Journal of Child Neurology

Two magnetic resonance imaging techniques, diffusion and perfusion imaging, are being used increasingly for evaluation of pathophysiology of stroke. This article introduces these techniques and reports some initial studies using these approaches, together with conventional T₂-weighted magnetic resonance imaging, for investigation of childhood stroke. It is shown that the combination of T₂-weighted and diffusion images can provide information about the timing of stroke events in childhood, and perfusion imaging can detect abnormalities not visible by other magnetic resonance imaging techniques. These magnetic resonance methods therefore should play an important role in investigation of children with stroke and could be of particular value in studies of at-risk populations of children such as those with sickle cell disease. (J Child Neurol 2000;15:279-283).

The clinical and radiographic findings of 68 children and adolescents with nontraumatic intraparenchymal brain hemorrhage were analyzed retrospectively. There were 43 boys and 25 girls, and the average age was 7.1 years (range, 3 months to 18 years). The most common presenting symptom was a combination of headache or vomiting (40 cases, or 58.8%). Hemiparesis was the major presenting sign in 11 (16.2%) of the children, seizures occurred in 25 (36.8%) patients, and 6 (8.8%) children were irritable. Only 2 (2.9%) children were comatose at presentation. One or more risk factors for hemorrhage were found in 61 (89.7%) of 68 children. A third (23 cases, or 33.8%) had an arteriovenous malformation or fistula; altogether 29 (42.6%) children had some type of congenital vascular anomaly. Hematologic or coagulation disorders were present in 22 (32.4%) patients, and 9 (13.2%) patients had brain tumors. Hemorrhage could not be attributed to systemic hypertension in any child. The likelihood of establishing the cause of bleeding was greater when evaluation included cerebral angiography (97.3% versus 80.4% without angiography). Half (34 cases, or 50.0%) of the patients regained normal neurologic function. Six (8.8%) patients died, either directly or partly as a consequence of the hemorrhage. The remaining patients had various neurologic sequelae, including 17 (25.0%) with hemiparesis, 5 (7.4%) with aphasia, 7 (10.3%) with epileptic seizures, and 3 (4.4%) with hydrocephalus. More detailed follow-up studies are needed to obtain more information about the frequency of cognitive sequelae. (J Child Neurol 2000;15:284-289).

This paper describes 59 patients, 3 months to 16 years of age, who were seen consecutively in the same center for cerebral arterial infarction. It focuses on the mechanism of stroke. The pathophysiologic process could be established for 78% of the children. Arteriopathic stroke (31 patients, or 53%) was the most common. The arteriopathies were either progressive (moyamoya in 4 patients, or 7%) or nonprogressive (27 patients, or 46%). The latter form occurred in two patterns: dissection of cervicocephalic arteries (12 patients, or 20%) and transient cerebral arteriopathy of unknown origin but probably angiitis (15 patients, or 25%). Cardiac or transcardiac embolic stroke occurred in 12% of the series and systemic diseases in 14%. There was a favorable outcome in 70% of patients having stroke due to nonprogressive arterial disease and stroke due to unidentified mechanisms. In contrast, only 26% of patients with embolic stroke, systemic disease, or moyamoya had a favorable outcome. Recurrences were more frequent and severe in this latter group. It is concluded that it is important to determine the mechanism of childhood stroke, because it strongly influences outcome, the recurrence risk, and treatment choice. (J Child Neurol 2000;15:290-294).

The aim of this study was to investigate a possible association among the thermolabile polymorphism, nucleotide 677 cytosine to thymidine point mutation (677 C→T) of the methylenetetrahydrofolate reductase (MTHFR) gene, hyperhomocysteinemia, serum folate, vitamins B₁₂ and B₆, and stroke in children. Allele and genotype frequencies for the 677 C→T polymorphism in 21 children with stroke and 28 healthy children of the same age were studied. No differences in allelic frequency were detected between the two populations. However, the prevalence of homozygous 677 C→T was doubled in the stroke population (28.6%) compared to the healthy group (14.3%). Total plasma homocysteine (tHcy) levels were significantly increased in children aged 2 months to 15 years with stroke compared to reference values. No association was observed between the homozygous genotype (T/T) and hyperhomocysteinemia, nor between the T/T genotype and low folate levels (below the 95th percentile) in this group of patients. Vitamin concentrations in patients were not significantly different from reference values. Significant negative correlations were found between tHcy and folate and between tHcy and cobalamin, but not between tHcy and B₆ concentrations. In summary, a higher prevalence of hyperhomocysteinemia and the 677 C→T polymorphism were observed in children with stroke, but were not always associated. The systematic study of both abnormalities in children with stroke is recommended, so that hyperhomocysteinemia of any genetic origin can be corrected with vitamin supplementation. Moreover, the 677 C→T genotype is a strong factor for predisposition to hyperhomocysteinemia and recurrent risk of stroke that might also be prevented with folate supplementation. (J Child Neurol 2000;15:295-298).

Since early recurrence occurs in at least 10% of patients presenting with their first stroke in childhood in the reported series, the search for modifiable risk factors should be a priority. Risk factors for stroke in adults include hypertension, diabetes, and smoking, as well as cardiac disease and sickle cell anemia; asymptomatic cerebrovascular disease and transient ischemic events may predict stroke in this age group. The investigation of a child with a stroke has traditionally focused on finding a single cause rather than looking for risk factors to which the patient may be exposed life long. Approximately half of children presenting with stroke have a known predisposing condition, but some have unexpected pathologies such as primary cerebrovascular disease associated with congenital heart anomalies, or may have modifiable risk factors such as hypertension associated with sickle cell disease. The literature on children presenting with initially unexplained (cryptogenic) stroke suggests that there is a daunting list of possible causes, but since the series have mainly been small, it has been difficult to evaluate the relative importance of the reported associations. This paper reviews the literature on congenital, genetic, and acquired risk factors for stroke in childhood, and includes data from the large series of patients seen at Great Ormond Street Hospital over the past 10 years. The majority have arteriographic abnormalities and there is little evidence for asymptomatic cardiac disease. Genetic predisposition, trauma, infection, and nutritional deficiencies appear to be important, although case-control studies will be required to prove causation. Appropriate screening for modifiable risk factors may lead to prevention of recurrence in some patients. In the long term, an understanding of the multiple etiologies of childhood cerebrovascular disease and ischemic stroke may lead to primary prevention in this age group, and perhaps in adults. (J Child Neurol 2000;15:299-307).

The study of genetic and metabolic etiologies of pediatric stroke, both vascular and metabolic, allows an understanding of the causes of acute focal neurologic deficits in childhood. Here, the mendelian and mitochondrial genetic causes of pediatric stroke syndromes are reviewed. This approach elucidates the etiology of childhood stroke and illustrates many of the genetic risk factors that are found in adult-onset cerebrovascular disease. Therefore, the study of childhood stroke serves as a model to elucidate the potential risk factors for all stroke. Ultimately this will serve to develop a more rational preventive and therapeutic approach for all cerebrovascular disease. (J Child Neurol 2000;15:308-315).

Ischemic stroke during infancy and childhood has the potential for life-long morbidity. Information on the neurologic outcome of children who survive ischemic stroke is lacking. Children surviving ischemic stroke between January 1, 1995 and July 1, 1999 were prospectively followed. Neurologic deficit severity was based on the Pediatric Stroke Outcome Measure (PSOM) developed in this study and parental response to two recovery questions. Predictor variables for poor outcome were tested. One-hundred twenty-three children with arterial ischemic stroke and 38 with sinovenous thrombosis were followed for a mean of 2.1 years (range, 0.8 to 6.6 years). The primary outcome based on PSOM assessment was: normal, 37%; mild deficit, 20%; moderate deficit, 26%; and severe deficit, 16%. The secondary outcome was full recovery in 45% of patients, based on parental response. The primary and secondary outcome measures were moderately correlated (P < .001; K = 0.5). In bivariate analysis, arterial stroke type, male gender, age of at least 28 days, presence of associated neurologic disorders, and need for rehabilitation therapy after stroke were predictors of poor outcome (P < .05). Multivariate analysis showed that only arterial ischemic stroke, associated neurologic disorders, and presence of rehabilitation therapy were independent predictors of poor outcome (P < .02). Poor outcome in children after ischemic stroke is therefore frequent and more likely in the presence of arterial stroke, rehabilitation therapy, and associated neurologic disorders, which justifies clinical trials of treatment strategies in childhood ischemic stroke. (J Child Neurol 2000;15:316-324).

Review of published clinical and neuropsychologic outcome studies reveals limited information about intellectual functioning after childhood stroke. The extant data are supplemented here by analysis of intelligence quotient (IQ) results obtained from 38 children in an ongoing study of unilateral middle cerebral artery ischemic stroke. Evidence so far indicates that, after stroke, mean IQ falls significantly below the population mean but remains within the average range. There is no significant difference between hemispheric side of injury; the Verbal and Performance IQ lateralization profile widely recognized in adults with unilateral injury is not apparent in younger children, and there is only a trend toward this profile in older children. The effects of a number of other variables, including sex, site of stroke, and longitudinal assessment, are also considered. Although the generally minor effect of stroke on IQ is encouraging, a number of children do require extra help on return to school. Some suggestions for future research are highlighted in order to encourage further consideration of the issues raised here. (J Child Neurol 2000;15:325-332).

After obtaining familial informed consent, between January 1996 and July 1997, 173 children (5 to 15 years old) with sickle cell disease were enrolled in a prospective multicenter study using blood screening, transcranial Doppler ultrasonography (n = 143), cerebral magnetic resonance imaging (n = 144), and neuropsychologic performance evaluation (n = 156) (Wechsler Intelligence tests WISC-III, WIPPSI-R), which were also performed in 76 sibling controls (5 to 15 years old). Among the 173 patients with sickle cell disease (155 homozygous for hemoglobin SS, 8 sickle cell β⁰ thalassemia, 3 sickle cell β ⁺ thalassemia, 7 sickle cell hemoglobin C disease SC), 12 (6.9%) had a history of overt stroke, and the incidence of abnormal transcranial Doppler ultrasonography (defined as mean middle cerebral artery velocity > 200 cm/sec or absent) was 8.4% in the overall study population and 9.6% in patients with homozygous sickle cell anemia. The silent stroke rate was 15%. Significantly impaired cognitive functioning was observed in sickle cell disease patients with a history of stroke (Performance IQ and Full Scale IQ), but also in patients with silent strokes (Similarities, Vocabulary, and Verbal Comprehension). However, infarcts on magnetic resonance imaging were not the only factors of cognitive deficit: Verbal IQ, Performance IQ, and Full Scale IQ were strongly impaired in patients with severe chronic anemia (hematocrit ≤ 20%) and in those with thrombocytosis (platelets > 500 × 10⁹/L). Multivariate logistic regression analysis showed that abnormal magnetic resonance imaging (odds ratio [OR] = 2.76) (P = .047), hematocrit ≤ 20% (OR = 5.85) (P = .005), and platelets > 500 × 10⁹/L (OR = 3.99) ( P = .004) were independent factors of cognitive deficiency (Full Scale IQ < 75) in sickle cell disease patients. The unfavorable effect of low hematocrit has already been suggested, but this is the first report concerning an effect of thrombocytosis and showing that silent stroke alone is not a factor of cognitive deficit when not associated with low hematocrit or thrombocytosis. The effect of hydroxyurea, which is known to increase hematocrit and decrease platelet count, on cognitive functioning of sickle cell patients should be evaluated prospectively. (J Child Neurol 2000;15:333-343).

Stroke is generally uncommon in children, but sickle cell disease is associated with a high risk of stroke in the early years of childhood. Large cerebral arteries, especially the middle cerebral and intracranial internal carotid, develop stenosis that predisposes to ischemic stroke. Noninvasive prediction of risk using transcranial Doppler ultrasonography made it possible to test primary stroke prevention in a clinical trial comparing chronic blood transfusion with standard care. A consortium of 14 clinical centers conducted a randomized clinical trial (Stroke Prevention in Sickle Cell Anemia—the "STOP" study) to test a strategy to prevent first stroke in children with sickle cell disease. Over 2000 children were screened with transcranial Doppler ultrasonography and of these, 130 with elevated blood velocity indicating high risk were enrolled in the trial. Regular red cell transfusions sufficient to reduce the percentage of Hb S gene product from over 90 to less than 30 of total hemoglobin was associated with a marked reduction in stroke. The untreated risk of 10% per year was reduced over 90% with treatment, an effect sufficient to cause early termination of the trial. Although treatment was unblinded, the design included blinded adjudication of possible stroke by a panel of neurologists remote from the study sites. The study led to a Clinical Alert, issued by the National Heart, Lung, and Blood Institute, recommending screening and consideration of treatment in children with sickle cell disease and 2 to 16 years of age who are at risk based on transcranial Doppler ultrasonography, and who have not had stroke. (J Child Neurol 2000;15:344-349).

Early diagnosis and treatment of moyamoya disease in children is essential to minimize residual mental and physiologic deficits. Current treatment of childhood moyamoya disease in Japan, preoperative evaluation of perfusion reserve as a surgical indication, and the role of noninvasive follow-up by magnetic resonance angiography are reported. Approximately 20% of children with definite moyamoya disease were observed or treated medically. Among surgical procedures, single indirect bypass surgery was used in approximately 30% of all patients; combinations of direct and indirect bypass surgery, 20%; and multiple-indirect bypass surgery, 18%. Both adequate understanding of the primary condition and determination of optimal treatment, including specific operative procedures, required evaluation of cerebral circulation and metabolism. Surgical indications included reduced perfusion reserve in affected brain by positron emission tomography or single photon emission tomography with administration of acetazolamide or a CO ₂ load. Postoperative improvements of cerebral perfusion reserve show better correlation with disappearance of ischemic attacks than does angiographically demonstrated collateral formation. Follow-up evaluation with magnetic resonance angiography has advantages over conventional angiography because it is noninvasive and avoids general anesthesia. (J Child Neurol 2000;15:350-356).