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]. Case-control studies also have confirmed an increased occurrence of antiphospholipid antibodies and lupus anticoagulant in childhood AIS [Kenet et al., 2000; Ganesan et al., 2003].

A systematic review of published case-control data has reported increased pooled odds ratios for childhood AIS for protein C deficiency (6.5) and methylene tetrahydrofolate reductase (MTHFR C677T) (1.7), but ratios were not significant for protein S deficiency (1.14), AT (antithrombosis) deficiency (1.02), APCr (activated Protein C resistance) (1.34), prothrombin G20210A (1.10), or elevated plasma homocysteine (1.36) [Haywood et al., 2005]. Presence of certain prothrombotic states increases stroke recurrence risk in children, including factor V Leiden, protein C deficiency, and elevated lipoprotein (a) [Ganesan et al., 2006; Strater et al., 2002], but not elevated ACLA (anticardiolipin antibody) antibodies [Lanthier et al., 2004]. Plasminogen activator inhibitor abnormalities do not appear increased in childhood AIS [Nowak-Gottl et al., 2001]. Additional prothrombotic factors of interest include abnormal levels of plasminogen, fibrinogen, and coagulation factors (VIII, IX, XI), and an increasing number of genetic polymorphisms. Although platelet abnormalities are likely of importance in arterial thrombosis, only limited studies have been conducted in childhood AIS [Herak et al., 2009; Barnes and deVeber, 2006].

Coagulation testing should be considered in any child with AIS, including children with other identified risk factors. Accurate testing requires an experienced laboratory with established age-appropriate normative values. The most accurate results will be in children who are off anticoagulants and without active thrombosis at the time of testing. However, genetic testing for factor V Leiden, MTFHR, and the prothrombin gene (20210A) are feasible in the setting of acute AIS. Depending on the clinical situation, coagulation testing in the acute phase may be required, with repeat testing at 3–6 months post AIS, or parental testing if abnormalities are detected acutely. Children with stroke and a significant prothrombotic disorder should be counseled in simple prevention strategies, such as the avoidance of episodic dehydration and possible prophylactic dosing of anticoagulation in high-risk situations. Rarely, children with severe thrombophilia require long-term stroke prophylaxis with anticoagulation. Advice of hematology colleagues experienced in thrombosis can be invaluable.

Additional Considerations

A comprehensive list of probable and possible additional disorders associated with childhood AIS are listed in Table 85-2. Migrainous infarction is uncommon in children [Feucht et al., 1995; Nezu et al., 1997; Santiago et al., 2001] and is a diagnosis of exclusion, requiring strict adherence to international headache society criteria. These include focal neurological symptoms consistent with a migrainous aura that do not resolve in the presence of migraine headache in an at-risk individual (past or family migraine history) with confirmation of acute infarction on MRI. Lesions tend to favor the posterior circulation. Migraine with aura is an important stroke risk factor in young women who are smokers on oral contraceptives [Rothrock, 1993; Bousser and Welch, 2005]. Special treatment considerations in migrainous infarction should address the role of possible vasospasm. Fortunately, good evidence supports the use of flunarizine for migraine prophylaxis in children, as the mechanism of calcium channel blockade appears well suited to preventing migrainous infarction. Such patients also should avoid vasoconstrictor agents, such as triptans, ergots, or sympathomimetics. Secondary stroke prevention in migrainous infarction also includes ASA.

Several inborn errors of metabolism predispose to AIS [Testai and Gorelick, 2010]. Homocystinuria leads to arterial and venous thrombosis, can be recognized by clinical features and laboratory markers, and often is treatable [Bodensteiner et al., 1992]. Fabry’s disease, due to X-linked α-galactosidase deficiency, results in a cerebral arteriopathy and stroke, in addition to ocular, peripheral nerve, and renal complications. Both of these conditions are essential to recognize, as they are highly treatable with vitamin B supplementation and enzyme replacement, respectively. In mitochondrial diseases, such as mitochondrial encephalopathy, lactic acidosis and strokelike episodes (MELAS), clinical presentations mimic AIS. However, evidence supports a metabolic rather than ischemic mechanism [Mudd et al., 1985; Testai and Gorelick, 2010]. Cerebral lesions are bilateral and predominantly posterior and do not respect arterial territories. Elevated serum or cerebrospinal fluid lactates may be present and routine genetic testing is sensitive. Treatment with l-arginine to promote vasodilatation has been suggested but is controversial, given evidence against a primary vascular mechanism [Koga et al., 2005]. The role of other genetic factors in causing stroke is increasingly complex, ranging from single-gene disorders imparting a high risk to complex, multigene polymorphisms influencing additional risk factors. These complexities are beyond the scope of this chapter, and are reviewed elsewhere [Dichgans, 2007]. The interaction of genes with other known risk factors is being explored in childhood stroke [Kirkham, 2004].

Use of medications and illicit drugs should be determined. The risk of ischemic stroke is increased in young women using oral contraceptives, even with newer low-estrogen preparations [Gillum et al., 2000]. The role of typical metabolic and lifestyle factors that are important in adult stroke – diabetes, hypertension, dyslipidemia, smoking, and obesity – is undetermined in children. Hypercholesterolemia has been found in up to 9 percent of children with stroke [Ganesan et al., 2003]. Fasting serum cholesterol, triglycerides, and high-density and low-density lipoprotein fractions should be obtained and compared to aged norms [Muhonen and Lauer, 1996]. Although unstudied, long-term preventative care after childhood AIS should include attention to modifiable risk factors to promote arterial health, particularly in children with arteriopathy. This would include healthy lifestyle measures, such as regular exercise, a balanced diet with minimization of saturated and trans fats, and the avoidance of smoking and street drugs. Such simple interventions might mitigate decades of added insult to an already injured cerebral artery [Roach et al., 2008].

Computed Tomography

Head CT usually is the initial type of neuroimaging performed in childhood AIS but is insufficient to confirm or exclude the diagnosis. Initial CT scan may miss childhood AIS diagnosis in an overwhelming proportion (84 percent) of children with AIS [Srinivasan et al., 2009], consistent with the 63 percent false-negative rate for initial CT in a Canadian pediatric AIS study [Rafay et al., 2009]. CT findings of AIS in children are otherwise similar to adults, with infarction represented by focal, increasing hypodensity conforming to an arterial territory (see Figure 85-10). CT can also demonstrate intra-arterial thrombus (“hyperdense artery sign”), hemorrhagic transformation, and malignant cerebral edema (see below). Contrast-enhanced CT angiography, available at most centers, can provide detailed images of cerebral arteries down to third-order arteries or better, and may confirm the characteristics of an arteriopathy or embolic occlusion (see Figure 85-10). Small but significant age-related risks of radiation exposure need to be considered with CT use in children [Brenner and Hall, 2007].

Magnetic Resonance Imaging

MRI has revolutionized the diagnosis, management, and study of cerebrovascular disease and avoids radiation exposure [Muir et al., 2006; Hunter, 2002]. Diffusion-weighted MRI (DWI) is exquisitely sensitive at detecting early brain ischemia (see Figures 85-5, 85-7, and 85-10). DWI is the gold standard for acute AIS imaging for diagnosis, and is the investigation of choice when time and access permit [Groenendaal et al., 1995; Warach and Baron, 2004]. Acute ischemic lesions demonstrate restricted diffusion, evidenced by combined DWI hyperintensity and apparent diffusion coefficient map hypointensity. This pattern typically normalizes over 1–2 weeks, helping to determine infarct age. Traditional MR sequences, including T2-weighted images and fluid-attenuated inversion recovery (FLAIR), can demonstrate AIS within several hours, and abnormalities persist into the long term. MRI is unquestionably superior to CT in detecting strokes in children, especially early and small lesions and those located in the posterior fossa [Ameri and Bousser, 1992; Fiebach et al., 2002; Kidwell et al., 2004; Paonessa et al., 2009]. Limitations of MRI include longer completion times, technical complexities, contraindications such as implanted metallic devices, and the need for sedation in younger children.

Advanced MR procedures are improving our understanding and assessment of pediatric stroke. Modalities such as gradient ECHO and susceptibility-weighted methods can detect small amounts of blood, possibly predicting the risk of hemorrhagic transformation (see Figure 85-10). Perfusion-weighted imaging demonstrates regional brain perfusion abnormalities but pediatric studies have been limited [Huisman and Sorensen, 2004]. Arterial spin labeling MRI also may assess perfusion, with abnormalities correlating with final infarct volume [Chen et al., 2009]. MR perfusion using dynamic susceptibility contrast reveals focal perfusion deficits in children with SCD [Kirkham et al., 2001a]. Single-photon emission computed tomography (SPECT) and CT perfusion also can evaluate perfusion. The ultimate goal of such modalities is to detect “at-risk” brain tissue, represented by diffusion–perfusion “mismatch,” though this method remains unproven, even for adult stroke. Other advanced MRI techniques include fMRI of cerebrovascular reserve to detect impaired autoregulation in the setting of chronic hypoperfusion [Mikulis et al., 2005; Mori et al., 2009], diffusion tensor imaging (DTI) and tractography, and localization of brain activity with fMRI. MRI “wall imaging” may demonstrate concentric vessel-wall enhancement, suggesting inflammation [Swartz et al., 2009], a potentially valuable marker in pediatric arteriopathies.

MR angiography of the intracranial and neck vessels should be performed simultaneously with brain MRI in children with AIS. MR angiography can provide reasonable images of the major first- and second-order cerebral arteries (see Figures 85-7 and 85-10) [Husson and Lasjaunias, 2004; Koelfen et al., 1995; Wiznitzer and Masaryk, 1991], but remains limited in smaller-vessel diseases [Ganesan et al., 1999; Husson et al., 2002]. MR angiography can suggest the nature and extent of underlying arteriopathy. An abrupt arterial “cutoff” suggests embolic stroke, while irregular stenosis favors arteriopathy. However, time-of-flight MR angiography relies on flow signal and, in areas of turbulent flow or stenosis, signal dropout can mimic occlusion. Gadolinium RA (MR angiography) has better resolution and specificity than “time-of-flight” imaging.

Conventional Angiography

Despite advances in noninvasive methods, conventional angiography (CA) remains the gold standard for cerebrovascular imaging [Hill et al., 2007] (see Figures 85-4, 85-5,and 85-7 to 85-9). Specific arteriopathies may be diagnosed only by seeing the detail that CA provides; these arteriopathies include “string,” “double lumen,” or intimal flap signs in dissection, “string of beads” in vasculitis, and arteriopathies limited to small-caliber arteries. CA should be performed in children with AIS when a specific etiology remains undetermined after initial MR angiography or CT angiography, and considered in others to characterize the nature and extent of a probable arteriopathy better. Ideally, CA should be performed where pediatric expertise is available. Several large experiences recently published suggest that the rate of combined intra- and postprocedural complications for diagnostic CA is below 0.5 percent [Burger et al., 2006; Wolfe et al., 2009], a lower rate than in adults [Johnston et al., 2001]. An additional concern with CA is radiation exposure, with recent estimates suggesting that a child undergoing diagnostic neuroangiography may incur a lifetime attributable risk of cancer approaching 1 percent [Raelson et al., 2009].

Certain causes of childhood AIS merit special imaging considerations. Inflammatory or postinfectious arteriopathies can be screened for and followed on MR angiography [Aviv et al., 2006]. However, CA will reveal the details and extent of disease, particularly when smaller vessels are affected. Small-vessel cerebral vasculitis presenting without AIS is typically negative on CA, requiring diagnosis with brain biopsy [Benseler et al., 2005]. Diagnosing arterial dissection can be challenging and may be missed on CT angiography and MR angiography [Tan et al., 2009b]. Axial fat saturation T1 can reveal wall hematoma (“crescent sign”) but, otherwise, CA may be required. Moyamoya patterns generally are detectable on MR angiography, but CA is required to visualize collaterals and the full stage and extent of disease, as well as for surgical planning [Scott and Smith, 2009].

Emergent Treatment

Urgent Treatment

Motor Disabilities

Motor disabilities after childhood AIS are common, functionally important, and readily amenable to evaluation [deVeber, 2000; Ganesan et al., 2000]. Common involvement of the MCA territory damages both cortical and subcortical motor systems, resulting in hemiparesis affecting the upper more than the lower extremity (see Figure 85-6). Problems of gait and lower-extremity morbidity, as well as effects of cerebellar and basal ganglia lesions, also occur and should not be overlooked. Neuroimaging may facilitate early prediction of poor motor outcomes in childhood AIS [Boardman et al., 2005; Domi et al., 2009], possibly identifying those in need of aggressive rehabilitation. Historical, commonsense physical and occupational therapy approaches typically are applied to enhance motor recovery after stroke [Aoyagi and Tsubahara, 2004; Dobkin, 2004]. Programs that combine strength and aerobic conditioning, task-specific training, and assistive devices form the basis of post-stroke motor rehabilitation in adults [Teasell et al., 2006], and generally are recommended in children [Paediatric Stroke Working Group, 2004]. Fortunately, evidence is now emerging to establish and expand the benefits of both traditional and novel strategies to improve motor function.

Abnormal Tone

Abnormal tone and the need for assistive devices should be considered in children with stroke. Both rate-dependent (spasticity) and rate-independent (e.g., dystonia) hypertonia complicate the lives of and limit function in children with AIS. Such morbidities can be complex and require a systematic approach, often with the collaboration of experts in physical medicine and orthopedics [Sommerfeld et al., 2004]. Spasticity interventions must include comprehensive, objective, and blinded pre- and post-interventional outcome measures of efficacy. Botulinum toxin may alleviate increased tone, though effects on motor function and quality of life in children have been questioned [Brashear et al., 2002; Redman et al., 2008], and issues of cost, frequency, and tolerability often are significant. Pharmacological spasticity therapies are not well evaluated in childhood stroke and may be complicated by systemic toxicity. Careful selection criteria and better evidence of efficacy also are required for surgical interventions, such as tendon-lengthening procedures. Assistive devices, including ankle-foot orthoses and Lycra hand splints, may facilitate joint positioning and function, and are supported by evidence in adult stroke [Lannin and Herbert, 2003; Aoyagi and Tsubahara, 2004]. Consensus pediatric stroke guidelines suggest splinting for carefully selected children [Paediatric Stroke Working Group, 2004]. An added challenge in young pediatric stroke patients is resulting asymmetries in physical growth, with leg-length discrepancy and scoliosis that may require orthopedic intervention.

Neuropsychological Impairments

Neuropsychological impairments are common in children with stroke, limiting academic, social, and independent functional success [Friefeld et al., 2004; Nass and Trauner, 2004]. Regular, age-appropriate neuropsychological evaluations should be considered in all at-risk children to determine educational and support needs. Serial assessments across development are required, as defects in higher brain function often emerge over time in young children [Westmacott et al., 2007a, 2009]. On average, childhood stroke survivors exhibit moderately compromised global intellectual function [Hetherington et al., 2005; McLinden et al., 2007]. Lesion side, size, and age at injury may influence outcome, though accurate prediction is challenging [Lansing et al., 2004; Max, 2004a; Ricci et al., 2008]. Younger age at stroke does not appear to predict better cognitive outcomes [Stiles, 2000; Lansing et al., 2004; Westmacott et al., 2007b]. Language function often is impaired also, usually related to dominant (left) hemisphere injury [Chilosi et al., 2001; Nass and Trauner, 2004]. While children may recover quickly from acute aphasias, residual deficits in complex language are common [Hertz-Pannier et al., 2002; Van Dongen et al., 1994]. Verbal learning and memory often are impaired in children following stroke [Max, 2004a; Lansing et al., 2004]. Comprehensive, serial testing of cognitive, language, and other higher brain functions by pediatric neuropsychologists using standardized measures is an important component of a childhood stroke rehabilitation program.

Emotional and behavioral disorders after childhood stroke are poorly understood but potentially affect all aspects of quality of life. Limited studies suggest that social function commonly is impaired following stroke in childhood [Mosch et al., 2005]. In children with perinatal stroke, rates of emotional and behavioral disturbances are increased, the effects often not emerging until preschool or later [Goodman and Graham, 1996a]. Lesion location has not been correlated well with neuropsychological outcomes [Max et al., 2002b; Trauner et al., 2001], but bilateral lesions may elevate the risk of emotional or behavioral problems [Nass and Trauner, 2004]. Rates of attention-deficit hyperactivity disorder also are increased [Max et al., 2002a, 2003, 2004b], particularly with lesions involving the putamen [Teicher et al., 2000]. Such potentially treatable psychiatric comorbidities should be screened for in children with stroke.

Stroke Recurrence

Stroke recurrence is significant, mandating a thorough approach to secondary stroke prevention over the long term. Previous studies suggested that stroke and TIA recurrence risks range from 7 to 35 percent [Isler, 1984; Chabrier et al., 2000; Lanthier et al., 2000, 2004; De Schryver et al., 2000; deVeber, 2000]. The rate of recurrence approaches 50 percent when antithrombotic agents are not given [Lanthier et al., 2004]. A more recent population-based study confirmed an overall 5-year recurrence risk of 20 percent and, more importantly, established that the majority of risk is carried by children with arteriopathy, in whom recurrence was 66 percent [Fullerton et al., 2007b]. That arteriopathy predicts recurrence is consistent with previous studies [Chabrier et al., 2000; Lanthier et al., 2004]. With no randomized trials, the relative efficacy of various secondary stroke prevention interventions is unknown. Consistent with clinical practice [Goldenberg et al., 2009] and published guidelines [deVeber and Kirkham, 2008], antiplatelet therapy with ASA (1–5 mg/kg/day) is the mainstay of long-term secondary stroke prevention in childhood AIS. Exceptions exist, however, and therapy must be tailored and adjusted over time to the individual patient. Insensitivity or intolerance of ASA may require an alternative antiplatelet agent, like clopidogrel. Certain cardiac and prothrombotic conditions may require long-term anticoagulation with warfarin. Additional treatments may include immunosuppression for inflammatory vasculitis, transfusions for SCD, and revascularization surgery for moyamoya. Attention to arterial health, with balanced diet, exercise, avoidance of smoking and drugs, and surveillance for hypertension, dyslipidemia, or insulin resistance, may also help prevent recurrence over the long term.

Epilepsy

Epilepsy will complicate childhood AIS in approximately 15–20 percent of cases [deVeber, 2000; deVeber et al., 2001; Yang et al., 1995; Fitzgerald et al., 2007]. Seizures likely arise from partially injured, perilesional brain parenchyma, and partial or secondary generalized events are expected. However, bilateral EEG abnormalities and generalized epileptic encephalopathies, including infantile spasms, can occur after unilateral, focal stroke in infants and young children [Kirton et al., 2008b; Soman et al., 2006b; Fitzgerald et al., 2007]. Concerns that on-going clinical seizures, or even subclinical pathological EEG activity, can affect plastic neurodevelopment and recovery adversely in children after stroke are theoretical but important. While some predictors of childhood epilepsy are appreciated in perinatal stroke [Fitzgerald et al., 2007; Kirton et al., 2008b], studies in older children are limited. Children with large cortical lesions may harbor the highest risk [Yang et al., 1995; deVeber, 2000]. Screening for seizures on history and use of supportive investigations, such as EEG, are required. Treatment requires anticonvulsants and attention to the extensive additional psychosocial impact of epilepsy on the entire family. As stroke typically represents a focal lesion in an otherwise healthy brain, children with AIS and epilepsy may be particularly good candidates for epilepsy surgery [Wyllie et al., 2007; Guzzetta et al., 2006].

Hyperkinetic Movement Disorders

Hyperkinetic movement disorders can follow childhood AIS, often not presenting for weeks or months after stroke [Kwak and Jankovic, 2002; Boardman et al., 2005; Nardocci et al., 1996]. Basal ganglia strokes carry the greatest risk. Prevalence may be underestimated because dystonia can be difficult to distinguish from spasticity. History, examination, and physical therapy consultation should be integrated to determine the relative balance of weakness, spasticity, and dystonia in an individual patient with motor dysfunction after AIS. Treatment options differ, based on this, and, as there has been little study specific to stroke, should employ the general principles of managing pediatric movement disorders (see Chapter 68) [Edgar, 2003]. Options include anticholinergic (e.g., trihexyphenidyl), antidopamine (e.g., pimozide), or dopamine-depleting (e.g., tetrabenazine) agents, as well as other medications and botulinum toxin injections. Such interventions should begin at low doses, with gradual titration to minimize side effects, combined with objective assessments of efficacy by blinded observers. The role of newer movement disorder medications and therapies, such as deep brain stimulation, have not been determined in children with stroke.

Headache Disorders

Headache disorders also appear to be increased following pediatric stroke, occurring in 33 percent of cases [deVeber, 2000]. Risk factors include pre-existing conditions (e.g., migraine), the nature of the underlying disease (e.g., moyamoya), and psychosocial stressors. Screening is important, as new or worsening headaches may be a marker of disease progression, including progression of small-vessel cPACNS, moyamoya, or migrainous infarction. Therefore, diagnoses of primary headache disorders, such as migraine or tension-type headache, must be made cautiously in accordance with International Headache Society criteria. Most established pharmacological and nonpharmacological interventions for headache (see Chapter 63) are safe in children with AIS, with a few exceptions. Regular use of nonsteroidal anti-inflammatory medications can decrease the efficacy of ASA modestly, but occasional use for abortive headache therapies is likely safe if alternatives such as acetaminophen are ineffective. In children with migrainous infarction, the calcium channel blocker flunarizine theoretically provides both headache and stroke prevention. Vasoconstricting agents, including triptans, probably should be avoided in those with migrainous infarction or arteriopathy. Attention to lifestyle, triggers, and psychological factors remains essential.

Psychosocial Family Support

Psychosocial family support also must be considered. Complete care of childhood stroke centers on the child and family. Complex psychosocial challenges are likely common and under-estimated. While resources are slowly improving, there is an on-going need for the development of educational and supportive resources to improve pediatric stroke care [Paediatric Stroke Working Group, 2004]. Adverse effects of stroke on quality of life are measurable in most childhood stroke survivors and their family [Gordon et al., 2002], and relate to both neurological deficits and psychosocial factors [Friefeld et al., 2004]. Social factors and environment have been shown to affect adult stroke recovery and may be even more important in children [Teasell et al., 2006]. Similarly, coping strategies may influence adult stroke outcome [Donnellan et al., 2006] but have not been studied in childhood, when such challenges are likely even greater. Each element of treatment and rehabilitation needs to consider the individual child’s lifestyle, goals, and level of functioning, and be well integrated into the school and home environments [Paediatric Stroke Working Group, 2004]. Parents require education and may need encouragement to avoid “overprotection” and to treat their children as normal. Alleviation of parental guilt also may provide substantial benefit. As the assignment of an exact etiology for many childhood strokes often is lacking, parents may assume unjustly that some modifiable factor within their control is somehow responsible. It is important, therefore, to screen parents for such misplaced interpretations and feelings of guilt, and to offer supportive education, reassurance, and discussion.

Family support also includes guidance in the interpretation of a growing number of unproven therapeutic options. Stem-cell therapies are an increasingly controversial topic [Patoine, 2009], and are many years away from consideration in the treatment of childhood stroke [Kurtzberg, 2009]. Giving more cause for concern is the preponderance of individuals and operations that prey on the vulnerable families of children with neurological disabilities [Rosenbaum, 2003]. Many “pseudotherapies” are marketed unfairly to families of children with stroke, offering incredible but unsubstantiated claims of efficacy. Hyperbaric oxygen lacks theoretical basis, risks multiple adverse effects [Nuthall et al., 2000; Muller-Bolla et al., 2006], and repeatedly has been proven ineffective [Collet et al., 2001; Hardy et al., 2002]. Despite this, it continues to be promoted at high cost by flagrantly conflicted organizations. The use of complementary and alternative medicines is common in pediatric stroke, despite no proof of efficacy and potential interference with medical therapies [Golomb et al., 2003b]. Few such pseudotherapies will ever undergo proper testing for safety and efficacy. The treating physician must, therefore, guide families to make informed decisions, respecting their motivation to help their children, while advocating on their behalf for responsible and equal regulation of all therapies offered to children with disabilities.

Sinovenous Circulation: Anatomy and Vascular Patterns

Cerebral venous drainage of the brain occurs through a network of cerebral veins and sinuses (Figure 85-11). A general pattern of distal venous drainage toward midline channels that flow in a posterior direction is recognized. In the superficial venous system, cortical veins drain cortical and subcortical areas medially toward the superior sagittal sinus. The deep venous network includes internal cerebral, medullary, thalamic, and choroidal veins, which converge centrally at the vein of Galen; this, in turn, drains into the straight sinus. These superficial and deep systems converge posteriorly at the torcula. Bilateral, often asymmetrical, transverse sinuses then drain laterally to the sigmoid sinuses, which connect to the jugular veins. Though variable, the superficial system frequently drains predominantly into a larger right transverse sinus, while the deep system empties via a smaller left transverse sinus. Additional venous drainage pathways connecting with this system at recognizable locations include the anterior cavernous and petrosal sinuses, as well several large superficial veins (e.g., Trolard, Labbé). Pathological thrombosis can occur anywhere within this system; however, the superficial venous system is involved more frequently [deVeber et al., 2001; Sebire et al., 2005].

Fig. 85-11 The major cerebral veins and dural venous sinuses.

The cerebral sinuses are external to the brain, enclosed between two layers of fibrous dura mater. Attachment of the outer layer to the calvarium maintains a fixed open lumen with venous sinus caliber unresponsive to changes in systemic blood pressure, facilitating passive venous drainage [Capra and Anderson, 1984]. However, the fixed lumen and absence of valves or surrounding muscles that characterize systemic veins results in slow, reversible flow within the sinuses. Gravity compensates in part for these differences; however, cerebral venous circulation remains sensitive to impaired venous return. In supine neonates and young infants with open posterior fontanels, mechanical compression of the superior sagittal sinus by the occipital bone may compromise venous drainage, resulting in venous stasis [Newton and Gooding, 1975; Tan et al., 2007]. As the superior sagittal sinus also is the primary site for cerebrospinal fluid reabsorption via the arachnoid granulations, thrombosis or venous hypertension here can result in communicating hydrocephalus [Bousser, 1997].

With a working knowledge of the above venous anatomy, clinical patterns of CSVT and venous infarction can be recognized. Bilateral, parasagittal infarcts, especially with hemorrhagic transformation, are likely secondary to sagittal sinus thrombosis. Deep venous thrombosis involving the internal cerebral veins, straight sinus, and/or vein of Galen will produce venous edema and infarction of the deep white matter, basal ganglia, and thalamus. Such hemorrhagic infarction in deep locations immediately adjacent to the ventricular system (e.g., thalamic lesions by third ventricle) can produce intraventricular hemorrhage (IVH). In term neonates with IVH, nearly one-third have an underlying deep CSVT [Wu et al., 2003]. As both venous drainage pathways and infarction mechanisms are heterogeneous, the imaging and clinical presentations of venous infarcts and hemorrhage lack the more predictable patterns of arterial infarcts, necessitating a higher index of clinical suspicion.

Mechanisms of Thromboembolism

Factors mediating thrombosis in cerebral venous channels differ in some respects to those underlying thrombosis in cerebral arteries. In contrast to AIS, the coagulation cascade and thrombin-rich thrombosis predominate in CSVT, with platelets playing a less significant role [Furie and Furie, 2008]. Inherited or acquired coagulation abnormalities (see below), including prothrombotic medications, are important in CSVT pathogenesis. There is a relative absence of thrombomodulin in the endothelial lining of cerebral sinuses compared with cerebral arteries, theoretically increasing the tendency for thrombosis [Lin et al., 1994]. Consideration of Virchow’s triad is highly relevant in the cerebral venous system, with thrombosis resulting from abnormalities of blood components, blood flow, or vessel wall. In many children with CSVT, the exact mechanism of thrombosis is not evident. Dehydration is a frequent and potent risk factor for CSVT, where decreased blood volume and hemoconcentration decrease venous flow rates, favoring thrombus formation and propagation. In septic CSVT, head or neck infection in tissues immediately adjacent to venous channels provokes cerebral venous thrombophlebitis. With mechanical damage or compression of venous structures, venous stasis and vessel wall damage may combine to cause thrombosis. Examples include trauma, neurosurgical procedures, insertion of venous catheters, compressive mass lesions, and occipital bone compression in supine young infants [Deitcher et al., 2004; Newton and Gooding, 1975; Tan et al., 2007].

Mechanisms of Infarction

Cerebral venous sinus occlusion causes a rise in venous pressure, with consequences developing over time in cerebral tissue. This may occur focally in a single venous territory, or more globally as a syndrome of diffuse increased intracranial pressure. In focal injury, the failure of venous emptying results in local tissue pressure elevation with transudation of fluid across venous or capillary channels. Initially, this may produce parenchymal vasogenic edema without true infarction, accompanied by focal clinical symptoms. However, further increases in regional tissue pressure eventually can exceed the incoming arterial perfusion pressure, resulting in permanent infarction. On MRI, DWI may differentiate venous edema from infarction [Forbes et al., 2001; Carvalho et al., 2001], although, in CSVT, some restricted diffusion may be reversible [Ducreux et al., 2001]. Venous drainage can occur via alternate routes, including redundant pathways and pial collaterals, but these may require time to develop. Therefore, very rapid or complete thrombotic venous occlusion carries an increased risk of tissue infarction [Bousser, 1997]. The increased “back pressure” of CSVT accounts for the high rate of transformation of infarcts from initially bland to hemorrhagic. The presence of hydrocephalus, either from IVH or communicating hydrocephalus, creates a further increase in compression of already compromised brain tissue, possibly accelerating injury.

Computed Tomography

Plain (non-contrast) CT is inadequate to exclude CSVT, and also may underestimate early edema or infarction [Ameri and Bousser, 1992; Barron et al., 1992; Bousser, 1997; Jacewicz and Plum, 1990]. Plain CT also can produce false-positive results [Hamburger et al., 1990], particularly in neonates and young infants, in whom higher hematocrit, slower venous flow, and unmyelinated brain hypodensity may create an illusion of sinus hyperdensity [Ludwig et al., 1980; Kriss, 1998; Davies and Slavotinek, 1994]. Tentorial subdural hemorrhage is common in the newborn and may mimic transverse sinus thrombosis. Despite these limitations, CSVT can appear as hyperdense sinuses or individual veins on noncontrast CT (see Figure 85-13). The combination of hyperdense straight sinus, thalamic hypodensity/bleeding, and IVH is a recognizable, life-threatening syndrome due to deep system CSVT [Linn et al., 2009].

Contrast-enhanced CTV is highly sensitive and specific for childhood CSVT diagnosis. Thrombus appears as a filling defect in the vein or sinus, where contrast may be either absent (complete occlusion) or focally reduced (incomplete occlusion) (Figures 85-13 and 85-14). The “empty triangle” or “empty delta” sign represents such a filling defect at the torcula. Multislice contrast-enhanced CT, with submillimeter slices and multiplanar reformations for axial, coronal, and sagittal views, has improved the ability to diagnose CSVT significantly. As CTV requires additional imaging and most children will require serial scanning, age-adjusted radiation dosages must be considered.

Fig. 85-14 Septic cerebral sinovenous thrombosis.

An 11 year-old girl presented with increasing headache and retroauricular pain. Initial examination was normal. Initial plain computed tomography demonstrated only opacification of the right mastoid air cells, consistent with mastoiditis, and she was started on antibiotics. Within 48 hours, she developed increasing headaches and diplopia, with bilateral sixth nerve palsy and papilledema on examination. A and B, Axial (A) and coronal (B) computed tomographic venography revealed a large filling defect in the dominant right transverse sinus (arrows). The patient was treated with anticoagulation and acetazolamide, and had a normal long-term outcome including visual fields. (C) bilateral papilledema on retinal examination.

Magnetic Resonance Imaging

In most circumstances, MRI is the diagnostic modality of choice in pediatric CSVT. MRI lacks radiation and may provide additional details of both brain parenchyma and the venous system. Combining MRI modalities sensitive to vasogenic edema (e.g., FLAIR), cytotoxic edema and infarction (e.g., diffusion), and blood product (e.g., gradient echo) can both confirm and characterize CSVT-related parenchymal changes (Figures 85-12, 85-13, and 85-15). MRI may also image thrombosis itself, possibly providing more information about the age and nature of the lesion. Subacute thrombus often appears hyperintense on T1- and T2-weighted images (see Figure 85-12). This hyperdense appearance can be particularly helpful in diagnosing cortical vein thrombosis, where a filling defect may be hard to demonstrate, however, numerous artifactual mimics also must be excluded [Leach et al., 2006]. Restricted diffusion within a thrombus appears to predict a longer time to recanalization [Favrole et al., 2004]. Susceptibility-weighted MRI, which is exquisitely sensitive to blood, also may help detect small, early, and/or isolated cortical vein thrombosis [Idbaih et al., 2006].

Fig. 85-15 Diffuse cerebral sinovenous thrombosis and coma.

A, A 16-year-old girl on oral contraceptives became dehydrated with an intercurrent illness. After 48 hours of headache, her level of consciousness suddenly deteriorated. Initial examination demonstrated a Glasgow Coma Scale score of 3 with papilledema. A, Plain computed tomography showed a hyperdense right internal cerebral vein and straight sinus (arrow). B, A hypodense right thalamus was also demonstrated (arrow). C, Diffusion magnetic resonance imaging showed restricted diffusion in the right thalamus (arrow). D, Computed tomographic venography demonstrated thrombosis of all major venous sinuses (arrows). E, Magnetic resonance venography confirmed the same, with engorgement of alternative venous drainage pathways (arrows). Emergent anticoagulation and neuroprotective care was initiated and the patient began improving within 12 hours. At 6 months, she has minimal infarction on imaging, moderate left-sided weakness, and moderate neuropsychological sequelae.

MR venography can employ time-of-flight or contrast-enhanced methods to image the cerebral venous system in a comparable fashion to CTV (see Figure 85-15). Time-of-flight venography depends on flow-signal characteristics and is therefore subject to significant artifacts, especially slow or turbulent flow [Ayanzen et al., 2000]. Thus, apparent “filling defects” must be interpreted with caution. Expert interpretation is essential and confirmatory CTV may be required. Gadolinium-enhanced MR venography is superior to time-of-flight venography and, possibly, to CTV in adults, and shows promise in children [Farb et al., 2003a; Rollins et al., 2005].

Emergent Treatment

Urgent Treatment

Urgent Treatment

Congenital Arteriopathies

In addition to AVM, cavernoma, and some aneurysms, numerous less common congenital arteriopathies have been associated with childhood HS. Hereditary hemorrhagic telangiectasia (HHT) or Osler–Weber–Rendu syndrome features systemic vascular malformations affecting the lung and liver, as well as the nervous system [Krings et al., 2005]. Dominantly inherited mutations in several genes within the transforming growth factor (TGF)-β signaling superfamily are responsible [Govani and Shovlin, 2009]. Connective tissue disorders, such as dominantly inherited COL4A1 mutations, can predispose to recurrent HS [van der Knaap et al., 2006]. Pediatric versions of fibromuscular dysplasia include intracranial aneurysms and HS [Kirton et al., 2006]. An increasing number of congenital conditions associated with cerebral vasculopathy and HS includes Majewski osteodysplastic primordial dwarfism (MOPD) II [Brancati et al., 2005], PHACES [Heyer et al., 2008], and Alagille’s [Emerick et al., 2005] syndromes.

Acquired Arteriopathies

The list of acquired arteriopathies predisposing children to HS overlaps with those causing AIS. Ischemic infarcts may undergo significant hemorrhagic transformation, some extensive enough to mimic primary HS. This is more common in CSVT ischemic stroke, of which at least 50 percent of cases are hemorrhagic [deVeber et al., 2001], but may also occur in 10–20 percent of childhood AIS [Kirton et al., 2007]. Intracranial arterial dissection may be more common in children as compared to adults in whom failure of arterial wall integrity leads to SAH [Fullerton et al., 2001]. In moyamoya disease, HS risk is lower than that of ischemic stroke, but still is substantial and may relate to unstable collateral vessels, diffuse arteriopathy, hypertension, and other factors. Both morbidity and long-term recurrence risk of moyamoya HS are high [Yoshida et al., 1999]. Additional arteriopathies that typically lead to AIS but in which HS has been reported include SCD, postradiation vasculopathy, and primary and secondary CNS vasculitides. Several infectious arteriopathies carry a much higher risk of HS, including mycotic aneurysms secondary to bacterial endocarditis (see Figure 85-8) [Venkatesan and Wainwright, 2008] and HIV vasculopathy [Shah et al., 1996]. The generalized cerebral arteriopathies and risk factors so prominent in adult HS, such as hypertension, amyloid, atherosclerosis, and smoking, are not seen in children. Hypertension is listed as a potential factor in several studies, with frequencies ranging from 5 to10 percent [Livingston and Brown, 1986; Meyer-Heim and Boltshauser, 2003]. However, most do not report the timing of measurement and a large study reporting acute hypertension in 45 percent of children with ICH did not identify it as a causative risk factor in any of 85 cases [Lo et al., 2008b].

Traumatic Hemorrhage

Traumatic hemorrhage can occupy epidural, subdural, subarachnoid, intracerebral, or intraventricular intracranial compartments (see Chapter 74). Traumatic ICH can appear as one or multiple hemorrhagic contusions or multifocal small hemorrhagic foci throughout the white matter. Traumatic SAH can result from the direct rupture of small subarachnoid vessels, or can occur as a complication of post-traumatic dissection of cerebral arteries. Any unexplained ICH in infants must raise the consideration of nonaccidental trauma. A large cohort study of shaken baby syndrome described the following hemorrhage patterns: subdural (94 percent), SAH (16 percent), ICH (8 percent), and epidural (1 percent) [Morad et al., 2002]. Retinal hemorrhages were present in 75 percent and were correlated with intracranial bleed severity. Dural arteriovenous fistulas (DAVF) are abnormal arteriovenous shunts within the dura mater of the sinuses that can predispose to HS and be either spontaneous or post-traumatic [Neumaier-Probst, 2009].

Hematological Factors

Hematological factors are a major consideration in any child with intracerebral bleeding. Compared to adult ICH, children are more likely to harbor a bleeding diathesis that may be related to numerous underlying conditions [Eyster et al., 1978; Roach and Riela, 1995]. A hematological factor is identified as the primary cause in 5–20 percent of childhood HS [Livingston and Brown, 1986; Blom et al., 2003; Lanthier et al., 2000; Meyer-Heim and Boltshauser, 2003; Kumar et al., 2009]. One large study identified hematological factors in 32 percent of cases, with examples including thrombocytopenias, multiple coagulation factor deficiencies, and SCD [Al Jarallah et al., 2000]. Additional intravascular considerations include coagulopathies secondary to hematological malignancies and their treatment, hepatic dysfunction, and factor deficiencies such as hemophilia. Thrombocytopenia may be secondary to infectious, immune, or neoplastic diseases, as well as their treatments. All children with otherwise unexplained HS require an immediate evaluation of their hemostatic system, including complete blood count, prothrombin and partial thromboplastin times, and specific hematological studies as indicated.

Additional etiologies for childhood HS include bleeding into brain neoplasms, described as the cause in 2–15 percent of cases [Al Jarallah et al., 2000; Lo et al., 2008b]. Iatrogenic causes include neurosurgical procedures and intravascular interventions, such as angioplasty or stenting and, occasionally, CA. Finally, exposure to medications and illicit substances should be considered. Potential substances include thrombolytics, anticoagulants, antiplatelet agents, sympathomimetic drugs, cocaine, and amphetamine [Forman et al., 1989; Levine et al., 1990]. Thorough history, examination, and appropriate investigations usually will uncover the cause of childhood HS, with less than 10 percent remaining idiopathic in most studies.

Vascular Malformations and Aneurysms

Vascular malformations traditionally have been defined as vascular developmental anomalies with preservation of abnormal connections between normally structured vessels. Such lesions are classically divided into four types, based on the caliber and histological structure of component vessels: AVMs, cavernous malformations, venous angiomas and capillary telangiectasias [Russell and Rubenstein, 1989]. Capillary telangiectasias are an infrequent cause of HS and usually are associated with neurocutaneous disorders (see Chapter 40). However, additional malformations of the vascular system do not meet these classical criteria entirely. They include vein of Galen malformations (below) and several diseases alluded to above, including DAVF [Neumaier-Probst, 2009] and many congenital arteriopathies (see Box 85-1). Many aneurysms in children are considered congenital and, as an important cause of HS, they also are included here.