Recurrent stroke: the role of thrombophilia in a large international pediatric stroke population.

Risk factors for arterial ischemic stroke in children include vasculopathy and prothrombotic risk factors but their relative importance to recurrent stroke is uncertain. Data on recurrent stroke from databases held in Canada (Toronto), Germany (Kiel-Lübeck/Münster), and the UK (London/Southampton) were pooled. Data were available from 894 patients aged 1 month to 18 years at first stroke (median age, 6 years) with a median follow-up of 35 months. Among these 894 patients, 160 (17.9%) had a recurrence between 1 day and 136 months after the first stroke (median, 3.1 months). Among 288 children with vasculopathy, recurrence was significantly more common [hazard ratio (HR) 2.5, 95% confidence interval (95% CI) 1.92-3.5] compared to the rate in children without vasculopathy. Adjusting for vasculopathy, isolated antithrombin deficiency (HR 3.9; 95% CI: 1.4-10.9), isolated elevated lipoprotein (a) (HR 2.3; 95% CI: 1.3-4.1), and the presence of more than one prothrombotic risk factor (HR 1.9; 95% CI: 1.12-3.2) were independently associated with an increased risk of recurrence. Recurrence rates calculated per 100 person-years were 10 (95% CI: 3-24) for antithrombin deficiency, 6 (95% CI: 4-9) for elevated lipoprotein (a), and 13 (95% CI: 7-20) for the presence of more than one prothrombotic risk factor. Identifying children at increased risk of a second stroke is important in order to intensify measures aimed at preventing such recurrences.

Clinical and radiological recurrence after childhood arterial ischemic stroke.

BACKGROUND: Data on rates and risk factors for clinical and radiological recurrence of childhood arterial ischemic stroke (AIS) might inform secondary prevention strategies. METHODS AND RESULTS: Consecutive Great Ormond Street Hospital patients with first AIS were identified retrospectively (1978-1990) and prospectively (1990-2000). Patients underwent repeat neuroimaging at the time of clinical recurrence or, if asymptomatic, at least 1 year after AIS. Cox and logistic regression analyses were used to explore the relationships between risk factors and clinical and radiological recurrence, respectively. A total of 212 patients were identified, of whom 97 had another prior diagnosis. Seventy-nine children had a clinical recurrence (29 strokes, 46 transient ischemic attacks [TIAs], 4 deaths with reinfarction 1 day to 11.5 years (median 267 days) later); after 5 years, 59% (95% confidence interval, 51% to 67%) were recurrence free. Moyamoya on angiography and low birth weight were independently associated with clinical recurrence in the whole group. Genetic thrombophilia was associated with clinical recurrence in previously healthy patients, independent of the presence of moyamoya. Sixty of 179 patients who had repeat neuroimaging had radiological reinfarction, which was clinically silent in 20. Previous TIA, bilateral infarction, prior diagnosis (specifically immunodeficiency), and leukocytosis were independently associated with reinfarction. Previous TIA and leukocytosis were also independently associated with clinically silent reinfarction. CONCLUSIONS: Clinical and radiological recurrence are common after childhood AIS. The risk of clinical recurrence is increased in children with moyamoya and, in previously healthy patients, in those with genetic thrombophilia. Preexisting pathology, including immunodeficiency, and persistent leukocytosis are risk factors for radiological recurrence, which suggests a potential role for chronic infection.

Physiological correlates of intellectual function in children with sickle cell disease: hypoxaemia, hyperaemia and brain infarction.

Lowered intelligence relative to controls is evident by mid-childhood in children with sickle cell disease. There is consensus that brain infarct contributes to this deficit, but the subtle lowering of IQ in children with normal MRI scans might be accounted for by chronic systemic complications leading to insufficient oxygen delivery to the brain. We investigated the relationship between daytime oxyhaemoglobin saturation (SpO2), cerebral blood flow velocity (CBFV) and intellectual function (IQ) using path-analysis in 30 adolescents with sickle cell disease (mean age 17.4 years, SD 4.2). Initial analyses revealed that the association between SpO2 and Full Scale IQ (FSIQ) was fully mediated by increased CBFV, whereby SpO2 was negatively correlated with CBFV and CBFV was negatively correlated with FSIQ, i.e. decreases in oxygen saturation are associated with increases in velocity, and increased velocity is associated with lowered IQ scores. The mediated relationship suggests that lowered IQ may be a function of abnormal oxygen delivery to the brain. Further analyses showed that the association between CBFV and IQ was significant for verbal but not for performance IQ. The pathophysiology characteristic of SCD can interfere with brain function and constrain intellectual development, even in the absence of an infarct. This supports the hypothesis that lowered intellectual function is partly explained by chronic hypoxia, and has wider implications for our understanding of SCD pathophysiology.

An exploratory study of physiological correlates of neurodevelopmental delay in infants with sickle cell anaemia.

This study aimed to investigate whether infants with sickle cell anaemia (SCA) are at risk of neurodevelopmental delay, and whether any delay is associated with SCA pathology. Twenty-eight infants (14 SCA; 14 age- and ethnic-similar controls) were assessed longitudinally with the Bayley Infant Neurodevelopmental Screener (BINS) at 3, 9 and 12 months. Transcranial Doppler (TCD) and pulse oximetry (SpO2) measures were recorded longitudinally in SCA infants, and a subgroup of controls. Haemoglobin values were obtained from SCA infants. At each age, SCA infants obtained BINS scores indicative of greater risk of neurodevelopmental delay compared with controls. The number of moderate-high BINS risk scores increased significantly between 3 and 9 months. At 9 months BINS raw scores correlated negatively with TCD velocity and positively with haemoglobin. This exploratory study suggests that SCA infants may be at greater risk of neurodevelopmental delay than previously considered, and may provide the impetus for further research into the very early precursors of cognitive impairment.

Sickle cell disease: ischemia and seizures.

Although the prevalence of seizures in children with sickle cell disease (SCD) is 10 times that of the general population, there are few prospectively collected data on mechanism. With transcranial Doppler and magnetic resonance imaging (MRI) and angiography, we evaluated 76 patients with sickle cell disease, 29 asymptomatic and 47 with neurological complications (seizures, stroke, transient ischemic attack, learning difficulty, headaches, or abnormal transcranial Doppler), who also underwent bolus-tracking perfusion MRI. The six patients with recent seizures also had electroencephalography. Group comparisons (seizure, nonseizure, and asymptomatic) indicated that abnormal transcranial Doppler was more common in the seizure (4/6; 67%) and nonseizure (26/41; 63%) groups than in the asymptomatic (10/29; 34%) group (chi2; p = 0.045), but abnormal structural MRI (chi2; p = 0.7) or magnetic resonance angiography (chi2; p = 0.2) were not. Relative decreased cerebral perfusion was found in all seizure patients and in 16 of 32 of the remaining patients with successful perfusion MRI (p = 0.03). In the seizure patients, the perfusion abnormalities in five were ipsilateral to electroencephalographic abnormalities; one had normal electroencephalogram results. These findings suggest that vasculopathy and focal hypoperfusion may be factors in the development of sickle cell disease-associated seizures.

Central nervous system abnormalities in asymptomatic young patients with Sbeta-thalassemia.

Twenty-one children and young adults with sickle/beta-thalassemia without overt stroke were examined with magnetic resonance imaging and angiography (MRA), transcranial Doppler (TCD), visual (VEP) and median nerve somatosensory (SEP)-evoked potential recordings, and neuropsychological testing (Wechsler Intelligence Scale [WISC-III]). Eight (38%) had silent infarction in the parietooccipital cortex, deep white matter, or basal ganglia, including two of three with previous seizures. Of 17 undergoing TCD, none had maximum middle cerebral artery (MCA) velocities greater than 126cm/sec, but 9 were abnormal, with low velocities and difficulty in tracking the MCA and/or asymmetry. Three patients had abnormal MRA, one of whom also had silent infarction. One patient had pathological VEP recordings, whereas all SEP recordings were normal. WISC-III was performed in all 11 children, 4 with silent infarction: all but 1 had IQ scores greater than 85 (mean, 97.7; standard deviation, 14.2). We conclude that Greek children and young adults with Sbeta-thalassemia and no history of clinical stroke have TCD abnormalities and silent infarction similar to those reported in children and adolescents with sickle cell anemia, but cognitive function is not necessarily compromised. International collaboration is needed to establish the risk factors for central nervous system sequelae in patients with sickle cell disease, including Sbeta-thalassemia, leading to evidence-based prevention.

Investigation of risk factors in children with arterial ischemic stroke.

We present data on the known risk factors encountered in children presenting with a first arterial ischemic stroke to a single tertiary center over 22 years. Two hundred twelve patients (54% male; median age, 5 years) were identified. One hundred fifteen (54%) were previously healthy. Cerebral arterial imaging was undertaken in 185 patients (87%) and was abnormal in 79%. Of 104 previously healthy patients investigated with echocardiography, only 8 had abnormal studies. Genetic or acquired conditions causing thrombophilia were rare. Forty percent of patients were anemic, and 21% either had elevated total plasma homocysteine or were homozygous for the t-MTHFR mutation. Trauma and previous varicella zoster infection were significantly more common in the previously healthy group. There was a significant association between cerebral arterial abnormalities and systolic blood pressure greater than 90th percentile and a trend for an association with varicella within the previous year. Clinical history and examination usually identify underlying risk factors and precipitating triggers for arterial ischemic stroke in childhood. Cerebral arterial imaging is usually abnormal, but echocardiography and prothrombotic screening are commonly negative.

Sickle cell disease: the neurological complications.

The genetic cause of sickle cell disease has been known for decades, yet the reasons for its clinical variability are not fully understood. The neurological complications result from one point mutation that causes vasculopathy of both large and small vessels. Anemia and the resultant cerebral hyperemia produce conditions of hemodynamic insufficiency. Sickled cells adhere to the endothelium, contributing to a cascade of activated inflammatory cells and clotting factors, which result in a nidus for thrombus formation. Because the cerebrovascular reserve becomes exhausted, the capacity for compensatory cerebral mechanisms is severely limited. There is evidence of small-vessel sludging, and a relative deficiency of nitric oxide in these vessels further reduces compensatory vasodilatation. Both clinical strokes and silent infarcts occur, affecting motor and cognitive function. New data suggest that, in addition to sickle cell disease, other factors, both environmental (eg, hypoxia and inflammation) and genetic (eg, mutations resulting in thrombogenesis), may contribute to a patient's stroke risk. The stroke risk is polygenic, and sickle cell disease can be considered a model for all cerebrovascular disease. This complex disease underscores the potential intellectual and practical distance between the determination of molecular genetics and effective clinical application and therapeutics.

Accidente cerebrovascular isquémico en la infancia / Ischemic cerebrovascular diseases in childhood

Introducción: El accidente cerebrovascular (ACV) isquémico en el niño presenta una incidencia epidemiológica baja en comparación con el adulto. Sin embargo la pluricausalidad etiológica y la orientación diagnóstica y terapéutica exigen una metodología seria protocolizada. De ello puede depender el pronóstico y la expectativa de vida de estos pacientes. Los objetivos buscados son la determinación etiológica del ACV isquémico y una mejor elección terapéutica para disminuir la recurrencia del ACV. Material y métodos: Se estudiaron 32 pacientes de ambos sexos, desde el 1-7-90 hasta el 1-7-95, siguiendo el protocolo de ACV de nuestro Servicio de Neurología Infantil, incluyendo todos los pacientes con ACV isquémico, excluyendo los ACV hemorrágicos. Para determinar si el paciente presentaba ACV isquémico se usaron criterios clínicos y neurorradiológicos. Se estudiaron las siguientes variables: distribución etaria, hallazgos clínicos, territorios vasculares comprometidos, evolución, hallazgos de morbimortalidad y estrategias de protocolo terapéutico de acuerdo a la etiología. Cabe destacar que este trabajo fue realizado con un diseño previo. Resultados obtenidos: Determinación de etiologías: Asociado a trombosis 46,8 por ciento (15 casos). Asociado a embolias 28,12 por ciento (9 casos). Asociado a vasoespasmo 6,25 por ciento (2 casos). Inciertas 18,57 por ciento (6 casos). Las causas trombóticas mostraron predominio de procesos vasculíticos infecciosos y angiodisplasias malformativas sobre las causas hematológicas (déficit de proteínas C y S y el síndrome antifosfolipídico primario y secundario) e inmunológicas. Distribución etaria: Predominio entre 0-6 años (total de la muestra 75 por ciento). Mediana 2 años y la media 4,25. Hallazgos clínicos semiológicos al debut: Encefalopatía aguda convulsiva y signología deficitaria (31,25 por ciento). Déficit motor y crisis convulsivas (25 por ciento) con tendencia a debut focalizado, como cuadros clínicos dominantes. Territorios vasculares afectados: Predominio de la arteria cerebral media (47 por ciento). Arteria carótida interna (25 por ciento). Factores involucrados más importantes: Infecciosos (25 por ciento). Cardiopatías (25 por ciento). Dislipidemias (12,5 por ciento). Coagulopatías (12,5 por ciento). Evolución: Mostró una mortalidad del 15,6 por ciento, con una morbilidad de un 60 por ciento y una recurrencia de ACV isquémico del 37 por ciento...(AU)

Accidente cerebrovascular isquémico en la infancia / Ischemic cerebrovascular diseases in childhood

Introducción: El accidente cerebrovascular (ACV) isquémico en el niño presenta una incidencia epidemiológica baja en comparación con el adulto. Sin embargo la pluricausalidad etiológica y la orientación diagnóstica y terapéutica exigen una metodología seria protocolizada. De ello puede depender el pronóstico y la expectativa de vida de estos pacientes. Los objetivos buscados son la determinación etiológica del ACV isquémico y una mejor elección terapéutica para disminuir la recurrencia del ACV. Material y métodos: Se estudiaron 32 pacientes de ambos sexos, desde el 1-7-90 hasta el 1-7-95, siguiendo el protocolo de ACV de nuestro Servicio de Neurología Infantil, incluyendo todos los pacientes con ACV isquémico, excluyendo los ACV hemorrágicos. Para determinar si el paciente presentaba ACV isquémico se usaron criterios clínicos y neurorradiológicos. Se estudiaron las siguientes variables: distribución etaria, hallazgos clínicos, territorios vasculares comprometidos, evolución, hallazgos de morbimortalidad y estrategias de protocolo terapéutico de acuerdo a la etiología. Cabe destacar que este trabajo fue realizado con un diseño previo. Resultados obtenidos: Determinación de etiologías: Asociado a trombosis 46,8 por ciento (15 casos). Asociado a embolias 28,12 por ciento (9 casos). Asociado a vasoespasmo 6,25 por ciento (2 casos). Inciertas 18,57 por ciento (6 casos). Las causas trombóticas mostraron predominio de procesos vasculíticos infecciosos y angiodisplasias malformativas sobre las causas hematológicas (déficit de proteínas C y S y el síndrome antifosfolipídico primario y secundario) e inmunológicas. Distribución etaria: Predominio entre 0-6 años (total de la muestra 75 por ciento). Mediana 2 años y la media 4,25. Hallazgos clínicos semiológicos al debut: Encefalopatía aguda convulsiva y signología deficitaria (31,25 por ciento). Déficit motor y crisis convulsivas (25 por ciento) con tendencia a debut focalizado, como cuadros clínicos dominantes. Territorios vasculares afectados: Predominio de la arteria cerebral media (47 por ciento). Arteria carótida interna (25 por ciento). Factores involucrados más importantes: Infecciosos (25 por ciento). Cardiopatías (25 por ciento). Dislipidemias (12,5 por ciento). Coagulopatías (12,5 por ciento). Evolución: Mostró una mortalidad del 15,6 por ciento, con una morbilidad de un 60 por ciento y una recurrencia de ACV isquémico del 37 por ciento...