|Year : 2007 | Volume
| Issue : 5 | Page : 19-27
Arterial ischemic stroke in childhood
Department of Neurology, Senior Lecturer in Pediatric Neurology, Institute of Child Health, University College, London, United Kingdom
Neurology Department, Level 3 Southwood Building, Great Ormond Street, Hospital for Children NHS Trust, London WC1N 3JH
| Abstract|| |
Arterial ischemic stroke is one of several childhood stroke syndromes, which has distinctive features according to age of onset. This article discusses clinical presentation, risk factors and outcomes of arterial ischemic stroke in newborns and older children. The majority of affected children have adverse outcomes; although recent research has identified important risk factors, facilitating a targeted clinical approach and research on treatment is still lacking. This will require multi-center international collaboration.
Keywords: Child, cerebrovascular disease, stroke
|How to cite this article:|
Ganesan V. Arterial ischemic stroke in childhood. Ann Indian Acad Neurol 2007;10:19-27
Stroke is defined by the World Health Organisation (WHO) as "a clinical syndrome typified by rapidly developing signs of focal or global disturbance of cerebral functions, lasting more than 24 hours or leading to death, with no apparent causes other than of vascular origin". In children the clinical presentation of acute stroke is not attributable to vascular pathology in at least a third of cases. Vascular stroke syndromes are an important problem in pediatrics, with an incidence of 3-8/100,000 in Europe and North America., In the USA vascular stroke syndromes are one of the top 10 causes of childhood death. There is a higher incidence in boys and people of black ethnicity, even after accounting for antecedent trauma and sickle cell disease (SCD). Whilst these demographic characteristics may be different in the developing world, incidence is likely to be even higher as stroke can be the end result of disorders more commonly seen in this setting, for example, meningitis or bacterial endocarditis. This article will focus on arterial ischemic stroke (AIS) in neonates and older children.
| Arterial Ischemic Stroke in Children Aged >28 Days|| |
Arterial ischemic stroke can be defined as "an acute focal neurological deficit attributable to cerebral infarction in an arterial distribution". Thus, this diagnosis can only be made after brain imaging. In adults clinical syndromes such as stroke, reversible ischemic neurologic deficits or transient ischaemic attack (TIA) are defined by the duration of clinical symptoms (>24 hours, <48 hours and <24 hours respectively). However, a significant number of children with relatively brief clinical symptoms will have ischemic brain injury and there is a growing consensus towards using imaging to define AIS.
| Clinical Presentation|| |
As AIS usually affects the anterior (carotid) circulation in children, its most common clinical presentation is with acute hemiparesis. However, this may be difficult to recognize in infants, in whom lateralizing signs may be relatively subtle. Seizures (generalized or focal) may be the only clinical manifestation of acute AIS in newborns. Children with sickle cell disease (SCD) may present with less florid clinical signs ("soft" neurological signs) and hemiparesis may manifest as a difficulty with handwriting or limping. Posterior circulation AIS accounts for around 15-20% of cases and presents with clinical features attributable to focal lesions in the occipital lobes, cerebellum or brainstem. The vast majority of cases of posterior circulation AIS described in the literature are in boys; the reasons for this gender bias are unclear, although recent data suggesting that stroke in patients with Fabry disease particularly affects the posterior circulation may provide a partial explanation. Seizures occur in around a fifth of children with acute AIS. Large hemispheric infarcts or those resulting in obstruction to CSF outflow may result in a depressed conscious level. Early recognition of the symptoms and signs of raised intracranial pressure is important in children with AIS as decompressive procedures, such as decompressive craniectomy, can be life-saving.
In children at high risk of AIS, especially those with SCD or moyamoya, cerebral infarction may be clinically "silent" and only identified on imaging. However, despite the lack of acute clinical features such lesions have a significant functional impact, especially in terms of cognitive outcome and functional independence., A recent study using voxel-based morphometry suggests that children with SCD have widespread white matter injury, even in the absence of frank infarction; this may also be the case in other high risk groups such as patients with moyamoya,
| Clinical Evaluation|| |
The first step in evaluating the child presenting with an acute focal neurological syndrome is to identify its underlying cause. Brain imaging is mandatory in the assessment of children with this presentation given the wide range of differential diagnoses. Brain CT will enable identification of pathologies requiring acute intervention e.g., intracranial hemorrhage. CT may be normal for up to 24h following an acute arterial or venous infarct; if MRI is not available CT may need to be repeated after an interval in order to identify cerebral infarction unless there is a clear alternative explanation for the clinical picture. Diagnoses such as Todd's paresis or hemiplegic migraine should be made only after exclusion of vascular pathology. Infarction secondary to venous thrombosis should be considered if the clinical circumstances or radiological pattern of injury are suggestive, e.g. multifocal infarction and investigations might need to be specifically targeted to identify this diagnosis.
Half of children with AIS seen at tertiary centers will have another diagnosis associated with AIS; the remainder are healthy prior to the stroke. Once the diagnosis of AIS has been confirmed by imaging, the focus of evaluation should be to identify potentially modifiable risk factors. These include infection, cardiac abnormalities, SCD, acute disorders of coagulation and cerebral arteriopathies. A detailed clinical history, focusing on common risk factors for AIS such as infection (including previous varicella), fever and head trauma and a thorough clinical examination (including examination of the skin for neurocutaneous abnormalities) is essential. Risk factors commonly co-exist in individual children.
SCD is the commonest cause of childhood AIS worldwide; 10% of the children with SCD have AIS before the age of 20. A further 20% have evidence of "silent infarcts", i.e., ischemic brain injury without an acute clinical correlate. While the HbSS phenotype is associated with the highest rate of stroke, patients with both HbSC and HbSbthal are also at risk. The risk of stroke associated with SCD varies in populations of different ethnicity due to variations in SCD phenotype. Risk factors for AIS in SCD include anemia, high white cell count, chest crises, silent infarction and nocturnal hypoxemia. Children with SCD who have a moyamoya pattern of arteriopathy are at high risk of recurrent events. Without intervention, two thirds of patients with SCD who have one AIS will have recurrence. Regular blood transfusion to maintain HbS <30% reduces this to around 10% but is associated with significant long-term morbidity. AIS is an indication for bone marrow transplantation (BMT) in SCD. Although early results of BMT are promising, lack of donors and cost means that this option is only feasible for a very small number of patients. Research into alternative treatments such as hydroxyurea, aspirin and oxygen supplementation is ongoing.
Over 80% of children with AIS have abnormalities of the cerebral circulation, most commonly stenosis or occlusion of large intracranial arteries. The high prevalence of arterial pathology was identified initially on studies using catheter angiography but is also evident if MR angiography is used for vascular imaging. Sebire et al. recently proposed a classification of childhood cerebral arteriopathies in order to standardize description and enable comparison between different populations. The most commonly identified of these is the transient cerebral arteriopathy (TCA), an entity manifesting as occlusive disease of the carotid fork or proximal PCA within three months of AIS and without evidence of progression on re-imaging within six months of AIS [Figure - 1]. In patients where the arteriopathy is associated with preceding varicella infection within 12 months it is termed postvaricella angiopathy. TCA is likely to have an underlying inflammatory basis although, other than after varicella infection, this has not been proven. Moyamoya describes a relatively rare cerebral arteriopathy with occlusive disease of the terminal internal carotid arteries and the formation of basal collateral vessels. Idiopathic momoyamoya is a condition with high prevalence in Japanese, although it has also been identified in many other ethnic groups. This pattern of arteriopathy has also been observed secondary to many conditions for example, Down syndrome, cranial irradiation and seems to be a marker for more aggressive disease course in sickle cell disease. It is also associated with a high rate of clinical and subclinical recurrence in children without SCD [Figure - 2].
An important exception to the dictum that arteriopathy in childhood AIS affects intracranial vessels is arterial dissection, which usually affects the cervical ICA or vertebral artery [Figure - 3]. This accounts for up to 15% of cases in some series, is more common in males and is commonly spontaneous, without antecedent trauma. Investigation of a child presenting with AIS thus requires imaging of the arterial vasculature from the aortic arch to the circle of Willis. Where MRI is available both the brain and the cerebral circulation can be imaged in a single examination. Ultrasound can be used to examine the cervical carotid arteries and in skilled hands is a reasonably sensitive means to identify dissection. CT angiography is becoming more widely available but as yet its sensitivity and specificity for detection of arteriopathy in childhood AIS has not been established. Catheter angiography remains the gold standard for cerebrovascular imaging and may be required to identify dissection of the posterior circulation or cerebral vasculitis. However, it is currently a second line investigation and is usually only undertaken if there is diagnostic uncertainty continues following investigation with noninvasive modalities.
AIS can be a presenting feature of both congenital and acquired cardiac disease. Children with congenital heart disease have multiple risk factors for AIS, including abnormal anatomy, poor cardiac function, anemia, polycythemia and, in particular, cardiac interventions, including catheterization and cardiopulmonary bypass. Although brain injury commonly becomes clinically symptomatic after invasive procedures, many of these children have evidence of focal arterial territory injury prior to intervention. Structural abnormalities of the heart or large arteries are common in children with cerebral arteriopathies such as moyamoya. A detailed clinical examination of the cardiovascular system, including examination of peripheral pulses and blood pressure, is essential. Echocardiography should be carried out to evaluate cardiac anatomy and function. There is no data regarding the relative yield of tranthoracic vs. transoesophageal echocardiography (TOE) in childhood AIS. In most centers TOE is reserved for children in whom no other AIS risk factors are identified, largely to exclude patent foramen ovale (PFO). The significance of PFO in childhood AIS remains unclear; although it is a risk factor for AIS in young adults, PFO is common in children. Moreover venous thrombosis, as a source for paradoxical embolism, is rare in this age group.
The proportion of AIS related to CNS infection, for example meningitis, is likely to be more significant in developing countries. Infection with varicella zoster has been shown to be associated with childhood AIS; the interval between varicella and AIS may be up to a year. Postvaricella cerebral infarction most commonly affects young children. Imaging shows an arteriopathy affecting the proximal segment of the middle cerebral artery and infarction typically affects basal ganglia structures. The arteriopathy is commonly transient and is thought to be inflammatory in origin.
Reported rates of genetically determined thrombophilia associated with first AIS vary greatly between different studies, reflecting the strong influence on factors such as ethnicity on thrombophilia prevalence in populations.,, Acquired prothrombotic states, such as deranged coagulation in the context of sepsis, have also been identified as potential risk factors for AIS. Data from the German multi-center study has suggested that protein C deficiency and reduced levels of lipoprotein (a) are risk factors for stroke recurrence. The role of thrombophilia screening in children with AIS remains contentious, as there is little evidence to support a role for genetic thrombophilia in arterial, as opposed to venous thrombotic disease. Moreover, identification of thrombophilia does not currently alter clinical management and thus it may be difficult to justify the cost involved, particularly in the context of limited resources.
Although many risk factors have been described for childhood AIS, in practical terms those which are potentially modifiable or which affect acute management are sepsis, hypoxia, SCD, anemia, cardiac disease, dissection and an active coagulopathy. Thus a minimum evaluation panel could comprise measuring oxygen saturation, hemoglobin, hemoglobin electrophoresis, standard coagulation profile, echocardiography and some form of cerebrovascular imaging, either with ultrasound or magnetic resonance, in addition to evaluation for of sepsis. Investigation could be extended to identify other risk factors with treatment implications, such as vasculitis or thrombophilia, if this initial evaluation is negative or of there are suggestive clinical features, for example, raised inflammatory markers or multisystem involvement. Although comprehensive evaluation is important in that the presence of multiple risk factors is associated with recurrence, in light of the limited treatment options currently available, it is reasonable to adopt a focused approach, particularly where resources might be limited.
| Management|| |
Initial management of the child with AIS should be directed towards identification and treatment of deranged homeostasis, for example, depressed conscious level, hypotension, hypoxia or fever. Blood pressure should be maintained at an adequate level to maximize cerebral perfusion; hypertension should not be treated unless the child is symptomatic. Likewise, fever should be treated as data from experimental models suggests that this may limit the extent of the eventual infarct. Children with depressed conscious level should be referred early for a neurosurgical opinion.
To date there is little evidence on which to base acute treatments for childhood AIS. There is much agreement but also some divergence of opinion between the two sets of clinical guidelines on pediatric stroke ("Chest" guidelines and Royal College of Physicians guidelines (available at http://www. rcplondon.ac.uk/pubs/books/childstroke)), reflecting the lack of data underpinning the recommendations. [Table - 1] summarizes these management recommendations. Essentially acute treatment options are (i) exchange transfusion for AIS in SCD (ii) anticoagulation for cardioembolic stroke or arterial dissection or (iii) aspirin. The UK guidelines recommend starting aspirin and then switching to anticoagulation if AIS is cardioembolic or secondary to dissection, whereas the "Chest" guidelines recommend a short period of anticoagulation in all patients pending further investigation. Although there are anecdotal reports of its use, thrombolysis, either systemic or intravascular, is not advocated for the acute treatment of childhood AIS. The risk to benefit ratios for thrombolysis are likely to be different in children compared with adults; however, few children are identified within the currently accepted time window for thrombolysis and the risk of intracranial hemorrhage is likely to be significant.
| Recurrence and Secondary Prevention|| |
Until relatively recently, childhood AIS was thought to usually be an isolated event. However, the recent literature reports rates of clinical recurrence of between 5 and 30%, [Ganesan et al. , in press]. It is also now recognized that children other than those with SCD and moyamoya may have recurrent infarction without clinical manifestation.
Chronic blood transfusion, maintaining HbS <30%, significantly reduces stroke recurrence rate in children with SCD; however, a proportion of patients recur despite transfusion. Adjunctive treatments, such as revascularization for moyamoya, may have a role in such patients. Patients with cardioembolic stroke may be anticoagulated to prevent recurrent events; the optimal duration and intensity of treatment will depend on the underlying etiology and is likely to be a matter of clinical judgement. Children with extracranial arterial dissection are usually anticoagulated for around six months, although the evidence that this is effective in secondary prevention is largely anecdotal.
Surgical revascularization (SR) describes group of operations, which have the end result of providing an alternative source of blood to the ischemic brain in patients with moyamoya. This can be achieved either by direct arterial anastomosis of branches of the internal and external carotid arteries or by introducing a source of blood, for example temporalis muscle, onto the surface of the brain. The role, timing and efficacy of SR in moyamoya remain contentious issues, particularly in non-Japanese patients and in patients with other disorders, such as SCD. Despite the lack of clinical trials, however, there is a substantial body of anecdotal evidence to supportive the efficacy of SR in patients with moyamoya.
| Outcome|| |
It is a common fallacy that children recover AIS. Although patterns of recovery after focal lesions are different in children compared with adults, two thirds of children have residual sequelae after AIS, most commonly affecting motor function., As childhood AIS commonly affects the basal ganglia, motor impairment often manifests as hemidystonia. This may only be apparent after a relatively "silent" interval. Whilst severity of impairment varies widely between individuals, they have a significant impact on the child's quality of life and on the family as a whole. Pediatric therapy services are commonly modeled on management of children with cerebral palsy and thus may find the management of a child with changing needs and pattern of impairment challenging.
Clinical experience suggests that childhood AIS has significant behavioral and cognitive sequelae; however, at present these effects are relatively under-researched and are frequently not identified. A third of parents report that their child's behavior was affected by AIS; over half of children were found to have abnormal scores on the Strengths and Difficulties questionnaire, with abnormal scores occurring in all domains (Wraige and Ganesan, unpublished observation). These relatively "invisible" impairments resulting from childhood AIS may not be apparent for some time until the child meets progressively more demanding cognitive and social challenges. Impairments related to childhood AIS have major consequences, not only for the individual but also for society as a whole; for example, half of children with SCD and silent infarction will require lifelong support or residential care.
| Primary Prevention|| |
The only studies of primary prevention of childhood AIS have been undertaken in patients with SCD. The landmark STOP study established that transcranial Doppler ultrasound could be used to identify presymptomatic children in whom blood transfusion was extremely effective in preventing stroke. Application of the screening and transfusion procedure recommended as a result of this study significantly reduced rates of stroke in Californian children; however, financial and logistic barriers, as well as the major morbidity associated with transfusion have meant that primary prevention has only been offered to a small proportion of children with SCD worldwide. Disappointingly, the results of STOP2, published recently, suggest that discontinuation of transfusion results in reversal of any improvement of vascular abnormalities, suggesting that transfusion has to be continued in order to prevent AIS.
| Perinatal AIS|| |
There are important distinctions in etiology, clinical presentation and outcome between AIS in neonates and in older children. This section will consider AIS occurring before 28 days of life and will therefore include patients with prenatal and perinatal AIS, defined as focal arterial territory infarction. Patients with global hypoxic or ischemic brain injury or watershed infarction are not considered here.
The incidence of perinatal AIS is difficult to estimate as only a proportion of affected patients present clinically at the time of the event (symptomatic AIS, estimated incidence 1 in 4000 live births); a further proportion present in the first year of life with signs of emergent hemiparesis. It is also likely that AIS is clinically silent in a proportion of children and thus comprehensive epidemiological studies are difficult. The literature on this topic is complicated by major variations in cases included. Despite the lack of comprehensive incidence data, it is striking that mortality related to stroke in the USA is higher in the first year of life than at any other time during childhood and young adulthood.
Arterial ischemic stroke is predominantly a disorder of term-born infants. Studies have consistently shown a higher rate in left sided brain injury, possibly related to anatomical factors and a higher rate in males. Clinical presentation of symptomatic AIS in the neonatal period is most commonly with seizures. Lateralizing clinical signs are frequently absent; however, subtle signs on assessments such as the assessment of general movements may be apparent from as early as -three to six weeks of ages in children who go on to manifest hemiplegia. Up to 15% of neonatal seizures are attributable to AIS. Other signs, such as poor feeding or lethargy, are relatively nonspecific.
Data regarding the mechanisms underlying perinatal AIS are largely speculative. Thromboembolism from the placenta is thought to be one such mechanism, with contributions from both prothombotic risk factors and the derangements in coagulation associated with pregnancy and infection. Estan and Hope did not find an excess of adverse perinatal factors in children with perinatal AIS compared with controls, other than a low one minute Apgar score and need for assisted ventilation. However, a recent case-control study from northern California reported an excess of several maternal, pregnancy and delivery related factors, such as primiparity, pre-eclampsia, oligohydramnios, abnormal fetal heart rate, emergency caesarean section, chorioamnionitis, prolonged rupture of membranes, prolonged second stage and vacuum extraction; some of these factors were also identified by other groups. However, it is difficult to know whether these are causal factors or whether some reflect the unfavorable condition of the baby secondary to recent AIS.
As with older children, variable data has been reported regarding the role of thrombophilia in perinatal AIS, with genetic and acquired abnormalities (elevated lipoprotein (a), FVL mutation, protein C deficiency andticardiopilin antibodies) being reported in 40 - 60% of cases. Many of these children will have other risk factors for thrombosis, such as sepsis or dehydration. Mercuri et al found that the presence of the FVL mutation was associated with worse outcome. While identification of many of these abnormalities will not affect clinical management, major prothrombotic abnormalities, such as protein C or S deficiency, will require specific treatment and thus prothrombotic screening is advocated in children with perinatal AIS. This should include identification of maternal antiphospholipid antibodies, which may have management implications for the mother. The exact range of disorders, which are screened for will be influenced by the local population characteristics. For economic reasons it would be reasonable to decide, in conjunction with a hematologist, to only look for those disorders which are going to directly affect treatment of the mother or child.
Less common causes of perinatal AIS include dissection of the cervical arteries during delivery, maternal cocaine abuse, neonatal meningitis or congenital heart disease. As with older children, risk factors commonly co-exist and their interaction is thought to be important in the genesis of perinatal AIS.,
Most lesions affect the territory of the middle cerebral artery. As with the older child, cerebral infarction in symptomatic newborns can be identified using MRI or CT. In neonates who are symptomatic in the first few days following birth, diffusion-weighted MRI may contribute to timing brain injury and, in particular, whether this occurred before birth or in the immediate perinatal period. Cranial ultrasound has a reasonable sensitivity but poorer specificity for identification of AIS and may serve as a useful screening test. However, more detailed imaging should be undertaken in cases where ultrasound remains equivocal or for improving prognostic prediction. There is little data on vascular imaging in prenatal AIS although studies investigating this are underway.
Currently only the "Chest" guidelines address the management of perinatal AIS. Anticoagulation is advocated for cardioembolic AIS but no treatment is recommended for the remainder of cases. Recurrence is rare in children with symptomatic AIS; Kurnik et al identified recurrent thrombosis in seven of 215 such children. Of note, six of these events involved the nervous system (AIS in four and venous sinus thrombosis in two) and five of these children had prothrombotic abnormalities, often in conjunction with another risk factor for thrombosis.
Perinatal AIS accounts for at least half of all cases of hemiplegic cerebral palsy. However, around half of children with perinatal AIS have no long term-sequelae. Motor outcome of perinatal AIS can be predicted to some extent in that concurrent involvement of the basal ganglia, internal capsule and cerebral cortex is associated with hemiplegia. However, such predictions are not possible in older children in whom neither site nor size of lesion enables confident prognostication., Data from the northern California group found that large lesions and those involving Broca's area, Wernicke's area, internal capsule or basal ganglia were more likely to be associated with cerebral palsy; however, this study only included children who had been imaged, presumably due to clinical concerns and thus may overestimate both the rate of adverse outcomes (around 80%) and the relative contribution of different lesion patterns. Longer term follow-up of newborns with perinatal infarction suggests that more subtle motor impairments are apparent at school age in some of those without early hemiparesis, especially if the lesion involves the internal capsule. Newer magnetic resonance techniques, such as diffusion tensor imaging, may enable improved characterization of processes such as Wallerian degeneration More Details which may correlate more closely with motor outcome., Early EEG may also provide prognostic information; Mercuri et al found that infants with an abnormal background, as opposed to epileptiform discharges, were more likely to develop hemiplegia. In the longer term, up to 40% of patients may have epilepsy. Visual function may be affected in around a quarter of children, especially those with larger lesions and hemiplegia. Interestingly, in the context of the discussion above regarding older children, a recent case control study did not identify an increased rate of emotional or behavioral sequelae in children with perinatal AIS (and other focal pathologies) compared with controls.
| References|| |
|1.||Ganesan V, Prengler M, McShane MA, Wade AM, Kirkham FJ. Investigation of risk factors in children with arterial ischemic stroke. Ann Neurol 2003;53:167-73. [PUBMED] [FULLTEXT]|
|2.||Lynch JK, Hirtz DG, DeVeber G, Nelson KB. Report of the National Institute of Neurological Disorders and Stroke workshop on perinatal and childhood stroke. Pediatrics 2002;109:116-23. [PUBMED] [FULLTEXT]|
|3.||Giroud M, Lemesle M, Gouyon JB, Nivelon JL, Milan C, Dumas R. Cerebrovascular disease in children under 16 years of age in the city of Dijon, France: A study of incidence and clinical features from 1985 to 1993. J Clin Epidemiol 1995;48:1343-8. [PUBMED] [FULLTEXT]|
|4.||Fullerton HJ, Chetkovich DM, Wu YW, Smith WS, Johnston SC. Deaths from stroke in US children, 1979 to 1998. Neurology 2002;59:34-9. [PUBMED] [FULLTEXT]|
|5.||Fullerton HJ, Wu YW, Zhao S, Johnston SC. Risk of stroke in children: Ethnic and gender disparities. Neurology 2003;61:189-94. [PUBMED] [FULLTEXT]|
|6.||Mercuri E, Faundez JC, Roberts I, Flora S, Bouza H, Cowan F, et al . Neurological 'soft' signs may identify children with sickle cell disease who are at risk for stroke. Eur J Pediatr 1995;154:150-6. [PUBMED] |
|7.||Rolfs A, Bottcher T, Zschiesche M, Morris P, Winchester B, Bauer P, et al . Prevalence of Fabry disease in patients with cryptogenic stroke: A prospective study. Lancet 2005;366:1794-6. |
|8.||Lee MC, Frank JI, Kahana M, Tonsgard JH, Frim DM. Decompressive hemicraniectomy in a 6-year-old male after unilateral hemispheric stroke. Case report and review. Pediatr Neurosurg 2003;38:181-5. |
|9.||Hoppe C. Defining stroke risk in children with sickle cell anaemia. Br J Haematol 2005;128:751-66. [PUBMED] [FULLTEXT]|
|10.||Schatz J, Brown RT, Pascual JM, Hsu L, DeBaun MR. Poor school and cognitive functioning with silent cerebral infarcts and sickle cell disease. Neurology 2001;56:1109-11. [PUBMED] [FULLTEXT]|
|11.||Baldeweg T, Hogan AM, Saunders DE, Telfer P, Gadian DG, Vargha-Khadem F, et al . Detecting white matter injury in sickle cell disease using voxel-based morphometry. Ann Neurol 2006;59:662-72. [PUBMED] [FULLTEXT]|
|12.||Lanthier S, Carmant L, David M, Larbrisseau A, de Veber G. Stroke in children: The coexistence of multiple risk factors predicts poor outcome. Neurology 2000;54:371-8. [PUBMED] [FULLTEXT]|
|13.||Kirkham FJ, Hewes DK, Prengler M, Wade A, Lane R, Evans JP. Nocturnal hypoxaemia and central-nervous-system events in sickle-cell disease. Lancet 2001;357:1656-9. [PUBMED] [FULLTEXT]|
|14.||Dobson SR, Holden KR, Nietert PJ, Cure JK, Laver JH, Disco D, et al . Moyamoya syndrome in childhood sickle cell disease: A predictive factor for recurrent cerebrovascular events. Blood 2002;99:3144-50. [PUBMED] [FULLTEXT]|
|15.||Kirkham FJ, Lerner NB, Noetzel M, DeBaun MR, Datta AK, Rees DC, et al . Trials in sickle cell disease. Pediatr Neurol 2006;34:450-8. [PUBMED] [FULLTEXT]|
|16.||Shirane R, Sato S, Yoshimoto T. Angiographic findings of ischemic stroke in children. Childs Nerv Syst 1992;8:432-6. [PUBMED] |
|17.||Husson B, Lasjaunias P. Radiological approach to disorders of arterial brain vessels associated with childhood arterial stroke-a comparison between MRA and contrast angiography. Pediatr Radiol 2004;34:10-5. [PUBMED] [FULLTEXT]|
|18.||Sebire G, Fullerton H, Riou E, deVeber G. Toward the definition of cerebral arteriopathies of childhood. Curr Opin Pediatr 2004;16:617-22. |
|19.||Fullerton HJ, Johnston SC, Smith WS. Arterial dissection and stroke in children. Neurology 2001;57:1155-60. [PUBMED] [FULLTEXT]|
|20.||Benninger DH, Georgiadis D, Gandjour J, Baumgartner RW. Accuracy of color duplex ultrasound diagnosis of spontaneous carotid dissection causing ischemia. Stroke 2006;37:377-81. [PUBMED] [FULLTEXT]|
|21.||Ganesan V, Savvy L, Chong WK, Kirkham FJ. Conventional cerebral angiography in children with ischemic stroke. Pediatr Neurol 1999;20:38-42. [PUBMED] [FULLTEXT]|
|22.||McQuillen PS, Hamrick SE, Perez MJ, Barkovich AJ, Glidden DV, Karl TR, et al . Balloon atrial septostomy is associated with preoperative stroke in neonates with transposition of the great arteries. Circulation 2006;113:280-5. [PUBMED] [FULLTEXT]|
|23.||Salih MA, Abdel-Gader AG, Al-Jarallah AA, Kentab AY, Gadelrab MO, Alorainy IA, et al . Infectious and inflammatory disorders of the circulatory system as risk factors for stroke in Saudi children. Saudi Med J 2006;27:S41-52. |
|24.||Sebire G, Meyer L, Chabrie S. Varicella as a risk factor for cerebral infarction in childhood: A case-control study. Ann Neurol 1999;45:679-80. |
|25.||Chabrier S, Husson B, Lasjaunias P, Landrieu P, Tardieu M. Stroke in childhood: Outcome and recurrence risk by mechanism in 59 patients. J Child Neurol 2000;15:290-4. [PUBMED] |
|26.||Nowak-Gottl U, Strater R, Heinecke A, Junker R, Koch HG, Schuierer G, et al . Lipoprotein (a) and genetic polymorphisms of clotting factor V, prothrombin and methylenetetrahydrofolate reductase are risk factors of spontaneous ischemic stroke in childhood. Blood 1999;94:3678-82. |
|27.||deVeber G, Monagle P, Chan A, MacGregor D, Curtis R, Lee S, et al . Prothrombotic disorders in infants and children with cerebral thromboembolism. Arch Neurol 1998;55:1539-43. [PUBMED] [FULLTEXT]|
|28.||Haywood S, Liesner R, Pindora S, Ganesan V. Thrombophilia and first arterial ischaemic stroke: A systematic review. Arch Dis Child 2005;90:402-5. [PUBMED] [FULLTEXT]|
|29.||Strater R, Becker S, von Eckardstein A, Heinecke A, Gutsche S, Junker R, et al . Prospective assessment of risk factors for recurrent stroke during childhood - a 5-year follow-up study. Lancet 2002;360:1540-5. |
|30.||Monagle P, Chan A, Massicotte P, Chalmers E, Michelson AD. Antithrombotic therapy in children: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:645S-87S. [PUBMED] [FULLTEXT]|
|31.||DeVeber G. In pursuit of evidence-based treatments for paediatric stroke: The UK and Chest guidelines. Lancet Neurol 2005;4:432-6. [PUBMED] [FULLTEXT]|
|32.||Gruber A, Nasel C, Lang W, Kitzmuller E, Bavinzski G, Czech T. Intra-arterial thrombolysis for the treatment of perioperative childhood cardioembolic stroke. Neurology 2000;54:1684-6. |
|33.||Gabis LV, Yangala R, Lenn NJ. Time lag to diagnosis of stroke in children. Pediatrics 2002;110:924-8. [PUBMED] [FULLTEXT]|
|34.||Roach ES. Immediate surgery for moyamoya syndrome? Not necessarily. Arch Neurol 2001;58:130-1. |
|35.||Fryer RH, Anderson RC, Chiriboga CA, Feldstein NA. Sickle cell anemia with moyamoya disease: Outcomes after EDAS procedure. Pediatr Neurol 2003;29:124-30. [PUBMED] [FULLTEXT]|
|36.||Fung LW, Thompson D, Ganesan V. Revascularisation surgery for paediatric moyamoya: A review of the literature. Childs Nerv Syst 2005;21:358-64. [PUBMED] [FULLTEXT]|
|37.||Ganesan V, Hogan A, Shack N, Gordon A, Isaacs E, Kirkham FJ. Outcome after ischaemic stroke in childhood. Dev Med Child Neurol 2000;42:455-61. [PUBMED] [FULLTEXT]|
|38.||deVeber GA, MacGregor D, Curtis R, Mayank S. Neurologic outcome in survivors of childhood arterial ischemic stroke and sinovenous thrombosis. J Child Neurol 2000;15:316-24. [PUBMED] |
|39.||Gordon AL, Ganesan V, Towell A, Kirkham FJ. Functional outcome following stroke in children. J Child Neurol 2002;17:429-34. [PUBMED] |
|40.||Schatz J, White DA, Moinuddin A, Armstrong M, DeBaun MR. Lesion burden and cognitive morbidity in children with sickle cell disease. J Child Neurol 2002;17:891-5. [PUBMED] |
|41.||Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, et al . Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998;339:5-11. [PUBMED] [FULLTEXT]|
|42.||Fullerton HJ, Adams RJ, Zhao S, Johnston SC. Declining stroke rates in Californian children with sickle cell disease. Blood 2004;104:336-9. [PUBMED] [FULLTEXT]|
|43.||Adams RJ, Brambilla D; Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) Trial Investigators. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N Engl J Med 2005;353:2769-78. [PUBMED] [FULLTEXT]|
|44.||Mercuri E, Cowan F, Gupte G, Manning R, Laffan M, Rutherford M, et al . Prothrombotic disorders and abnormal neurodevelopmental outcome in infants with neonatal cerebral infarction. Pediatrics 2001;107:1400-4. [PUBMED] [FULLTEXT]|
|45.||Nelson KB, Lynch JK. Stroke in newborn infants. Lancet Neurol 2004;3:150-8. [PUBMED] [FULLTEXT]|
|46.||Golomb MR, Dick PT, MacGregor DL, Curtis R, Sofronas M, deVeber GA. Neonatal arterial ischemic stroke and cerebral sinovenous thrombosis are more commonly diagnosed in boys. J Child Neurol 2004;19:493-7. [PUBMED] |
|47.||Estan J, Hope P. Unilateral neonatal cerebral infarction in full term infants. Arch Dis Child Fetal Neonatal Ed 1997;76:F88-93. [PUBMED] [FULLTEXT]|
|48.||Guzzetta A, Mercuri E, Rapisardi G, Ferrari F, Roversi MF, Cowan F, et al . General movements detect early signs of hemiplegia in term infants with neonatal cerebral infarction. Neuropediatrics 2003;34:61-6. [PUBMED] [FULLTEXT]|
|49.||Lee J, Croen LA, Backstrand KH, Yoshida CK, Henning LH, Lindan C, et al . Maternal and infant characteristics associated with perinatal arterial stroke in the infant. JAMA 2005;293:723-9. [PUBMED] [FULLTEXT]|
|50.||Mercuri E, Rutherford M, Cowan F, Pennock J, Counsell S, Papadimitriou M, et al . Early prognostic indicators of outcome in infants with neonatal cerebral infarction: A clinical, electroencephalogram and magnetic resonance imaging study. Pediatrics 1999;103:39-46. [PUBMED] [FULLTEXT]|
|51.||Chalmers EA. Perinatal stroke - risk factors and management. Br J Haematol 2005;130:333-43. [PUBMED] [FULLTEXT]|
|52.||Cowan F, Mercuri E, Groenendaal F, Bassi L, Ricci D, Rutherford M, et al . Does cranial ultrasound imaging identify arterial cerebral infarction in term neonates? Arch Dis Child Fetal Neonatal Ed 2005;90:F252-6. [PUBMED] [FULLTEXT]|
|53.||Kurnik K, Kosch A, Strater R, Schobess R, Heller C, Nowak-Gottl U, et al . Recurrent thromboembolism in infants and children suffering from symptomatic neonatal arterial stroke: A prospective follow-up study. Stroke 2003;34:2887-92. |
|54.||Boardman JP, Ganesan V, Rutherford MA, Saunders DE, Mercuri E, Cowan F. Magnetic resonance image correlates of hemiparesis after neonatal and childhood middle cerebral artery stroke. Pediatrics 2005;115:321-6. [PUBMED] [FULLTEXT]|
|55.||Ganesan V, Ng V, Chong WK, Kirkham FJ, Connelly A. Lesion volume, lesion location and outcome after middle cerebral artery territory stroke. Arch Dis Child 1999;81:295-300. [PUBMED] [FULLTEXT]|
|56.||Lee J, Croen LA, Lindan C, Nash KB, Yoshida CK, Ferriero DM, et al . Predictors of outcome in perinatal arterial stroke: A population-based study. Ann Neurol 2005;58:303-8. [PUBMED] [FULLTEXT]|
|57.||Mercuri E, Barnett A, Rutherford M, Guzzetta A, Haataja L, Cioni G, et al . Neonatal cerebral infarction and neuromotor outcome at school age. Pediatrics 2004;113:95-100. [PUBMED] [FULLTEXT]|
|58.||Khong PL, Zhou LJ, Ooi GC, Chung BH, Cheung RT, Wong VC. The evaluation of Wallerian degeneration in chronic paediatric middle cerebral artery infarction using diffusion tensor MR imaging. Cerebrovasc Dis 2004;18:240-7. [PUBMED] [FULLTEXT]|
|59.||de Vries LS, Van der Grond J, Van Haastert IC, Groenendaal F. Prediction of outcome in new-born infants with arterial ischaemic stroke using diffusion-weighted magnetic resonance imaging. Neuropediatrics 2005;36:12-20. [PUBMED] [FULLTEXT]|
|60.||Mercuri E, Anker S, Guzzetta A, Barnett A, Haataja L, Rutherford M, et al . Neonatal cerebral infarction and visual function at school age. Arch Dis Child Fetal Neonatal Ed 2003;88:F487-91. [PUBMED] [FULLTEXT]|
|61.||Trauner DA, Nass R, Ballantyne A. Behavioural profiles of children and adolescents after pre- or perinatal unilateral brain damage. Brain 2001;124:995-1002. [PUBMED] [FULLTEXT]|
[Figure - 1], [Figure - 2], [Figure - 3]
[Table - 1]