e11 Abstract Hypoxic ischemic encephalopathy (HIE) in children surviving cardiac arrest is a significant public health problem that confers a lifelong burden on patients and families Despite the lack[.]
e11 Abstract: Hypoxic-ischemic encephalopathy (HIE) in children surviving cardiac arrest is a significant public health problem that confers a lifelong burden on patients and families Despite the lack of new targeted therapies for HIE, outcomes for some children after in-hospital pediatric cardiac arrest are improving, which is likely multifactorial This chapter reviews the epidemiology, outcomes, and pathobiology of HIE with emphasis on cellular mechanisms, pathophysiology, and histopathology Differences between the most prevalent etiologies of cardiac arrest in children (asphyxia versus cardiac arrhythmia) are examined, and an appraisal of traditional and novel therapies is presented Finally, any discussion of HIE in children is complicated not only by the specific mode of arrest in children but also by the unique nature of these young patients The child’s brain is still developing, adding another layer of variability in terms of age-specific pathologic and reparative mechanisms, potential for therapies to afford benefit, evaluation of therapeutic effectiveness, and neurologic outcome Therefore the effect of the host’s immaturity on the pathobiology of postarrest encephalopathy also is examined Key words: cardiac arrest, hypoxic-ischemic encephalopathy, child, outcome, brain, postarrest care 66 Pediatric Stroke and Intracerebral Hemorrhage CATHERINE AMLIE-LEFOND AND JEFFREY OJEMANN PEARLS • Childhood stroke includes arterial ischemic stroke, cerebral sinus venous thrombosis, and intracranial hemorrhage • Diagnosis of acute stroke in childhood is often delayed owing to failure to detect neurologic deficit in a child, low clinical suspicion of stroke, frequency of stroke mimics, and delays in diagnostic imaging • Compared with adults, the causes of pediatric stroke are much more heterogeneous, and often risk factors, rather than definitive causes, are identified • Supportive care in an ICU—with careful attention to optimizing cerebral perfusion and oxygenation, decreasing metabolic demands on the brain, and preventing early stroke recurrence—is critical Significance Cerebral Arteriopathy The incidence of childhood stroke ranges from 2.3 to 13 per 100,000 children.1,2 Following an episode of stroke, 10% of children die, approximately 10% to 20% will have another stroke, and most survivors will have long-term neurologic or neuropsychological deficits, including emerging deficits over time Childhood stroke encompasses arterial ischemic stroke, hemorrhagic stroke, and cerebral sinus venous thrombosis (CSVT) Approximately half of childhood strokes are ischemic and half are hemorrhagic The diverse etiologies, risk factors, presentations, treatments, and potential complications of acute stroke in childhood must be considered to minimize morbidity and mortality in the intensive care setting Cerebral arteriopathy is well associated with primary and recurrent stroke.3,4 In the Vascular Effects of Infection in Pediatric Stroke (VIPS) study, definite or possible arteriopathy was present on vascular imaging in 46% of all patients and in 55% of the subset of patients who were previously healthy, that is, had no previously known risk factors for stroke.5 In addition, cerebral arteriopathy has been found in children with acute AIS who have other stroke risk factors, such as congenital heart disease.6 Focal cerebral arteriopathy (FCA) is a discrete intracranial arterial stenosis that accounts for approximately one-quarter of arteriopathies in childhood AIS.7,8 FCA has been well associated with varicella zoster virus (VZV) infection.9 A subset of FCA is transient cerebral arteriopathy (TCA), which is defined as FCA that improves or shows no progression after months.8 Moyamoya is a progressive steno-occlusive disease of the distal internal carotid arteries and proximal middle cerebral arteries and, not infrequently, the anterior cerebral arteries, associated with collateral formation at the base of the brain, producing the moyamoya (Japanese for “puff of smoke”) configuration seen on catheter cerebral angiogram Moyamoya usually presents with AIS in childhood, whereas adults frequently present with hemorrhagic stroke Moyamoya may be idiopathic, termed moyamoya disease, or occur in association with predisposing syndromes, such as sickle cell disease, trisomy 21, or neurofibromatosis type 1, termed moyamoya syndrome (Fig 66.1) Moyamoya disease is likely a genetic disease, most probably polygenic, based on the high prevalence of moyamoya in Asia, as well as familial aggregation in 5% to 10% of cases.10,11 The only effective treatment for moyamoya is surgical revascularization to decrease the risk of further transient ischemic attacks (TIAs), and ischemic and hemorrhagic stroke Arterial Ischemic Stroke Acute arterial ischemic stroke (AIS) is defined as the acute onset of a neurologic deficit consistent with infarction in a vascular territory, with imaging or pathologic confirmation Secondary hemorrhage due to tissue and vascular injury within the ischemic core can occur (hemorrhagic conversion); however, unlike hemorrhagic stroke, the initial event is ischemic Etiologies and Risk Factors Approximately half of all children presenting with initial AIS have an underlying condition that increases the risk of stroke (symptomatic stroke) and the other half have cryptogenic stroke After extensive evaluation, most children will have at least one risk factor for stroke identified It is likely that most AISs in childhood are multifactorial 811 812 S E C T I O N V I Pediatric Critical Care: Neurologic A B • Fig 66.1 Magnetic resonance images of a 13-year-old boy with sickle cell disease and bilateral moy- amoya High T2 signal and parenchymal volume loss represents sequelae of multiple infarcts seen in the bilateral anterior circulation (A) There is occlusion of the bilateral distal internal carotid arteries (B) and associated bilateral lenticulostriate and thalamoperforator collaterals consistent with moyamoya Cervicocephalic arterial dissection (CCAD) accounts for 7.5% to 20% of childhood AIS.7,8,12 Because children with CCAD are at risk for recurrent stroke, anticoagulant therapy is recommended,13 although antiplatelet therapy such as aspirin is also used, which is consistent with the recommendation of antiplatelet or anticoagulant treatment of CCAD in adults.14 Often, a history of trauma to the head or neck is obtained in children presenting with CCAD, such as can occur with sports injuries However, CCAD can also present spontaneously Dissection can also be complicated by subarachnoid hemorrhage due to aneurysmal dilation and recurrent dissection Children with collagenopathies or elastinopathies—such as Ehlers-Danlos syndrome, Marfan syndrome, Loeys-Dietz syndrome, and arterial tortuosity syndrome— are at increased risk for initial and recurrent CCAD.15 Central nervous system (CNS) vasculitis is an inflammatory cerebral arteriopathy that can be primary, idiopathic, or secondary to a systemic cause—most commonly, systemic rheumatologic disease or infection In childhood primary angiitis of the CNS (cPACNS), inflammation involves only the arteries of the CNS.16 cPACNS can be divided into large-medium-vessel disease, in which arteriopathy can be detected on cerebral catheter angiogram, and small-vessel cPACNS, in which it is not visible on a catheter angiogram Children with large-medium-vessel cPACNS typically present with hemiparesis or aphasia, and stuttering onset of symptoms is common Systemic inflammatory markers are often unremarkable in large-medium-vessel cPACNS, and cerebrospinal fluid (CSF) pleocytosis or elevated protein is present in only one-third of children Treatment of progressive large-medium-vessel cPACNS requires immunosuppression The use of anticoagulation or antiplatelet treatment may decrease the risk of stroke.17 In small-vessel cPACNS, patients often present with diffuse neurologic deficits and headache Brain magnetic resonance imaging (MRI) is usually abnormal, but findings are nonspecific Biomarkers—including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), leukocytosis, anemia, and thrombocytosis— are frequently, but not consistently, abnormal Brain biopsy is necessary to diagnose small-vessel CNS vasculitis However, it may yield a false-negative result in a significant number of patients.17 Secondary CNS vasculitis is a common manifestation of underlying systemic inflammatory diseases such as Takayasu arteritis, polyarteritis nodosa, and systemic lupus erythematosus Arteritis is also commonly seen with acute bacterial meningitis Heparin and aspirin have been used to prevent recurrent stroke in childhood bacterial meningitis.18 VZV infection, both primary infection and reactivation, is associated with vasculopathy and stroke in children and adults.9,19–21 VZV vasculopathy is diagnosed by the detection of VZV deoxyribonucleic acid or anti-VZV immunoglobulin G (IgG) antibody in CSF, or both.20 Treatment of VZV vasculopathy with both acyclovir and corticosteroids is recommended.22 Sickle Cell Disease Stroke is a common complication of sickle cell disease (SCD) Without treatment, 11% of children will have a stroke by 20 years of age23 (see Chapter 88) The incidence of initial stroke is markedly decreased by regular red blood cell transfusions in children with elevated transcranial Doppler velocity in the middle cerebral artery.24,25 Following initial stroke, the risk of a recurrent stroke is approximately 20% even with the use of chronic red blood cell transfusion Many patients with SCD-associated stroke have an underlying cerebral arteriopathy, a risk factor for primary and recurrent stroke.26–28 In addition, patients with SCD are at risk for aneurysmal hemorrhage The possibility of stroke needs to be considered in any child with SCD with transient or persistent focal weakness or deficit in addition to a history of new seizures or severe headache regardless of presence of pain Blood should be sent for type and to crossmatch sickle-negative, antigen-selected, leuko-reduced (minor CHAPTER 66 Pediatric Stroke and Intracerebral Hemorrhage antigen-matched red blood cells if available) blood for exchange transfusion Risk factors for stroke include increased blood pressure, lower hemoglobin concentrations, high leukocyte count, prior transient ischemic attacks, history of meningitis, presentation with seizure, surgery, priapism, acute anemia, recent acute chest syndrome and transfusion within the past weeks, and a history of overt or silent stroke.23,29,30 An emergent head computed tomography (CT) scan without contrast can be used to assess for possible hemorrhage or other intracranial process Head MRI and magnetic resonance angiography (MRA) with diffusion weighted imaging is the best way to assess for possible acute stroke in a child with SCD and clinical presentation of possible stroke Current guidelines recommend urgent erythrocyte transfusion in neuroimaging-confirmed stroke.31 However, some recommend that transfusion not be delayed while awaiting confirmatory neuroimaging There is a risk of ischemia due to increased viscosity if hemoglobin rises to greater than 13 g/dL following transfusion Oxygen supplementation is used to maintain oxygen saturation greater than 93% through the completion of the transfusion and through the following first night to minimize nocturnal hypoxemia Cooling blankets should be avoided in patients with SCD Cardiology consultation should be obtained prior to exchange transfusion if there is clinical suspicion of cardiac dysfunction, to assist with cardiac monitoring during exchange transfusion Although SCD did not increase the risk of intravenous tissue plasminogen activator (t-PA) for acute stroke in adults,32 there is no data with which to guide the use of t-PA for stroke in children with SCD In addition, the pathophysiology of stroke in children with SCD may not be particularly responsive to thrombolysis Congenital and Acquired Heart Disease Cardioembolic stroke secondary to congenital and acquired cardiac disease accounts for almost one-third of AIS in children, with children with complex congenital heart disease (CHD) and rightto-left shunts at highest risk.4 Among children with heart disease and stroke, one-quarter of strokes occurred in the setting of cardiac surgery or catheterization.4 Not infrequently, the child with cardiac disease and stroke is acutely ill and sedated, and the stroke is not discovered until sedation or paralytics are weaned Prothrombotic factors increase the risk of both initial33 and recurrent stroke in the setting of CHD.34 The risk of recurrent stroke in children with CHD is 27% at 10 years, with the highest risk immediately following the initial stroke.34 Hypercoagulable States A prothrombotic state is identified in 13% of children with AIS,4 and the risk of AIS is increased when multiple thrombophilias are present or when combined with other risk factors such as CHD Protein S deficiency, protein C deficiency, factor V Leiden mutation, antithrombin III deficiency, elevated lipoprotein(a), homocystinuria, and antiphospholipid antibodies have been associated with AIS in childhood (Box 66.1).4,35 Pathophysiology Ischemic stroke occurs when blood supply to an area of the brain is not adequate for metabolic needs This may occur due to occlusion of flow caused by thrombus or embolus or due to critical stenosis Decreased cerebral blood flow (CBF) below a critical 813 • BOX 66.1 Risk Factors Reported in Acute Arterial Ischemic Stroke in Childhood Cerebral Arteriopathy Infection Cervicocephalic arterial dissection Moyamoya Focal cerebral arteriopathy Primary central nervous system vasculitis Secondary vasculitis Varicella-associated vasculopathy Bacterial meningitis Varicella zoster virus Mycotic meningitis Tuberculous meningitis Hematologic Disorders Sickle cell disease Iron deficiency anemia Thrombocytosis Leukemia Heart Disease Drugs Asparaginase Estrogen Illicit drugs (cocaine, methamphetamine) Inflammatory/Autoimmune Systemic lupus erythematosus Rheumatoid arthritis Vasculitis (as above) Congenital heart disease Acquired heart disease Hypercoagulable State Protein C deficiency Protein S deficiency Homocysteinemia Anticardiolipin antibodies Elevated lipoprotein A threshold results in neuronal injury and, potentially, neuronal death The central region with absence of CBF (“no flow”) is the ischemic core, which will not survive The surrounding area of ischemic penumbra is not irreversibly injured and potentially viable but will not survive without prompt restoration of blood flow (see Chapter 65) The goal of reperfusion using intravenous t-PA or acute endovascular intervention is to “rescue” the penumbra by restoring adequate perfusion to prevent cell death The size of an infarct is determined by the extent and duration of ischemia, cerebral perfusion pressure, and extent of collateral circulation Fever may increase infarct size due to increased metabolic demands Therefore, strategies to minimize injury include ensuring adequate cerebral perfusion pressure and aggressively treating fever As energy failure at the cellular level results in neuronal hyperexcitability, seizures—including status epilepticus—can occur following acute stroke Although prophylactic antiepileptic medication is not recommended, close monitoring for seizures, including the use of electroencephalography monitoring for subclinical seizures, is recommended Seizures can be refractory in the immediate poststroke period Presentation Recognition of stroke in childhood is challenging Identifying neurologic deficits in children, particularly young children, is difficult; stroke is often not considered in the child presenting with acute neurologic deficit In addition, mimics of childhood stroke are common, and the differential diagnosis is broad, including other conditions requiring urgent diagnosis and treatment, such as brain tumors, hypertensive encephalopathy, demyelinating disorders, infection, postictal hemiparesis, and metabolic disorders.36,37 Signs and symptoms of anterior circulation stroke in childhood include hemiparesis, hemisensory loss, aphasia, visual 814 S E C T I O N V I Pediatric Critical Care: Neurologic A B • Fig 66.2 Head magnetic resonance images of a 1-year-old boy with acute onset of right-sided hemiplegia, with edema on T2 imaging (A) and restricted diffusion on diffusion-weighted imaging (B) in the left middle cerebral artery territory field cuts with gaze preference, and neglect Posterior circulation strokes can present with ataxia, vomiting, vertigo, dysarthria, diplopia, and dysmetria Diagnosis of cerebellar stroke is particularly challenging, as cerebellar stroke often presents with nonspecific symptoms such as headache and vomiting, or with ataxia, which mimics acute cerebellar ataxia From 10% to 20% of childhood AISs are heralded by seizures New neurologic deficit following a seizure in a child with acute stroke may be mistaken for postictal paresis Critical initial data to be collected in a child presenting with possible stroke include history of predisposing factors, time since the child was last seen well, recent trauma or infection, and medications A baseline neurologic assessment, such as the pediatric version of the National Institutes of Health Stroke Scale (PedNIHSS)38 should be performed Neuroimaging The potential for acute treatment and intervention will determine the urgency of neuroimaging studies (see Chapter 61) Head CT is usually the imaging modality used for a child presenting with acute neurologic symptoms or signs because of speed and availability, along with sensitivity for acute intracranial hemorrhage (ICH), cerebral edema, and impending herniation Head CT is the first-line imaging study for the child with suspected ICH, trauma, or if MR is contraindicated However, it is much less sensitive for early ischemic stroke than MRI using diffusionweighted imaging (DWI).39 Although head CT and brain MRI will both evaluate for acute hemorrhage in children, the need to confirm AIS and rule out stroke mimics and desire to limit radiation exposure results in MRI as the optimal first-line study in most cases A rapid stroke MR protocol that can be done in 20 to 30 minutes may be used Sequences should include DWI/apparent diffusion coefficient (ADC), which is very sensitive for early ischemia although not specific, and T1- and T2-weighted (or T2 FLAIR [fluid attenuation inverse recovery]) sequences, and MRA of the head and neck (Fig 66.2) FLAIR is less useful in children under years of age owing to immature cerebral myelination Susceptibility-weighted imaging or gradient echo will increase the sensitivity for detection of hemorrhage Young children and those unable to cooperate will need sedation for acquired neuroimaging, which will require maintenance of blood pressure to optimize brain perfusion, particularly in the setting of flow-limiting arteriopathy MRA will reveal arteriopathy, including stenosis and dissection, in half to three-quarters of children with acute stroke 3,7,40,41; however, MRA cannot detect lesions in smaller arteries Related imaging of the cerebral venous system is indicated if there are concerns about cerebral venous thrombosis Vessel wall imaging is increasingly used in adults to evaluate the arterial wall itself, including for the presence of inflammation, rather than just the lumen, as seen with MRA, CT angiography (CTA) and catheter angiograms, and is being used more often in children as well CTA of the head and neck can diagnose arteriopathy but requires sedation in the younger child and entails significant radiation exposure For the latter reason, if head MRA can be obtained, CTA may be avoided in some instances If cerebral arteriopathy is strongly suspected despite a normal MRA, cerebral catheter angiography may be preferable to CTA due to greater sensitivity in diagnosing cerebral arteriopathy, particularly medium- and smallvessel arteriopathy.42 It requires radiation and anesthesia; however, periprocedural complications are rare with experienced angiographers.43 A cerebral catheter angiogram can be used for diagnosis of arteriopathy as well as for mechanical thrombectomy, treatment of aneurysm, and other neurointerventions Even when hyperacute treatment is not being considered, diagnosis of underlying etiologies such as CCAD, cardiac embolus, and CSVT will modify immediate treatment Cerebral arteriopathy ... hemorrhage due to aneurysmal dilation and recurrent dissection Children with collagenopathies or elastinopathies—such as Ehlers-Danlos syndrome, Marfan syndrome, Loeys-Dietz syndrome, and arterial... AIS in childhood, whereas adults frequently present with hemorrhagic stroke Moyamoya may be idiopathic, termed moyamoya disease, or occur in association with predisposing syndromes, such as sickle... with imaging or pathologic confirmation Secondary hemorrhage due to tissue and vascular injury within the ischemic core can occur (hemorrhagic conversion); however, unlike hemorrhagic stroke, the