Cardiac Abnormalities

Cardiac procedures, including catheterization, extracorporeal membrane oxygenation, and surgery, are all considered risk factors for childhood AIS. These cardiac procedures are all likely mediated from a heart embolus. Congenital heart disease ( Fig. 1 ), valvular heart disease, cardiac arrhythmias, and cardiomyopathy are also risk factors for childhood AIS. Abnormalities of the cardiac valves, major vessels, and myocardium may result in turbulent blood flow and the formation of a thrombus that can embolus to the cerebral vessels, which is particularly a problem in children with a right-to-left shunt. In a retrospective national database review of children with AIS, the most frequent comorbidity was noted to be congenital heart disease. Almost 25% of children diagnosed with AIS in the Canadian Registry had cardiac disease at presentation. In another childhood AIS cohort study, 28% of the children had cardiac abnormalities.

A 1-year-old child who presented with lethargy, encephalopathy, and seizures with a history of an atrial septal defect, ventricular septal defect, and transposition of great vessels. ( A ) Axial contrast-enhanced CT thorax ( white arrow ) shows a large ventricular septal defect (VSD). ( B ) Axial diffusion-weighted MRI of the brain shows abnormal high signal within the right frontal lobe, basal ganglia, and thalamus ( white arrow ); this is low signal on the corresponding apparent diffusion coefficient (ADC) ( C ). ( D ) Axial diffusion-weighted MRI image of the brain in same patient shows areas of high signal within both frontal lobes, which is low signal on the corresponding ADC map ( E ). These findings are consistent with embolic AIS in multiple vascular distributions from the patient’s congenital heart disease.

Hypertension may also be a risk factor for childhood AIS. Ganesan and colleagues showed an association with vasculopathy and systolic hypertension. Lo and colleagues also found that hypertension was a risk factor for pediatric stroke. It is hypothesized that hypertension in children may be related to chronic anemia, comorbid medical conditions, or a systemic response to an acquired vasculopathy.

It is uncertain if a patent foramen ovale (PFO) is a significant risk factor for childhood AIS. In 4 of 6 children with idiopathic AIS, transcranial Doppler with Valsalva suggested a right-to-left shunt. PFO is a known risk factor for AIS in the adult literature; however, the incidence of a PFO in healthy children is unknown.

Sickle Cell Disease

Sickle cell disease (SCD) is one of the most common causes for AIS in childhood, particularly among individuals such as African Americans, of recent historical descent from populations inhabiting malaria-endemic regions. The prevalence of cerebrovascular events in patients with SCD is reported to be 4.0% and the incidence 0.6 per 100 patient-years. The highest risk for stroke is between the ages of 2 and 5 years of age. The risk of recurrence is as high as 67%. AIS in SCD is largely related to occlusive disease of in the terminal internal carotid artery (TICA)/proximal middle cerebral artery (MCA)/anterior cerebral artery (ACA), which is caused by endothelial injury from the deformed erythrocytes. Other factors, such as anemia and hypoxemia, may additionally predispose to AIS. Pathologic features of SCD are often associated with thrombotic occlusion and the presence of collateral vessels. Blood transfusion, aiming to reduce the circulating level of Hemoglobin S (HbS) and correct anemia sufficiently to suppress bone marrow production of HbS, is extremely effective in both primary and secondary prevention of AIS. The standard of care in many countries is now to institute screening for cerebrovascular disease in children with SCD using transcranial Doppler ultrasound from the age of 2 years, at annual intervals, and instituting blood transfusion for those with abnormally elevated velocity in the middle cerebral arteries. Blood transfusion is also recommended for children who have had clinical AIS, for secondary prevention. Unfortunately, despite its efficacy, blood transfusion places a major burden on the child and family, as well as carrying medical risks such as blood-borne infection. The logistics of blood transfusion also make it impossible in resource-poor settings. There is ongoing research into the role of other therapies, such as hydroxyurea. Bone marrow transplantation may be considered in children with AIS but the major hurdle with this is identifying a suitable donor. Patients with SCD who have a moyamoya morphology of occlusive disease terminal internal carotid artery (TICA), M1 segment of the middle cerebral artery (M1), A1 segment of the anterior cerebral artery (A1) (TICA/M1/A1 occlusive disease with basal collaterals) are at highest risk of recurrence. Surgical revascularization may have a role in such individuals but the role of surgery in the context of the overall management of SCD is as yet unclear.

Moyamoya

Moyamoya is a radiological term characterized by bilateral stenosis of the distal internal carotid arteries with lenticulostriate collateralization that results in the pathognomonic “puff of smoke” appearance ( Fig. 2 ) on conventional cerebral angiogram and is diagnosed in up to 20% of childhood AIS. The condition is common in Japan and East Asia, where familial cases are also clearly recognized. Currently several genetic loci have been implicated in these. The disease definition relates to Japanese patients and the degree of radiological and phenotypic overlap between them and patients of other ethnicities is not clear. Moyamoya may be apparently idiopathic (moyamoya disease) or secondary to a large variety of other conditions (moyamoya syndrome), including trisomy 21, neurofibromatosis type 1, and cranial irradiation. This wide spectrum of associations suggests multiple mechanisms are implicated in the genesis of the arteriopathy. Unfortunately the term is used very loosely in clinical practice and in the literature and is commonly applied in cases of bilateral TICA disease, whether or not the other radiological features are present. The genetics literature describing moyamoya as a feature of many disorders is likely, in fact, to reflect a variety of entities. An example of this is the very distinctive radiological phenotype of cerebral arteriopathy associated with mutations in the alpha-actin-2 (ACTA2) gene, initially described as “moyamoya.” In contrast, these patients have several distinctive radiological features, namely proximal ectasia, distal occlusive disease, absence of basal collaterals, and an unusually straight morphology of the intracranial arteries. Because this mutation is dominantly inherited and predisposes to aortic aneurysms, it is an important condition to identify by the radiological signature. There are likely to be further examples of distinctive phenotypes, currently subsumed under imprecise application of the term “moyamoya.”

A 7-year-old boy who presented with headache and weakness in the right upper extremity. ( A ) Axial fluid-attenuated inversion recovery (FLAIR) MRI of the brain shows an area of chronic ischemia with the watershed distribution of the left anterior cerebral artery (ACA) and middle cerebral artery (MCA) ( white arrow ). ( B ) Axial CTA image of the circle of Willis shows a “puff of smoke” in the bilateral basal ganglia ( white arrow ). ( C ) Frontal right internal carotid angiogram shows narrowing of the right supraclinoid, A1, and M1 segments with a “puff of smoke” in the basal ganglia ( white arrow ). ( D ) Frontal left internal carotid angiogram also shows narrowing of the left supraclinoid, A1, and M1 segments with a “puff of smoke” in the basal ganglia ( white arrow ). There is a decreased capillary blush between the left ACA and MCA, consistent with the findings on the MRI shown in ( A ). These findings are consistent with moyamoya and an old watershed infarct between the left ACA and left MCA territory.

Arterial Dissection

Dissection of the cervical arterial arteries is said to account for 15% to 20% of AIS in children; this is largely seen in older children and adolescents and is usually spontaneous. Cases may be attributed to significant or even mild traumatic events, and some to connective tissue disorders, such as Ehlers-Danlos or Marfan syndrome. The radiological features required to diagnose dissection can be elusive; absolute evidence comes from visualization of a dissection flap, double vascular lumen, or hematoma within the arterial wall. Indirect evidence includes tapering vascular occlusion (string sign) or irregular caliber change. Vertebral artery (VA) dissection is the most common risk factor for posterior circulation AIS in children and should be actively excluded, by catheter angiography if necessary, unless there is a clear alternative diagnosis ( Fig. 3 ). The V3 loop of the VA is the commonest site of dissection and is often not clearly visualized on MRA. Abnormalities of the cervical spine (eg, calcified arcuate ligament) may be associated with VA dissection and should be excluded by plain radiographs of the neck in flexion and extension. Dissection of the intracranial arteries undoubtedly exists but is difficult to identify and distinguish from other entities, such as focal cerebral arteriopathy (FCA), with confidence. The importance of identifying arterial dissection is that it is one of the diagnoses which, based on current treatment recommendations, alters the treatment approach. Furthermore, the literature suggests that patients with an index event are at increased risk of recurrent dissection in the future. It is likely that affected patients have an underlying genetically determined predisposition, potentially exacerbated by environmental triggers, such as infection or trauma.

A 2½-year-old boy who fell from a chair and presented with vertigo, ataxia, and vomiting. ( A ) Axial diffusion-weighted MRI of the brain shows an area of high signal in the right cerebellar hemisphere. ( B ) Axial corresponding ADC map shows an area of restricted diffusion in the right cerebellar hemisphere ( white arrow ). ( C ) Axial FLAIR MRI of the brain, same level as A and B , shows a majority of these areas of abnormality demonstrate high signal consistent with T2 shine through, or subacute ischemia. ( D ) Frontal and ( E ) lateral left vertebral angiogram shows a dissection in the V3 segment ( white arrow ). These findings are consistent with multiple embolic events of different ages from a vertebral artery dissection.

Focal Cerebral Arteriopathy of Childhood

To promote consistency, the International Pediatric Stroke Study group has advocated application of standard disease definitions. The most commonly identified cerebral arteriopathy in childhood is focal occlusive disease of the TICA/proximal MCA or ACA; this morphology of disease was originally termed “transient cerebral arteriopathy,” a definition that required demonstration of disease stability or regression over time. More recently, this term has been superseded by the term “focal cerebral arteriopathy of childhood” (FCA) ( Fig. 4 ) to refer to this pattern of focal proximal occlusive disease identified at a single time point. The FCA pattern of arteriopathy is commonly seen in children after varicella cerebral infarction and in these cases it is hypothesized that the disease represents a focal inflammatory response to the viral infection. The role of infection and vascular inflammation in the genesis of arteriopathy in other cases remains controversial; however, there does seem to be an increased rate of antecedent upper respiratory tract infection in children with FCA. The distinction between FCA and primary angiitis of the central nervous system (PACNS) is controversial. Although vascular inflammation is thought to be a disease mechanism common to both entities, they are distinguished by their clinical course, with PACNS typically having a multifocal and progressive course, in contrast to the monophasic course observed in FCA. Currently there are no biomarkers that robustly distinguish between FCA and PACNS and there is confusion in the literature, with cases that appear identical in terms of imaging being cited as examples of one or another entity. Catheter angiography may be useful in cases of suspected PACNS if there is multifocal disease affecting smaller arteries. If this is undertaken, it is worth considering systemic angiography, looking for evidence of systemic vascular involvement.

A 7-year-old girl who presented with headache and right-sided weakness. ( A ) Axial diffusion-weighted MRI of the brain shows an area of high signal in the left mesial temporal lobe, amygdala, and left internal capsule with tiny foci in the left parietal occipital lobe. The corresponding ADC map ( B ) shows low signal in these areas. ( C ) Frontal left internal carotid angiogram at the time of stroke shows a filling defect within the L A1 segment ( white arrow ) with delayed filling of the L ACA; there is also mild narrowing of the L M1 segment. ( D ) Frontal left internal carotid angiogram 1 month after the stroke shows near interval resolution of the filling defect within the L A1 segment; however, there is now narrowing of the left supraclinoid, L A1, and L M1 segments ( white arrow ). ( E ) Frontal left internal carotid angiogram 6 months after the stroke shows resolution of the filling defect and areas of narrowing. ( F ) Five-year follow-up MRA shows a normal circle of Willis. These findings are consistent with a stroke related to focal cerebral arteriopathy (FCA) from a varicella infection.

Inflammatory Arteriopathy

Inflammatory arteriopathy of the central nervous system may be part of a systemic vasculitis or isolated PACNS. A variety of vessel sizes may be involved; small vessel vasculitis (confirmed histologically) may be associated with normal catheter angiography. Central nervous system vasculitis is notoriously difficult to identify and no investigation, including leptomeningeal biopsy, has a sensitivity of more than 40%. Thus the diagnostic approach has to be broad, including serology and cerebrospinal fluid (CSF) examination, looking for evidence of disease in other organ systems. It is important to have a high level of clinical vigilance, especially in patients with recurrent AIS, multifocal infarction, progressive arteriopathy, or a more diffuse, encephalopathic presentation.

Idiopathic—Other Causes

Although the Sebire classification captures most cerebral arteriopathies seen in association with AIS, it is not entirely comprehensive. In the context of a specialist pediatric neurovascular service, a significant proportion of patients cannot be placed in a category using this scheme; common features in them are multifocal arteriopathy ( Fig. 5 ), involvement of other organs (especially renal arteries), a genetic or syndrome diagnosis, and the coexistence of occlusive and aneurysmal cerebrovascular disease in the same individual. It is likely that these patients have genetically mediated disease, potentially exacerbated by environmental triggers.

A 3-year-old girl who presented with right-sided weakness and a systolic blood pressure of 200 mm Hg. ( A ) Axial FLAIR MRI demonstrates no evidence of ischemia with hyperintense cortical vessels. ( B ) Frontal and lateral ( C ) right common carotid angiogram shows severe narrowing and a “string of beads” in the right internal carotid artery. The right external carotid artery is hypertrophied filling collateral vessels to the intracranial circulation. In addition, there is narrowing of the supraclinoid, R A1, and R M1 segments. ( D ) Arch aortogram shows no evidence of narrowing of the great vessels. ( E ) Abdominal aortogram shows severe narrowing and a “string of beads” involving the celiac axis, superior mesenteric artery, and right and left renal arteries. These findings are consistent with moyamoya disease and renal artery stenosis related to fibromuscular dysplasia.

Genetic/Metabolic Conditions

Inherited metabolic disorders are associated with childhood AIS. Some examples include Fabry disease, an X-linked deficiency of α-galactosidase; cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy; Menkes syndrome, a copper transport disorder; and homocystinuria, a deficiency of cystathionine-β-synthase that results in hyperhomocysteinemia.

Sympathomimetic Drugs

Recreational drugs in adolescents is a possible cause of childhood AIS. AIS may be associated with cocaine or amphetamine use related to hypertension and vasospasm. It is unclear whether other sympathomimetic agents used in the treatment of migraine headaches or attention deficit disorder are a risk factor for AIS.

Hypercoagulable States

Several prothrombotic conditions seem to contribute to the risk of childhood AIS. A meta-analysis of 22 observational cohort studies showed a significant association between the first AIS and the following prothrombotic conditions: inherited deficiency of protein C, protein S, antithrombin III, factor V Leiden, factor II methylene tetrahydrofolate reductase polymorphism, elevated level of lipoprotein (a), and the presence of antiphospholipid antibodies. Thrombophilia may also be an independent risk factor for AIS.

In a study of 50 children with AIS followed for a mean duration of 21 months, elevated d -dimer levels were noted most commonly in children with cardiac disease. d -dimer is a marker of coagulation activation, suggesting an underlying thrombophilia state in cardiac disease, which was also identified in children with AIS and cardiac disease by Strater and colleagues.

Additional hematologic factors that may confer an increased risk of AIS include SCD, iron deficiency anemia, thrombocytosis, and polycythemia.