RESUMEN
BACKGROUND: Sickle cell disease (SCD) is associated with an increased risk of cardiovascular disease that may be due to a variety of possible risk factors, including abnormal blood pressure. Blood pressure (BP) of children and adolescents with SCD has been reported to be lower compared to the BP of the general pediatric population. METHODS: To confirm this prior observation, we compared reference BP values for children with SCD with reference BP values of the general pediatric population. We hypothesized that children with SCD do not have lower BPs than children without SCD. RESULTS: Systolic BP differed for both males and females, over the different age groups between pediatric subjects with and without SCD. Systolic BP was higher in children with SCD, in both obese and non-obese populations. Diastolic BP did not differ between the groups. CONCLUSIONS: Our analysis demonstrated that systolic BP values are indeed higher in children with SCD than in the general pediatric population. This finding is consistent with the most recent literature showing abnormal BP patterns in the SCD pediatric population utilizing 24-hour BP monitoring devices. This is an important step for recognizing abnormal BP as a risk factor for cardio- and neurovascular events in SCD.
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Anemia de Células Falciformes , Enfermedades Cardiovasculares , Adolescente , Anemia de Células Falciformes/complicaciones , Presión Sanguínea , Niño , Femenino , Humanos , Masculino , Obesidad/complicaciones , Factores de RiesgoRESUMEN
BACKGROUND AND PURPOSE: To assess whether initial imaging characteristics independently predict 1-year neurological outcomes in childhood arterial ischemic stroke patients. METHODS: We used prospectively collected demographic and clinical data, imaging data, and 1-year outcomes from the VIPS study (Vascular Effects of Infection in Pediatric Stroke). In 288 patients with first-time stroke, we measured infarct volume and location on the acute magnetic resonance imaging studies and hemorrhagic transformation on brain imaging studies during the acute presentation. Neurological outcome was assessed with the Pediatric Stroke Outcome Measure. We used univariate and multivariable ordinal logistic regression models to test the association between imaging characteristics and outcome. RESULTS: Univariate analysis demonstrated that infarcts involving uncinate fasciculus, angular gyrus, insular cortex, or that extended from cortex to the subcortical nuclei were significantly associated with poorer outcomes with odds ratios ranging from 1.95 to 3.95. All locations except the insular cortex remained significant predictors of poor outcome on multivariable analysis. When infarct volume was added to the model, the locations did not remain significant. Larger infarct volumes and younger age at stroke onset were significantly associated with poorer outcome, but the strength of the relationships was weak. Hemorrhagic transformation did not predict outcome. CONCLUSIONS: In the largest pediatric arterial ischemic stroke cohort collected to date, we showed that larger infarct volume and younger age at stroke were associated with poorer outcomes. We made the novel observation that the strength of these associations was modest and limits the ability to use these characteristics to predict outcome in children. Infarcts affecting specific locations were significantly associated with poorer outcomes in univariate and multivariable analyses but lost significance when adjusted for infarct volume. Our findings suggest that infarcts that disrupt critical networks have a disproportionate impact upon outcome after childhood arterial ischemic stroke.
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Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Accidente Cerebrovascular Isquémico/patología , Recuperación de la Función , Adolescente , Edad de Inicio , Niño , Preescolar , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , MasculinoRESUMEN
Cerebrovascular disease (stroke) is one of the ten leading causes of death in children and adolescents. Multiple etiologies, from arteriopathies to prothrombic states, can cause stroke in youth. In adult stroke, hypertension has been shown to be the single most important modifiable risk factor. Although hypertension has not been strongly identified as a risk factor in childhood stroke to date, there is preliminary evidence that suggests that hypertension may also be associated with stroke in children. In this review, we summarize the literature that may link hypertension to stroke in the young. We have identified a series of barriers and limitations in the fields of pediatric hypertension and pediatric neurology that might explain why hypertension has been overlooked in childhood stroke. We suggest that hypertension may be a relevant risk factor that, alone or in combination with other multiple factors, contributes to the development of stroke in children. Currently, there are no consensus guidelines for the management of post-stroke hypertension in children. Thus, we recommend that blood pressure be assessed carefully in every child presenting with acute stroke in order to better understand the effects of hypertension in the development and the outcome of childhood stroke. We suggest a treatment algorithm to help practitioners manage hypertension after a stroke.
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Hipertensión , Accidente Cerebrovascular , Adolescente , Adulto , Presión Sanguínea , Niño , Consenso , Humanos , Hipertensión/complicaciones , Hipertensión/epidemiología , Factores de Riesgo , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiologíaRESUMEN
Background and Purpose- Sickle cell disease (SCD) and arteriopathy are pediatric stroke risk factors that are not mutually exclusive. The relative contributions of sickled red blood cells and arteriopathy to stroke risk are unknown, resulting in unclear guidelines for primary and secondary stroke prevention when both risk factors are present. We hypothesized that despite similarities in clinical presentation and radiographic appearance of arteriopathies, stroke evaluation and management differ in children with SCD compared with those without SCD. Methods- We compared presentation and management of children with and without SCD enrolled in the IPSS (International Pediatric Stroke Study) with acute arterial ischemic stroke, according to SCD and arteriopathy status. Regression modeling determined relative contribution of SCD and arteriopathy in variables with significant frequency differences. Results- Among 930 childhood arterial ischemic strokes, there were 98 children with SCD, 67 of whom had arteriopathy, and 466 without SCD, 392 of whom had arteriopathy. Arteriopathy, regardless of SCD status, increased likelihood of hemiparesis (odds ratio [OR], 1.94; 95% CI, 1.46-2.56) and speech abnormalities (OR, 1.67; 95% CI, 1.29-2.19). Arteriopathy also increased likelihood of headache but only among those without SCD (OR, 1.89; 95% CI, 1.40-2.55). Echocardiograms were less frequently obtained in children with SCD (OR, 0.58; 95% CI, 0.37-0.93), but the frequency of identified cardiac abnormalities was similar in both groups ( P=0.57). Children with SCD were less likely to receive antithrombotic therapy, even in the presence of arteriopathy (OR, 0.14; 95% CI, 0.08-0.22). Arteriopathy was associated with a significantly higher likelihood of antithrombotic therapy in children without SCD (OR, 5.36; 95% CI, 3.55-8.09). Conclusions- Arteriopathy, and not SCD status, was most influential of stroke presentation. However, SCD status influenced stroke management because children with SCD were less likely to have echocardiograms or receive antithrombotic therapy. Further work is needed to determine whether management differences are warranted.
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Anemia de Células Falciformes/diagnóstico por imagen , Isquemia Encefálica/diagnóstico por imagen , Manejo de la Enfermedad , Accidente Cerebrovascular/diagnóstico por imagen , Adolescente , Anemia de Células Falciformes/epidemiología , Anemia de Células Falciformes/terapia , Isquemia Encefálica/epidemiología , Isquemia Encefálica/terapia , Niño , Preescolar , Femenino , Humanos , Masculino , Estudios Prospectivos , Sistema de Registros , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/terapiaRESUMEN
BACKGROUND: Children with congenital heart disease (CHD) have a higher prevalence of motor impairment secondary to brain injury, resulting in cerebral palsy (CP). The purpose of this study is to determine the prevalence of CP in CHD in a single-center cohort, stratify risk based on surgical mortality using Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STAT) categories and identify risk factors. METHODS: Retrospective cohort study of pediatric patients registered in the University of Florida (UF) Society of Thoracic Surgeons Congenital Heart Surgery database from 2006 to 2017 with a diagnosis of CHD who continued follow-up for more than two years at UF. RESULTS: A total of 701 children with CHD met inclusion criteria. Children identified to have CP were 54 (7.7%). Most common presentation was spastic hemiplegic CP with a Gross Motor Function Classification System of level 2. Analysis of surgical and intensive care factors between the two groups showed that children with CHD and CP had longer time from admission to surgery (P = 0.003), higher STAT categories 4 and 5 (P = 0.038), and higher frequency of brain injury and seizures (P < 0.001). Developmental disabilities and rehabilitation needs were significantly greater for children with CHD and CP when compared with those with CHD alone (P < 0.001). CONCLUSIONS: In our cohort, 7.7% children with CHD develop CP; this is significantly higher than the 2010 US population estimate of 0.3%. Our study suggests higher STAT categories, brain injury, and seizures are associated with developing CP in children with CHD.
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Parálisis Cerebral , Cardiopatías Congénitas , Humanos , Parálisis Cerebral/epidemiología , Parálisis Cerebral/complicaciones , Parálisis Cerebral/etiología , Masculino , Femenino , Cardiopatías Congénitas/cirugía , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/mortalidad , Estudios Retrospectivos , Prevalencia , Factores de Riesgo , Lactante , Preescolar , Niño , AdolescenteRESUMEN
Data on neurocognitive function in hypertensive children are limited. In this review, we summarize recent preliminary, early studies that suggest that children with elevated blood pressure demonstrate evidence of worse performance on direct neurocognitive testing, as well as evidence of executive dysfunction based on parent ratings, compared with matched normotensive comparison groups. Furthermore, hypertensive children may have increased prevalence of learning disabilities as well as a blunted cerebrovascular reactivity compared with normotensive controls. Larger, prospective studies are needed to confirm and further explore these emerging but preliminary findings.
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Presión Sanguínea , Trastornos del Conocimiento/etiología , Cognición , Función Ejecutiva , Hipertensión/complicaciones , Discapacidades para el Aprendizaje/etiología , Adolescente , Factores de Edad , Circulación Cerebrovascular , Niño , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/fisiopatología , Trastornos del Conocimiento/psicología , Humanos , Hipertensión/fisiopatología , Hipertensión/psicología , Discapacidades para el Aprendizaje/diagnóstico , Discapacidades para el Aprendizaje/fisiopatología , Discapacidades para el Aprendizaje/psicología , Memoria , Pruebas NeuropsicológicasRESUMEN
OPINION STATEMENT: Current treatment options for stroke in sickle cell disease (SCD) and thalassemia are limited. Hypercoagulation occurs in both diseases partly due to activated platelets and red blood cell dysmorphology and dysfunction, resulting in chronic anemia. This overlapping pathophysiology of the nervous system promotes the role of some common treatment modalities for these similar diseases. The current evidence suggests that chronic exchange transfusion and stem cell transplantation/bone marrow transplant (BMT) can be used in both diseases. Exchange transfusion is the mainstay of therapy of acute stroke in SCD whereas blood transfusions and hydroxyurea appear to be the most effective current treatments. However, evidence suggests that exchange transfusion should be initiated in acute ischemic stroke (AIS) and chronic transfusion continued in both diseases after AIS. Exchange transfusion can also be used acutely in AIS with thalassemia as this disorder is also associated with hypervolemia at baseline, occurring secondary to chronic anemia. The ideal length of chronic transfusions for both primary and secondary stroke prevention still needs to be better defined. Stem cell transplant or BMT is the only curative treatment for both diseases. However, timing needs to be further investigated. If transplantation is effective, it may need to be done before the child with SCD expresses disease, such as in infancy. However, in infancy, we cannot predict the severity of the phenotype in SCD with certainty, so an individual decision about transplantation is difficult to make. In thalassemia, transplantation may be effective later because vasculopathy is not the problem as in SCD. Furthermore, cerebrovascular disease occurs later in thalassemia than in SCD. Finally, aspirin is a treatment modality that also warrants further investigation. There are limited studies on the effectiveness of aspirin in SCD and thalassemias. Few studies have demonstrated clinical improvement of stroke in patients with hemoglobinopathies. Given the successful use of aspirin in the treatment and prevention of recurrent cardioembolic events in patients without hemoglobinopathies, diseases with hypercoagulability, such as SCD and thalassemia, may also benefit from the use of aspirin for treatment and prevention. However, the evidence available is based on case and retrospective studies, necessitating future larger and more valid studies to evaluate safety and effectiveness.
RESUMEN
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome was one of the first mitochondrial disorders to be identified and characterized, being described as early as 1984. The clinical manifestations of MELAS vary but stroke-like episodes are a defining feature. Mutations in at least 17 mitochondrial DNA (mtDNA) located genes have been shown to be associated with this disorder. Mary Ann, the youngest child of Josiah and Sarah Wedgwood, was born in August 1778 when Sarah was aged 44 years. Mary Ann was of short stature and was physically and mentally retarded. She suffered from partial and generalized seizures and episodes of cortical blindness. She died at the age of eight years. Descriptions of her illness remain and she is depicted with disabilities as can be seen in a family portrait. Her illness is consistent with MELAS. The illnesses of her elder siblings and of their mother are in keeping with a maternally inherited pathological mtDNA mutation, supporting this diagnosis. Her illness is the key to the remarkable illnesses that affected the Wedgwood family. Through her eldest sibling, Susannah, married to Robert Darwin, the disorder was passed to the next generation, a generation that included Charles Darwin and his elder brother, Erasmus.
RESUMEN
BACKGROUND AND PURPOSE: Chronic hypertension impairs cerebrovascular regulation in adults, but its effects on the pediatric population are unknown. The objective of this study was to investigate cerebrovascular abnormalities in hypertensive children and adolescents. METHODS: Sixty-four children and adolescents aged 7 to 20 years underwent transcranial Doppler examinations of the middle cerebral artery at the time of rebreathing CO2. Time-averaged maximum mean cerebral blood flow velocity and end-tidal CO2 were used to quantify cerebrovascular reactivity during hypercapnia. Patients were clinically categorized as hypertensive, prehypertensive, or white coat hypertensive based on 24-hour ambulatory blood pressure measurements. Their reactivities were compared with 9 normotensive control subjects and evaluated against baseline mean blood pressure z-scores and loads. RESULTS: Untreated hypertensive children had significantly lower hypercapnic reactivity than normotensive children (2.556 +/- 1.832 cm/s x mm Hg versus 4.256 +/- 1.334 cm/s x mm Hg, P < 0.05). Baseline mean diastolic blood pressure z-scores (r = -0.331, P = 0.037) and diastolic blood pressure loads (r = -0.351, P = 0.026) were inversely related to reactivity. CONCLUSIONS: Untreated hypertensive children and adolescents have blunted reactivity to hypercapnia, indicating deranged vasodilatory reactivity. The inverse relationship between diastolic blood pressure indices and reactivity suggests that diastolic blood pressure may be a better predictor of cerebral end organ damage than systolic blood pressure.
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Encéfalo/fisiopatología , Circulación Cerebrovascular/fisiología , Hipertensión/fisiopatología , Adolescente , Adulto , Presión Sanguínea , Monitoreo Ambulatorio de la Presión Arterial , Dióxido de Carbono/metabolismo , Niño , Femenino , Humanos , Hipercapnia/complicaciones , Hipertensión/complicaciones , Masculino , Pediatría , Ultrasonografía Doppler/métodosRESUMEN
BACKGROUND: Transcranial Doppler ultrasonography (TCD) is used to predict stroke risk in children with sickle cell anemia (SCA), but has not been adequately studied in children under age 2 years. PROCEDURE: TCD was performed on infants with SCA enrolled in the BABY HUG trial. Subjects were 7-17 months of age (mean 12.6 months). TCD examinations were successfully performed in 94% of subjects (n = 192). RESULTS: No patient had an abnormal TCD as defined in the older child (time averaged maximum mean TAMM velocity > or =200 cm/sec) and only four subjects (2%) had velocities in the conditional range (170-199 cm/sec). TCD velocities were inversely related to hemoglobin (Hb) concentration and directly related to increasing age. CONCLUSION: Determination of whether the TCD values in this very young cohort of infants with SCA can be used to predict stroke risk later in childhood will require analysis of exit TCD's and long-term follow-up, which is ongoing (ClinicalTrials.gov number, NCT00006400).
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Anemia de Células Falciformes/complicaciones , Accidente Cerebrovascular/prevención & control , Ultrasonografía Doppler Transcraneal , Factores de Edad , Circulación Cerebrovascular , Ensayos Clínicos Fase III como Asunto , Femenino , Humanos , Lactante , Modelos Lineales , Masculino , Análisis Multivariante , Ensayos Clínicos Controlados Aleatorios como Asunto , Accidente Cerebrovascular/diagnóstico por imagenRESUMEN
OBJECTIVE: To analyze the available literature on papilledema in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), report the first detailed pediatric case, and explore the underlying pathophysiology. METHODS: First, we conducted a comprehensive literature review of all cases of papilledema in CIDP. Next, we reviewed each case, incorporating only those including cerebrospinal fluid analysis into the results. Finally, we present our pediatric patient. RESULTS: Our literature review yielded a total of 9 adult and no pediatric cases. Cerebrospinal fluid protein and opening pressures were elevated in all cases. They were also elevated in our pediatric case. CONCLUSION: Prolonged periods of active immune-mediated inflammation is likely a cause of papilledema in adult CIDP, and possibly also in our pediatric case.
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Papiledema/complicaciones , Papiledema/diagnóstico , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/complicaciones , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Cauda Equina/diagnóstico por imagen , Diagnóstico Diferencial , Femenino , Humanos , Inmunoglobulinas/uso terapéutico , Imagen por Resonancia Magnética/métodos , Papiledema/tratamiento farmacológico , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/tratamiento farmacológico , Adulto JovenRESUMEN
BACKGROUND: Sickle cell anemia (SCA) frequently results in damage to the central nervous system (CNS), but the age of onset of these effects is uncertain. We performed MRI examinations of the brain in infants with SCA, who were evaluated as part of the multicenter randomized double-blinded Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG). METHODS: Determination of eligibility for enrollment in the trial originally required baseline MRI and magnetic resonance angiography (MRA) of the brain. A standardized imaging protocol was utilized across eight clinical centers. MRI/MRA exams were reviewed by a panel of three neurology/neuroradiology readers and interpretations reported to the coordinating center. Results were correlated with patient age, gender, history, WBC count, platelet count, hemoglobin (Hb), HbF level, score on the Bayley Scales of Infant Development, and velocity on transcranial Doppler ultrasonography (TCD). RESULTS: Twenty-three subjects with HbSS were examined at average age 13.7 months (range 10-18 months); 13 were male. Three (13%, CI: 3-34%) had silent infarcts on MRI, two in the right frontal area and one bilaterally. None had MRA abnormalities. The lesions were correlated with increased right-sided TCD velocity and low HbF level, but not with age, history, Hb level, developmental score, or left-sided velocity. CONCLUSIONS: Silent brain infarcts occur in a small but significant number of infants with SCA as early as a year of age. This finding indicates a need for thorough evaluation of the CNS very early in life in children with SCA in order to develop timely intervention strategies.
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Anemia de Células Falciformes/complicaciones , Infarto Encefálico/complicaciones , Infarto Encefálico/patología , Encéfalo/patología , Infarto Encefálico/epidemiología , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Hypertension has not been strongly identified as a risk factor in childhood stroke. This report describes a case of a teenager with a lacunar stroke, the type often observed in adults with hypertensive-associated infarction, and masked hypertension. The patient had normal blood pressure on initial presentation, but on further investigation demonstrated ambulatory hypertension with evidence of hypertensive end-organ damage. This case suggests that hypertension may be a risk factor in children with stroke, especially in cases of lacunar infarct. Evaluation for possible hypertension should be undertaken thoroughly to identify children who may benefit from antihypertensive therapy and therefore, prevent recurrences.
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Infarto Encefálico/etiología , Hipertensión/complicaciones , Accidente Cerebrovascular/etiología , Adolescente , Presión Sanguínea , Monitoreo Ambulatorio de la Presión Arterial , Infarto Encefálico/epidemiología , Infarto Encefálico/patología , Humanos , Hipertensión/diagnóstico , Hipertensión/epidemiología , Imagen por Resonancia Magnética , Masculino , Factores de Riesgo , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/patologíaRESUMEN
Hypertension is the single most important modifiable risk factor for adult stroke. Stroke mortality has significantly decreased over the last 5 decades; this decline has been mainly associated to improved blood pressure control. Though much less prevalent than in adults, stroke is an increasingly recognized cause of morbidity and mortality in children. Although hypertension has not been strongly identified as a risk factor in childhood stroke yet, there is preliminary evidence that suggests that elevated blood pressure may be associated with stroke in children. This review summarizes the literature that may link elevated blood pressure to the development of childhood ischemic and hemorrhagic stroke. The authors suggest that elevated blood pressure may be a significant risk factor that, alone or in combination with other multiple risk factors, leads to the development of stroke in childhood. It is therefore recommend that blood pressure be measured and assessed carefully in every child presenting with acute stroke.
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Hipertensión/epidemiología , Hipertensión/fisiopatología , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/fisiopatología , Adolescente , Presión Sanguínea/fisiología , Niño , HumanosRESUMEN
CONTEXT: LHX3 encodes LIM homeodomain class transcription factors with important roles in pituitary and nervous system development. The only previous report of LHX3 mutations described patients with two types of recessive mutations displaying combined pituitary hormone deficiency coupled with neck rigidity. OBJECTIVE: We report a patient presenting a unique phenotype associated with a novel mutation in the LHX3 gene. PATIENT: We report a 6-yr, 9-month-old boy born from a consanguineous relationship who presented shortly after birth with cyanosis, feeding difficulty, persistent jaundice, micropenis, and poor weight gain and growth rate. Laboratory data, including an undetectable TSH, low free T4, low IGF-I and IGF binding protein-3, prolactin deficiency, and LH and FSH deficiency were consistent with hypopituitarism. A rigid cervical spine leading to limited head rotation was noticed on follow-up examination. Magnetic resonance imaging revealed an apparently structurally normal cervical spine and a postcontrast hypointense lesion in the anterior pituitary. RESULTS: Analysis of the LHX3 gene revealed homozygosity for a novel single-base-pair deletion in exon 2. This mutation leads to a frame shift predicted to result in the production of short, inactive LHX3 proteins. The results of in vitro translation experiments are consistent with this prediction. The parents of the patients are heterozygotes, indicating a recessive mode of action for the deletion allele. CONCLUSIONS: The presence of a hypointense pituitary lesion and other clinical findings broadens the phenotype associated with LHX3 gene mutation.
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Proteínas de Homeodominio/genética , Mutación , Hormonas Hipofisarias/deficiencia , Secuencia de Aminoácidos , Niño , Consanguinidad , Femenino , Humanos , Proteínas con Homeodominio LIM , Masculino , Datos de Secuencia Molecular , Hipófisis/patología , Eliminación de Secuencia , Factores de TranscripciónRESUMEN
A conference entitled "Towards the establishment of clinical trials in pediatric and newborn stroke" assembled stroke animal model researchers, pediatric stroke researchers, adult stroke trialists, and members of the Food and Drug Administration and National Institute of Neurological Disorders and Stroke to focus on the obstacles and opportunities for conducting randomized trials in pediatric stroke. The need for good prospective clinical data in newborn and pediatric stroke in regard to outcome and recurrence risk was stressed. For clinical trials, there should be a scientific rationale. Preclinical data should be as promising and as complete as possible. Adult data should be explored, both positive and negative. For medication trials, reasonable safety and bioavailability data for the agent in question should be available. Commitment of researchers, collaboration with colleagues in primary care, emergency rooms, and intensive care units, and most importantly the willingness to participate of children and their families will all be crucial. Most children with cancer in the United States are enrolled in clinical trials and have an outcome superior to the adult patient with cancer, who is less likely to be enrolled in a trial. We should strive for enrollment and outcome results in pediatric stroke similar to those found in pediatric oncology trials.
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Ensayos Clínicos como Asunto , Accidente Cerebrovascular/terapia , Adulto , Animales , Niño , Modelos Animales de Enfermedad , Humanos , Recién NacidoRESUMEN
Before designing epidemiologic, genetic, or treatment trials in pediatric stroke, we should learn from adult trials which preceded. Adult trialists state that there is a need for improved animal models to mimic human disease. Dose-response curves with blinded outcome measures would improve preclinical data. Functional and histologic outcome measures would improve the animal model. In regard to human Phase 2 medication trials, safety, delivery, end points, and surrogate markers are necessary. The detection of biologic activity can be defined in Phase 2B trials. For Phase 3 trials, the experiment needs to be simple with global outcome measures as end points. New statistical designs such as futility analysis may improve and streamline trials in both adults and children. Clinical trials are a long process, and care needs to be incorporated at every step. Why is there a propensity of failed studies for acute ischemic stroke in adults? The reasons include (a) the animal model fails us, (b) the Phase 2 trials are ineffective in defining dose, and (c) the Phase 3 trials are poorly done. Because clinical trials, more often than not, fail to give positive (effective treatment) results, it seems reasonable to attempt to learn from others' past experiences before initiating pediatric stroke trials.