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Strokes and congenital heart disease in infants and children
Seminars in Cerebrovascular Diseases and Stroke Vol. 3 No. 4 2003
Strokes and Congenital Heart Disease in Infants and Children RANDALL L. CALDWELL Indianapolis, Indiana
ABSTRACT This article examines the incidence, mechanisms, recognition, prevention, and management of strokes associated with congenital heart disease in infants and children. Key words: stroke, focal ischemia, congenital heart disease, infants, children.
increased incidence of ischemic strokes due to right-toleft shunting and increased blood viscosity caused by polycythemia and microcytic anemia.8 In microcytic anemia, the red blood cell is less deformable and thus more prone to sludging. Children having congenital heart disease also have a higher frequency of genetic or acquired abnormalities that predispose them to thrombosis. Invasive diagnostic cardiac tests (eg, cardiac catheterization) and cardiovascular surgical procedures also predispose these children to thrombosis and subsequent stroke. Current practice is the heparinization of all children undergoing a diagnostic cardiac catheterization to decrease the risk of ischemic injury to the leg, (femoral artery) and decrease the risk of thrombus formation within the sheath, the vessels, or the heart. Kirkham9 estimated a 6% incidence of postoperative neurologic abnormalities in children undergoing open heart surgery, the majority of which were seizures. Not all risk factors for stroke in children are congenital or iatrogenic, but some are self-imposed. Unfortunately, our patients do not always take only the medications prescribed. Cocaine use has been shown to cause marked vasoconstriction and can lead to stroke or myocardial infarction; thus, a drug screen is not inappropriate in the adolescent presenting with signs and symptoms of a stroke or myocardial infarction with elevated troponin. The death rates for childhood ischemic strokes have declined by 19%10 since 1979; however, there continues to be significant morbidity and mortality11 as well as the risk of recurrence. There is evidence that neurologic outcome may be improved by appropriate emergency management and that recurrence may be
Stroke is defined as a focal neurologic deficit lasting longer than 24 hours based on a vascular insult. A similar event that persists for a shorter period is defined as a transient ischemic attack. The incidence of strokes in children has been reported at 2.51 to 3.12 cases per 100,000 per year. Strokes have been reported to recur in up to 20% of children having an initial stroke.3 This includes both ischemic and hemorrhagic causes of strokes. Pediatric stroke is often underrecognized and underreported. The risk factors for stroke in children are numerous and different from those seen in adults (Table 1). Congenital heart disease and hemoglobinopathies are the most common causes of ischemic stroke in children.4 The Canadian Pediatric Stroke Registry demonstrated cardiac disease in 25% of children with ischemic stroke.5 The incidence of congenital heart disease is 1 in 125 live births.6 Children having congenital heart disease are at an increased risk for neurologic complications including stroke, cerebral abscesses, developmental delay, and mental retardation. These problems have been reported in as many as 25% of children with congenital heart disease.7 The rate of strokes in children with congenital heart disease has not been defined; however, the risk is related to the specific underlying cardiac abnormality. Children with cyanotic congenital heart defects have an From the Section of Pediatric Cardiology, Indiana University School of Medicine, Indianapolis, IN. Address reprint requests to Randall L. Caldwell, MD, Section of Pediatric Cardiology, Indiana University School of Medicine, Indianapolis, IN 46202. E-mail: [email protected] © 2004 Elsevier Inc. All rights reserved. 1528-9931/03/0304-0003$30.00/0 doi:10.1053/j.scds.2004.02.005
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Strokes and Heart Disease in Children ● Table 1. Cardiovascular Associations with Stroke in Children Cardiac disease Cyanotic congenital heart disease Tetralogy of Fallot Transposition of the great vessels Single ventricle physiology Hypoplastic left heart syndrome Tricuspid atresia Pulmonary atresia Unbalanced atrioventricular canal Coarctation of the aorta Bacterial endocarditis Pulmonary arteriovenous fistulas Arrhythmias Cardiomyopathy Paradoxic embolization through a patent foramen ovale Blood vessel diseases Aneurysms Moyamoya Coagulation problems Patients having mechanical heart valves but not compliant in following anticoagulation recommendations Cyanotic congenital heart disease with hyperviscosity Gastroenteritis producing dehydration Factor V Leiden mutation Antiphospholipid antibodies Protein C deficiency Protein S deficiency Prothrombin 20210A mutation
preventable. Specific strategies for primary and secondary stroke prevention are dependent on the underlying abnormality predisposing a patient to a stroke. Our institution reported12 the subtypes of ischemic stroke in children and young adults. The most common identifiable cause of stroke was cardioembolic. Although the proportion of cardioembolic events was similar in children and young adults, the etiologies were different. The children were more likely to have had a cyanotic heart defect, whereas the young adults were more likely to have had a paradoxical right-toleft embolus through a patent foramen ovale. Other identifiable causes of ischemic stroke in children were sickle-cell disease and moyamoya.13 A common mechanism of ischemic stroke in congenital heart disease is venous thrombosis associated with polycythemia and cyanosis resulting in embolization to the brain. Cerebral vascular aneurysms and dissections have also been reported14 in aortic arch anomalies such as coarctation of the aorta and interrupted aortic arch. Moyamoya has been associated with several congenital heart abnormalities including ventricular septal defect, aortic stenosis, mitral stenosis, coarctation of the aorta, and tetralogy of Fallot.15 Conotruncal or aortic arch abnormalities have been linked to anomalies of the embryonic neural crest, which has been associated with chromosome 22. Moyamoya has also been associated Down,16 Williams,17 Turner,18 and Alagille19 syndromes. All of these genetic syndromes also have a high inci-
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dence of congenital heart abnormalities. Moyamoya should be considered in the differential diagnosis of seizures or stroke in a patient having congenital heart disease. Prompt diagnosis and surgical revascularization may lead to improved neurologic outcomes in these patients. William’s syndrome itself has been linked to a higher risk of stroke unrelated to Moyamoya syndrome.20
Prothrombotic Risk Factors Children with congenital heart disease may also have coexistent prothrombotic disorders such as factor V Leiden mutation, protein C deficiency, protein S deficiency, methylene tetrahydrofolate reductase mutation, prothrombin 20210A mutation, lipoprotein (a), elevated factor VIIIc, and antiphospholipid antibodies.21 The presence of factor V Leiden and/or an elevated factor VIIIc have been associated with poor neurologic outcome in children with neonatal stroke.22 The presence of factor V Leiden mutation and antiphospholipid antibodies have both been shown to be significant risk factors for ischemic stroke risk in children.23 A significant risk factor we have seen for the development of a stroke is the noncompliant child (or their parents), an adolescent, or a young adult who has a mechanical heart valve. These patients are all prescribed warfarin and are to have regular measurement of prothrombin times and an international normalized ratio (INR) to maintain an INR of 2.5 to 3.5. The Mayo Clinic24 also reported a high risk for thromboembolic events in patients having high variability of prothrombin times or INR. For this reason, we attempt to use a tissue valve (eg, porcine, homograft, Ross procedure, or bovine jugular valve) rather than a mechanical valve if possible in a child or adolescent. Adults with cyanotic congenital heart defects had previously been phlebotomized due to a presumed risk of arterial thrombotic stroke associated with hyperviscosity. Perloff et al.25 demonstrated no significant benefit to phlebotomy even with hematocrit levels of 65. He found that repeated phlebotomies depleted iron stores, induced microcytosis, increased whole blood viscosity, impaired oxygen delivery, and increased lactate production in skeletal muscle. Perloff further suggested that iron-deficiency anemia should be suspected in symptomatic hyperviscos cyanotic patients with a hematocrit of up to and including 65. When iron is supplemented, the erythrocyte response should be monitored closely as the hematocrit tends to rise rapidly. Even though a child has congenital heart disease, childhood stroke should always be approached from the standpoint of presenting symptoms and should include diagnostic imaging and evaluation for plasma-phase prothrombotic risk factors. Children having congenital heart
202 Seminars in Cerebrovascular Diseases and Stroke Vol. 3 No. 4 December 2003 disease are at no lesser risk to CNS trauma or infection than the general population.
Types of Congenital Heart Disease at Risk for Stroke Cyanotic Congenital Heart Defects The most common cyanotic congenital heart defect is tetralogy of Fallot, whereas the most common cyanotic congenital heart defect to present at birth is complete transposition of the great vessels (D-transposition of the great vessels). In the past, these two lesions accounted for the majority of congenital heart patients presenting with a stroke.26 With the advent of earlier repair of tetralogy of Fallot, we have seen a significantly decreased occurrence of stroke in these children. The risk of stroke in patients with D-transposition of the great vessels was significant in the days of the Mustard or Senning surgeries. The Mustard and Senning procedures consisted of an atrial switch in which the atrial septum was removed and a spiral “C”-shaped patch was inserted to redirect blood flow within the atria. Following these repairs, the flow was as follows: vena cava 3 right atrium 3 across the mitral valve into the left ventricle 3 left ventricle across the pulmonary valve into the pulmonary artery 3 lungs 3 pulmonary veins 3 left atrium 3 across the tricuspid valve into the right ventricle 3 right ventricle across the aortic valve into the ascending aorta. Thus, the blood flow was “doubly crossed” at the atrial and arterial levels and resulted in normal arterial saturations. These procedures were typically performed at 9 to 18 months of age. Before the Mustard or Senning procedures, these children were hypoxic with arterial saturations typically between 60 and 75%. There was a significant incidence of stroke in the intervening months waiting until these children were large enough to undergo the Mustard or Senning procedures. With the development of microvascular techniques, the arterial switch procedure became possible with acceptable morbidity and mortality. The arterial switch procedure consists of amputating the ascending aorta and main pulmonary artery above the sinuses of Valsalva. These two arteries are then switched such that the aorta arises from the left ventricle and the pulmonary artery arises from the right ventricle. That is the easy part! The coronary arteries must also be moved from the anterior to the posterior great vessel. The right and left main coronary arteries in a newborn infant are about 1 mm in diameter. Before the development of microvascular techniques, there was an unacceptably high mortality due to coronary ischemia following the arterial switch procedure. Now the mortality for an arterial switch procedure in D-transposition of the great vessels
is less than 5%. The arterial switch procedure must be done shortly after birth before the left ventricle deconditions as it is pumping against pulmonary vascular resistance rather than systemic vascular resistance. These children with D-transposition of the great vessels are now repaired in the first couple weeks of life and are no longer at risk for stroke. Advances in cardiovascular surgery have significantly decreased the risk of stroke in tetralogy of Fallot and D-transposition of the great vessels. Children having congenital heart disease now facing higher risks of stroke are those with single-ventricle physiology. Fifteen to twenty years ago, children having single-ventricle physiology all did poorly and did not survive long. We are now much better able to palliate them. These lesions include hypoplastic left heart syndrome, tricuspid atresia, pulmonary atresia with an intact ventricular septum, and an unbalanced atrioventricular canal with hypoplasia of either the right or the left ventricle. These lesions all have significant right-to-left intracardiac shunting leading to the risk of stroke and are all eventually palliated by the Fontan procedure. The Fontan procedure in essence consists of routing the systemic blood flow from the body (inferior vena cava and superior vena cava) directly to the pulmonary arteries. The pulmonary venous return enters the left atrium and flows into the functional single ventricle (either morphologic right or left ventricle), which pumps into the systemic circulation. The Fontan procedure works only if the pulmonary vascular resistance is low and the systemic ventricle has normal function. Since the newborn infant is born with high pulmonary vascular resistance, the Fontan procedure cannot be done until several months of age, after the pulmonary vascular resistance has dropped. This necessitates a systemic-to-pulmonary artery shunt (eg, Blalock Taussig type shunt) be done shortly after birth. With the systemic to pulmonary shunt, the systemic arterial saturations are typically in the 70 to 80% range. The right-to-left shunting in these patients makes them at risk for an embolic stroke. At the time of the completion of the Fontan procedure, it was demonstrated that fenestration of the baffle significantly improved surgical outcomes by decreasing pleural effusions, shortening hospital length of stay, and decreasing the need for additional postoperative procedures.27 The fenestration is performed by the cardiovascular surgeon punching a 2.5 to 3.0 mm hole in the baffle patch, allowing a small intracardiac right-to-left shunt. This decompresses the pulmonary circulation, allowing it to adapt to the low pressure of the systemic venous flow. This improved cardiac output comes at the expense of a small intracardiac right-to-left shunt at the atrial level. This small right-to-left intracardiac shunting unfortunately still may place these children at an increased risk for the development of a stroke. These children are typically treated with low-dose aspirin (5
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mg/kg/d) as an antiplatelet drug. It has yet to be shown in a randomized clinical trial whether these children would be better protected against a stroke by the use of warfarin. We studied 164 patients at Riley Children’s Hospital having undergone either a Fontan or hemi-Fontan palliation between January 1, 1988 and December 1, 2000. Eleven strokes occurred in nine patients (9/164, 5.5%). Two patients died; four had severe neurologic residua; one has mild neurologic residua; and two are normal neurologically. Previous pulmonary artery banding (P ⫽ 0.006) was associated with an increased risk for stroke. This finding was also noted by Oski and coworkers.28 Ventricular morphology (P ⫽ 0.999) and fenestration (P ⫽ 0.718) were not statistically associated with an increased risk of stroke. One of our patients, having had a previous pulmonary artery banding and subsequent Fontan procedure, presented with an acute right middle cerebral infarction documented by magnetic resonance angiography. She successfully underwent thrombolytic therapy within 3 hours of onset and is doing extremely well clinically while maintained on warfarin. Since stroke is not commonly seen in children, the diagnosis is often delayed at the referring institution and the children present to the tertiary care hospital beyond the time frame that allows for good salvage with thrombolysis. Coarctation of the Aorta A strong association has been noted between cerebral vascular disease, intracranial aneurysms, and congenital heart disease.14 This is not surprising as the muscular arteries of the head and neck are derived from the neural crest as are the cardiac conotruncus and aortic arch. The prevalence of intracranial aneurysms in patients having coarctation of the aorta has been estimated to be as low as 2.5% to as high as 50%.29 The presence of systemic hypertension has been proposed as a contributing cause of rupture of these aneurysms. With earlier repair being performed, the frequency of stroke has decreased but has not been eliminated. Even with a good surgical repair of the coarctation, the aorta remains abnormal at the coarctation site. There is at least scar tissue at the repair if not residual narrowing. Recurrent hypertension is common despite successful repair of coarctation and is a major risk for the development of cardiovascular morbidity.30 This residual narrowing may not cause a significant resting gradient but may create an increasing gradient with activity or exercise. It is not uncommon to have a resting gradient of 10 to 15 mm Hg, whereas the gradient with maximal exercise stress testing may approach 40 to 50 mm Hg. These patients cause us great consternation as pediatric cardiologists. The low resting gradient prevents the development of significant collateral arterial blood flow to protect the spinal cord if a surgical repair
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is again attempted. The risk of vascular insult to the spinal cord is about 2%. Evoked potentials are monitored in the lower extremities during all coarctation repairs to help minimize this complication. As improved balloon angioplasty catheters and stents are developed, we may find these patients better helped in the cardiac catheterization laboratory rather than the operating room suites. Only time will tell which procedure is better. Patients having a previous coarctation repair should have their right-arm blood pressures measured yearly. It is important to use the right-arm blood pressure, as many have previously undergone a left subclavian flap angioplasty, an end-to-end, or Dacron patch repair proximal to the left subclavian artery. Thus the left-arm blood pressure may not be accurate and may underestimate the degree of systemic hypertension. Persistent systemic hypertension predisposes these patients to subsequent stroke and/or myocardial infarction. Bacterial Endocarditis Acute and subacute bacterial endocarditis remains a problem. Bacterial endocarditis is more common in cyanotic congenital heart defects and in lesions that cause turbulence (stenotic lesions). The risk for embolization of these vegetation fragments is related to the particular bacterial pathogen as well as the location of the vegetation. Left-sided vegetations on the mitral or aortic valves are at risk of embolization to the head, whereas rightsided vegetations do not predispose to stroke or cerebral abscess unless there is intracardiac right-to-left shunting. A septic embolus to the brain may also lead to a brain abscess. Treatment of bacterial endocarditis is based on bacterial antibiotic sensitivities as well as the patient’s homodynamic stability. Pulmonary Arteriovenous Fistulas Pulmonary arteriovenous fistulas (PAVF) or pulmonary arteriovenous malformations (PAVM) have been associated with cyanotic congenital heart defects requiring the Fontan palliation (eg, tricuspid atresia, pulmonary atresia, hypoplastic left heart syndrome, and asymmetric atrioventricular canal). These are thought to be related to abnormal systemic venous return in which the hepatic venous return bypasses the pulmonary artery circulation. PAVF have also been associated with hereditary hemorrhagic telangiectasia (also known as Rendu–Osler–Weber syndrome). In some of these patients, neurologic symptoms such as headache, seizures, hemiplegia, brain abscesses, transient ischemic attacks, and stroke dominate the clinical picture. Approximately 37% of these patients having PAVF are at risk for paradoxic embolization leading to transient ischemic at-
204 Seminars in Cerebrovascular Diseases and Stroke Vol. 3 No. 4 December 2003 tacks or stroke.31 The annual risk for stroke is approximately 1.5% per year among patients with these lesions. Arrhythmias The major cardiac arrhythmia that predisposes a patient to cerebral emboli is atrial flutter or fibrillation. In adults, 11% of octogenarians suffer from atrial fibrillation due to chronic left atrial enlargement.32 In children, we also see atrial flutter-fibrillation due to chronic left or right atrial dilation. It is common to have the rhythm spontaneously change back and forth from flutter to fibrillation in children. Lesions that predispose to the development of atrial flutter-fibrillation include mitral regurgitation, mitral stenosis, Fontan procedure, or a cardiomyopathy. These patients are commonly treated with antiarrhythmic medications or ablation procedures. There have been no controlled studies in children on the prevention of stroke in association with atrial flutterfibrillation; however, studies in adults have shown benefit in the prevention of secondary stroke with the use of antiplatelet drugs and anticoagulation.33,34 The American Heart Association, American College of Cardiology, and the European Society of Cardiology issued practice guidelines for the management of patients with atrial fibrillation.35 Cardiomyopathy Children may have three distinct types of cardiomyopathies: dilated congestive, hypertrophic obstructive, and restrictive cardiomyopathies. Patients having a hypertrophic obstructive or restrictive cardiomyopathy are not at great risk for stroke; however, patients having a dilated congestive cardiomyopathy are at significant risk for the development of a stroke due to stasis of blood within the heart. These patients are treated vigorously with anticongestive measures including digoxin, diuretics, angiotensin converting enzyme inhibitors, beta blockers, dobutamine, dopamine, cyclic AMP phosphodiesterase inhibitors, and even implantable ventricularassist devices. Our goal, if possible, is to maintain cardiac function with oral medications such that the patients have few if any symptoms. If their ventricular function deteriorates, we then proceed to intravenous agents. If they cannot be supported on intravenous medications, we then consider an implantable ventricular assist device if they are a transplant candidate. As the left ventricle becomes more dilated with worsening systolic and diastolic function, the risk of a mural thrombus formation increases. Patients with a mild or moderate decrease in left ventricular systolic function are treated with antiplatelet doses of aspirin at 5 to 10 mg/kg/d. As the left ventricular systolic function worsens, or if a mural thrombus is noted by echocardiography, warfarin or hep-
arin is then used. If the patient requires a ventricularassist device to be implanted, full anticoagulation with heparin is imperative. The development of a significant cerebrovascular accident in a patient on the UNOS waiting list for a heart transplant would preclude their being a transplant candidate due to the extreme shortage of donor candidates. Even a minor stroke would increase the posttransplant risk for seizures with the use of calcineuron inhibitors such as cyclosporine or tacrolimus for the prevention of acute cellular rejection. Patent Foramen Ovale Patent foramen ovale is found by autopsy in 34.3% in the first three decades of life and decreases to 20.2% by the ninth decade.36 A patent foramen ovale is obviously present in all newborns and then the flap between the primum and secundum septae begins closing. A study in adults utilizing contrast transthoracic echocardiography found the incidence of patent foramen ovale to be 40% in those who had an ischemic stroke.37 In a clinical series using transthoracic echocardiography the prevalence of a patent foramen ovale in patients without a stroke was 10 to 18%.38 With the increasing use of intraoperative transesophageal echocardiography, the frequency of a patent foramen ovale was reported at 26% in patients who had not had a stroke.39 Thus the frequency of a patent foramen ovale discovered by transesophageal echocardiography approaches the incidence noted by autopsy. A paradoxic embolism refers to embolic entry of a venous thrombus into the systemic circulation via a right-to-left shunt. In the absence of a cyanotic congenital heart defect, paradoxic emboli could occur if there were a deep vein thrombus and presence of a favorable pressure gradient to promote a right-to-left shunt across the patent foramen ovale. Normally any shunting at the atrial level is left to right due to the increased compliance of the right ventricle and low pulmonary vascular resistance. For a right-to-left shunt to occur, there would need to be either elevated pulmonary vascular resistance or a significant increase in intrathoracic pressure such as caused by a Valsalva maneuver, cough, defecation, or micturition. Children being evaluated for an embolic stroke should have a contrast echocardiographic study done with a Valsalva maneuver. A higher frequency of detecting a patent foramen ovale in adults was noted by transesophageal versus transthoracic echocardiography. Adults, in general, have much poorer transthoracic echocardiographic windows than children. No controlled similar studies have been reported in children to date. In most children, transthoracic echocardiography with contrast and a Valsalva maneuver is sufficient to exclude an intracardiac right-to-left shunt. If the images are insufficient (eg, due to thoracic abnormalities, lung hyperexpansion, obesity, or insufficient patient cooperation),
Strokes and Heart Disease in Children ●
then a sedated transesophageal echocardiographic study may be indicated to rule out a potential source for a paradoxic embolus. If a patent foramen ovale with rightto-left shunting has been shown in a patient with a previous embolic stroke, consideration should be made for closure in the cardiac catheterization laboratory by an experienced physician. Over the past 18 months, we have closed over 60 atrial septal defects in the cardiac catheterization laboratory. Twenty-two of these were in patients having a patent foramen ovale and a previous stroke. It is still unproven whether or not this will completely eliminate the risk of further stroke in these patients. Prevention of Recurrent Stroke in Children
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Until Kirkham’s article on stroke in children in 1999,11 ischemic strokes in children were thought to have a good prognosis and a low recurrence rate. The previous assumption that management would not significantly alter outcomes resulted in failure to prospectively evaluate pediatric stoke patients in a controlled manner. Stra¨ ter and coworkers40 evaluated 135 consecutive German children between the ages of 6 months and 18 years who presented with first episode of ischemic stroke. These patients were prospectively assigned to either aspirin or low molecular weight heparin in a nonrandomized fashion. The study endpoint was recurrent stroke. Recurrent stroke was noted in 9.6% (13/135) at a median time of 5 months (range 2-13 months). No significant difference was noted with respect to antithrombotic medication used. Neither aspirin nor low molecular weight heparin was superior to the other. During the study period no patient in the aspirin group developed hemorrhage, allergic reactions, Reye syndrome, or gastrointestinal symptoms. The low molecular weight heparin patient group experienced neither heparin-induced thrombocytopenia nor local or systemic hemorrhage. Even with these efforts at secondary prevention, recurrent stroke was diagnosed in 6.7% of the children with stroke of cardiac origin. Further randomized trials of adequate size are clearly needed to elucidate reliable information on safety and efficacy for the prevention of recurrent stroke with antithrombotic medications in children.
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Stroke in children within a major metropolitan area: the surprising importance of intracerebral hemorrhage. J Child Neurol 8:250-255, 1993 Isler W: Stroke in childhood and adolescence. Eur Neurol 23:421-424, 1984 Hunter JV: Magnetic resonance imaging in pediatric stroke. Top Magn Reson Imaging 13:23-28, 2002 De Veber G: Canadian Pediatric Ischemic Stroke Registry [abstract]. Pediatr Child Health 2000, A17 Strauss A, Toth B, et al: Prenatal diagnosis of congenital heart disease and neonatal outcome—a six years experience. Eur J Med Res 6:66-70, 2001 Tyler HR, Clark DB: Incidence of neurologic complications in congenital heart disease. Arch Neurol Psych 77: 17-22, 1957 Cottrill CM, Kaplan S: Cerebral vascular accidents in cyanotic congenital heart disease. Am J Dis Child 125:484487, 1973 Kirkham FJ: Recognition and prevention of neurological complications in pediatric cardiac surgery. Pediatr Cardiol 19:331-345, 1998 Fullerton HJ, Chetkovich DM, Wu YW, Smith WS, Johnston SC: Deaths from stroke in children, 1979 to 1998. Neurology 59:34-39, 2002 Kirkham FJ: Stoke in childhood. Arch Dis Child 81:85-89, 1999 Williams LS, Garg BP, Cohen M, Fleck JD, Biller J: Subtypes of ischemic stroke in children and young adults. Neurology 49:1541-1545, 1997 Roach ES, Riela AR: Pediatric Cerebrovascular Disorders, 2nd Ed. Futura, New York, 1995 Schievink WI, Mokri B, Piepgras DG, Gittenberger-deGroot AC: Intracranial aneurysms and cervicocephalic arterial dissections associated with congenital heart disease. Neurosurgery 39:685-690, 1996 Geva T: Moyamoya syndrome associated with congenital heart disease. Pediatrics 101:57-60, 1998 Berg JM, Armstrong D: On the association of moyamoya disease with Down’s syndrome. J Ment Defic Res 35:398403, 1991 Kawai M, Nishikawa T, Tanaka M: An autopsied case of Williams syndrome complicated by moyamoya. Acta Paediatr Jpn 35:63-67, 1993 Ajimi Y, Uchida K, Kawase T, Toya S: A case of Turner’s syndrome associated with moyamoya disease. Neurol Surg 20:1021-1024, 1992 Rachmel A, Zeharia A, Neuman-Levin M, Weitz R, Shamir R, Dinari G: Alagille syndrome associated with moyamoya disease. Am J Med Genet 33:89-91, 1989 Rothman M: Stroke in Williams’s syndrome. Stroke 27: 143-146, 1996 Nestoridi E, Buonanno FS, Jones RM, Krishnamoorthy K, Grant PE, Van Cott EM, Grabowski EF: Arterial ischemic stroke in childhood: the role of plasma-phase risk factors. Curr Opin Neurol 15:139-144, 2002 Mercuri E, Cowan F, Gupte G, Manning R, Laffan M, Rutherford M, Edwards AD, Dubowitz L, Roberts I: Prothrombotic disorders and abnormal neurodevelopment outcome in infants with neonatal cerebral infarction. Pediatrics 107:1400-1404, 2001
206 Seminars in Cerebrovascular Diseases and Stroke Vol. 3 No. 4 December 2003 23. Kenet G, Sadetzki S, Murad H: Factor V Leiden and antiphospholipid antibodies are significant risk factors for ischemic stroke in children. Stroke 31:1283-1288, 2000 24. Chesebro JH: Variability in anticoagulation control predicts thromboembolism after mechanical valve replacement: a 23 year population-based study. Mayo Clin Proc 72:1103-1110, 1997 25. Perloff JK, Marelli AJ, Miner PD: Risk of stroke in adults with cyanotic congenital heart disease. Circulation 87: 1954-1959, 1993 26. Phornhuntkul C, Rosenthal A, Nadas AS, Berenberg W: Cerebrovascular accidents in infants and children with cyanotic congenital heart disease. Am J Cardiol 32:329334, 1973 27. Lemler MS, Scott WA, Leonard SR, Stromberg D, Ramaciotti C: Fenestration improves clinical outcome of the Fontan procedure: a prospective randomized study. Circulation 105:207-212, 2002 28. Oski JA, Canter CE, Spray TL, Kan JS, Cameron DE, Murphy M: Embolic stroke after ligation of the pulmonary artery in patients with functional single ventricle. Am Heart J 132:836-840, 1996 29. Shearer WT, Rutman JY, Weinberg WA, Goldring D: Coarctation of the aorta and cerebrovascular accident: a proposal for early surgery. J Pediatr 1970;77:1004-1009 30. Jenkins NP: Coarctation of the aorta: natural history and outcome after surgical treatment. QJM 92:365-371, 1999 31. Swanson KL, Prakash UB, Stanson W: Pulmonary arteriovenous fistulas: Mayo Clinic experience, 1982-1997. Mayo Clin Proc 74:671-680, 1999 32. Khairy P, Nattel S: New insights into the mechanisms and
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Strokes and Congenital Heart Disease in Infants and Children RANDALL L. CALDWELL Indianapolis, Indiana
ABSTRACT This article examines the incidence, mechanisms, recognition, prevention, and management of strokes associated with congenital heart disease in infants and children. Key words: stroke, focal ischemia, congenital heart disease, infants, children.
increased incidence of ischemic strokes due to right-toleft shunting and increased blood viscosity caused by polycythemia and microcytic anemia.8 In microcytic anemia, the red blood cell is less deformable and thus more prone to sludging. Children having congenital heart disease also have a higher frequency of genetic or acquired abnormalities that predispose them to thrombosis. Invasive diagnostic cardiac tests (eg, cardiac catheterization) and cardiovascular surgical procedures also predispose these children to thrombosis and subsequent stroke. Current practice is the heparinization of all children undergoing a diagnostic cardiac catheterization to decrease the risk of ischemic injury to the leg, (femoral artery) and decrease the risk of thrombus formation within the sheath, the vessels, or the heart. Kirkham9 estimated a 6% incidence of postoperative neurologic abnormalities in children undergoing open heart surgery, the majority of which were seizures. Not all risk factors for stroke in children are congenital or iatrogenic, but some are self-imposed. Unfortunately, our patients do not always take only the medications prescribed. Cocaine use has been shown to cause marked vasoconstriction and can lead to stroke or myocardial infarction; thus, a drug screen is not inappropriate in the adolescent presenting with signs and symptoms of a stroke or myocardial infarction with elevated troponin. The death rates for childhood ischemic strokes have declined by 19%10 since 1979; however, there continues to be significant morbidity and mortality11 as well as the risk of recurrence. There is evidence that neurologic outcome may be improved by appropriate emergency management and that recurrence may be
Stroke is defined as a focal neurologic deficit lasting longer than 24 hours based on a vascular insult. A similar event that persists for a shorter period is defined as a transient ischemic attack. The incidence of strokes in children has been reported at 2.51 to 3.12 cases per 100,000 per year. Strokes have been reported to recur in up to 20% of children having an initial stroke.3 This includes both ischemic and hemorrhagic causes of strokes. Pediatric stroke is often underrecognized and underreported. The risk factors for stroke in children are numerous and different from those seen in adults (Table 1). Congenital heart disease and hemoglobinopathies are the most common causes of ischemic stroke in children.4 The Canadian Pediatric Stroke Registry demonstrated cardiac disease in 25% of children with ischemic stroke.5 The incidence of congenital heart disease is 1 in 125 live births.6 Children having congenital heart disease are at an increased risk for neurologic complications including stroke, cerebral abscesses, developmental delay, and mental retardation. These problems have been reported in as many as 25% of children with congenital heart disease.7 The rate of strokes in children with congenital heart disease has not been defined; however, the risk is related to the specific underlying cardiac abnormality. Children with cyanotic congenital heart defects have an From the Section of Pediatric Cardiology, Indiana University School of Medicine, Indianapolis, IN. Address reprint requests to Randall L. Caldwell, MD, Section of Pediatric Cardiology, Indiana University School of Medicine, Indianapolis, IN 46202. E-mail: [email protected] © 2004 Elsevier Inc. All rights reserved. 1528-9931/03/0304-0003$30.00/0 doi:10.1053/j.scds.2004.02.005
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Strokes and Heart Disease in Children ● Table 1. Cardiovascular Associations with Stroke in Children Cardiac disease Cyanotic congenital heart disease Tetralogy of Fallot Transposition of the great vessels Single ventricle physiology Hypoplastic left heart syndrome Tricuspid atresia Pulmonary atresia Unbalanced atrioventricular canal Coarctation of the aorta Bacterial endocarditis Pulmonary arteriovenous fistulas Arrhythmias Cardiomyopathy Paradoxic embolization through a patent foramen ovale Blood vessel diseases Aneurysms Moyamoya Coagulation problems Patients having mechanical heart valves but not compliant in following anticoagulation recommendations Cyanotic congenital heart disease with hyperviscosity Gastroenteritis producing dehydration Factor V Leiden mutation Antiphospholipid antibodies Protein C deficiency Protein S deficiency Prothrombin 20210A mutation
preventable. Specific strategies for primary and secondary stroke prevention are dependent on the underlying abnormality predisposing a patient to a stroke. Our institution reported12 the subtypes of ischemic stroke in children and young adults. The most common identifiable cause of stroke was cardioembolic. Although the proportion of cardioembolic events was similar in children and young adults, the etiologies were different. The children were more likely to have had a cyanotic heart defect, whereas the young adults were more likely to have had a paradoxical right-toleft embolus through a patent foramen ovale. Other identifiable causes of ischemic stroke in children were sickle-cell disease and moyamoya.13 A common mechanism of ischemic stroke in congenital heart disease is venous thrombosis associated with polycythemia and cyanosis resulting in embolization to the brain. Cerebral vascular aneurysms and dissections have also been reported14 in aortic arch anomalies such as coarctation of the aorta and interrupted aortic arch. Moyamoya has been associated with several congenital heart abnormalities including ventricular septal defect, aortic stenosis, mitral stenosis, coarctation of the aorta, and tetralogy of Fallot.15 Conotruncal or aortic arch abnormalities have been linked to anomalies of the embryonic neural crest, which has been associated with chromosome 22. Moyamoya has also been associated Down,16 Williams,17 Turner,18 and Alagille19 syndromes. All of these genetic syndromes also have a high inci-
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dence of congenital heart abnormalities. Moyamoya should be considered in the differential diagnosis of seizures or stroke in a patient having congenital heart disease. Prompt diagnosis and surgical revascularization may lead to improved neurologic outcomes in these patients. William’s syndrome itself has been linked to a higher risk of stroke unrelated to Moyamoya syndrome.20
Prothrombotic Risk Factors Children with congenital heart disease may also have coexistent prothrombotic disorders such as factor V Leiden mutation, protein C deficiency, protein S deficiency, methylene tetrahydrofolate reductase mutation, prothrombin 20210A mutation, lipoprotein (a), elevated factor VIIIc, and antiphospholipid antibodies.21 The presence of factor V Leiden and/or an elevated factor VIIIc have been associated with poor neurologic outcome in children with neonatal stroke.22 The presence of factor V Leiden mutation and antiphospholipid antibodies have both been shown to be significant risk factors for ischemic stroke risk in children.23 A significant risk factor we have seen for the development of a stroke is the noncompliant child (or their parents), an adolescent, or a young adult who has a mechanical heart valve. These patients are all prescribed warfarin and are to have regular measurement of prothrombin times and an international normalized ratio (INR) to maintain an INR of 2.5 to 3.5. The Mayo Clinic24 also reported a high risk for thromboembolic events in patients having high variability of prothrombin times or INR. For this reason, we attempt to use a tissue valve (eg, porcine, homograft, Ross procedure, or bovine jugular valve) rather than a mechanical valve if possible in a child or adolescent. Adults with cyanotic congenital heart defects had previously been phlebotomized due to a presumed risk of arterial thrombotic stroke associated with hyperviscosity. Perloff et al.25 demonstrated no significant benefit to phlebotomy even with hematocrit levels of 65. He found that repeated phlebotomies depleted iron stores, induced microcytosis, increased whole blood viscosity, impaired oxygen delivery, and increased lactate production in skeletal muscle. Perloff further suggested that iron-deficiency anemia should be suspected in symptomatic hyperviscos cyanotic patients with a hematocrit of up to and including 65. When iron is supplemented, the erythrocyte response should be monitored closely as the hematocrit tends to rise rapidly. Even though a child has congenital heart disease, childhood stroke should always be approached from the standpoint of presenting symptoms and should include diagnostic imaging and evaluation for plasma-phase prothrombotic risk factors. Children having congenital heart
202 Seminars in Cerebrovascular Diseases and Stroke Vol. 3 No. 4 December 2003 disease are at no lesser risk to CNS trauma or infection than the general population.
Types of Congenital Heart Disease at Risk for Stroke Cyanotic Congenital Heart Defects The most common cyanotic congenital heart defect is tetralogy of Fallot, whereas the most common cyanotic congenital heart defect to present at birth is complete transposition of the great vessels (D-transposition of the great vessels). In the past, these two lesions accounted for the majority of congenital heart patients presenting with a stroke.26 With the advent of earlier repair of tetralogy of Fallot, we have seen a significantly decreased occurrence of stroke in these children. The risk of stroke in patients with D-transposition of the great vessels was significant in the days of the Mustard or Senning surgeries. The Mustard and Senning procedures consisted of an atrial switch in which the atrial septum was removed and a spiral “C”-shaped patch was inserted to redirect blood flow within the atria. Following these repairs, the flow was as follows: vena cava 3 right atrium 3 across the mitral valve into the left ventricle 3 left ventricle across the pulmonary valve into the pulmonary artery 3 lungs 3 pulmonary veins 3 left atrium 3 across the tricuspid valve into the right ventricle 3 right ventricle across the aortic valve into the ascending aorta. Thus, the blood flow was “doubly crossed” at the atrial and arterial levels and resulted in normal arterial saturations. These procedures were typically performed at 9 to 18 months of age. Before the Mustard or Senning procedures, these children were hypoxic with arterial saturations typically between 60 and 75%. There was a significant incidence of stroke in the intervening months waiting until these children were large enough to undergo the Mustard or Senning procedures. With the development of microvascular techniques, the arterial switch procedure became possible with acceptable morbidity and mortality. The arterial switch procedure consists of amputating the ascending aorta and main pulmonary artery above the sinuses of Valsalva. These two arteries are then switched such that the aorta arises from the left ventricle and the pulmonary artery arises from the right ventricle. That is the easy part! The coronary arteries must also be moved from the anterior to the posterior great vessel. The right and left main coronary arteries in a newborn infant are about 1 mm in diameter. Before the development of microvascular techniques, there was an unacceptably high mortality due to coronary ischemia following the arterial switch procedure. Now the mortality for an arterial switch procedure in D-transposition of the great vessels
is less than 5%. The arterial switch procedure must be done shortly after birth before the left ventricle deconditions as it is pumping against pulmonary vascular resistance rather than systemic vascular resistance. These children with D-transposition of the great vessels are now repaired in the first couple weeks of life and are no longer at risk for stroke. Advances in cardiovascular surgery have significantly decreased the risk of stroke in tetralogy of Fallot and D-transposition of the great vessels. Children having congenital heart disease now facing higher risks of stroke are those with single-ventricle physiology. Fifteen to twenty years ago, children having single-ventricle physiology all did poorly and did not survive long. We are now much better able to palliate them. These lesions include hypoplastic left heart syndrome, tricuspid atresia, pulmonary atresia with an intact ventricular septum, and an unbalanced atrioventricular canal with hypoplasia of either the right or the left ventricle. These lesions all have significant right-to-left intracardiac shunting leading to the risk of stroke and are all eventually palliated by the Fontan procedure. The Fontan procedure in essence consists of routing the systemic blood flow from the body (inferior vena cava and superior vena cava) directly to the pulmonary arteries. The pulmonary venous return enters the left atrium and flows into the functional single ventricle (either morphologic right or left ventricle), which pumps into the systemic circulation. The Fontan procedure works only if the pulmonary vascular resistance is low and the systemic ventricle has normal function. Since the newborn infant is born with high pulmonary vascular resistance, the Fontan procedure cannot be done until several months of age, after the pulmonary vascular resistance has dropped. This necessitates a systemic-to-pulmonary artery shunt (eg, Blalock Taussig type shunt) be done shortly after birth. With the systemic to pulmonary shunt, the systemic arterial saturations are typically in the 70 to 80% range. The right-to-left shunting in these patients makes them at risk for an embolic stroke. At the time of the completion of the Fontan procedure, it was demonstrated that fenestration of the baffle significantly improved surgical outcomes by decreasing pleural effusions, shortening hospital length of stay, and decreasing the need for additional postoperative procedures.27 The fenestration is performed by the cardiovascular surgeon punching a 2.5 to 3.0 mm hole in the baffle patch, allowing a small intracardiac right-to-left shunt. This decompresses the pulmonary circulation, allowing it to adapt to the low pressure of the systemic venous flow. This improved cardiac output comes at the expense of a small intracardiac right-to-left shunt at the atrial level. This small right-to-left intracardiac shunting unfortunately still may place these children at an increased risk for the development of a stroke. These children are typically treated with low-dose aspirin (5
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mg/kg/d) as an antiplatelet drug. It has yet to be shown in a randomized clinical trial whether these children would be better protected against a stroke by the use of warfarin. We studied 164 patients at Riley Children’s Hospital having undergone either a Fontan or hemi-Fontan palliation between January 1, 1988 and December 1, 2000. Eleven strokes occurred in nine patients (9/164, 5.5%). Two patients died; four had severe neurologic residua; one has mild neurologic residua; and two are normal neurologically. Previous pulmonary artery banding (P ⫽ 0.006) was associated with an increased risk for stroke. This finding was also noted by Oski and coworkers.28 Ventricular morphology (P ⫽ 0.999) and fenestration (P ⫽ 0.718) were not statistically associated with an increased risk of stroke. One of our patients, having had a previous pulmonary artery banding and subsequent Fontan procedure, presented with an acute right middle cerebral infarction documented by magnetic resonance angiography. She successfully underwent thrombolytic therapy within 3 hours of onset and is doing extremely well clinically while maintained on warfarin. Since stroke is not commonly seen in children, the diagnosis is often delayed at the referring institution and the children present to the tertiary care hospital beyond the time frame that allows for good salvage with thrombolysis. Coarctation of the Aorta A strong association has been noted between cerebral vascular disease, intracranial aneurysms, and congenital heart disease.14 This is not surprising as the muscular arteries of the head and neck are derived from the neural crest as are the cardiac conotruncus and aortic arch. The prevalence of intracranial aneurysms in patients having coarctation of the aorta has been estimated to be as low as 2.5% to as high as 50%.29 The presence of systemic hypertension has been proposed as a contributing cause of rupture of these aneurysms. With earlier repair being performed, the frequency of stroke has decreased but has not been eliminated. Even with a good surgical repair of the coarctation, the aorta remains abnormal at the coarctation site. There is at least scar tissue at the repair if not residual narrowing. Recurrent hypertension is common despite successful repair of coarctation and is a major risk for the development of cardiovascular morbidity.30 This residual narrowing may not cause a significant resting gradient but may create an increasing gradient with activity or exercise. It is not uncommon to have a resting gradient of 10 to 15 mm Hg, whereas the gradient with maximal exercise stress testing may approach 40 to 50 mm Hg. These patients cause us great consternation as pediatric cardiologists. The low resting gradient prevents the development of significant collateral arterial blood flow to protect the spinal cord if a surgical repair
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is again attempted. The risk of vascular insult to the spinal cord is about 2%. Evoked potentials are monitored in the lower extremities during all coarctation repairs to help minimize this complication. As improved balloon angioplasty catheters and stents are developed, we may find these patients better helped in the cardiac catheterization laboratory rather than the operating room suites. Only time will tell which procedure is better. Patients having a previous coarctation repair should have their right-arm blood pressures measured yearly. It is important to use the right-arm blood pressure, as many have previously undergone a left subclavian flap angioplasty, an end-to-end, or Dacron patch repair proximal to the left subclavian artery. Thus the left-arm blood pressure may not be accurate and may underestimate the degree of systemic hypertension. Persistent systemic hypertension predisposes these patients to subsequent stroke and/or myocardial infarction. Bacterial Endocarditis Acute and subacute bacterial endocarditis remains a problem. Bacterial endocarditis is more common in cyanotic congenital heart defects and in lesions that cause turbulence (stenotic lesions). The risk for embolization of these vegetation fragments is related to the particular bacterial pathogen as well as the location of the vegetation. Left-sided vegetations on the mitral or aortic valves are at risk of embolization to the head, whereas rightsided vegetations do not predispose to stroke or cerebral abscess unless there is intracardiac right-to-left shunting. A septic embolus to the brain may also lead to a brain abscess. Treatment of bacterial endocarditis is based on bacterial antibiotic sensitivities as well as the patient’s homodynamic stability. Pulmonary Arteriovenous Fistulas Pulmonary arteriovenous fistulas (PAVF) or pulmonary arteriovenous malformations (PAVM) have been associated with cyanotic congenital heart defects requiring the Fontan palliation (eg, tricuspid atresia, pulmonary atresia, hypoplastic left heart syndrome, and asymmetric atrioventricular canal). These are thought to be related to abnormal systemic venous return in which the hepatic venous return bypasses the pulmonary artery circulation. PAVF have also been associated with hereditary hemorrhagic telangiectasia (also known as Rendu–Osler–Weber syndrome). In some of these patients, neurologic symptoms such as headache, seizures, hemiplegia, brain abscesses, transient ischemic attacks, and stroke dominate the clinical picture. Approximately 37% of these patients having PAVF are at risk for paradoxic embolization leading to transient ischemic at-
204 Seminars in Cerebrovascular Diseases and Stroke Vol. 3 No. 4 December 2003 tacks or stroke.31 The annual risk for stroke is approximately 1.5% per year among patients with these lesions. Arrhythmias The major cardiac arrhythmia that predisposes a patient to cerebral emboli is atrial flutter or fibrillation. In adults, 11% of octogenarians suffer from atrial fibrillation due to chronic left atrial enlargement.32 In children, we also see atrial flutter-fibrillation due to chronic left or right atrial dilation. It is common to have the rhythm spontaneously change back and forth from flutter to fibrillation in children. Lesions that predispose to the development of atrial flutter-fibrillation include mitral regurgitation, mitral stenosis, Fontan procedure, or a cardiomyopathy. These patients are commonly treated with antiarrhythmic medications or ablation procedures. There have been no controlled studies in children on the prevention of stroke in association with atrial flutterfibrillation; however, studies in adults have shown benefit in the prevention of secondary stroke with the use of antiplatelet drugs and anticoagulation.33,34 The American Heart Association, American College of Cardiology, and the European Society of Cardiology issued practice guidelines for the management of patients with atrial fibrillation.35 Cardiomyopathy Children may have three distinct types of cardiomyopathies: dilated congestive, hypertrophic obstructive, and restrictive cardiomyopathies. Patients having a hypertrophic obstructive or restrictive cardiomyopathy are not at great risk for stroke; however, patients having a dilated congestive cardiomyopathy are at significant risk for the development of a stroke due to stasis of blood within the heart. These patients are treated vigorously with anticongestive measures including digoxin, diuretics, angiotensin converting enzyme inhibitors, beta blockers, dobutamine, dopamine, cyclic AMP phosphodiesterase inhibitors, and even implantable ventricularassist devices. Our goal, if possible, is to maintain cardiac function with oral medications such that the patients have few if any symptoms. If their ventricular function deteriorates, we then proceed to intravenous agents. If they cannot be supported on intravenous medications, we then consider an implantable ventricular assist device if they are a transplant candidate. As the left ventricle becomes more dilated with worsening systolic and diastolic function, the risk of a mural thrombus formation increases. Patients with a mild or moderate decrease in left ventricular systolic function are treated with antiplatelet doses of aspirin at 5 to 10 mg/kg/d. As the left ventricular systolic function worsens, or if a mural thrombus is noted by echocardiography, warfarin or hep-
arin is then used. If the patient requires a ventricularassist device to be implanted, full anticoagulation with heparin is imperative. The development of a significant cerebrovascular accident in a patient on the UNOS waiting list for a heart transplant would preclude their being a transplant candidate due to the extreme shortage of donor candidates. Even a minor stroke would increase the posttransplant risk for seizures with the use of calcineuron inhibitors such as cyclosporine or tacrolimus for the prevention of acute cellular rejection. Patent Foramen Ovale Patent foramen ovale is found by autopsy in 34.3% in the first three decades of life and decreases to 20.2% by the ninth decade.36 A patent foramen ovale is obviously present in all newborns and then the flap between the primum and secundum septae begins closing. A study in adults utilizing contrast transthoracic echocardiography found the incidence of patent foramen ovale to be 40% in those who had an ischemic stroke.37 In a clinical series using transthoracic echocardiography the prevalence of a patent foramen ovale in patients without a stroke was 10 to 18%.38 With the increasing use of intraoperative transesophageal echocardiography, the frequency of a patent foramen ovale was reported at 26% in patients who had not had a stroke.39 Thus the frequency of a patent foramen ovale discovered by transesophageal echocardiography approaches the incidence noted by autopsy. A paradoxic embolism refers to embolic entry of a venous thrombus into the systemic circulation via a right-to-left shunt. In the absence of a cyanotic congenital heart defect, paradoxic emboli could occur if there were a deep vein thrombus and presence of a favorable pressure gradient to promote a right-to-left shunt across the patent foramen ovale. Normally any shunting at the atrial level is left to right due to the increased compliance of the right ventricle and low pulmonary vascular resistance. For a right-to-left shunt to occur, there would need to be either elevated pulmonary vascular resistance or a significant increase in intrathoracic pressure such as caused by a Valsalva maneuver, cough, defecation, or micturition. Children being evaluated for an embolic stroke should have a contrast echocardiographic study done with a Valsalva maneuver. A higher frequency of detecting a patent foramen ovale in adults was noted by transesophageal versus transthoracic echocardiography. Adults, in general, have much poorer transthoracic echocardiographic windows than children. No controlled similar studies have been reported in children to date. In most children, transthoracic echocardiography with contrast and a Valsalva maneuver is sufficient to exclude an intracardiac right-to-left shunt. If the images are insufficient (eg, due to thoracic abnormalities, lung hyperexpansion, obesity, or insufficient patient cooperation),
Strokes and Heart Disease in Children ●
then a sedated transesophageal echocardiographic study may be indicated to rule out a potential source for a paradoxic embolus. If a patent foramen ovale with rightto-left shunting has been shown in a patient with a previous embolic stroke, consideration should be made for closure in the cardiac catheterization laboratory by an experienced physician. Over the past 18 months, we have closed over 60 atrial septal defects in the cardiac catheterization laboratory. Twenty-two of these were in patients having a patent foramen ovale and a previous stroke. It is still unproven whether or not this will completely eliminate the risk of further stroke in these patients. Prevention of Recurrent Stroke in Children
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Until Kirkham’s article on stroke in children in 1999,11 ischemic strokes in children were thought to have a good prognosis and a low recurrence rate. The previous assumption that management would not significantly alter outcomes resulted in failure to prospectively evaluate pediatric stoke patients in a controlled manner. Stra¨ ter and coworkers40 evaluated 135 consecutive German children between the ages of 6 months and 18 years who presented with first episode of ischemic stroke. These patients were prospectively assigned to either aspirin or low molecular weight heparin in a nonrandomized fashion. The study endpoint was recurrent stroke. Recurrent stroke was noted in 9.6% (13/135) at a median time of 5 months (range 2-13 months). No significant difference was noted with respect to antithrombotic medication used. Neither aspirin nor low molecular weight heparin was superior to the other. During the study period no patient in the aspirin group developed hemorrhage, allergic reactions, Reye syndrome, or gastrointestinal symptoms. The low molecular weight heparin patient group experienced neither heparin-induced thrombocytopenia nor local or systemic hemorrhage. Even with these efforts at secondary prevention, recurrent stroke was diagnosed in 6.7% of the children with stroke of cardiac origin. Further randomized trials of adequate size are clearly needed to elucidate reliable information on safety and efficacy for the prevention of recurrent stroke with antithrombotic medications in children.
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