Rudolph's Pediatrics, 22nd Ed.

CHAPTER 552. Stroke and Cerebrovascular Disease

Michael J. Rivkin

Stroke denotes the sudden onset of a focal neurologic deficit and most often includes the abrupt appearance of weakness. Interruption of blood flow to a part of the central nervous system (CNS) usually underlies the resultant weakness. Because most strokes in children are related to focal cerebral involvement, the most common clinical manifestation is the abrupt appearance of hemiparesis. Less frequently, the cause of stroke involves the brainstem, cerebellum, or spinal cord. The functional consequences always reflect the neuroanatomic features of the affected CNS region. Either focal cerebral ischemia or hemorrhage may cause the clinical manifestations of stroke. Further, ischemic stroke in children is attributable to either arterial ischemic stroke (AIS) or to cerebral sinovenous thrombosis (CSVT). This chapter addresses these causes of focal cerebral injury in children. First, epidemiologic features of stroke in children will be presented. Consideration will then be directed to the occurrence of pediatric cerebrovascular disease in neonates as well as in older children. Emphasis will be placed on the pathogenetic, clinical, diagnostic, and therapeutic aspects of the varied causes of strokes in children.

EPIDEMIOLOGY

Stroke in children follows a biphasic pattern of occurrence. Its occurrence is highest among newborns and occurs less frequently in children greater than 30 days of age. Among neonates, studies indicate an occurrence of stroke that approximates a frequency of 1 in 4000 births.1-3 Arterial ischemic stroke accounts for 80% of these occurrences, although 20% are due to cerebral sinovenous thrombosis (CSVT) and hemorrhage (excluding intraventricular and subarachnoid hemorrhages).4,5

Several studies of stroke in children older than age 1 month, performed over the last three decades have reported an occurrence of stroke at a rate of approximately 2 in 100,000 per year.6-8 However, recent studies suggest that the frequency may be greater and as high as 13 in 100,000 per year.5,9 Strokes occur more often in males than in females and more frequently in African Americans and Caucasians.

PATHOGENESIS

Ischemic injury to the brain occurs as a result of one of three different mechanisms: embolism, thrombosis, or diminished systemic perfusion. Embolic damage to the brain occurs when material formed at a site in the vascular system proximal to the brain lodges in a blood vessel, blocking cerebral perfusion. Emboli originate most commonly from the heart, arising from clots on cardiac chamber walls or from vegetations on valve leaflets. Congenital heart disease that includes right-to-left shunt predisposes to such embolus formation. Artery-to-artery emboli are composed of clot or platelet aggregates that originate in vessels proximal to the brain but ultimately come to rest and to occlude flow in vessels critical for cerebral perfusion. Intravascular embolus formation is promoted by some forms of thrombophilia (see below). Thrombosis denotes vascular occlusion resulting from a localized process within a blood vessel or vessels. Although atherosclerosis underlies most thrombotic processes affecting adults, it is a very uncommon cause of thrombosis in children. Localized luminal clot formation occurs in polycythemia or in a hypercoaguable state. Alternatively, anatomic abnormalities may lead to clot formation or mechanical obstruction in fibromuscular dysplasia, focal arteriopathies, or vascular malformations. Should systemic pressure decline enough to compromise cerebral perfusion, the central nervous system may suffer injury as a result of diminished systemic perfusion. Cardiac pump failure (related to congenital heart disease and its surgical repair), as well as systemic hypotension due to hypovolemia, represents common causes of hypotensive cerebral ischemic injury. Often, in the circumstance of diminished cerebral perfusion, brain injury is much more diffuse than that found in the more focal injuries characteristic of thrombotic and embolic cerebral events. Cerebral ischemia serves as the final common pathway leading to brain injury irrespective of whether an embolic, thrombotic, or hypoperfusive mechanism has caused the stroke.

Both thrombotic and embolic strokes may be heralded by the occurrence of transient ischemic attacks (TIAs). Transient ischemic attacks are brief episodes of focal, nonconvulsive neurologic deficit attributable to interruptions of cerebral perfusion. Similar to stroke, the onset is abrupt. However, a TIA episode lasts less than 24 hours and recovery is complete. Despite full recovery, the TIA can serve as a sentinel event of subsequent episodes that may result in fixed deficits. Importantly, signal correlates of a TIA may not be present on magnetic resonance imaging (MRI) of the brain.10

Hemorrhage occurs when blood is released into the extravascular, intracranial, or intraspinal space. In this circumstance, focal injury of brain or spinal tissue occurs as a result of pressure exerted by the space-occupying mass of blood, as well as hemorrhage-related ischemia. Such injury can be exacerbated by the damaging effects upon neural tissue of substances released in the blood. Epi- and subdural hemorrhages represent intracranial collections of blood separated from brain parenchyma by dural or arachnoid membranes. Subarachnoid hemorrhage occurs when blood flows out of the intracranial vascular bed and onto the surface of the brain to admix with cerebrospinal fluid in the subarachnoid space. Intracerebral hemorrhage denotes bleeding into the parenchyma of the brain.

NEONATAL STROKE

Stroke in neonates may be considered as perinatal stroke, which has been defined to occur during the fetal or neonatal periods but before 28 days after birth.4,11 Stroke differs from the intraventricular hemorrhage observed in premature infants and discussed in Chapter 58. Eighty percent of strokes in neonates are arterial and ischemic (AIS). The remaining 20% are attributable to either cerebral sinovenous thrombosis (CSVT) or hemorrhage. Interestingly, a left hemispheric location has been noted to be the most common in neonatal AIS, a lateralization for which no proven explanation has been found.12Neonatal CSVT may cause focal infarction or hemorrhage. Cerebral veins conduct deoxygenated blood from the parenchyma to the dural sinuses. These sinuses—the sagittal, straight, transverse, cavernous, and petrous—convey the blood to the jugular vein for return to the cardiopulmonary circulation. Thrombotic occlusion of flow anywhere in these venous conduits can lead to increased venous pressure, ischemia, and sometimes, infarction that can be hemorrhagic (Fig. 552-1).13

Risk factors associated with perinatal stroke have received limited investigation but include maternal and placental disorders, perinatal asphyxia, blood disorders including polycythemia, congenital cardiac disorders, infection, trauma, and drug exposures. In particular, the role of hypercoaguable states associated with prothrombotic risk factors such as factor V Leiden (FVL), prothrombin 20210 mutations, elevated concentrations of lipoprotein (a), homocysteine, factor VIIIC, anticardiolipin antibodies (ACA), and deficiencies of protein C and protein S have been implicated14 (see also Chapter 438). Although recurrent thromboembolic stroke is not common in infants, abnormality of lipoprotein (a), hyperhomocysteinemia, and protein C deficiency in the setting of underlying systemic disease may increase the chance of recurrence. Both maternal and infant characteristics may be related to the occurrence of cerebral sinovenous thrombosis (CSVT). Maternal risk factors may include preeclampsia, gestational diabetes, and chorioamnionitis.15,16 Frequent association between systemic illness and CSVT has been recognized in infants and includes dehydration, sepsis, congenital cardiac defects, extracorporeal membrane oxygenation, and meningitis.13,16,17 Although the role of thrombophilia in neonatal CSVT has not been proven, factor V Leiden (FVL), prothrombin 20210, and methylene tetrahydrofolate reductase (MTHFR) mutations have been suggested as factors that may promote the occurrence of CSVT in neonates.15,18 Importantly, more than one risk factor has been found simultaneously among many infants with CSVT.16,19 Thus, a combinatorial or synergistic mechanism may underlie many occurrences.

Seizure often is the first indication of AIS in the neonate.20,21 However, seizure may also be accompanied by signs of encephalopathy in newborns with AIS.22 Neonatal CSVT also commonly presents as seizure.15,23,24 However, other symptoms can include apnea, respiratory distress, feeding difficulty, hypotonia, and apnea. Indeed, CSVT can present in an infant as unexplained lethargy, alone.24

Because both AIS and CSVT in the newborn commonly present as seizure, an electroencephalogram (EEG) is often obtained. Evidence of localized dysfunction of the brain found on an EEG consists of focal persistent voltage reduction or of marked focal slowing and sharp wave activity. Periodic lateralized epileptiform discharges (PLEDS) may be present. In some instances electrographic evidence of clinically observed seizures may be found. Each of these findings may exist while the EEG remains relatively less affected over other regions of the brain. The areas of electrical abnormality should correspond to the affected areas of the brain revealed by neuroimaging.

Head ultrasound (HUS) serves as a noninvasive method of neuroimaging that offers the considerable advantage of bedside use. The sensitivity of head ultrasound is low and acute stroke in the neonate can be missed.25 Cranial computerized tomography (CCT) provides good fidelity in the identification of focal ischemia. However, magnetic resonance imaging (MRI) provides superior ability to identify ischemic foci in brain. The addition of diffusion tensor MR imaging provides superior sensitivity to that of CCT for identification of early focal ischemia. Moreover, MRI imparts no exposure to ionizing radiation, a considerable advantage of this modality over CCT.26 A combination of T1-weighted (T1W), T2-weighted (T2W), and diffusion weighted imaging (DWI) is most effective in the early identification of focal stroke in the neonate.27

FIGURE 552-1. Neonate with cerebral sinovenous thrombosis (CSVT). Sagittal T1-weighted image shows enlarged and thrombosed superior sagittal sinus (arrows). An associated area of hemorrhagic infarction is seen within the subjacent frontal lobe (asterisk).

Treatment is supportive and symptomatic. Anticonvulsant treatment is given if seizures have occurred. Phenobarbital remains the preferred drug and is administered as a loading dose of 20 mg/kg. Maintenance therapy of 3 to 5 mg/kg/day can be divided into twice daily doses. Attention should be given to hydration state, acid-base balance, and hematocrit. Deficits should be corrected. Treatment of underlying infection, metabolic disarray, or coagulopathy is necessary. Anticoagulation therapy with low molecular weight heparin (LMWH) or unfractionated heparin (UFH) is not used as a matter of routine in this age group but can be considered in selected neonates with severe thrombophilic disorders, multiple emboli to brain, or evidence of propagating CSVT despite supportive therapy (see below).28 Further investigation on the use of anticoagulation in neonates with focal stroke is needed.

Both motor and cognitive disabilities have been associated with perinatal stroke. Seizure during the neonatal period or neurologic abnormality on discharge have been associated with both these deficits.12Infants with perinatal stroke due to thrombophilia have been identified to be at risk for long-term neurologic deficit.29 Cognitive deficits often manifest by two years of age.30 Magnetic resonance imaging appears to be helpful in predicting outcome. Concomitant involvement of ipsilateral basal ganglia, corpus callosum, and the posterior limb of the internal capsule has been found to predict lasting hemiparesis.31 Further work is needed concerning neurodevelopmental outcome.

ETIOLOGIES AND CLINICAL FEATURES OF STROKE IN CHILDREN OLDER THAN ONE YEAR

Stroke occurs less frequently in older children than it does in newborns. Despite its relative infrequency in this age group, myriad etiologies exist. Nonetheless, the etiologies may be grouped according to whether the stroke is attributable to an embolic, thrombotic, or hemorrhagic cause. Causes of stroke in children are listed in Table 552-1 and are discussed below

THROMBOSIS

Vascular Dysplasia

Moyamoya disease is observed most commonly in children under the age of 15 years. This chronic condition is characterized by stenosis or occlusion of the terminal internal carotid arteries resulting in a characteristic development of an abnormal vascular network in the vicinity of the arterial occlusion (Fig. 552-2). The Japanese word moyamoya (meaning “puff of cigarette smoke”) was selected to describe this condition because of the characteristic appearance of this reactive vascular network on angiography. The network of collateral vessels arises principally from the external carotid circulation in response to relative tissue hypoxia. This phenomenon has been associated with increased central nervous system concentrations of angiogenic factors and creates an intricate latticework of compensatory blood flow.32,33Most commonly, moyamoya disease presents bilaterally, but unilateral presentations have been reported.34 Affected children most commonly come to medical attention due to stroke or transient ischemic attacks (TIA). Commonly, Moyamoya disease causes acute hemiplegia resulting from uncompensated occlusion of the internal carotid artery. When the condition is present bilaterally, bilateral motor deficits may be found. Both fine motor and extrapyramidal motor function can be adversely affected. It has been found as a sequela to a diverse array of conditions in children including sickle cell disease, neurofibromatosis, postcranial irradiation vasculopathy, Down syndrome, and Williams syndrome. Recently, genetic linkage analyses have revealed associations between Moyamoya disease and loci at 3p24-p26.1, 8q23, and 17q25.3.35 No specific medical therapy has been identified to halt progression of this disorder. However, aspirin has been used to prevent thrombotic events. Importantly, two surgical revascularization techniques have been employed to treat this condition (see below).

Table 552-1. Etiologies of Stroke in Children

Fibromuscular dysplasia may involve multiple sites throughout the systemic arterial tree, most commonly the renal arteries. However, cervicocephalic vasculature comprises the second most common site of this vasculopathy.36Pathologic or radiologic evidence of fibromuscular dysplasia has been found in carotid, vertebral, and intracranial arteries. Commonly, fibromuscular dysplasia involves irregularly spaced focal zones of dysplastic fibrous tissue in the media muscularis of the arterial wall. These findings can extend to the intima, as well.37 The resulting constricted regions of vascular fibrosis alternate with regions of lumenal dilation to create the characteristic beaded appearance on angiography. Its association with alpha-1-anti-trypsin disease has led to speculation about its possible relationship to other connective tissue disorders. Fibromuscular dysplasia is more common in adult females who range in age from the third decade to middle age, but has been found in adolescent and younger children. Familial occurrence has also been described. If renal arteries are affected, hypertension may be present. Neurologic symptoms signifying cerebrovascular involvement consist of headache, TIA, and stroke. A thrombotic mechanism for stroke has been postulated but has not been proven.

Vasculopathy

Acute hemiplegia due to stroke may occur in children with sickle cell disease. By age 14, up to 11% of children with sickle cell disease will have had clinical stroke and 22% will have had silent cerebral infarction. Low hemoglobin concentration and saturation, high hemoglobin S concentration, and chronically increased cerebral blood flow have all been observed to bear a relationship to the increased occurrence of stroke among children with sickle cell disease.38-41 However, large and middle-sized vessel vasculopathy comprises an important mechanism related to stroke in this patient population. Cerebral vessels can reveal endothelial proliferation, disruption of the elastic lamina, fibrin deposition, and stenosis. Stenosis is found most commonly in the distal internal carotid artery at the site where it bifurcates into the middle cerebral and anterior cerebral arteries.42 The stenoses may be severe in this region producing Moyamoya disease detectable by magnetic resonance imaging (MRI) or catheter angiography (Fig. 552-2).43 Indeed, among children with sickle cell disease, the presence of Moyamoya disease is associated with a twofold increase in the risk of stroke as compared to children undergoing transfusion therapy but who do not have this finding.44

The neurologic signs of stroke in this patient group often consist of hemiparesis, aphasia or visual disturbances. Magnetic resonance imaging studies reveal that clinically evident infarction frequently involves both gray matter and white matter although silent cerebral infarction most commonly involves white matter alone.45 Not only motor but cognitive deficits found among children with sickle cell disease correlate with MRI findings.46 Blood transfusion therapy has proven effective for the prevention of stroke in patients with sickle cell disease. The goal of therapy has become reduction of the hemoglobin S concentration to below 30% with transfusions given roughly monthly. Chronic transfusion therapy imparts increased risk for iron overload. Recently, encouraging results have been obtained with hydroxyurea therapy as an adjunct to transfusion therapy.47-49

A transient form of cerebral vasculopathy unrelated to atherosclerosis has emerged as an important clinical associate of stroke in children. Neurovascular imaging reveals stenoses of the distal internal carotid artery or of the proximal anterior, middle, or posterior cerebral arteries. The arteriopathy is monophasic and reversible. It has been associated with viral pathogens, such as parvovirus, enterovirus, and cytomegalovirus. In addition, mycoplasma pneumoniae and borrelia burgdorferii have been suspected as etiologic agents.50 When neuroimaging prompted by the occurrence of stroke in a child leads to the discovery of such a pattern of mulitfocal stenoses and has been preceded in the previous 12 months by the occurrence of varicella, postvaricella arteriopathy can be contemplated as the cause of the cerebrovascular event.51 The recurrent association of cerebral vasculopathy and stroke with viral infection underscores the importance of these agents in the pathogenesis of stroke in children.

FIGURE 552-2. Moyamoya disease. A: Injection of left internal carotid artery (ICA) on percutaneous cerebral angiogram of a 13-year-old male with sickle cell disease. The ICA (indicated by arrows) ends abruptly at the supraclinoid portion of the artery (marked by arrow and diamond. Note the consequent dearth of middle cerebral artery (MCA) vasculature due to the ICA occlusion (asterisk). While collateral circulation is abundant throughout the brain, especially numerous and tiny vessels are apparent within the circled region indicating intense compensatory vascular proliferation in response to the ICA occlusion. B: Left ICA injection from a normal child in which the full extent of the ICA is evident. A greater extent of vasculature from the MCA (asterisk) and anterior cerebral artery (arrowheads) territories is evident but is not found in (A).

Cervical vessel injury caused by head, neck, or intraoral trauma may cause stroke. Neurologic symptoms may be delayed more that 24 hours relative to the time of inciting trauma. Stroke due to carotid artery injury has been well documented. A typical presentation follows intraoral trauma to the internal carotid artery in a toddler who falls with a pencil or other object in the mouth. In older children, these cerebrovascular events occur after head/neck trauma sustained during motor vehicle or bicycle accidents, or following fights or falls. Conventional angiography may reveal internal carotid artery occlusion. Neuropathologic findings vary from an intimal tear with resulting thrombus formation leading, to arterial occlusion or frank arterial dissection. Vertebral artery injury may also lead to stroke in the posterior circulation of the brain. The serpentine course of the vertebral arteries through the cervical spine imparts vulnerability to traction injury. Thus, neurologic signs referable to brainstem, cerebellar, thalamic, temporal, or occipital lesions should lead to consideration of a vertebrobasilar etiology of stroke. Indeed, spontaneous arterial dissection of vessels in the anterior and posterior cerebral circulations have been reported in children.52-55 Finally, cranial radiation therapy, received as part of cancer therapy, may induce an occlusive vasculopathy leading to focal cerebral ischemia.56,57

Vasculitis

Bacterial infection constitutes an important and treatable cause of stroke in children. Inflammation of cerebral arteries and veins may occur in the course of bacterial meningitis. The subarachnoid arteries become immersed in purulent exudate and smaller vessels are affected as exudate moves down the Virchow-Robin spaces. Autopsy studies have revealed white cell invasion beneath the arterial intima; focal necrosis and mural thrombi have been observed in veins.58 Stroke may occur due to occlusion of either arteries or veins. Antibiotic treatment early in the course of the infection forms the cornerstone of therapy. Viral infections may promote vascular inflammation that may involve the cerebral vessels and culminate in stroke (see above). Indeed, cerebral vasculitis and stroke have been described in association with HIV infection in children.

Autoimmune disorders can include vasculitis that may involve the central nervous system (Table 552-2). Cerebrovascular involvement is well documented. Central nervous system symptoms of abrupt onset have long been associated with systemic lupus erythematosus (SLE). A CNS vasculitis had been presumed to underlie the brain cerebrovascular manifestations of SLE. However, autopsy study of patients suffering from SLE revealed a virtual absence of cerebrovascular inflammation. Rather, small areas of infarction relate to proliferative changes in cerebral arterioles leading to luminal occlusion.59 Large areas of infarction are sometimes found and may be related to anitphospholipid antibody related thromboembolism or to lupus-related embolism from sterile cardiac leaflet vegetations associated with SLE.60

Table 552-2. Autoimmune Disorders Associated with Central Nervous System (CNS) Involvement

Stroke may occur in the course of polyarteritis nodosa. Involvement of the CNS is found in 20% to 40% of patients.61,62 Mixed connective tissue disease (MCTD), which clinically overlaps with polymyositis, SLE, and progressive systemic sclerosis, can involve the CNS. Cranial neuropathy, most commonly trigeminal nerve dysfunction has been the most frequently cited deficit. However, stroke has been reported in children afflicted with MCTD.63 Necrotizing arteritis with inflammatory infiltrate has been found in both meningeal and cerebral vessels of children suffering from Henoch-Schoenlein purpura. Both fixed and transient central neurologic deficits may occur in this disorder. Treatment with steroid or with other immunosuppressive agents may prove helpful. Long-term anticoagulation has not been studied. Neurologic complications have been reported to accompany Kawasaki disease. Hemiplegia and neuroimaging findings indicative of focal cerebral infarction have been observed.64-66 Takayasu arteritis involving the aorta and its principal branches has been associated with thrombotic stroke. Inflammation-induced luminal constriction leading to thrombosis is thought to cause cerebral ischemia in these children. Angiographic improvement of vessels in the carotid tree has been observed following immunosuppressive therapy. The central nervous system may be involved in children with hemolytic-uremic syndrome (HUS). Stroke accompanied by radiographic evidence of focal CNS injury has been observed in 5% of children with HUS. Focal infarction is found primarily in cerebral hemisphere and basal ganglia. Damage to endothelial vascular lining due to Shiga toxin produced by Escherichia coli O157:H7 is thought to activate platelets and coagulation cascades to culminate in thromboembolic stroke.67,68

Vasospasm

Stroke may occur in the setting of migraine headache. The occurrence of focal deficits during migraine headache denotes a complicated migraine and is believed to reflect the involvement of either the carotid or vertebrobasilar circulation. Symptoms may include hemiparesis, ataxia, cortical blindness, and cranial nerve dysfunction and may be either fixed or transient. Angiographic studies have been performed on patients suffering focal deficits consistent with stroke in the setting of migraine headache. Vasoconstriction of vessels in either the vertebrobasilar or carotid circulations has been documented. In these cases, the neuroan-atomic position of the constricted vessels correlated with the location of the observed deficits. As a result, ischemia provoked by vasoconstriction during prolonged migraine has been hypothesized as a mechanism of stroke in these patients.

Drug abuse may promote thrombotic stroke. Cerebral infarction and peripheral neuropathy have been associated with glue sniffing in children. Cerebral infarction and subarachnoid hemorrhage have both been observed in association with cocaine use. Cocaine blocks the reup-take of catecholamines at the synaptic cleft. As a result of elevated synaptic concentration of epinephrine and norepinephrine, the neural activity of adrenergic systems is markedly enhanced. Tachycardia, hypertension, and vasoconstriction result. The probability of subarachnoid hemorrhage is higher in cocaine users with occult intracranial vascular abnormalities than in those with normal cerebral vasculature. The resultant sudden rise in systemic blood pressure is thought to precipitate subarachnoid hemorrhage. Ischemic lesions have also been found in patients who have used cocaine or who have been exposed to it prenatally. The physiologic evidence favors vasoconstriction as the underlying etiology of ischemic stroke found after cocaine use.69

Hematologic Etiologies

Several disorders of coagulation have been associated with embolic or thrombotic stroke. Adverse consequences of antiphospholipid antibodies including the lupus anticoagulant (LAC) and anticardiolipin antibody (aCL) have been identified in all age groups. However, cerebrovascular consequences of these antibodies are found in children, adolescents, and young adults. Antiphospholipid antibodies are polyclonal antibodies in serum which can bind to both neutral and negatively charged phospholipids. Recently, antibodies to beta-2-glycoprotein-1, a plasma cofactor that facilitates the binding of anticardiolipin antibodies to phospholipid, has also been demonstrated to be elevated in young children with cerebral thrombosis.70-72 Antiphospholipid antibodies prolong the partial thromboplastin time (PTT) in vitro, but act as a procoagulant in vivo. In addition to a prolonged PTT, its presence is indicated by a falsely positive serum Venereal Disease Research Laboratory (VDRL) test result and can be confirmed by functional and immunologic tests for antiphospholipid antibodies. Its presence has been associated with up to a six-fold increase in risk of stroke in children.73 Further, transplacental passage of the antibody from mother to infant has been invoked as a cause of presumed prenatal, perinatal, and neonatal stroke.74

Absence of specific serum proteins that act as inhibitors of coagulation may lead to stroke in children. Deficiencies of protein S and protein C have been associated with thrombotic or embolic cerebrovascular disease in the young. Protein C and its cofactor protein S act as anticoagulants and synergistically attenuate coagulation by deactivating the thrombin-activated forms of factors V and VIII. Absence of either of these proteins may tip the scale of balanced coagulation toward increased spontaneous clotting and can result in stroke. Anti-thrombin-III inhibits serine esterase activity and opposes not only the action of thrombin but also the activated forms of II, IX, X, XI, and XII. Deficiencies of protein S or C or of antithrombin-III may cause arterial thrombotic or embolic stroke or venous infarction.14,75,76 Although these deficiencies are often congenital, they may be acquired through liver disease (reduced synthesis), inflammatory bowel disease, or nephritic syndrome (protein wasting).77 Screening tests, including prothrombin time (PT), partial thromboplastin time (PTT), and specific immunologic and functional testing of the proteins suspected of being deficient are essential for diagnosis.

Elevation of lipoprotein (a) represents a recently identified characteristic that has been suggested as a risk factor for stroke in both neonates and older children. Lipoprotein (a) is a low-density lipoprotein with apolipoprotein (a) as a substituent. Bearing regions of homology very similar to the fibrin binding sites of plasminogen, lipoprotein (a) appears to compete with plasminogen and thereby contributes to a procoaguable state. It has been associated with stroke in neonates and in older children.78-80

Cancer and its treatment may predispose children to cerebrovascular ischemic events. Promyelocytic leukemia and its treatment have been observed to provoke disseminated intravascular coagulation leading to stroke. Lymphoreticular cancers, more than solid tumors, have been linked to thrombotic and embolic strokes. Transient ischemic attacks (TIAs) following induction chemotherapy for acute lymphoblastic leukemia have been reported. In addition, dural sinus and cerebral sinovenous thrombosis (CSVT) have been found after therapy with L-asparaginase.81

Oral contraceptives continue to engender concern as a risk factor for stroke among young women, especially those with migraine. Migraine in young women is associated with increased risk for ischemic stroke. This risk is higher in migraine with aura and is further increased by tobacco smoking and use of oral contraceptives. As a result, among young women who are prescribed oral contraceptives, abstinence from tobacco use and use of low-estrogen-content oral contraceptive pills, or those with progestogens only, has been advised.82 Pregnancy and the post partum state have been considered periods of hypercoaguability. In addition, venous stasis increases. These two factors are believed to promote the occurrence of cerebral venous thrombosis and cerebral infarction, often venous in nature, in pregnant and immediately postpartum females. Frequently, the initial manifestation is headache. Seizures, either focal or generalized, are common. Acute hemiparesis is the most common focal finding on the neurologic examination. Papilledema can appear as a consequence of increased intracranial pressure resulting from obstruction of cerebral venous outflow. The appearance of these signs or symptoms in a gravid or postpartum adolescent should raise suspicion about the existence of the underlying cerebral venous thrombosis. Finally, insect stings have caused focal cerebral infarction in children. Wasp and scorpion venom activate platelets, promoting thrombogenesis, which can culminate in focal infarction.

Genetic and Metabolic Etiologies

Table 552-3 provides a summary of the genetic and metabolic causes of stroke. Three genetic mutations have been found to lead to protein dysfunction that has been associated with prothrombotic features that may culminate in stroke. These are the factor V Leiden mutation (FVL), the prothrombin 20210 mutation, and deficiency of methylene tetrahydofolate reductase (MTHFR). The factor V Leiden mutation, due to a single nucleotide G→A transition in exon 10 of the factor V gene, results in replacement of arginine by glutamine at amino acid 506 in the protein. This substitution imparts striking resistance of the factor to inactivation by protein C and consequently abnormally sustained ability to advance coagulation. It accounts for greater than 95% of activated protein C resistance. Neonatal stroke and stroke in older children has been associated with this mutation.83,84

The prothrombin 20210 (PTG20210A) mutation, like the FVL mutation, involves a G→A transition and occurs at nucleotide 20210 in the prothrombin gene. Although this occurs in the terminal untranslated portion of the gene, it nonetheless imparts an increased level of activity to the prothrombin protein. The prothrombin 20210 mutation has been associated with childhood and neonatal stroke.78,79,85 In addition, it has been associated with recurrence of stroke in children.86

Genetically determined dysfunction of cystathionine reductase is widely recognized for consequent elevation of serum homocysteine level (see below). However, the level of this amino acid can become abnormally high by other means. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) catalyzes the regeneration of fully reduced methyl tetrahydrofolate, the major circulating form of folate. Folate participates in the remethylation of homocysteine to methionine. A mutation at the 677 position of the MTHFR gene causes an alanine to valine substitution in the resulting protein and impairs enzyme function that results in elevated plasma homocysteine levels in the setting of folate deficiency. Although increased risk for childhood stroke has been associated with both homozygosity and heterozygosity for this mutation, it remains unclear whether this increased risk relates to elevation of the homo-cysteine level or to some other consequence of the genetic mutation itself.87-92

Table 552-3. Genetic and Metabolic Causes of Stroke

Thrombotic/Embolic Stroke

Factor V Leiden mutation

Prothrombin 20210 mutation

MTHFR meficiency

Homocystinuria

Sickle cell disease

Fibromuscular dysplasia

Fabry disease

Hemorrhage

Factor VIII deficiency

Factor IX deficiency

Factor XI deficiency

Sickle cell disease

Familial cavernous angioma

Familial intracranial aneurysm

Methylmalonic acidemia

Propionic acidemia

Unknown Mechanism

Organic acidemia

Mitochondrial disorder

Urea cycle disorder

Sulfite oxidase deficiency

Homocystinuria, a disorder of homocysteine metabolism, can cause thrombotic stroke in children. Abnormal homocysteine metabolism results from one of three heritable enzymatic defects. The most striking phenotype results from deficiency of cystathionine synthetase, the enzyme that catalyzes the catabolism of homo-cysteine to cystathionine. In this disorder, accumulation of both homocysteine and methionine result. Children affected by this autosomal recessive disorder manifest marfanoid habitus, global developmental delay, lens dislocation, and thromboembolism. Serum hyperhomocystinemia injures the vascular endothelium. The denuded vessel wall then becomes a site for thrombosis. The resulting thrombus may remain at its site of origin or it may embolize to a distal location. Therefore, stroke may have thrombotic or embolic characteristics and both arterial and venous infarcts may result. Treatment is dietary, aimed principally at reduction of homocysteine levels in serum.

Sulfite oxidase deficiency, an autosomal recessive disorder of sulfur amino acid metabolism, results in the accumulation of serum sulfites. The associated phenotype may result from deficiency of either the enzyme or its associated and essential pterin-containing molybdenum cofactor. The clinical picture of this disorder consists of mental retardation, seizures, lens displacement, and can include acute onset of hemiparesis. The cause of hemiparesis is not determined; it is possible that ischemic mechanisms are not involved but that direct metabolic neurotoxicity accounts for sudden onset of deficits that resemble those of stroke.

Fabry disease, a lipid storage disease attributable to ceramide trihexosidase deficiency, results in accumulation of sphingolipid, globotriaosylceramide in kidney, vascular endothelium, and cornea. Symptoms include angiokeratomas and painful paresthesiae, often first apparent in adolescence. Due to endothelial accumulation of sphingolipid in vessel walls, cerebrovascular occlusion may occur and culminate in stroke. Recurrent stroke is not uncommon in this rare X-linked disorder.

Mitochondrial disorders may be manifested by recurrent and sometimes catastrophic stroke-like episodes. The clinical constellation of mitochondrial encephalomyopathy, lactic acidosis, and stroke (MELAS) presents in childhood and most commonly derives from a mutation of mitochondrial DNA. The most common biochemical finding is a deficiency of complex I of the electron transport chain. An elevated serum lac-tate concentration, or more consistently CSF lactate level, supports the diagnosis. Molecular diagnosis may be secured from blood. While Leigh syndrome and myoclonic epilepsy and red ragged fibers (MERRF) syndrome may also feature strokelike events, hemiparesis of abrupt onset, often accompanied by hemianopia is characteristic of MELAS. Seizures, sensorineural hearing loss, dementia, and short stature are frequently present. Neuropathologic study of brain from patients with MELAS has revealed cystic cavities and necrosis of cortex, especially of posterior cerebrum with relative sparing of white matter. Interestingly, cerebrovascular degeneration associated with mitochondrial encephalopathy has been described and offers an alternative mechanism for stroke-like episodes observed in these patients.93

Other metabolic disorders have been associated with stroke in childhood. Urea cycle defects, especially ornithine transcarbamylase deficiency presenting in hemizygous girls, can cause stroke. Organic acidemia has also been associated with stroke. Methylmalonic, propionic, and type 2 glutaric acidemia have been associated with striatal necrosis. In addition, both methylmalonic and propionic academia have been associated with intracranial hemorrhage. Both 3-methyl crotonyl-CoA carboxylase deficiency and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency have been associated with stroke.94

EMBOLUS

Congenital heart disease is a very common cause of stroke in childhood. Children with cyanotic congenital heart disease face the greatest risk. An embolic stroke constitutes the most common cerebrovascular event. Cardiac defects involving right-to-left shunts allow emboli originating in the peripheral circulation to bypass filtration and removal by the pulmonary vascular bed. Thus, emboli entering the heart via venous return may be shunted to the peripheral arterial circulation, only to lodge in the cerebrovascular tree (Fig. 552-3).

Patent foramen ovale (PFO) is associated with the occurrence of stroke in children and young adults. Echocardiographic evaluation of young patients who have suffered stroke reveal patent foramen ovale or evidence of right-to-left shunting in greater than 3-fold more patients suffering stroke relative to control patients. Notably, PFO is the most commonly detected cardiac anomaly in patients studied with echocardiography. Transesophageal echo-cardiography conducted with Valsalva bubble studies for evidence of direct right-to-left conduction is the most useful diagnostic test. Treatment possibilities include PFO closure, anticoagulation or antiplatelet therapy. Data from adult studies indicate treatment equivalence between anticoagulation and antiplatelet therapy. Further, while the presence of right to left shunt across the PFO at rest has been associated with stroke recurrence, the effect of PFO size upon outcome or stroke recurrence rate has been questioned.95-97

Congenital valvular defects such as aortic stenosis and mitral stenosis can result in stroke. Rheumatic valve disease, once a common cause of embolic stroke, has become infrequent. However, infected valves found in subacute bacterial endocarditis (SBE) still pose considerable risk for the occurrence of embolic stroke. Infective mitral and aortic valvular vegetations may dislodge, travel distally, and, ultimately, occlude cerebral arteries. Even after vegetations have been successfully sterilized they may still embolize and cause stroke. Emboli from infected valvular vegetations may also lead to other vascular lesions. For example, emboli may travel to the cerebral vasculature and there seed the adventitia of the cerebral vessel. The resultant infection and inflammation result in weakening of the vessel and development of a mycotic aneurysm. Typically located in distal cerebral vasculature, they may lie dormant for some time before their rupture leads to subarachnoid or intraparenchymal hemorrhage and the possibility of lasting neurologic deficit.

FIGURE 552-3. Child with tetralogy of fallot who sustained an embolic stroke. A: An embolus was found in the left distal internal carotid artery and proximal middle cerebral artery and caused sudden onset of right hemiparesis, aphasia, and stupor. The axial T1 weighted image shows involvement of the entire middle cerebral artery territory (see arrows that indicate the anterior and posterior extents of the middle cerebral artery territory). B: Diffusion weighted imaging of the same slice as in (A) shows the corresponding region of restricted diffusion in injured tissue which is distinguished by a brighter signal than is found in uninjured brain tissue.

Fat or air emboli can ramify in cerebral vasculature. Most commonly found in patients with long bone fractures or following surgery, including procedures that employ cardiopulmonary bypass, these emboli have been observed with nontraumatic conditions such as pancreatitis, sickle cell disease, connective tissue diseases, and intravenous lipid administration. Because fat or air emboli occur as showers, multiple sites in the central nervous system may be involved leading to generalized symptoms such as impaired consciousness, delirium, or coma. Focal or lateralized neurologic signs are found in only one third of patients.

Clinically explicit recurrence of stroke is rare in neonates but has been reported to occur in up to 25% of older children. Both vasculopathy and prothrombotic mutations, especially, have been reported to impart increased likelihood of stroke recurrence.86,98 Among these, deficient protein C, elevated lipoprotein (a), the presence of at least one prothrombotic genetic defect, and antecedent TIAs have emerged as clinical characteristics associated with stroke recurrence. Importantly, the possibility of synergy between features associated with stroke occurrence and constitutional features such as systemic inflammation or dehydration to culminate in stroke is of increasing interest, as this has emerged as a clinical profile of many children who present with stroke. Among children with sickle cell disease, stroke recurrence is increased among those who are not adequately treated with exchange transfusion and those with Moyamoya disease.44,99

HEMORRHAGE

Nontraumatic intracranial hemorrhage occurs more commonly in males than females. Hemorrhage may be subdural, subarachnoid, intraparenchymal, or intraventricular in location. Recent data indicate that the most common cause of nontraumatic hemorrhage is vascular abnormality (arteriovenous malformation, cavernous malformation, venous angioma, aneurysm, and Moyamoya disease). However, brain tumor and hemorrhage associated with congenital heart disease contribute significantly to its occurrence. Whereas younger children present with nonspecific symptoms such as mental status change, seizure, and vomiting, older children may manifest focal neurologic symptoms in addition to nausea and vomiting. Blood pressure may be greater than the 90th percentile for age. Investigation has revealed that approximately 50% of children with nontraumatic intracranial hemorrhage have no lasting deficit. However, children with intraparenchymal hemorrhage resulting from vascular abnormality appear to have a better prognosis than other groups.100,101

Arteriovenous malformation (AVM) of the brain is a common cause of intracranial hemorrhage in preadolescent children. The malformation represents a developmental anomaly that presents with hemorrhage more frequently in children than in adults. The AVM consists of dilated vascular channels some of which exhibit the highly muscularized walls of arterioles. Gliotic neural tissue resides in and among the vascular branches of the malformation. More common in males, the most frequently observed events associated with AVM in children are seizures and hemorrhage. The vast majority of AVMs are located in the cerebral hemispheres, whereas 10% to 15% arises in the posterior fossa. The clinical features of hemorrhage due to AVM may consist of acute onset of focal neurologic deficit, features of which depend upon the area of brain in which the hemorrhage has occurred. Mortality is higher in children than in adults.102

Intracranial aneurysm constitutes an important cause of hemorrhagic stroke in patients less than 20 years of age. Mycotic aneurysm found in association with subacute bacterial endocarditis (SBE) has already been discussed. Saccular aneurysms are more frequent in males than in females. Unlike aneurysms in adults, the most common site of aneurysmal bleeding in children is along the intracranial portion of the internal carotid artery. The vertebral and basilar arteries are other common sites of intracranial aneurysm in children. In addition, intracranial aneurysms discovered in children tend to be larger than those found in adults. While most aneurysms constitute vascular developmental anomalies, other associations exist. These include disorders of connective tissue (such as Ehler-Danlos and Marfan syndromes), children with polycystic renal disease, and those with aortic coarctation.

Some coagulation disturbances may predispose to intracranial bleeding. The hemophilias, both A and B, are X-linked disorders that may result in intracranial bleeding (Table 552-3). Bleeding may occur in either intraparenchymal or subarachnoid locations. Hemophilia A arises because of factor VIII deficiency. Males affected by this disorder may experience intracranial bleeding in association with head trauma. However, hemorrhage may also occur spontaneously. The risk of spontaneous hemorrhage increases as the severity of factor VIII deficiency rises. Hemophilia B derives from a deficiency of factor IX. Intracranial bleeding is seen less frequently in these patients than in those with hemophilia A. Hemophilia B is encountered much less frequently than hemophilia A and this may account for the less frequent observation of intracranial bleeding. If the bleeding occurs in the subarachnoid space, symptoms of severe headache, nuchal rigidity, and meningismus can be found; mental status change may also occur. If parenchymal brain bleeding occurs, focal and central signs may be evident.

Severe thrombocytopenia leads to cerebral hemorrhage in very few patients. Significant risk of intraparenchymal hemorrhage appears to occur only after platelet counts of 20,000 per mm3 or less are reached. Small petechial hemorrhages into white matter are more common than parenchymal hemorrhage. Causes of thrombocytopenia include idiopathic thrombocytopenic purpura, infection, and malignancy.

Intracranial hemorrhage, often with subarachnoid involvement, occurs among children with sickle cell disease. Hemorrhage may be subarachnoid, intraparenchymal, or intraventricular. Recently, intracranial bleeding in children with sickle cell disease has been observed to be related to hypertension or to treatment with transfusion or corticosteroids.103

DIAGNOSIS AND EVALUATION OF STROKE

Clinical suspicion of stroke in a patient with suggestive symptoms constitutes the most salient element of diagnosis. Despite presentation of focal symptoms including hemiparesis, headache, aphasia, dysarthria, diplopia, and mental status change, the diagnosis of stroke is often not considered during initial assessment of children who ultimately prove to have sustained a stroke. Mean time to accurate diagnosis from onset of symptoms has been found to be more than 35 hours.104

Once stroke has been suspected, diagnostic efforts concentrate on documentation of its occurrence and discovery of its underlying cause. Neuroradiologic and laboratory evaluations are conducted simultaneously. A suggested approach to diagnostic evaluation is provided in Figure 552-4. Cranial computerized tomography (CCT) and magnetic resonance imaging (MRI) provide rapid and topographic evidence of infarction or intracranial hemorrhage. Cranial CT images are more rapidly acquired than MRI at many centers, particularly during nighttime hours and provide clear evidence of acute intracranial hemorrhage. Magnetic resonance imaging, which provides greater resolution and structural detail than CCT, demonstrates infarctions that are smaller and newer than those detected with CCT. Diffusion weighted MR imaging permits visualization of CNS infarction very early in its course. Magnetic angiography (MRA) yields reliable information about blood flow in and structure of large cervicocephalic and intracranial vessels. Small intracranial vessels still are poorly resolved by MRA. Invasive angiography remains the neuroradiologic procedure of choice when detailed knowledge of the cerebral vasculature is required.

Laboratory testing should screen for conditions that predispose a child to stroke. In addition, laboratory evidence of inflammation should be sought. Serum electrolytes will provide initial evidence of a metabolic acidosis that may accompany a mitochondrial disorder or an organic acid disturbance. Toxicology screen should be performed if drug-induced stroke is suspected. A lumbar puncture should be considered if CNS infection, inflammation, or neo-plastic involvement is suspected. However, a lumbar puncture should not be performed if either physical examination or neuroimaging indicates the presence of a focal space-occupying abnormality causing increased intracranial pressure. Performance of this procedure in a patient with a unilateral intracranial lesion could precipitate transtentorial or transmagnal herniation.

FIGURE 552-4. Diagnostic evaluation of stroke in children.

If a stroke is clinically or radiologically documented and the aforementioned laboratory studies yield normal results, further investigation is warranted. Evidence of coagulopathy, systemic inflammation, antiphospholipid antibodies, rheumatologic diseases, and elevated serum lipoprotein (a) should be sought. In addition, serum or CSF lactate and pyruvate and urine organic acids concentrations should be determined. DNA and functional assays should be considered for mutations in FVLPT20210, and MTHFR. If the patient’s clinical picture suggests Fabry disease or urinary sulfite oxidase deficiency, the appropriate blood or urine tests should be obtained for diagnosis. Echocardiography should be performed in a child who has sustained a stroke and in whom a cardiac murmur is heard or in whom mural or valvular thrombus is suspected. If concern exists regarding the possibility of a right-to-left cardiac shunt, an echocardiogram bubble study should be included in hope of documenting an existing intracardiac shunt. Either transesophageal or transthoracic echocardiography may be employed though the transesophageal method will often provide the best view of intracardiac anatomy.

TREATMENT OF STROKE

The axis of treatment for stroke consists of two arms: acute response and prophylactic response. In neonates, supportive elements of treatment in the acute phase consist of correction of thrombocytopenia, anemia, and dehydration, if present. Similarly, low levels of coagulation factors and vitamin K deficiency should be corrected in an age-appropriate fashion. External ventricular drain or shunt placement should be considered for infants with intracranial hemorrhage and consequent intractable hydrocephalus. Although thrombolytic therapy has been studied and used in adult patients, there are few data regarding its safety and efficacy in children with stroke and virtually none available in neonates. Use of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) has been studied to some extent in this patient population.18,24,105 Consideration of anticoagulation treatment with UFH or LMWH has been suggested for neonates with cerebral sinovenous thrombosis (CSVT) and radiologic evidence of clot propagation, with severe thrombophilia disorders or with evidence of multiple cerebral and systemic embolic events.28

There is keen interest in the safety and efficacy of thrombolytic therapy for older children who present in the acute phase of stroke. Currently, data on use of thrombolytic agents (tissue plasminogen activator (tPA) or urokinase) in children are available by case report only. These case reports suggest that use of these agents may provide benefit to children with stroke if diagnosed early enough in the course of the event. However, the lack of uniformity in choice of agent, time of thrombolytic administration after stroke onset, and method of administration prevent any conclusion to be drawn regarding the safest and best use of these agents in children.106-111

Anticoagulation with unfractionated heparin (UFH) or low molecular weight heparin (LMWH) is appropriate for certain children after presentation with acute stroke resulting from the comparatively high occurrence of embolism in complex congenital heart disease, arterial dissection, and hypercoaguable states among children relative to adults.28,105 Warfarin is chosen for long-term anticoagulation. Although LMWH can be used for this purpose, warfarin dosing is oral and offers an alternative to the subcutaneous injection needed for LMWH administration. Warfarin has been used for prophylactic treatment in children with substantial risk of recurrence of embolic events, such as those with complex congenital heart disease. Although effective, the benefit of the drug must be considered relative to the risk of hemorrhage which occurs at a rate of less than 3.2% per patient-year as found in children treated for mechanical prosthetic cardiac valve placement. If cardioembolic stroke and arterial dissection are ruled out as a cause of stroke, treatment with aspirin is often instituted.105

Prophylactic therapy remains the cornerstone of therapy in thrombotic stroke. Exchange transfusion diminishes the fraction of blood composed of hemoglobin S-containing RBCs and reduces the risk of recurrent strokes in children with sickle cell anemia.39,99,112,113 Hydroxyurea may well reduce the occurrence of stroke among sickle cell patients and is of great interest as a prophylactic therapy.48,49,114 Stroke due to coagulation factor deficit can be treated with anticoagulation or with factor replacement. Similarly, patients symptomatic from the presence of antiphospholipid antibodies may be treated with anticoagulation using either LMWH or warfarin.60

Metabolic diseases that may lead to recurrent stroke generally lack effective therapy and carry a poor prognosis. However, homocystinuria may be treated with oral vitamin B6 therapy.92 If serum homocysteine level is elevated and is related to a documented mutation in the MTHFR gene, treatment with folate may be instituted.91 Patients with Fabry disease may benefit from enzyme replacement therapy for defective ceramide trihexosidase.115,116

Vascular abnormalities may be treated prophylactically to prevent stroke. Arteriovenous malformations (AVMs) may be partly or selectively embolized. Embolization may constitute definitive treatment or may represent preliminary treatment prior to surgical extirpation. Ischemic injury to brain due to Moyamoya disease can be prevented through surgical revascularization techniques. Two types of revascularization procedures are in use; “direct” procedures anastamose arteries from the external cranial circulation to those of the internal cranial circulation while indirect procedures mobilize the superficial temporal artery or other vascularized tissue to the surface of the brain to induce revascularization.34,117-119 Both have demonstrated clinical efficacy. Each procedure is designed to reconstitute cerebral perfusion distal to the critical stenosis. Clinical trials to determine which may be most effective have not yet been conducted.