprising 4482 IS or transient ischemic attack patients. The discovery cohort was prospectively recruited and included 1494 patients, 6.2% of them developed a new IS during the first year of follow-up. Replication analysis was performed in 2988 patients using SNPlex or HumanOmni1-Quad technology. We generated a predictive model using Cox regression (GRECOS score [Genotyping Reurrence Risk of Stroke]) and generated risk groups using a classification tree method., Results: The analyses revealed that rs1800801 in the MGP gene (hazard ratio, 1.33; P =9×10 - 03 ), a gene related to artery calcification, was associated with new IS during the first year of follow-up. This polymorphism was replicated in a Spanish cohort (n=1.305); however, it was not significantly associated in a North American cohort (n=1.683). The GRECOS score predicted new IS ( P =3.2×10 - 09 ) and could classify patients, from low risk of stroke recurrence (1.9%) to high risk (12.6%). Moreover, the addition of genetic risk factors to the GRECOS score improves the prediction compared with previous Stroke Prognosis Instrument-II score ( P =0.03)., Conclusions: The use of genetics could be useful to estimate vascular recurrence risk after IS. Genetic variability in the MGP gene was associated with vascular recurrence in the Spanish population., (© 2017 American Heart Association, Inc.)

Objective: To update the Spanish Society of Neurology's guidelines for subarachnoid haemorrhage diagnosis and treatment., Material and Methods: A review and analysis of the existing literature. Recommendations are given based on the level of evidence for each study reviewed., Results: The most common cause of spontaneous subarachnoid haemorrhage (SAH) is cerebral aneurysm rupture. Its estimated incidence in Spain is 9/100 000 inhabitants/year with a relative frequency of approximately 5% of all strokes. Hypertension and smoking are the main risk factors. Stroke patients require treatment in a specialised centre. Admission to a stroke unit should be considered for SAH patients whose initial clinical condition is good (Grades I or II on the Hunt and Hess scale). We recommend early exclusion of aneurysms from the circulation. The diagnostic study of choice for SAH is brain CT (computed tomography) without contrast. If the test is negative and SAH is still suspected, a lumbar puncture should then be performed. The diagnostic tests recommended in order to determine the source of the haemorrhage are MRI (magnetic resonance imaging) and angiography. Doppler ultrasonography studies are very useful for diagnosing and monitoring vasospasm. Nimodipine is recommended for preventing delayed cerebral ischaemia. Blood pressure treatment and neurovascular intervention may be considered in treating refractory vasospasm., Conclusions: SAH is a severe and complex disease which must be managed in specialised centres by professionals with ample experience in relevant diagnostic and therapeutic processes., (Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.)

Introduction: Uric acid is an antioxidant with neuroprotective effects in experimental models of stroke. We assessed whether uric acid therapy would improve functional outcomes at 90 days in patients with acute ischaemic stroke., Methods: URICO-ICTUS was a randomised, double-blind, placebo-controlled, phase 2b/3 trial that recruited patients with acute ischaemic stroke admitted to ten Spanish stroke centres. Patients were included if they were aged 18 years or older, had received alteplase within 4·5 h of symptom onset, and had an eligible National Institutes of Health Stroke Scale (NIHSS) score (>6 and ≤25) and premorbid (assessed by anamnesis) modified Rankin Scale (mRS) score (≤2). Patients were randomly allocated (1:1) to receive uric acid 1000 mg or placebo (both infused intravenously in 90 min during the infusion of alteplase), stratified by centre and baseline stroke severity. The primary outcome was the proportion of patients with excellent outcome (ie, an mRS score of 0-1, or 2 if premorbid score was 2) at 90 days, analysed in the target population (all randomly assigned patients who had been correctly diagnosed with ischaemic stroke and had begun study medication). The study is registered with ClinicalTrials.gov, number NCT00860366., Findings: Between July 1, 2011, and April 30, 2013, we randomly assigned 421 patients, of whom 411 (98%) were included in the target population (211 received uric acid and 200 received placebo). 83 (39%) patients who received uric acid and 66 (33%) patients who received placebo had an excellent outcome (adjusted risk ratio 1·23 [95% CI 0·96-1·56]; p=0·099). No clinically relevant or statistically significant differences were reported between groups with respect to death (28 [13%] patients who received uric acid vs 31 [16%] who received placebo), symptomatic intracerebral haemorrhage (nine [4%] vs six [3%]), and gouty arthritis (one [<1%] vs four [2%]). 516 adverse events occurred in the uric acid group and 532 in the placebo group, of which 61 (12%) and 67 (13%), respectively, were serious adverse events (p=0·703)., Interpretation: The addition of uric acid to thrombolytic therapy did not increase the proportion of patients who achieved excellent outcome after stroke compared with placebo, but it did not lead to any safety concerns., Funding: Institute of Health Carlos III of the Spanish Ministry of Health and Fundación Doctor Melchor Colet., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background and Objective: To update the ad hoc Committee of the Cerebrovascular Diseases Study Group of The Spanish Neurological Society guidelines on prevention of ischaemic stroke (IS) and Transient Ischaemic Attack (TIA)., Methods: We reviewed the available evidence on ischaemic stroke and TIA prevention according to aetiological subtype. Levels of evidence and recommendation levels are based on the classification of the Centre for Evidence-Based Medicine., Results: In atherothrombotic IS, antiplatelet therapy and revascularization procedures in selected cases of ipsilateral carotid stenosis (70%-90%) reduce the risk of recurrences. In cardioembolic IS (atrial fibrillation, valvular diseases, prosthetic valves and myocardial infarction with mural thrombus) prevention is based on the use of oral anticoagulants. Preventive therapies for uncommon causes of IS will depend on the aetiology. In the case of cerebral venous thrombosis oral anticoagulation is effective., Conclusions: We conclude with recommendations for clinical practice in prevention of IS according to the aetiological subtype presented by the patient., (Copyright © 2011 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.)

Introduction: Update of Acute Ischaemic Stroke Treatment Guidelines of the Spanish Neurological Society based on a critical review of the literature. Recommendations are made based on levels of evidence from published data and studies., Development: Organized systems of care should be implemented to ensure access to the optimal management of all acute stroke patients in stroke units. Standard of care should include treatment of blood pressure (should only be treated if values are over 185/105 mmHg), treatment of hyperglycaemia over 155 mg/dl, and treatment of body temperature with antipyretic drugs if it rises above 37.5 °C. Neurological and systemic complications must be prevented and promptly treated. Decompressive hemicraniectomy should be considered in cases of malignant cerebral oedema. Intravenous thrombolysis with rtPA should be administered within 4.5 hours from symptom onset, except when there are contraindications. Intra-arterial pharmacological thrombolysis can be considered within 6 hours, and mechanical thrombectomy within 8 hours from onset, for anterior circulation strokes, while a wider window of opportunity up to 12-24 hours is feasible for posterior strokes. There is not enough evidence to recommend routine use of the so called neuroprotective drugs. Anticoagulation should be administered to patients with cerebral vein thrombosis. Rehabilitation should be started as early as possible., Conclusion: Treatment of acute ischaemic stroke includes management of patients in stroke units. Systemic thrombolysis should be considered within 4.5 hours from symptom onset. Intra-arterial approaches with a wider window of opportunity can be an option in certain cases. Protective and restorative therapies are being investigated., (Copyright © 2011 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.)

Objective: To update the ad hoc Committee of the Cerebrovascular Diseases Study Group of The Spanish Neurological Society guidelines on prevention of ischaemic stroke (IS) and transient ischaemic attack (TIA)., Methods: We reviewed available evidence on risk factors and means of modifying them to prevent ischaemic stroke and TIA. Levels of evidence and recommendation grades are based on the classification of the Centre for Evidence-Based Medicine., Results: This first section summarises the recommendations for action on the following factors: blood pressure, diabetes, lipids, tobacco and alcohol consumption, diet and physical activity, cardio-embolic diseases, asymptomatic carotid stenosis, hormone replacement therapy and contraceptives, hyperhomocysteinemia, prothrombotic states and sleep apnea syndrome., Conclusions: Changes in lifestyle and pharmacological treatment for hypertension, diabetes mellitus and dyslipidemia, according to criteria of primary and secondary prevention, are recommended for preventing ischemic stroke., (© 2011 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.)

Objective: Wide interindividual variability exists in response to tissue plasminogen activator (t-PA) treatment in the acute phase of ischemic stroke. We aimed to find genetic variations associated with hemorrhagic transformation (HT) and mortality rates after t-PA. We then generated a clinical-genetic model for predicting t-PA response., Methods: Our prospective study used SNPlex to genotype 140 single nucleotide polymorphisms (SNPs) from 97 candidate genes in 3 patient cohorts. The cohorts included 1,172 patients who were treated with t-PA; 20.9% of them developed HT as evaluated by systematic brain computed tomography scan, and 10.6% died. A predictive model was generated by logistic regression (LR). Functional studies included real time quantitative polymerase chain reaction, nephelometry, and Western blot for alpha-2-macroglobulin (A2M) and activated partial thromboplastin time measurement for coagulation factor XII (FXII)., Results: Replication analysis revealed that the SNP rs669 (Val1000Ile) in A2M was associated with HT, and rs1801020 (-4C>T) of F12 was associated with in-hospital death. The rs669 SNP withstood Bonferroni correction for HT (p < 3.57E-4). LR-based scores predicted HT occurrence (p = 9.13E-15) and in-hospital mortality (p = 8.7E-9) and were validated in an independent cohort. Val1000Ile modified A2M serum levels at baseline and after t-PA infusion, but not mRNA expression or protein structure; -4C>T affected FXII activity both prior to and after t-PA treatment., Interpretation: Two functional polymorphisms were consistently associated with t-PA safety. Our validated LR-based score predicts t-PA safety in the Spanish population., (Copyright © 2012 American Neurological Association.)

Background and Purpose: There is a great interindividual variability among patients with acute ischemic stroke regarding the response to intravenous tissue-type plasminogen activator treatment. The aim of this study was to identify genetic variants associated with recanalization, and thus treatment efficacy, after tissue-type plasminogen activator administration., Methods: A total of 140 single nucleotide polymorphisms from 97 candidate genes were successfully genotyped by SNPlex in 2 cohorts, accounting for 497 prospectively recruited tissue-type plasminogen activator-treated patients, of whom 33% recanalized during tissue-type plasminogen activator infusion. Functional studies were then performed, including assessment of interleukin 1B mRNA levels and von Willebrand factor, FIII, FVII, FVIII, and FX protein activity., Results: After replication, the following single nucleotide polymorphisms were associated with early recanalization: rs1143627 in IL1B gene (CC: 53.1% of recanalization, A-carriers: 32.7%; P=0.022; replication cohort: P=0.046), rs16944 in IL1B gene (AA: 50% of recanalization, G-carriers: 32%; P=0.038; replication cohort: P=0.049), and rs1063856 in the vWF gene (GG: 53.8% of recanalization, A-carriers: 31.5%; P=0.006; replication cohort: P=0.046). The functional studies revealed an association between the rs1063856 single nucleotide polymorphisms in vWF and FVIII activity (AA: 115.93%, AG: 156.07%, GG: 83.42%; P=0.005)., Conclusions: Three single nucleotide polymorphisms were associated with tissue-type plasminogen activator efficacy in the Spanish population, and their mechanism of action might be associated with the activity of coagulation factors.

Background and Purpose: Despite the benefits of tissue-type plasminogen activator treatment, some stroke patients experience adverse hemorrhagic transformations (HT). Plasma protein levels of MMP9 have been associated with HT occurrence. We aimed to analyze the association of the MMP9 gene with HT occurrence., Methods: We analyzed the MMP9 gene in blood samples from 885 stroke patients treated with tissue-type plasminogen activator by tag-SNP, imputed SNP, direct sequencing, and RNA expression., Results: We did not observe any significant association between MMP9 genetic variations or MMP9 expression and HT occurrence. Moreover, no association was found between MMP9 expression and MMP9 polymorphisms., Conclusions: Genetic variations in the MMP9 gene are not associated with HT occurrence in tissue-type plasminogen activator-treated patients.

Background: in-hospital strokes (IHS) are relatively frequent. Avoidable delays in neurological assessment have been demonstrated. We study the clinical characteristics, neurological care and mortality of IHS., Methods: multi-centre 1-year prospective study of IHS in 13 hospitals. Demographic and clinical characteristics, admission diagnosis, quality of care, thrombolytic therapy and mortality were recorded., Results: we included 273 IHS patients [156 men; 210 ischaemic strokes (IS), 37 transient ischaemic attacks (TIA) and 26 cerebral haemorrhages]. Mean age was 72 ± 12 years. Cardiac sources of embolism were present in 138 (50.5%), withdrawal of antithrombotic drugs in 77 (28%) and active cancers in 35 (12.8%). Cardioembolic stroke was the most common subtype of IS (50%). Reasons for admission were programmed or urgent surgery in 70 (25%), cardiac diseases in 50 (18%), TIA or stroke in 30 (11%) and other medical illnesses in 71 (26%). Fifty-two per cent of patients were evaluated by a neurologist within 3 h of stroke onset. Thirty-three patients received treatment with tPA (15.7%). Thirty-one patients (14.7%) could not be treated because of a delay in contacting the neurologist. During hospitalization, 50 patients (18.4%) died, 41 of them because of the stroke or its complications., Conclusions: cardioembolic IS was the most frequent subtype of stroke. Cardiac sources of embolism, active cancers and withdrawal of antithrombotic drugs constituted special risk factors for IHS. A significant proportion of patients were treated with thrombolysis. However, delays in contacting the neurologist excluded a similar proportion of patients from treatment. IHS mortality was high, mostly because of stroke.

Background: Ischaemic stroke (IS) is a complex disease that involves genetic and environmental factors. The role of factor XI (FXI) in arterial thrombosis is unclear. We have investigated the risk of IS related to FXI levels in a case-control study., Methods: We studied 445 individuals: 218 diagnosed with IS and 227 age-gender-ethnic matched control subjects. We measured factor VIIIc, fibrinogen and factor XIc levels. FXI < 144% was taken as the reference group in the statistical analysis., Results: There were 104 women and 114 men in the IS group and 108 women and 119 men in the control group. The crude odds ratio (OR) of IS in dyslipidaemic patients with high levels of FXI was 4.2 [95% confidence interval (CI): 1.2-14.8] compared with dyslipidaemic controls and low levels of FXI, but the OR in the non-dyslipidaemic with high levels of FXI subgroup was 1.2 (95% CI: 0.4-3.2). The adjusted OR of IS in dyslipidaemic patients with high levels of FXI was 6.4 (95% CI: 1.6-26.1) compared with dyslipidaemic controls, but the OR in non-dyslipidaemic subgroup with high levels of FXI was 0.6 (95% CI: 0.2-2.1)., Conclusion: We found almost a sixfold higher risk of IS in patients with dyslipidaemia and high levels of FXI. Further studies should elucidate the role of FXI in IS and therapeutic approaches should become apparent for patients with dyslipidaemia and high-FXI plasma levels.

Background and Purpose: Ischemic stroke (IS) is a complex disease that involves genetic and environmental factors. In a family-based study (the Genetic Analysis of Idiopathic Thrombophilia [GAIT] Project) that included a genome-wide scan, we demonstrated that a common polymorphism (46 C-->T) in the exon 1 of the F12 gene jointly influences variability of plasma Factor XII levels and susceptibility to thrombotic disease. We have investigated the risk of IS related to this polymorphism in a case-control study., Methods: We studied 436 individuals: 205 diagnosed with IS and 231 age-gender-ethnic control subjects. We measured Factor VIIIc, fibrinogen, and Factor XIIc levels, and we genotyped the 46 C-->T polymorphism in the F12 gene., Results: There were 91 women and 114 men in the IS group and 109 women and 122 men in the control group. We confirmed our previous observation that individuals with different genotypes for the 46 C-->T polymorphism showed significant differences in Factor XIIc levels. Most importantly, the mutated T allele in the homozygous state (genotype T/T) was associated with an increased risk of IS with an adjusted odds ratio of 4.1 (95% CI, 1.1 to 15.9)., Conclusions: This study suggests that the 46 C-->T polymorphism is a genetic risk factor for IS in the Spanish population. In addition, our results confirm that the use of genetic linkage studies along with a case-control association study is an extremely valuable approach for identifying DNA variants that affect complex diseases.

Background and Purpose: Recently, a novel procarboxypeptidase B-like proenzyme, called thrombin-activatable fibrinolysis inhibitor (TAFI), has been described. It plays an important role in the delicate balance between coagulation and fibrinolysis. TAFI leads to potent inhibition of tissue plasminogen activator-induced fibrinolysis. The relevance of TAFI in thromboembolic disease is unclear. We have investigated the risk of ischemic stroke (IS) in relation to plasma levels of functional TAFI., Methods: In a case-control study, we enrolled 264 individuals; 114 had IS, and 150 were recruited as controls who were age and sex matched and had no history of arterial disease. The individuals supplied information on their personal and family histories of cardiovascular diseases and conventional cardiovascular risk factors. Functional TAFI assays were performed by use of a method based on the activation of TAFI with thrombin-thrombomodulin and the measure of the TAFI activity generated. Other hemostatic parameters assayed were factor VIIIc, anti-phospholipid antibodies,fibrinogen, factor V Leiden, and the prothrombin gene G20210A mutations (PT20210A)., Results: Functional TAFI levels were significantly higher in patients with IS (113.7+/-25%; range, 57% to 209%) than in controls (102.6+/-19%). The odds ratio for IS in patients with functional TAFI levels >120% was 5.7 (95% confidence interval, 2.3 to 14.1)., Conclusions: We found that functional TAFI levels in plasma (>120%) increased the risk of IS approximately 6-fold. Further studies should elucidate the physiological role of TAFI in arterial disease and possibly provide clues to therapeutic approaches.

Objective: To evaluate the presence of thallium-201 brain uptake determined by thallium-201 brain SPECT (Tl-201 SPECT) in patients with progressive multifocal leukoencephalopathy (PML) and AIDS., Material and Methods: Six AIDS patients with stereotactic biopsy diagnosis of PML were prospectively evaluated with Tl-201 SPECT, Magnetic Resonance Imaging (MRI), and proton magnetic resonance spectroscopy (1H-MRS). Tl-201 SPECT results were compared with 2 patients with AIDS and biopsy proven primary CNS lymphoma., Results: In all patients with PML, Tl-201 SPECT studies showed lack of uptake while MRI demonstrated subcortical white matter focal brain lesions and 1H-MRS disclosed metabolic abnormalities. Intense thallium uptake (uptake ratios of 3.2 and 5.6) was demonstrated in the 2 patients with primary CNS lymphoma., Conclusions: The present study shows that PML lesions are not detectable on Tl-201 SPECT while MRI and 1H-MRS demonstrate abnormalities, and intense thallium-201 uptake may be detected in primary CNS lymphoma. These results suggest that Tl-201 SPECT is a method which, combined with other non-invasive techniques such as MRI and 1H-MRS, may help in the diagnostic approach of PML and to differentiate PML from other high proliferative brain lesions characterized by positive thallium uptake.