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The differential diagnosis can be vast, including infections and metabolic imbalances. A few key stroke masqueraders should also be considered. Familial hemiplegic migraine is characterized by family history and EEG pattern of unilateral slow background rhythm.5 Postictal or "Todd" paralysis is a consideration when focal weakness occurs after a seizure, and can closely mimic stroke. Patients should be treated with the urgency of an acute cerebral infarction until proven otherwise.
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Physicians must be aware of predisposing conditions and risk factors to have the index of suspicion required to diagnose stroke. This involves awareness of three main categories of cerebrovascular events: arterial ischemic, hemorrhagic, and sinovenous thrombosis. Risk factors overlap for stroke subtypes, but treatment may differ.
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Definitions and Epidemiology
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A number of ischemic and hemorrhagic insults may affect the developing fetal or neonatal brain. It is therefore important for the clinician to be aware of the different types of events that can cause perinatal stroke, as the evaluation, management, and expected outcome may be related to the type of lesion. Perinatal arterial ischemic stroke refers to a cerobrovascular event occurring during fetal or neonatal life, before 28 days after birth, with pathologic or radiologic evidence of focal arterial infarction of brain.6 Sinovenous thrombosis describes thrombosis in one or more of the cerebral venous sinuses and may be associated with secondary hemorrhage.7 Primary hemorrhagic stroke and other types of intracranial hemorrhages that tend to affect near-term and term infants tend to be associated with specific risk factors responsible for the hemorrhage. Periventricular hermorrhagic infarction, a lesion that mainly affects preterm infants, is a serious complication of germinal matrix-intraventricular hemorrhage.
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Clinical Presentation
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Although these lesions tend to have significant overlap in terms of being hemorrhagic or ischemic, the effects of these types of events on the neonate may result in immediate or eventual death, with other long-term complications including cerebral palsy, epilepsy, blindness, behavioral disburbances, and congnitive dysfunction. Despite the type of lesion, symptoms may be subtle and are often nonspecific. The acute and chronic manifestations of perinatal stroke are reviewed in Table 18-1.
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Perinatal Arterial Ischemic Stroke
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Definitions and Epidemiology
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Perinatal arterial ischemic stroke, occurring more frequently in the near-term and term infant, has a prevalence ranging from 17 to 93 per 100,000 live births.7-10 Most lesions occur in the left hemisphere within the distribution of the middle cerebral artery. Rarely, multifocal lesions occur but tend to be embolic in origin.7
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A wide range of risk factors have been implicated in the etiology of perinatal arterial ischemic stroke, and these are listed in Table 18-2.7,9,11-13 However, some studies report no finding of an obvious precipitating event in as many as 25% to 77% of cases.14-16 The difficulty with identifying a specific risk factor for the development of the lesion is that neonates often have multiple risk factors present, making it likely that a combination of environmental risk factors interacting with genetic vulnerabilities is often responsible for the ischemic event.6 The exact role of genetic thrombophilias in the pathogenesis of perinatal arterial ischemic stroke is yet to be defined,17 but disorders such as factor V Leiden mutation, the prothrombin 20210 promoter mutation, hyperhomocystinemia, elevated lipoprotein (a) levels, antiphospholipid antibodies, and relative protein C deficiency have been described with increased frequency in infants who have perinatal arterial ischemic stroke when compared with healthy control subjects.18-24 Other genetic thrombophilias have also been implicated and are provided in Table 18-3. Further studies are required to better define the potential role of infantile thrombophilia in the pathogenesis and outcome of perinatal arterial ischemic stroke, but experts in the field do recommend a comprehensive thrombophilia assessment for all infants presenting with perinatal arterial ischemic stroke, regardless of other risk factors present.17,25
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Clinical Presentation
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The difficulty with identifying perinatal arterial ischemic stroke in the neonate is that symptoms tend to be nonspecific and often are difficult to identify. In many cases, the symptoms may not become evident until quite some time after the stroke. The acute and chronic manifestations of perinatal arterial ischemic stroke are reviewed in Table 18-1. Figure 18-1 reveals a multifocal infarction on diffusion-weighted MRI involving the pons and temporal lobe.
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Sinovenous Thrombosis
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Clinical Presentation
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Most cases of sinovenous thrombosis occur in term infants and present with nonspecific clinical features as listed in Table 18-1. The superficial and lateral sinuses are most frequently involved, and venous infarction has been reported in up to 30% of cases.26 An example of magnetic resonance venography (MRV) in a normal patient is shown in Figure 18-2.
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Risk factors for the development of sinovenous thrombosis are similar to those for perinatal arterial ischemic stroke and are listed in Table 18-3, although a significant number of cases are reported as idiopathic.16
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Definitions and Epidemiology
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Primary hemorrhagic stroke and other types of intracranial hemorrhage include subdural, primary subarachnoid, intracerebellar, intraventricular hemorrhage, and other miscellaneous types such as focal hemorrhages into the thalamus, basal ganglia, brainstem, or spinal cord.4
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Periventricular hemorrhage (PVHI) is a venous hemorrhagic infarct in the drainage area of the periventricular terminal vein.27,28 A complication mainly associated with prematurity, a recent study found that 1% of infants less than 2500 g met the diagnostic criteria for PVHI, with the highest percentage (9.9%) being those less than 750 g.28
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The majority of these types of hemorrhages tend to be antepartum or during the stresses of delivery and associated with specific risk factors as outlined in Table 18-3. Intrapartum risk factors associated with the development of PVHI include emergent cesarean section, low Apgar scores, and need for respiratory resuscitation; while postnatal factors include pneumothorax, pulmonary hemorrhage, patent ductus arteriosus, acidosis, hypotension requiring pressure support, and significant hypercarbia.28 Although an exact cause/effect relationship of these risk factors and correct knowledge of when these events occur has been difficult to prove, it is felt that disturbances in systemic and cerebral hemodynamics occurring around the intrapartum and early neonatal period are important in the development of PVHI.28
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Clinical Presentation
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Figure 18-3 shows a hemorrhage in the thalamic region on CT. In general, primary subarachnoid hemorrhages are more frequently seen in the premature infant but tend to be clinically benign; in contrast to intracerebellar hemorrhages which, although also more frequently observed in premature infants, tend to be serious.27 Subdural and other miscellaneous types of hemorrhages tend to affect full-term infants, and their outcome is variable. Although intraventricular hemorrhages tend to predominately occur in premature infants (discussed later), they have been reported to occur in term infants as well.
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PVHI usually accompanies a large germinal matrix-intraventricular hemorrhage.28 See Figures 18-4 and 18-5 for examples of PVHI.
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Arterial Ischemic Stroke
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Definitions and Epidemiology
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Arterial ischemic stroke can be related to a number of vascular, hematologic, cardiac, and metabolic risk factors. Potential causes of ischemic stroke in children are presented in Table 18-4.
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Arterial dissection most commonly occurs after trauma. These injuries occur more frequently in boys than girls. Traumatic dissection can result from head or cervical trauma, including whiplash, shaken baby, or intraoral trauma such as falling with a pencil in the mouth.2 Rarely, dissection occurs atraumatically due to a connective tissue disease such as fibromuscular dysplasia. See Table 18-5.
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The C1-2 vertebral level is the most common location for a vertebral artery dissection. Artery to artery embolism from the site of endothelial injury is the usual pathogenic mechanism for infarction.29 In one meta-analysis, 15% of posterior circulation and 5% of anterior circulation dissections were followed by recurrent ischemic events.30
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Diagnosis is made via characteristic findings on MRI and MRA of the head and neck, extracranial vascular ultrasound, or cerebral angiography. Because C1-2 is the most common location for a vertebral artery dissection, findings of a double lumen, intimal flap, or bright crescent on T1 fat suppression images confirm the diagnosis. Also, the finding of occlusion or segmental narrowing of an artery within 6 weeks of a known trauma, or of vertebral artery occlusion at the C2 vertebral level even without trauma, should raise the possibility of dissection.31
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Cardiac Causes of Stroke
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Definitions and Epidemiology
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Cardiac risk factors rise in importance in pediatric stroke relative to the adult population. Congenital heart disease is one of the major risk factors for stroke in pediatric patients. The Canadian Pediatric Ischemic Stroke Registry reported that 19% of children with arterial ischemic stroke had heart disease.2 The risk is particularly high during surgical procedures.32 Right-to-left shunting can lead to hypoxia and polycythemia, creating a hyperviscous state. Infective endocarditis additionally poses risk for embolic stroke, and patent foramen ovale is a risk for thromboembolic strokes due to venous-arterial communication. PFO (patent foramen ovale) is three times more prevalent in pediatric stroke patients than in the general population.2
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Definitions and Epidemiology
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Vasculitis is another source of stroke risk in the pediatric population. Primary vasculitides include those affecting large and medium vessel such as Takayasu arteritis, and those affecting small vessels such as primary CNS angiitis and Wegener. Unique to children is the importance of secondary, postinfectious vasculitis. Varicella zoster infection was detected in the preceding 12 months in 31% of children in one study of acute ischemic stroke as opposed to 9% of healthy controls.33
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Clinical Presentation
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Strokes caused by postinfectious vasculitis typically involved the basal ganglia with typical vascular abnormalities of focal stenosis of the distal internal carotid and proximal segments of anterior cerebral (A1), middle cerebral (M1), and posterior cerebral artery (P1).31,33 Other pathogens including HIV and CMV may produce similar vasculitis and stroke risk. Radiation to the brain can also be a risk factor for secondary vasculitis.2
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Moyamoya is a vascular condition with risk of recurrent stroke. Primary moyamoya disease is an autosomal dominant disease most common in Japanese patients, hence the Japanese name meaning "puff of smoke." This describes the angiographic blush that occurs due to extensive collateralization in response to occlusion of large intracranial arteries, often with bilateral carotid artery occlusion. Moyamoya syndrome can also occur secondary to sickle cell disease, Down syndrome, cranial radiation, or neurofibromatosis.2,5,31
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Definitions and Epidemiology
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Sickle cell disease (SCD) is one of the most prevalent hematologic risk factors for pediatric stroke. An astounding (9%) of patients with SCD will have an acute ischemic stroke by the age of 14, and approximately 20% will have MRI evidence of silent ischemic insults.31 Risk is greatest in the younger years (ages 2-8), and two-thirds will have a recurrent event if untreated.34,35
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The sickled erythrocytes can cause thrombosis in large blood vessels or occlusion of small blood vessels leading to hypoperfusion in watershed areas.2
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Other Hematologic Conditions
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Further hematologic variables relevant to ischemic stroke include high concentrations of lipoprotein (a), protein C deficiency, and factor V Leiden mutation.36 These hypercoaguable states are most highly associated with risk of recurrent stroke.35,36 Other prothrombotic states include positivity for antiphospholipid antibodies including anticardiolipin antibodies and lupus anticoagulant, protein S deficiency, factor V Leiden mutation, prothrombin gene mutation (G20210A), and antithrombin III deficiency.2 Extensive discussion of each of these is beyond the scope of this chapter. Hyperviscosity or "sludging effect" can also be caused by dehydration, thrombocytosis, and polycythemia. Malignancies including leukemia and lymphoma can also create hypercoaguable states with increased risk of stroke. Several chemotherapeutic agents have also been implicated in cerebral infarction, including adriamycin, asparaginase, and methotrexate. Severe anemia, often seen in developing countries, can result in cerebral infarction secondary to the poor oxygen-carrying capacity.
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Other etiologies to consider are toxic or iatrogenic sources such as cocaine or oral contraceptive pills. Metabolic sources of stroke risk include homocysteinuria, ornithine transcarbamylase deficiency, and MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes). CADASIL and hyperhomocyteinemia can lead to endothelial damage and platelet aggregation and are treated with folate and vitamin B.2 MELAS is a heritable mitochondrial disease that presents in childhood with proximal muscle weakness, episodic vomiting and lactic acidosis, migraine headaches, and stroke-like episodes. The areas of infarction can be inconsistent with any single vascular distribution. Diagnosis is made by muscle biopsy finding ragged red fibers, and the disease is usually progressive. Hearing and visual loss may occur as well.2 Neurocutaneous diseases of childhood such as (Sturge-Weber and NF1) can be associated with increased risk of stroke.
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Hemorrhagic stroke in children, in contrast to adults, occurs with equal frequency to ischemic stroke.2 Trauma and bleeding diathesis are important risk factors for hemorrhagic stroke. Risk factors for hemorrhagic stroke are outlined in Table 18-6. Vascular malformations such as aneurysm or AVM may result in an intracerebral hemorrhage (see Figure 18.6).
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Aneurysm in Subarachnoid Hemorrhage
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Definitions and Epidemiology
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Intracranial aneurysms are common in the general population. The prevalence of unruptured intracranial aneurysms has been largely determined through autopsy studies and through angiographic series. In adults, the prevalence ranges from 0.2% to 9%, with a mean of approximately 2%. The prevalence is thought to be lower in children.
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The incidence of aneurysm rupture or subarachnoid hemorrhage (number of aneurysm ruptures/ 100,000 population/year) varies depending upon factors such as the population being studied (Finnish and Japanese persons have a greater disposition) or the age distribution of the population (a younger population will have a lower incidence). The incidence of aneurysmal subarachnoid hemorrhage ranges from approximately 7 to 21 per 100,000 persons per year, with an average of 10 per 100,000 persons per year. In the United States alone, there are approximately 28,000 new patients with subarachnoid hemorrhage each year. The incidence of subarachnoid hemorrhage has remained stable over the last three decades.
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Aneurysms are relatively uncommon in children and become more common with increasing age, with a peak incidence occurring between the ages of 50 and 60. There is a clear female gender predilection (approximately 1.6 times higher incidence in females). Smoking and hypertension may predispose to aneurysm formation and/or rupture.
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Although most cases of subarachnoid hemorrhage are sporadic, in those families with a history of subarachnoid hemorrhage in more than one family member, the prevalence of unruptured aneurysms in other family members is markedly increased (a fourfold to tenfold increased prevalence). Autosomal polycystic kidney disease is unequivocally associated with a higher prevalence of intracranial aneurysms. Other conditions that may predispose to intracranial aneurysm formation include connective tissue disorders such as Ehlers-Danlos syndrome type IV, Graphic Jump Location
1-antitrypsin deficiency, Marfan syndrome, neurofibromatosis I, and pseudoxanthoma elasticum, although the association is less well determined in some of these conditions.
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Clinical Presentation
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ICH is suggested by the rapid onset of neurological dysfunction and signs of increased intracranial pressure (ICP), such as headache, vomiting, and decreased level of consciousness.
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The symptoms of ICH are related primarily to the anatomic location and pressure resulting from the expanding hematoma. Findings such as hypertension, tachycardia, or bradycardia (Cushing response), and abnormal respiratory patterns, are common effects of elevated ICP and brainstem compression.
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Confirmation of ICH cannot rely solely on the clinical exam and requires the use of emergent CT scan or MRI. Widespread use of non-enhancing CT scan of the brain has dramatically changed the diagnostic approach of this disease, becoming the method of choice to evaluate the presence of ICH. CT scan evaluates the size and location of the hematoma, extension into the ventricular system, degree of surrounding edema, and anatomic disruption. Contrast-enhanced CT scan is not done routinely in most centers, but may prove helpful in predicting hematoma expansion and outcome. MRI techniques such as gradient-echo (GRE, T2*) are highly sensitive for the diagnosis of ICH but may be more difficult to obtain in the pediatric patient (often requiring sedation). Sensitivity of MRI for ICH is 100%. MRI and CT are equivalent for the detection of acute ICH, but MRI is significantly more accurate than CT for the detection of chronic ICH.
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Further discussion of unruptured aneurysms and subarachnoid hemorrhage is undertaken in the chapters on these disorders.