Josep Lluís Martí-Vilalta

Almost perfect concordance between simultaneous transcranial Doppler and transesophageal echocardiography in the quantification of right-to-left shunts.

Background and Purpose. Transesophageal echocardiography (TEE) and transcranial Doppler (TCD) are the methods of choice to study patent foramen ovale (PFO), but there are discrepancies between the 2 concerning PFO detection. No study has analyzed right‐to‐left shunt (RLS) quantification concordance. The 2 methods are carried out in different hemodynamic states, and the Valsalva maneuver (VM) required in each also differs. The authors compared PFO detection and concordance of RLS quantification classifications performing the 2 studies simultaneously. Methods. The authors prospectively included consecutive stroke patients undergoing TEE and applied the TCD protocol of the Consensus Conference. Echocardiographic PFO was diagnosed when at least 3 microbubbles (MBs) were detected in the left atrium within 3 heartbeats after opacification of the right atrium. RLS quantification was (1) TCD: minimum (1‐10 MBs), moderate (11‐25 MBs), and massive (>25 MBs) and (2) TEE: small (3‐10 MBs), moderate (11‐30 MBs), and large (>30 MBs). Statistics: contingency tables (χ2 and K test). Results. The authors studied 110 patients whose mean age was 56.7 ± 12.1 years, and 60.9% were men. PFO was detected at the first VM in 30% of patients with TCD and in 31.8% with TEE. At the second VM, both methods detected the same patients (32.7%). RLS was minimum (14), moderate (5), and massive (17) in TCD and small (13), moderate (3), and large (20) in TEE. There was an almost perfect concordance in RLS quantification (K = 0.928, P= .001), with only 4 discrepancies. Conclusions. Simultaneous study with TCD and TEE showed an almost perfect concordance in PFO detection and RLS quantification.

New Concepts in Lacunar Stroke Etiology: The Constellation of Small-Vessel Arterial Disease

Objective: To update the less frequent etiologies causing lacunar infarcts (LIs). To highlight recent advances in risk factors, clinical syndromes, topography, complementary tests and long-term prognosis in this subtype of ischemic stroke. Patients and Methods: The most important studies are analyzed, from CM Fisher works, selecting those referring to LIs of unusual etiology, and recent advances and controversies in the clinical management of LI are discussed. Results: LIs are found in approximately 11% of patients admitted with stroke. The pure motor hemiparesis (55%) constitutes the most usual lacunar syndrome. However, lacunar syndromes may not be caused by LIs in 10–20% of cases. LIs caused by microembolism and cholesterol embolism from the aortic arch are reviewed. Hematological diseases can also cause LI, such as polycythemia rubra vera, essential thrombocythemia and primary antiphospholipidic antibody syndrome. Other etiologies are carotid plaque embolism, severe stenosis of a perforated arteriole and amyloid angiopathy. Infectious arteritis by neurolues, neurocysticercosis, neuroborreliosis, by AIDS or Helicobacter pylori infection have also been associated with the presence of LIs. Likewise, inflammatory arteritis in systemic lupus erythematosus or granulomatous angiitis, cocaine abuse and panarteritis nodosa have been related to LI, although in the latter LI would be caused by a thrombotic microangiopathy and not by vasculitis. Conclusions: LI is an ischemic stroke subtype with a characteristic clinical presentation and a short-term favorable prognosis. Although high blood pressure constitutes the main risk factor and the main etiology, LIs may be caused, in less than 5% of cases, by various etiologies, mainly hematological diseases and infectious or inflammatory arteritis. It is essential to make a correct etiological diagnosis for LI as treatment will be different according to its etiology.

Advancements in understanding the mechanisms of symptomatic lacunar ischemic stroke: translation of knowledge to prevention strategies

Symptomatic lacunar ischemic stroke (25% of all brain infarctions) results from occlusion of a single penetrating artery by microatheromas or lipohyalinosis and rarely from an intracranial atheromatous branch disease. Recurrent lacunar stroke may be associated with more severe clinical features and has been involved in producing lacunar state and vascular subcortical dementia. In the first multicenter randomized clinical trial (SPS3) focused on stroke prevention among patients with recent lacunar stroke, the addition of clopidogrel to aspirin not only did not reduced significantly the risk of recurrent stroke, but also increased significantly the likelihood of hemorrhage and fatal outcome. If lacunar stroke is primarily non-atherothromboembolic, secondary prevention aimed at preventing atheroma progression may not be very effective. The efficacy of drugs that improve endothelial function in lacunar stroke patients remains to be studied in the future.

Influence of Antiplatelet Pre-Treatment on the Risk of Symptomatic Intracranial Haemorrhage after Intravenous Thrombolysis

Background: The influence of antiplatelet agents (AP) in the development of a symptomatic intracranial haemorrhage (SICH) after intravenous rt-PA is not well known. We assessed the hypothesis that pre-treatment with AP may increase that risk. Methods: We studied data from consecutive patients with ischaemic stroke treated with intravenous rt-PA within the first 3 h after symptom onset. We recorded the antecedent of any AP therapy previous to thrombolysis. A follow-up CT was performed routinely 24–36 h after the infusion of rt-PA. Intracranial bleeding was categorized according to the criteria of the European Cooperative Acute Stroke Study II (ECASS II) into haemorrhagic infarction type 1 and 2 and parenchymal haemorrhage type 1 and 2. SICH was diagnosed if it was of the parenchymal haemorrhage type, occurred within the first 36 h and was associated with neurological deterioration. Results: Of a total of 605 patients, 137 (22.6%) were pre-treated with AP, most of them (n = 106) with aspirin. Any type of intracranial haemorrhage was observed in 119 patients (19.7%), without differences between the AP (18.4%) and the non-AP (20.2%) groups. Parenchymal haemorrhage was observed in 41 patients (8.5%) and SICH in 26 (4.3%). There was a non-significant rise in the frequency of SICH in the AP group compared with the non-AP group (6.6 vs. 3.6% p = 0.10). Conclusions: Pre-treatment with AP non-significantly increases the risk of SICH and therefore this antecedent should not be a contraindication for intravenous thrombolysis.

Cerebrovascular Disease as a Complication of Cardiac Transplantation

Background and Objectives: To characterize the frequency, risk factors, clinical presentation and etiological subtypes of cerebrovascular diseases (CVD) following cardiac transplantation (CTX). Methods: In a retrospective review of our CTX database (period 1984–2002), we assessed demographic data, vascular risk factors, surgery and donor details. We classified ischemic stroke (IS) using the clinical criteria of the Oxfordshire Community Stroke Project and the etiological criteria of the TOAST study. Logistic regression analysis and survival curves were carried out. Results: CTX was performed in a total of 314 patients (age 46 ± 14 years, 78% male) and mean follow-up was 54 ± 57 months. Twenty-two patients (7%) presented CVD: hemorrhagic stroke in 12%, transient ischemic attack in 28% and IS in 60%. CVD were early postoperative (less than 2 weeks) in 20% of patients and late in 80%. The clinical presentation in patients with IS was total anterior circulation (23.1%), partial anterior (38.4%), lacunar (15.4%) and posterior circulation (23.1%), and the etiological classification was large artery atherosclerosis (15.4%), cardioembolism (14.4%), small vessel disease (15.4%), unusual causes (15.4%) and undetermined cause (38.4%). The only independent predictor of CVD was a prior CVD event with an odds ratio of 8.2 (95% CI, 2.2–30.2, p < 0.02). The estimated risk of CVD at 5 years was greater (p < 0.02) in patients with prior CVD (4.1%) than in those without (1.1%). Conclusions: CVD are a relatively frequent complication after CTX (7%) and usually occur in the late postoperative phase. CVD prior to transplantation increase the risk of CVD after this procedure.

Mutations in the NKX2-5 gene in patients with stroke and patent foramen ovale.

OBJECTIVE Patent foramen ovale (PFO) has been related to stroke but its existence has not been explained to date. NKX2-5 is the most implicated gene in fetal atrial septation. We studied NKX2-5 with respect to the presence or absence of PFO in stroke patients. METHODS A prospective analysis of NKX2-5 regarding age, gender, PFO, right-to-left shunt (RLS) size and atrial septal aneurysm (ASA) was performed in consecutive stroke patients and in 50 controls. The entire coding region and intron-exon boundaries of NKX2-5 gene were analyzed by PCR and sequencing of DNA from peripheral lymphocytes. RESULTS One hundred patients participated in the study (mean age 56.5+/-12.4 years, 58% males) and PFO was diagnosed in 34% of them by transesophageal echocardiography. RLS was small (12%), moderate (2%) and large (20%). ASA was present in four patients. DNA revealed a novel c.2357G>A change in one PFO patient with cryptogenic stroke. Furthermore, c.182C>T, a mutation previously described in patients with cardiac defects, was detected in two non-PFO women with cryptogenic stroke. None of these changes were detected in our controls. The c.172A>G polymorphism was found in 21% of controls. It appeared more frequently in ASA patients (p=0.084), in cryptogenic PFO stroke patients (p=0.097) and in patients with known causes of stroke (p=0.037). The c.2850C>A polymorphism was also detected in our series with no differences in PFO, RLS size or ASA. CONCLUSION Despite the fact that the NKX2-5 could account for the persistence of PFO, mutations of this gene in peripheral blood DNA were barely detected in our study.

Tratamiento intravenoso con activador del plasminógeno tisular en la isquemia cerebral aguda

Fundamento y objetivo: Se desconoce si el riesgo de transformacion hemorragica sintomatica (THS) del infarto cerebral por el uso de activador del plasminogeno tisular (t-PA) en la practica clinica es superior al observado en los ensayos clinicos. El objetivo de este estudio fue analizar la seguridad y la evolucion clinica de los pacientes con isquemia cerebral aguda que recibieron tratamiento abierto con t-PA en hospitales espanoles. Pacientes y metodo: Estudio observacional y prospectivo que incluyo a 155 pacientes consecutivos con isquemia cerebral de menos de 3 h de evolucion, o de menos de 6 h en ausencia de signos tempranos de infarto cerebral extenso en la tomografia computarizada (TC) craneal. Se administraron 0,9 mg/kg de t-PA intravenoso, el 10% en bolo y el resto en infusion continua durante 60 min. El deterioro neurologico se cuantifico con la escala del ictus del NIH (NIHSS). Se evaluaron la THS en la TC realizada a las 24-36 h, la mortalidad y la capacidad funcional a los 3 meses. Los pacientes fueron atendidos por neurologos expertos, y controlados en unidades de ictus. Resultados: La mediana de la NIHSS al ingreso fue de 16, y el tiempo medio desde el inicio de los sintomas hasta el tratamiento, de 163 min. Se observo THS en 12 pacientes (7,7%; intervalo de confianza [IC] del 95%, 4,0-13,1), que fue fatal en 7 (4,5%; IC del 95%, 1,8-9,1). La mortalidad global a los 90 dias fue del 16,8% (IC del 95%, 11,2-23,6). A las 24 h, el 48% (IC del 95%, 39,7-55,9) de los pacientes habia mejorado en 4 puntos o mas en la NIHSS, y el 29% (IC del 95%, 22,0-36,8) habia mejorado en 10 puntos o mas o se habia recuperado. En el dia 90, el 56% (IC del 95%, 47,9-64,1) de los pacientes era independiente. Conclusiones: Este estudio demuestra que en la practica clinica la administracion intravenosa de t-PA por neurologos con experiencia, en centros espanoles con unidades o equipos de ictus, es segura y se asocia a una evolucion clinica favorable, comparable a la observada en los ensayos clinicos.

Predictive clinical factors of very early in-hospital mortality in subarachnoid hemorrhage

This study was conducted to determine clinical predictors of very early in-hospital mortality (within the first 72 h) in patients with non-traumatic subarachnoid hemorrhage. Data of 184 patients with subarachnoid hemorrhage were obtained from consecutive stroke patients included in the prospective Barcelona Stroke Registry. Demographic, anamnestic, clinical, neurological and neuroimaging variables in the subgroup of patients who died within 72 h after the onset of symptoms were compared with those in the subgroup of patients that had survived this initial period. The independent predictive value of each variable on the development of very early death was assessed with a logistic regression analysis. Very early in-hospital death was observed in 18 patients (9.8%). These patients were significantly more likely to have progressive deficit, seizures, altered consciousness, limb weakness, sensory involvement and basal ganglia hematoma than patients without very early death. After multivariate analysis, only progressive deficit (odds ratio (OR) 6.90; 95% confidence interval (95% CI) 2-23.80) and limb weakness (OR 5.46; 95% CI 1.78-16.77) were independent clinical predictors of very early mortality. Progressive neurological deficit and limb weakness at the onset of stroke was independent predictive factors of very early death in patients with non-traumatic subarachnoid hemorrhage. These results further emphasize the need to establish an early etiological diagnosis and to manage these patients aggressively including early surgery in selected cases.

Mortalidad hospitalaria en la hemorragia subaracnoidea. Experiencia del «Registro Barcelona de Enfermedades Cerebrovasculares»

Fundamento Conocer los factores predictores de la mortalidad hospitalaria en los pacientes con hemorragiasubaracnoidea (HSA). Pacientes y metodos Se seleccionaron los 184 pacientes con HSA del «Registro Barcelona de EnfermedadesCerebrovasculares». Las variables demograficas, clinicas, de neuroimagen y evolutivas en elgrupo de pacientes que fallecieron durante el ingreso hospitalario se compararon con el grupo de supervivientes.El valor predictor independiente de cada variable para la presencia de mortalidad hospitalariafue valorado mediante tres modelos de regresion logistica. El primero, basado en 10 variablesdemograficas y clinicas; el segundo, basado en 17 variables demograficas, clinicas y de neuroimagen;y el tercero, en 21 variables demograficas, clinica de neuroimagen y evolutivas. Resultados Durante el ingreso hospitalario fallecieron 44 pacientes (24%). La presencia de un deficitneurologico transitorio (OR = 13,92; IC del 95%: 1,01-191,95), el inicio progresivo de la enfermedad(OR = 4,21; IC del 95%: 1,28-13,86), la presencia de un deficit motor (OR = 3,24; IC del 95%:1,49-7,08) y la edad (OR = 1,05; IC del 95%: 1,02-1,09) fueron factores predictores de mortalidadhospitalaria en el primer modelo. Junto a estas cuatro variables, la presencia de hemorragia intraventricular(OR = 5,51; IC del 95%: 1,65-1,84) fue seleccionada en el segundo modelo. La presencia deun deficit neurologico transitorio (OR = 41,2; IC del 95%: 1,61-1056,2), de complicaciones neurologicas(OR = 11; IC del 95%: 3,85-31,74), de una malformacion arterial carotidea (OR = 6,61; IC del95%: 1,23-35,43), de hemorragia intraventricular (OR = 5,51; IC del 95%: 1,65-18,4), el inicio progresivode la enfermedad (OR = 5,35; IC del 95%: 1,11-25,90) y la coexistencia de una hemorragiacerebral hemisferica (OR = 4,32; IC del 95%: 1,35-13,90) fueron las variables predictoras seleccionadasen el tercer modelo multivariante. Conclusiones Varios datos clinicos –facilmente obtenibles en la cabecera de la cama del enfermo– yreurorradiologicos –facilmente objetivables en los examenes complementarios de neuroimagen– ayudana predecir la mortalidad hospitalaria en los pacientes con HSA. La presencia de manifestaciones neurologicastransitorias previas a la HSA definitiva constituye el principal factor predictor de mortalidad.

Addendum to “Mutations in the NKX2-5 gene in patients with stroke and patent foramen ovale” [Clin. Neurol. Neurosurg. 111 (2009) 574–578]

Concerning our paper “Mutations in theNKX2-5 gene in patientswith stroke andpatent foramenovale” that has been recently published in Clinical Neurology and Neurosurgery, [2009 September;111(7)574–8], we want to shed light on some aspects of the nomenclature of the mutations employed. According to the nomenclature recommended for description of variations in the human genome, if using the coding sequence as reference starting with nucleotide A in the ATG initiation, mutation pGlu21Glu can be defined at the nucleotide level as c.63A>G (c. 172A>G in i