Arterial Circulation: Anatomy and Vascular Patterns

Understanding the pathophysiology, clinical presentation, possible etiologies, and potential outcomes of childhood AIS requires an understanding of craniocervical arterial circulation. The brain receives arterial blood via two principal systems: the “anterior” circulation, consisting of the paired internal carotid arteries, and the “posterior” circulation, consisting of the paired vertebral arteries that join to form the basilar artery (“vertebrobasilar system”) (Figures 85-1 to 85-3). The anterior and posterior communicating arteries link these systems to form the circle of Willis. The major cerebral arteries arising from the circle of Willis are the paired anterior, middle, and posterior cerebral arteries. The anterior and middle cerebral arteries are the major branches of the internal carotid artery, and the posterior cerebral arteries are the major branches of the vertebrobasilar system. Small “perforating arteries” arise from these proximal vessels to supply deep brain regions, such as the basal ganglia and thalamus. These include lenticulostriate branches from the anterior circulation, and thalamostriate vessels from the posterior vessels. Circulation to the posterior fossa includes perforating arteries into the midline of brainstem, and major circumferential arteries supplying the lateral brainstem and cerebellum (the posterior inferior, anterior inferior, and superior cerebellar arteries). Inter-individual variability in the anatomy of the circle of Willis is frequent and can be relevant clinically. Anastomoses, both proximally at the circle of Willis and distally through smaller leptomeningeal vessels, can provide collateral blood flow, the degree of which significantly affects the territory of brain perfused by a major cerebral artery.

Fig. 85-1 Lateral view of the cerebral arteries detailing the branches of the anterior and middle cerebral arteries.

Fig. 85-2 Anteroposterior view of the cerebral arteries. Anterior circulation only.

Fig. 85-3 The vertebral-basilar posterior circulation artery system.

Vascular patterns of AIS can be classified as large- or small-vessel infarcts. Infarction due to occlusion of large-caliber cerebral arteries usually results in peripheral wedge-shaped lesions involving the cerebral cortex and subjacent white matter in characteristic distributions (Figure 85-4). Most AIS involves the middle cerebral artery (MCA), which, like the other major vessels, courses to the cerebral surface where pial branches supply the cortex and underlying white matter. AIS often occurs in recognizable patterns within the MCA territory, including:

Fig. 85-4 Large-vessel arterial infarct in the right middle cerebral artery territory associated with “transient cerebral arteriopathy” of childhood in an 11-year-old female presenting with hemiparesis.

A, T2-weighted magnetic resonance imaging shows right middle cerebral artery infarct maximally involving the cortex. B, Conventional angiogram shows irregular stenosis in the proximal right middle cerebral artery.

(B, Courtesy of Division of Neuroradiology, Hospital for Sick Children, Toronto, Ontario, Canada.)

As end-arteries, lenticulostriate lesions lack collaterals, conferring a higher risk of permanent infarction. Despite being small, such lesions also tend to affect critical structures and functional tracts, such as the internal capsule (Figures 85-5 and 85-6). Such specific recognizable patterns also help predict the underlying etiology, with isolated lenticulostriate AIS commonly associated with parainfectious or inflammatory arteriopathy [Askalan et al., 2001; Chabrier et al., 1998; Braun et al., 2009]. In population-based studies, such small-vessel-distribution infarcts account for 50 percent of childhood AIS. For unknown reasons, AIS more frequently affects the left hemisphere [deVeber, 2000].

Fig. 85-5 Postvaricella angiopathy in a 4-year-old male presenting with hemiparesis and speech loss 3 months following chickenpox.

A, Initial magnetic resonance imaging shows a “macro-lacune” involving the left basal ganglia. B, Initial angiogram shows normal lumen diameter with abnormal striae in the stem (arrow) of the left middle cerebral artery (MCA). C, Follow-up angiogram 8 weeks later shows stenosis in the MCA stem (arrow) at the site of the prior abnormality. D, Repeat angiogram after another 10 months shows persistence without progression of MCA stem (arrow) stenosis.

(Courtesy of Derek Armstrong, Division of Neuroradiology, Hospital for Sick Children, Toronto, Ontario, Canada.)

Fig. 85-6 Small-vessel arterial infarct of unknown etiology in a 10-month-old male.

A, T2-weighted magnetic resonance imaging shows a right caudate and putamen infarct. B, The same patient 4 months after stroke: residual left hemiparesis with left hand fisting is seen.

(Courtesy of Division of Neuroradiology, Hospital for Sick Children, Toronto, Ontario, Canada.)

Additional AIS patterns can be defined within the posterior circulation, involving brainstem, cerebellum, thalamus, and occipital and mesial temporal lobes. Patterns include P1 (proximal posterior cerebral artery [PCA]) occlusion, with large-vessel territory infarction in the occipital and mesial temporal lobes, and small-vessel infarcts in perforating artery territories in the thalamus and splenium. Basilar artery thrombosis can be a life-threatening condition, often combining multiple infarcts involving brainstem perforators, cerebellar branches, and the PCA. Cervical arteries are a frequent site for arterial dissection, both in the anterior and posterior circulations. Cervical dissections cause infarction primarily via artery-to-artery emboli. Ischemic lesions caused by diffuse hypoperfusion occur in typical watershed zones at the anterior, middle, and/or posterior cerebral artery junctions. Although typically bilateral, these can be asymmetrical and unilateral, requiring differentiation from vaso-occlusive AIS. In the setting of proximal arterial stenosis or occlusion including moyamoya, low-flow infarcts also appear in distal arterial zones, typically the periventricular white matter.

Mechanisms of Thromboembolism

Thrombotic occlusion of a cerebral artery is the principal mechanism for the focal ischemia underlying AIS. The pathological thrombus may develop locally within cerebral arteries or travel there from an embolic source. Local thrombosis arising within cerebral arteries can result from diseases of the cerebral arteries (e.g., vascular inflammation), blood (e.g., prothrombotic state), blood flow (e.g., slow-flow stenosis), or a combination of these factors.

Thrombosis is a product of the coagulation and platelet hemostatic systems. In situations of blood stasis or slow flow, such as the venous system, the coagulation system predominates, resulting in fibrin-rich thrombi. However, in arteries, platelet activation with platelet-rich thrombi is a significant contributor to thrombus formation, combining with coagulation activation. The balance of which system predominates varies with flow rate, shear stresses, endothelial integrity, concentrations of circulating anticoagulants (e.g., protein C and S), and other factors. Under physiologic circumstances, arterial endothelium provides an anticoagulant surface, helping to maintain blood in a fluid phase. When the arterial wall is damaged by disease or injury, thrombosis may develop through several mechanisms. Exposure of blood to arterial wall inflammation (e.g., vasculitis) or disruption of the endothelium with exposure to collagen and tissue factor (e.g., dissection) activates both platelets and fibrin formation. In situations of blood stasis or slow blood flow, including arterial occlusion or severe stenosis, the coagulation system may predominate. In contrast, rapid arterial blood flow with high “shear” forces favors platelet activation. Therefore, coagulation- and platelet-mediated thrombotic processes likely coexist in many children with AIS, the relative balance depending on the specific disease. Important developmental differences in both systems through early infancy and childhood are likely also important [Andrew et al., 1990; Carcao et al., 1998; Israels et al., 2001; Roschitz et al., 2001; Monagle, 2008a].

Arterial emboli causing AIS are usually thromboemboli, arising from the heart or another vessel more proximal in the arterial tree. These are termed cardiogenic embolism and artery-to-artery embolism, respectively. Cerebral thromboemboli can also originate in the venous system, reaching the arterial circulation via right-to-left intracardiac shunts, such as patent foramen ovale, atrial septal defects, and both repaired and unrepaired complex congenital heart lesions. Shunts with predominantly left-to-right shunting may reverse intermittently with Valsalva or other changes in intrathoracic pressure, resulting in paradoxical embolism. Cardiac or paradoxical venous thromboemboli tend to be primarily fibrin-rich due to activation of the coagulation system. Alternatively, mechanisms of in situ arterial occlusion in AIS also need to be considered with local arterial diseases, including vasculitis and dissection. Finally, nonthrombotic cerebral embolizations can occur, including infectious emboli in endocarditis, fat embolism, and inert materials during intravascular procedures.

Mechanisms of Infarction and Developmental Brain Injury

In AIS, the severity of cerebral tissue damage and resultant neurological impairments are a function of multiple factors. These include:

Ischemic neuronal dysfunction can be reversible initially, but will shift to irreversible infarction with increasing duration and/or degree of ischemia or increased rates of neuronal metabolic activity. In a transient ischemic attack (TIA), no permanent parenchymal lesion responsible for the symptoms is seen on MRI [Albers et al., 2002]. This is consistent with the transient symptomatology (resolution typically within 60 minutes) and reversible ischemic neuronal dysfunction without permanent damage. In contrast, AIS clinical deficits persist and are accompanied by radiographic confirmation of infarction. Despite this logical clinical-radiographic correlation, pathological processes at the tissue level are certainly more complex and dependent on a number of factors. In AIS, a marked decrease in focal cerebral perfusion results in a central core zone of irreversibly damaged brain. Surrounding this is a less severely compromised penumbral zone where tissue is partially injured but remains potentially viable [Schlaug et al., 1999]. In the penumbra, clinical factors that increase the discrepancy between cerebral metabolic rate and the delivery of oxygen and glucose result in additional tissue injury and cell death. Secondary insults, including seizures and alterations in temperature, blood pressure, and serum glucose, increase this discrepancy between energy supply and demand. The primary objective of acute neuroprotective and fibrinolytic stroke treatment is to rescue this “at-risk” penumbral tissue to salvage functional brain.

Focal brain ischemia results in regional hypoxia and depletion of high-energy compounds (adenosine triphosphate) and carbohydrate stores. Compared to other tissues, the brain has relatively higher baseline metabolic rates and fewer energy storage systems [Trescher, 1992]. The cerebral metabolic rate for oxygen is 3.5 mL/100 g/min and, with virtually no oxygen reserve available, neuronal dysfunction results quickly when supply ceases. Brain glucose reserve is greater, allowing tissue survival up to 90 minutes with adequate oxygenation. The newborn can use lactate as a substrate for the production of energy but this capability is lost quickly. When regional hypoxia develops during ischemia, there is a shift from oxidative metabolism to glycolysis. Glucose is metabolized to lactate, and accumulating acidosis further exacerbates injury. Final infarct volume is determined in part by the balance between the rate of delivery of oxygen and glucose, and regional metabolic brain activity, particularly in the penumbra.

Several elements of pediatric cerebral hemodynamics are relevant in AIS. Cerebral perfusion is a direct function of the mean arterial pressure, intracranial pressure, and vascular resistance, and is age-related [Volpe, 2001a]. Adult cerebral blood flow (CBF) is 50 mL/100 g brain tissue/minute. Neonatal CBF is approximately 40 percent of this, while children under 3 years average 30–50 mL/mg/min. Children of 3–10 years have high CBF (approximately 100 mL/mg/min) that returns toward adult values by the end of adolescence [Altman et al., 1988]. CBF represents 10–20 percent of cardiac output in early infancy, peaks at over 50 percent by 2–4 years, and stabilizes at approximately 15 percent by 8 years [Wintermark et al., 2004]. Cerebral autoregulation refers to homeostatic regional adjustments in cerebral perfusion accomplished through caliber changes in cerebral arteries in response to alterations in perfusion pressure, carbon dioxide levels, and other metabolic factors. Developmental changes in cerebral autoregulation are recognized, though not well studied in AIS. Autoregulation is present across normal blood pressures in term newborns; however, it is impaired in preterm neonates [Volpe, 2001a]. Further maturation of cerebral autoregulatory systems occurs through at least adolescence [Vavilala et al., 2005]. Disturbed cerebrovascular autoregulation surrounding an evolving infarct may further contribute to a mismatch between cerebral metabolic demands and substrate delivery.

Neonatal and juvenile animal stroke models are providing exciting basic science knowledge regarding the cellular pathophysiology of ischemic stroke, including age-related processes distinct from adult stroke [Hou and MacManus, 2002]. Details of the neurotoxic cascade initiated by acute focal hypoxia-ischemia continue to evolve. In AIS, cell death proceeds over time by two primary mechanisms. Acute necrosis occurs over hours, whereas apoptosis (delayed cell death) occurs over days and, in neonates, likely over weeks. More detailed discussion of cell death mechanisms in the brain is found in Chapter 14. Accumulation of extracellular glutamate and activation of glutamate receptors play a major initiating role in this cascade [Aarts et al., 2002]. Accumulation of excess cytosolic calcium results in activation of pathological calcium-mediated intracellular events. The role of nitric oxide and free-radical generation, with resulting damage to critical intracellular components, is also likely important [Wang and Shuaib, 2007]. Complex neuroinflammatory processes have also emerged as potential targets for stroke neuroprotection [Shah et al., 2009].

Pharmacological and other neuroprotective strategies designed to interrupt this multifaceted ischemic cascade in stroke continue to be developed. Unfortunately, none has been successful in human stroke clinical trials, and no such trials have involved children. Hypothermia has shown benefit in the management of neonatal global HIE [Wyatt et al., 2007], but not childhood traumatic brain injury [Hutchison et al., 2008], is unproven in adult stroke [van der Worp et al., 2010] and untested in childhood stroke. Future animal models of stroke in the developing brain will be required to understand the unique aspects of these neuroprotective mechanisms in childhood AIS. Ideally, juvenile animal stroke models would incorporate features relevant to childhood AIS, including inflammatory cerebral arteriopathy, age-dependent coagulation systems and disorders, and inclusion of pediatric age-appropriate outcomes, including achievement of new learning, rather than just relearning previously acquired skills. Since the infant brain relies on programmed cell death for normal development, infant animal models studying anti-apoptotic agents will need to evaluate brain development after treatment. Translation of such results into clinical trials in the pediatric population will be challenging.

Ever since Kennard described better outcomes in younger monkeys following focal brain injury [Kennard, 1936], neuroscientists have sought to understand developmental neuroplasticity and harvest its benefits. Multiple subsequent animal models have confirmed evolving susceptibilities and potentials for recovery across the age spectrum that are dependent on many factors [Yager and Thornhill, 1997; Kolb et al., 2000; Kolb and Cioe, 2003]. AIS represents focal injury in an otherwise healthy brain, providing an ideal model for studies of plasticity. Knowledge regarding plastic changes in the brain following adult stroke has grown exponentially in the past decade [Murphy and Corbett, 2009]. Similar studies have not been performed widely in children. However, the widely held belief that increased plasticity confers an advantage to recovery after brain injury in childhood compared to adults remains unproven, and most children with AIS suffer adverse long-term outcomes. Childhood AIS outcome studies correlating age and recovery show mixed results [Bates et al., 1999; Goodman and Yude, 1996b; Westmacott et al., 2007b, 2009; Max, 2004a; Lansing et al., 2004] Fortunately, modern neurotechnologies, such as functional MRI (fMRI) [Heller et al., 2005], diffusion tensor imaging [Seghier et al., 2004], and transcranial magnetic stimulation [Frye et al., 2008], allow new windows into the study of brain plasticity in childhood AIS. Combining these basic and applied neuroscience methods in children with AIS will be critical to the development of improved interventions and better outcomes.

Arteriopathies

Diseases that directly affect the arteries supplying the brain have emerged as the leading cause of childhood AIS and are associated with an increased risk of both recurrence and poor outcome [Goldenberg et al., 2009; Fullerton et al., 2007b]. Recent studies have demonstrated consistently that arteriopathy is present in more than 50 percent of childhood AIS [Chabrier et al., 2000; Ganesan et al., 2003; Fullerton et al., 2007b; Amlie-Lefond et al., 2009a; Sebire et al., 2006; Braun et al., 2009]. Since arteriopathy is likely the single strongest predictor of stroke recurrence, thorough vascular imaging is essential for accurate detection and classification of arteriopathy [Lanthier et al., 2004; Strater et al., 2002; Askalan et al., 2001; Fullerton et al., 2007b; Braun et al., 2009]. Surveillance for a progressive nature in some arteriopathies is important, as it may dictate specific treatment [Danchaivijitr et al., 2006a; Kirkham, 2006; Braun et al., 2009].

Different systems have been proposed to classify childhood cerebral arteriopathies [Sebire et al., 2004], although some disagreement about terminology and proposed underlying pathophysiological processes still exists among experts. The three most important categories are discussed below:

Other, more rare, specific genetic cerebral arteriopathies include PHACES syndrome [Heyer et al., 2008], Alagille’s syndrome [Emerick et al., 2005], progeria [Merideth et al., 2008], primordial dwarfisms [Brancati et al., 2005], childhood forms of fibromuscular dysplasia [Kirton et al., 2006], and dominantly inherited COL4A1 mutations [van der Knaap et al., 2006].

Infectious/inflammatory arteriopathy

A common syndrome of cerebral arteriopathy seen in previously healthy, school-aged children with AIS shares the following features:

1. localized unilateral intracranial arteriopathy affecting proximal middle and/or anterior cerebral arteries and/or distal internal carotid artery

2. infarcts involving small perforating (lenticulostriate) artery territories, typically in the basal ganglia

3. irregular narrowing or stenosis of the affected vessel wall

4. serial arterial imaging showing increased stenosis in the initial 3–6 months, followed by stabilization as a chronic or improving stenosis (termed “non-progressive”).

Many descriptions of this condition have been published under the name “transient cerebral arteriopathy” (TCA) [Chabrier et al., 1998; Shirane et al., 1992; Sebire, 2006] An example of the angiographic appearance of TCA is shown in Figure 85-4. Studies have suggested that such intracranial unilateral arteriopathy, even with features suggesting vasculitis on angiography, are non-progressive in more than 90 percent of cases [Braun et al., 2009]. When serial imaging demonstrates increased stenosis or extension to new arterial segments 6 months after onset, a chronic or progressive vasculitis or unilateral moyamoya may be suspected [Sebire, 2004]. Arterial occlusion, moyamoya vessels, and ACA (anterior cerebral artery) involvement may be associated with a progressive course.

Despite being very common, the exact cause or causes of Trasient cerebral Arteriopathy remain undetermined in most cases. This has resulted in the emergence of inconsistent terminology, diagnostic criteria, and treatment considerations; the debate continues. Recent efforts to acknowledge this uncertainty have used the more general term of “focal cerebral arteriopathy” (FCA) for any stenosing arteriopathy without evidence of a well-established arteriopathy, such as moyamoya or dissection [Amlie-Lefond et al., 2009a]. The most consistently suggested etiologies for TCA include infectious, postinfectious, and/or inflammatory mechanisms [Chabrier et al., 1998; Shirane et al., 1992]. TCA is considered by some to be a form of focal and self-limited vasculitis, and the term “nonprogressive childhood primary angiitis of the central nervous system” (cPACNS) has been applied [Elbers and Benseler, 2008]. However, similarities to postvaricella angiopathy (see below) [Askalan et al., 2001] have led to suspicion of parainfectious mechanisms. Still other possibilities, such as intracranial dissection, are often impossible to exclude.

The role of infection in AIS is recognized increasingly [Emsley and Hopkins, 2008; Amlie-Lefond et al., 2009a]. The strongest example in childhood AIS is postvaricella angiopathy (PVA), which demonstrates the imaging features of TCA but occurs within 12 months of clinical varicella infection [Askalan et al., 2001; Lanthier et al., 2005]). PVA also typically affects lenticulostriate arteries, with an irregular, unilateral stenosis centered on the proximal ACA or MCA that resolves over months [Askalan et al., 2001; Lanthier et al., 2005]. An example of this disease is shown in Figure 85-5. PVA is well established as occurring in adults following facial “shingles” [Gilden et al., 2009; Amlie-Lefond et al., 1995]. Proposed mechanisms include viral reactivation from the trigeminal ganglion, with spread along the trigeminovascular bundle that innervates proximal cerebral arteries [Kleinschmidt-DeMasters and Gilden, 2001]. Elevated cerebrospinal fluid antibody titers to varicella zoster virus are found rarely [Ueno et al., 2002], though cerebrospinal fluid polymerase chain reaction and/or antibodies may increase sensitivity [Kronenberg et al., 2002; Gilden et al., 2009]. Histopathological studies can reveal viral particles or antigens in cerebral artery smooth-muscle cells [Eidelberg et al., 1986; Linnemann and Alvira, 1980; Reshef et al., 1985], as was the case in two 4-year-old children who died of PVA-associated stroke [Berger et al., 2000]. With varicella vaccination becoming routine, naturally occurring PVA is expected to decrease. However, AIS has been described in proximity to varicella immunization [Wirrell et al., 2004].

The role of other infections in arteriopathic childhood AIS is undergoing active investigation. Fever and recent “viral infection” symptoms commonly are present in children with AIS. One study of childhood AIS reported fever in 50 percent and leucocytosis in 26 percent [Ganesan et al., 2003]. In another recent international study of 673 children with AIS, an association between viral upper respiratory tract infection and arteriopathy was found, particularly in children with TCA/FCA [Amlie-Lefond et al., 2009a]. Whether a common inflammatory pathophysiology underlies arteriopathy provoked by active viral infection, postviral infection, or “idiopathic” inflammation remains to be established definitively.

More obvious and malignant infections also predispose to ischemic stroke. Arterial or venous stroke associated with bacterial meningitis has been identified in 5–12 percent of children and as many as 75 percent of infants [Chiu et al., 1995; Silverstein and Brunberg, 1995; Chang et al., 2003]. Tuberculous meningitis is an important infectious cause of childhood AIS in certain countries [Springer et al., 2009]. Extension of subarachnoid meningeal infection and inflammation, causing thrombophlebitis of the perforating arteries, is the likely mechanism. Children with human immunodeficiency virus (HIV) often develop a unique arteriopathy that predisposes to both ischemic and hemorrhagic stroke [Patsalides et al., 2002; Visudtibhan et al., 1999; Kleinschmidt-DeMasters and Gilden, 2001]. While limited to small numbers of cases, AIS has been associated with mycoplasma, toxoplasmosis, Rocky Mountain spotted fever, Lyme disease, cryptococcosis, Japanese encephalitis, coxsackie B4 and A9, influenza A, enterovirus, parvovirus B19, and chlamydia [Guidi et al., 2003; Takeoka and Takahashi, 2002]. Regional infectious agents also must be considered, such as malaria, which was commonly associated with stroke in children in Cameroon [Obama et al., 1994]. Only a small portion of these studies have described the possible mechanism, such as TCA with enterovirus or HIV [Ribai et al., 2003; Leeuwis et al., 2007].

Arterial inflammation without a clear connection to active or previous infection is also a well-established form of cerebral arteriopathy, termed vasculitis. Recent reviews of childhood cerebral vasculitis are available [Elbers and Benseler, 2008]. Primary cerebral vasculitis is increasingly well described [Lanthier et al., 2001], and typically is referred to now as cPACNS [Elbers and Benseler, 2008; Benseler et al., 2006]. In contrast to “nonprogressive” cPACNS, which is very similar to TCA [Benseler et al., 2003; Elbers and Benseler, 2008], “progressive” cPACNS is frequently bilateral, and involves both proximal and distal cerebral arteries. Aggressive treatment may be required to prevent rapid deterioration and multifocal strokes. An example is shown in Figure 85-7. While the anterior circulation is involved more commonly, cPACNS diseases also can be isolated to the posterior circulation (Figure 85-8).

Fig. 85-7 Childhood primary angiitis of the central nervous system.

An 8-year-old boy presented with sudden onset of mild right-sided weakness and word-finding difficulty. A, Diffusion-weighted magnetic resonance imaging (MRI) showed a small acute infarct of the left putamen and disease of the left middle cerebral artery. Twelve hours later, the boy suddenly became aphasic and completely hemiplegic. B, Repeat MRI showed evolution to include large areas of the frontal, parietal, and temporal lobes. Conventional angiography shows severe irregularity and alternating areas of stenosis of the entire M1 segment. Arteriopathy stabilized over time, though the child was left with moderate to severe motor and language impairments.

Fig. 85-8 Progressive, presumed vasculitis of the vertibrobasilar system in a 4-year-old male with pontine infarction.

A, Initial MRI shows a pontine infarct. B, Initial angiogram demonstrates basilar artery occlusion (arrow) with normal vertebral arteries. C, Although the clinical course had not changed, follow-up angiogram 4 months later shows presumed vasculitis involving the distal right vertebral artery (arrow). D, Again, although the clinical course had not changed, a repeat angiogram after the child was on steroid therapy for 5 months shows progression of the presumed vasculitis involving the cervical portion of the vertebral artery (arrow). Biopsy was not performed.

(Courtesy of Derek Armstrong, Division of Neuroradiology, Hospital for Sick Children, Toronto, Ontario, Canada.)

Some forms of cPACNS appear to be limited to distal, small cerebral arteries. Such small-vessel cPACNS lacks the acute stroke presentations described above, typically presenting with insidious symptoms such as headaches, cognitive decline, and personality change, and with MRI changes of multifocal enhancing lesions [Elbers and Benseler, 2008; Rafay et al., 2005; Benseler et al., 2005, 2006]. While conventional angiography is indicated, it may be negative in small-vessel cPACNS and brain biopsy is required for definitive diagnosis [Aviv et al., 2006; Benseler et al., 2005]. Small-vessel vasculitis may also be secondary to a variety of conditions, including infections, collagen vascular diseases, systemic vasculitides, and malignancies [Benseler and Schneider, 2004]. Systemic vasculitides and connective tissue diseases possibly associated with cerebral artery involvement include Kawasaki’s disease, Henoch–Schönlein purpura, polyarteritis nodosa, Wegener’s granulomatosis, systemic lupus erythematosus, Behçet’s syndrome, mixed connective tissue disease, Sjögren’s syndrome, and inflammatory bowel disease [Morfin-Maciel et al., 2002; Belostotsky et al., 2002; Berman et al., 1990; Morales et al., 1991; von Scheven et al., 1998; Graf et al., 1993; Benseler and Schneider, 2004]. Although systemic lupus erythematosus is often associated with AIS, vasculitis as the etiology for stroke is uncommon [Devinsky et al., 1988]. Large arteries can also be affected by secondary vasculitis, as in polyarteritis nodosa, or in Takayasu’s arteritis, where major branches off the aorta, including cervical arteries, are stenosed at their origin. Takayasu’s arteritis presents with asymmetrical and diminished pulses, renovascular hypertension, and stroke [Morales et al., 1991; Ringleb et al., 2005].

The range of infectious/inflammatory arteriopathies must be a primary consideration in all children with AIS, since they have important implications for investigation, treatment, and outcome. Diagnostic investigations should be tailored clinically, but may include screening for specific infections (serology, virology, polymerase chain reaction), in addition to routine hematological blood work, and inflammatory (erythrocyte sedimentation rate, C-reactive protein) and vasculitic (antinuclear antibodies, extractable nuclear antigens, complement, etc.) markers. In primary cPACNS, results of blood and cerebrospinal fluid studies are often negative [Elbers and Benseler, 2008; Riou et al., 2008]. More advanced studies to determine the markers and the relationship between infarction, inflammation, and arteriopathic AIS in children are under way. No specific treatment trials have been performed for the infectious/inflammatory cerebral arteriopathies in children. Whether an antiviral agent like acyclovir could alter the clinical course of PVA has not been determined but should certainly be considered in an immunocompromised child. Once a noninfectious inflammatory vasculitis is diagnosed, immunosuppression, with agents including corticosteroids, cyclophosphamide, azathioprine, or others, should be considered [Benseler and Schneider, 2004; Elbers and Benseler, 2008]. The advice of a pediatric rheumatologist in diagnosing and treating inflammatory cerebral arteriopathy should be sought.

Moyamoya disease and syndrome

Moyamoya describes the progressive occlusion of the cerebral arteries at the circle of Willis, leading to formation of abnormal networks of small collateral vessels with a “puff of smoke” appearance on angiography (Figure 85-9) [Scott and Smith, 2009; Kuroda and Houkin, 2008]. The classic pattern involves the distal internal carotid arteries bilaterally, but unilateral variants and involvement of additional anterior and posterior circulation vessels are well described. Moyamoya disease is the idiopathic version described primarily in Asian populations, while moyamoya syndrome occurs in association with other conditions, including sickle cell disease (see below), Down syndrome, neurofibromatosis type 1, Williams’ syndrome, postradiation vasculopathy, and congenital arteriopathies (see below) [Jea et al., 2005; Scott and Smith, 2009]. Familial forms of moyamoya increasingly are described, with several potential genetic mechanisms proposed [Ikeda and Yoshimoto, 2005]. Moyamoya is, therefore, a heterogeneous syndrome and not a single disease, but recognizing the shared patterns of presentation is clinically relevant to ensure accurate investigation and treatment.

Fig. 85-9 Moyamoya disease.

An 8-year-old boy presented with acute-onset left hemiplegia after 10 months of transient alternating hemiplegia related to hyperventilation. A, A large arterial ischemic stroke of the right frontal lobe is accompanied by additional large-vessel and watershed lesions bilaterally. The patient has severe motor disability bilaterally, with cognitive delays, and is nonverbal. B, His 15-year-old sister mentioned having headaches at her brother’s follow-up visit and was imaged. She has several small ischemic lesions in the periventricular white matter (arrow), but is an honours student with a normal examination. Both children have moyamoya. C and D, The girl’s angiogram (anteroposterior view) shows severe narrowing (C) and occlusion (D) of the distal internal carotid arteries, with abnormal collateral development (arrows). Both patients have been asymptomatic following bilateral revascularization surgery.

Moyamoya presents with unique clinical syndromes and patterns of stroke. In contrast to most other forms of AIS, an important mechanism for moyamoya-associated infarction is hypoperfusion. In the setting of internal carotid artery occlusion, perfusion is compromised most severely in the distal perfusion zones of the MCA and ACA in the deep hemispheric white matter. As a result, small (<1 cm) collections of adjacent infarcts accumulate in these “deep watershed” zones. Impaired cerebrovascular autoregulation in chronically underperfused brain territories appears to be an important underlying mechanism for these infarcts [Mikulis et al., 2005]. Therefore, TIA symptoms may be precipitated by alterations in PCO₂, such as during hyperventilation (cerebral vasoconstriction) or breath holding (cerebral vasodilatation with “steal”). These infarcts may be subclinical, often with gradual cognitive or behavioral decline, although clear stepwise neurological deteriorations may occur. Moyamoya progresses slowly over time, causing accumulating injury and poor neurological outcomes [Suzuki and Kodama, 1983]. Progression of moyamoya may be faster in preschool-aged children [Kim et al., 2004]. In addition, artery-to-artery embolism of larger cerebral arterial branches can result in more typical AIS in moyamoya. Hemorrhagic stroke also can occur from the compensatory basal collateral vessels (“rete mirabile”), and this risk increases in early adulthood [Yoshida et al., 1993]. Headaches, often with migrainous features, are common in moyamoya and may precede other neurological symptoms.

MRI can suggest moyamoya with small flow voids in the basal ganglia and the infarct patterns described above. MR angiography is highly but incompletely sensitive at detecting moyamoya arteriopathy. Advanced fMRI and other perfusion studies may demonstrate impaired autoregulation [Mikulis et al., 2005; Mori et al., 2009]. However, conventional angiography is required in all children with moyamoya to confirm the presence of collaterals, characterize disease extent and severity, and image the external carotid circulation to determine options for revascularization surgery (see Figure 85-9) [Satoh et al., 1988]. Hypertension is common in moyamoya and may be secondary to associated renal artery stenosis [Kirton et al., 2006]. Doppler ultrasound and/or renal angiography during cerebral studies are indicated in such patients to exclude renovascular involvement.

Treatment of moyamoya is complex. Antiplatelet therapy with acetylsalicylic acid (ASA) often is employed and is likely safe. The chronic, progressive occlusion of distal internal carotid arteries, and consequent low perfusion, result in cerebral autoregulation shifting toward maximal vasodilatation in order to maintain cerebral perfusion. Carbonic anhydrase inhibitors, including acetazolamide, may shift acid–base balance to favor vasodilatation in moyamoya [Ikezaki, 2000]. However, in severe moyamoya, such medications may cause a “steal” or “reverse Robin Hood” phenomenon, whereby dilatation of healthier arteries diverts perfusion away from the most critically affected areas, which subsequently infarct. Such interventions must be considered carefully in severely affected children. Use of antihypertensives in children with moyamoya and hypertension must also be considered carefully, as even small decreases in cerebral perfusion can lead to infarction.

Surgical revascularization procedures are highly successful at improving cerebral perfusion in children with moyamoya [Scott and Smith, 2009]. Direct procedures connect extracranial blood vessels, such as the superficial temporal artery, to distal portions of intracranial vessels, usually the MCA. Direct revascularizations are technically limited in small children and carry some risk of reocclusion. In children, indirect procedures are now employed more frequently where extracranial vessels are approximated to the cortical surface overlying areas of decreased perfusion. Angiogenic signals from ischemic parenchyma subsequently result in neovascularization of the affected areas over a course of months. Encephalodural synangiosis (EDAS) and encephalodural myosynangiosis (EDMS) are common procedures transferring extracranial arteries alone or within scalp muscle, respectively, to the pial surface. A study of 143 children undergoing pial synangiosis found that more than 90 percent enjoyed symptom-free survivals with follow-up of more than 5 years [Scott et al., 2004]. Studies comparing the different surgical approaches are lacking. Indirect procedures are now used widely and sometimes combined with direct methods [Fung et al., 2005]. Perioperative infarctions likely occur in less than 10 percent of cases [Fung et al., 2005; Kim et al., 2004]. Younger age of onset in moyamoya may carry an increased risk of recurrent stroke and poor outcome, suggesting that early surgery is indicated [Kim et al., 2004]. Preliminary evidence suggests revascularization also may be helpful in some cases of sickle-related moyamoya [Hankinson et al., 2008]. Success of revascularization surgery can be evaluated with serial angiography, as well as new cerebrovascular reserve MRI methods [Mikulis et al., 2005].

Cardiac Risk Factors

Heart disease is a major risk factor for AIS in infancy and childhood, present in 12–28 percent of cases [Chabrier et al., 2000; Ganesan et al., 2003; deVeber, 2000]. Abnormalities in cardiac structure, flow, rhythm, endothelium, ventricular function, valves, blood viscosity, and other factors may contribute to thrombus generation and subsequent cerebral embolization. Multiple AIS in multiple, distinct vascular territories (e.g., left and right) suggests a cardiac source. Complete cardiac evaluations should be expedited in acute stroke of unknown etiology, to guide acute medical management and emergency cardiac treatment when indicated.

Complex congenital heart disease, particularly cyanotic lesions, carries the highest stroke risk. Both catheterization procedures and surgical repairs increase risk further. A recent single-center case-control study of more than 5500 children undergoing cardiac surgery documented a symptomatic AIS risk of 5.4 per 1000 (1:185), with reoperation being an independent risk factor [Domi et al., 2008]. This risk is comparable to or higher than the figure in previous studies [Menache et al., 2002]. Certain surgeries carry elevated short- and long-term risk. With the Fontan procedure, risk estimates of immediate or delayed stroke range from 3 to 19 percent [Monagle and Karl, 2002; Barker et al., 2005; Kaulitz et al., 2005]. Risk of symptomatic stroke following cardiac catheterization in children is estimated at 1:600–700 [Liu et al., 2001] with interventional more risky than diagnostic catheterizations [Hamon et al., 2006]. Balloon atrial septostomy prior to transposition switch surgery carries a stroke risk approaching 50 percent, according to one study of 29 patients [McQuillen et al., 2006]. Many ischemic brain lesions related to congenital heart disease are asymptomatic in young children and often are present preoperatively [Miller et al., 2004].

Intracardiac septal defects, such as atrial septal defect and patent foramen ovale, remain controversial risk factors for stroke in the young [Kizer and Devereux, 2005] and have not been well studied in children. Atrial septal lesions create the potential for intermittent right-to-left intracardiac shunting with paradoxical embolization of systemic venous clots to the brain [DiTullio et al., 1992]. When such right-to-left intracardiac shunts are detected, further investigation for systemic venous thrombosis may be indicated [Mas et al., 2001]. Septal lesions such as patent foramen ovale are common in the pediatric population. Associations between patent foramen ovale and otherwise unexplained stroke have been demonstrated repeatedly in young adults [Mas et al., 2001; Handke et al., 2007], although patent foramen ovale may not increase the risk of recurrent stroke [Almekhlafi et al., 2009]. A recent adult analysis suggests that a high proportion of patent foramen ovale in young cryptogenic stroke patients are likely incidental [sheikh-Ali et al., 2009]. Patent foramen ovale associated with atrial septal aneurysm [Mas et al., 2001] and thrombophilias carries increased stroke risk [Pezzini et al., 2003; Rodriguez and Homma, 2003]. The indications for medical and surgical (closure) treatment of uncomplicated patent foramen ovale remain controversial [Tamayo and Harrer, 2009].

Several acquired cardiac etiologies predispose to AIS. Infective endocarditis carries a high risk of multifocal embolic AIS and risk of mycotic aneurysm and intracerebral hemorrhage (Figure 85-10). Detection of signs of infective endocarditis, including fever, physical markers (Janeway lesions, Roth spots), and history of subacute constitutional symptoms or recent dental work, enables early diagnosis and treatment. Anticoagulation is relatively contraindicated in infective endocarditis due to bleed risk from mycotic aneurysms, and recent adult studies have demonstrated frequent subclinical microbleeds with susceptibility-weighted MRI [Klein et al., 2009]. Other acquired cardiac etiologies include poor left ventricular function secondary to cardiomyopathy (infectious, metabolic) [Hays et al., 2006], valvular heart disease (e.g., rheumatic fever, artificial valves), arrhythmia, and atrial myxoma [Omeroglu et al., 2006].

Fig. 85-10 Acute cardioembolic arterial ischemic stroke.

An 11-year-old girl presented with weeks of fatigue, low-grade fever, and skin lesions. She suddenly developed left-sided hemiplegia in hospital. A, Computed tomography (CT) scan at 90 minutes shows hypodensity (arrows) and loss of cortical ribbon in the right frontal lobe. She did not receive thrombolysis due to suspicion of endocarditis. B, Diffusion-weighted magnetic resonance imaging (MRI; B) and magnetic resonance angiography (C) confirm arterial ischemic stroke secondary to occlusion (arrow, C). The patient subsequently grew streptococcus and required aortic valve replacement. D, Follow-up imaging at 6 months included gradient ECHO MRI, which demonstrated hypodensity in the area of previous occlusion (arrow). E and F, CT angiography confirmed a mycotic aneurysm (arrow, F), which grew over the next month and was clipped surgically with success.

All children with AIS of undetermined cause should have prompt cardiac evaluation, including electrocardiogram and echocardiography. Agitated saline “bubble studies” can help establish the presence of patent foramen ovale and atrial septal defects. In adults, transesophageal echocardiography is superior to transthoracic echocardiography in diagnosing a cardiac stroke source, detecting 31 percent more treatable lesions [de Abreu et al., 2008; de Bruijn et al., 2006]. However in young children with a thin chest wall, transthoracic echocardiography may suffice. The roles of cardiac MRI and ambulatory cardiac rhythm monitoring in childhood AIS have not been investigated.

Consensus across published guidelines suggests that proven or suspected cardiogenic AIS requires specific management [deVeber and Kirkham, 2008]. With a presumed dominant role of the coagulation system, acute anticoagulation with low-molecular-weight heparin (LMWH) usually is indicated. If detected, bacterial endocarditis also requires urgent antibiotic treatment and investigation for mycotic aneurysm [Venkatesan and Wainwright, 2008]. Duration of anticoagulation depends on individual factors that determine recurrence risk, including circumstances of the initial stroke (spontaneous or procedure-related), corrected or uncorrected cardiac defect, prothrombotic testing results, and others.

Prothrombotic and Hematological Disorders

Thrombophilia, or prothrombotic disorders, refers to abnormalities of the coagulation, fibrinolytic, and platelet systems that predispose to pathological thrombus formation. Studies in childhood stroke are complicated by the developmental evolution of the hemostatic system in childhood, a complex variety of disorders, few case-control studies, and inconsistent testing and laboratory methods. With these limitations in mind, a role for prothrombotic disorders likely exists in childhood AIS, though most patients likely have an additional “triggering” risk factor at the time of AIS [Barreirinho et al., 2003; Strater et al., 2002]. Detailed reviews are available [Mackay and Monagle, 2008; Barnes and deVeber, 2006].

Inherited or acquired coagulation disorders have been identified in 20–50 percent of children with AIS [Bonduel et al., 1999; deVeber et al., 1998b; Barnes and deVeber, 2006; Herak et al., 2009]. Factor V Leiden is one of the strongest associations [Strater et al., 2002], with a meta-analysis of five case-control studies suggesting a combined odds ratio of 4.3 for stroke with heterozygote factor V Leiden [Chan et al., 2000]. Elevated levels of lipoprotein (a) and Protein C deficiency are both more common in children with AIS compared to controls [Nowak-Goettl et al; 1999; Barnes and deVeber, 2006]. Although mutations in methylene tetrahydrofolate reductase (MTHFR) are associated with childhood stroke, they are also common in the population and their significance without hyperhomocysteinemia is unclear [Nowak-Goettl, 1999; Ganesan et al., 2003; Mackay and Monagle, 2008]. In contrast to most prothrombotic states that promote venous thrombosis, prothrombin G20210A mutations are associated more frequently with arterial thrombosis in children [Young et al., 2003]. Meta-analysis of studies to date suggests an odds ratio of 3.5 in childhood AIS [Barnes and deVeber, 2006