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Structural evidence of injury or malformation in the brains of children with congenital heart disease
S t r u c t u r a l E v i d e n c e of I n j u r y or M a l f o r m a t i o n in the B r a i n s of C h i l d r e n W i t h C o n g e n i t a l H e a r t D i s e a s e Geoffrey Miller and Hannes Vogel Neurological and developmental deficits are common in children with congenital heart disease (CHD). These are due to multiple factors that include the etiology of the CHD, the effects of abnormal cardiovascular function, and the possible sequelae of open heart surgery. CHD is frequently part of a multiple malformation syndrome that includes the brain. The causes of these syndromes include known or putative genetic defects. Abnormal cardiovascular function may be associated with poor brain growth, embolic infarction, cerebrovascular thrombosis, and abscess formation. Perioperative neurological complications include diffuse hypoxic-ischemic injury (particularly in neonates who undergo more than 45 to 60 minutes of hypothermic circulatory arrest), cerebral macro- and micro-emboli, dural sinus thrombosis, and cerebral hemorrhage. Neuroimaging, especially magnetic resonance imaging, is a useful prognostic instrument, can easily display gross congenital and acquired lesions, and should be performed preoperatively in addition to genetic studies. In some instances poor brain function may not be predicted unless slow head growth or microcephaly is present and thorough preoperative neurodevelopmental evaluation is encouraged. Copyright 9 1999 by W.B. Saunders Company
LTHOUGH GREAT advances have been made in the reduction of mortality and morbidity in children with congenital heart disease (CHD), there remains an association with a significant incidence of neurological and developmental disorders. These include seizures, cerebral palsy, chorea, cognitive dysfunction and learning, and neuropsychiatric disorders.l,2 The causes of these neurodevelopmental disorders are complex and are related to multiple factors, such as the cause of the CHD itself; neurological consequences of CHD before any surgery; and complications that occur during and after surgical management. Evidence of this brain involvement may be found from neuroimaging and neuropathological studies. 3 This evidence includes developmental malformations, embolism and hemorrhage, hypoxic-ischemic injury, infection, venous thrombosis, and poor brain growth (Fig 1). It is clear that the immature brain is especially dependent on normal cardiovascular function, and CHD poses a number of significant risks to normal development. Structural abnormalities of the brain may result as part of a spectrum of other congenital malformations including CHD, and through a host of acquired phenomena in both the natural course of CHD or its surgical management. The significance of either phenomenon lies in the fact that
A
From the Departments of Pediatrics and Pathology, Baylor College of Medicine, Houston, TX. Address reprint requests" to Geoffrey Miller, MD, Pediatric Neurology Section, Texas Children ~ Hospital, 6621 Fannin St, MC 3-3311, Houston, TX 77030. Copyright 9 1999 by W.B. Saunders Company 1071-9091/99/0601-0004510.00/0 20
neurological disease represents the single most important determinant of extra cardiac morbidity and mortality in CHD. Any assessment of the occurrence of neuropathological sequelae in children with CHD most likely will fall short of the actual incidence. Neurological manifestations of either congenital or acquired lesions may be clinically apparent or over-shadowed by serious complications, often multisystemic, of CHD and of its surgical management. Furthermore, in our experience, there are a disproportionately high incidence of autopsies limited to the chest or heart only, preventing a fuller understanding of both gross and subtle neuropathological findings in CHD. CONGENITAL CAUSES OF BRAIN DISORDER Many children with CHD have a genetic defect and even in those without a demonstrable chromosomal, single gene, or contiguous gene defect, extracardiac anomalies are more frequent than in the general population. Central nervous system (CNS) dysfunction is more common in patients with both cardiac and extracardiac anomalies. 4-8 Certain syndromes predictably involve the heart and CNS. Many of these are associated with chromosomal and gene defects, some of which are listed in the Table 1. The most common association is found in children with trisomy 21. The gross structural changes of the brain in Down's syndrome consist of a narrow superior temporal gyrus, a disproportionately small cerebellum and brainstem, and other morphological abnormalities imposed by the altered bony structure of the cranial cavity. None of these changes account for the mental Seminars in Pediatric Neurology, Vol 6, No 1 (March), 1999: pp 20-26
NEUROPATHOLOGY OF CONGENITAL HEART DISEASE
21
myotonic muscular dystrophy, and some mitochondrial disorders and defects of beta oxidation of fatty acids. It is probable that adverse teratogenic events occurring during early pregnancy may also affect the development of both the brain and heart. However, the exact relationship between this occurrence and specific teratogens remains unclear. An exception to this is the viral teratogen rubella, which causes an embryopathy characterized by CHD, such as patent ductus arteriosus, atrial and ventricular septal defects, and pulmonary artery stenosis, in addition to varying levels of cognitive dysfunction often associated with microcephaly. Fig 1. Intrauterineand postnatallyacquired neuropathological changes in CHD. Coronal section of brain from a 2-monthold infant born at 38 weeks' gestation, with intrauterine growth retardation who underwent repair of esophageal atresia and tracheoesophageal fistula, coarctation of aorta, VSD repair, and closure of PFO. Then the infant developed superior vena cava (SVC) syndrome and underwent thrombectomy from SVC and right atrium followed by eventual renal failure. Autopsy revealed systemic CMV infection. Brain examination showed micrencephaly. Note enlargement of the lateral ventricles bilaterally and the third ventricle, attesting to possible intrauterine damage to developing white matter, and severe periventricular leukomalacia (arrow) and superimposed superior sagittal sinus thrombosis.
retardation found in Down's syndrome, which is thought to be due to abnormalities in dendritic morphology and function. 9 Many cases of CHD with or without congenital brain involvement do not necessarily have a multifactorial cause. Velocardiofacial, DiGeorge, and the CATCH 22 syndromes are due to deletions of chromosome 22q11. 28 Dominantly inherited supravalvar aortic stenosis and sporadic Williams syndrome are due to gene deletion at the elastin gene locus on chromosome 7. 29 It has been reported that deletions of 22qll may be involved in 5% of all newborns with heart defects. 3~ Microcephaly occurs in 40% of individuals with a 22ql 1 deletion and learning difficulties occur in essentially 100%, with mild to moderate mental retardation in 40% to 50%. 31 Psychiatric disorders develop in 10% to 22%. Brain anomalies are also common and include a small vermis and posterior fossa, cysts adjacent to the anterior horns, dysgenesis of the corpus callosum, focal white matter hyperintensities on Tz-weighted magnetic resonance imaging, and anomalies of the internal carotid arteries. 11,12 Other examples of gene defects that affect both brain and heart include the dystrophinopathies,
A C Q U I R E D C A U S E S OF BRAIN D I S O R D E R
Before the use of open heart surgery for the surgical management of CHD in children acquired neurological complications were common, occurring in about 25%. 32,33Severe cyanosis and polycythemia may lead to gradual deterioration of cerebral function and an increased risk of stroke or abscess. However, these neurological risks can be improved by early surgical correction. 34 Without this correction, children with CHD may have significant brain injury from cerebral venous thrombosis, thromboembolism and infarction, abscesses, mycotic aneurysms, and hypoperfusion. 32-35 These risks may still exist regardless of surgery if there is continuing cyanosis, hypoperfusion, right-to-left shunting of blood, and any abnormal cardiac or vascular surface that might provide a thromboembolic source. 3 The advent of increasingly sophisticated surgical techniques has expanded the spectrum of acquired sequelae, at the same time altering the incidence of complications related to the natural history of CHD, which was previously not surgically manageable. Since the technique of profound hypothermia and circulatory arrest was introduced more than 40 years ago, there have been spectacular improvements in the surgical management of CHD, which has enabled correction of complex heart defects early in life. 36,3~ Although most children Who undergo the procedure have an uneventful neurological outcome, there is significant morbidity in some. Factors that affect this outcome include profound hypothermic circulatory arrest for more than 45 to 60 minutes and perioperative embolic cerebrovascular events (Fig 2). Neuropathological studies performed on children who have died
22
MILLER AND VOGEL Table 1. Some Congenital Syndromes That Involve Both Brain and Heart Syndrome
Trisomy 13 Trisomy 18
Trisomy 21
Trisomy 9 and trisomy 9 mosaic 22q 11-deletion syndrome (CATCH 22, Velocardiefacial, DiGeorge)
Williams syndrome
Hydrolethalus syndrome
Miller-Dieker syndrome
PHACE syndrome Ritscher-Schinzel syndrome (craniocerebello-cardiac syndrome, 3C syndrome) VACTERL association with hydrocephalus Steinfeld syndrome Acrocallosal syndrome Cardio-facial-cutaneous syndrome Ellis-van Creveld syndrome
Congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD syndrome) Deletion or duplication of (2) (q31q33)
Heart Defect:
Brain Anomaly
ASD, VSD, coarctation of aorta
Holoprosencephaly, cerebellar heterotopias, microscopic neuronal dysplasias ASD, VSD Gyral and lobar anomalies, hypoplastic pontine gray matter, cerebellar hypoplasia, microscopic neuronal dysplasias Endocardial cushion defects, VSD, ASD, Dendritic abnormalities,9 small superior PDA, aberrant subclavian artery temporal gyrus, small cerebellum and brainstem ASD, VSD, complex malformations Dandy-Walker malformation, agenesis of corpus callosum 10 Conotruncal defects Small vermis, small posterior fossa, cysts adjacent to anterior horns, white matter hyperintensities seen on T2 weighted MRI, anomalies of internal carotid arteries11,12 Supravalvular aortic stenosis, Microcephaly, abnormal neuronal cytoarperipheral pulmonary artery chitecture, cerebrovascular stenoses13,14 stenosis, pulmonary valve stenosis AV canal defects Prenatal onset hydrocephalus, absent corpus callosum and septum pellucidum, abnormal gyration ~5 Tetralogy of Fallot, VSD, pulmonary ste- Lissencephaly, pachygyria, dysgenesis of nosis (these are only occasional corpus callosum ~6 associations) Coarctation of the aorta Dandy-Walker malformation ~7 ASD, VSD Dandy-Walker malformation 18
VSD and other cardiac defects Pentalogy of Fallot ASD, VSD, pulmonary valve abnormalities ASD, pulmonary stenosis Usually ASD of ostium primum or secundum type, single atrium, Ebstein anomaly ASD, VSD, single ventricle, single coronary ostium
Aqueductal stenosis and hydrocephalus16 Holoprosencephaly19 Dysgenesis of corpus callosum, megalencephaly20 Hydrocephalus, cortical atrophy, frontal lobe hypoplasia, small brainstem 2~ Dandy-Walker malformation, heterotopias22
Ipsilatera( hypoplasia of brain, cranial nerves, spinal cord 23
Pulmonary artery stenosis, ASD, Ventriculomegaly, gyral and lobar anomacoarctation of aorta, total anomalous lies, dysgenesis of corpus callosum, optic pulmonary venous return nerve hypoplasia, hydrocephalus, fusion of quadrigeminal bodies24 4p-(Wolf-Hirschhorn syndrome) VSD, ASD Microcephaly, dysgenesis of corpus callosum 2s Recombinant aneusomy of chromosome 5 Tetralogy of Fallot Holoprosencephaly with premaxillary associated with severe congenital malforagenesis26 mations Craniosyostosis-radial aplasia (BallerPolymicrogyria, hydrocephalus27 Subaortic valvular hypetrophy, VSD, Gerold) syndrome Tetralogy of Fallot CHARGE association Tetralogy of Fallot, double outlet right Arhinencephaly, facial palsy, mental retarventricle with common AV canal, dation 16 ASD, VSD, right sided aortic arch Xp21 linked dystrophinopathy Cardiomyopathy Unknown Myotonic dystrophy Cardiomyopathy Ventriculomegaly, abnormal white matter signals seen with MRI Friedreich ataxia Cardiomyopathy Spinal cord atrophy particularly involving posterior columns; occasional cerebellar atrophy
NEUROPATHOLOGY OF CONGENITAL HEART DISEASE
23
Fig 2. Neuropathology of small embolic infarctions. Resolving infarction (arrows) in the internal capsule and border of caudate nucleus in a 14-month-old girl with complex congenital heart disease, having undergone repair 2 weeks before death. The infarct is showing early features of organization. Microscopy indicated an age consistent with onset in the perioperative period.
following open heart surgery have reported ischemic lesions and infarcts along arterial border zones and hemorrhage in both gray and white matter. 38 Furthermore, cardiopulmonary bypass in adult humans and dogs is associated with many focal dilatations or small aneurysms in terminal cerebral arteries and capillaries that may be sites of gas bubbles or fat emboli. 39 These microemboli arise from air, fibrin, fat, cellular debris, platelet,
Fig 3. Infant aged 6 months with spastic quadriplegia who underwent prolonged hypothermic circulatory arrest. Coronal Tl-weighted scan at level of basal ganglia shows diffuse widening of cortical sulci and ventriculomegaly. Basal ganglia show high signal intensity (arrows).
Fig 4. Child aged 3 years who underwent prolonged hypothermic circulatory arrest at age 10 days and 28 months and has asymmetric spastic diplegia and an IQ of 68. Axial Tl-weighted image shows asymmetric bilateral low signal intensity in the region of the medial occipital lobe (arrows) and bilateral atrial dilation associated with atrophy.
Fig 5. Large embolic infarction. The patient was a 25-yearold woman with congenital tricuspid atresia who underwent initial repair in infancy, and further repair at age 10 years. Patient died after complications following correction of stenotic and thrombosed anastomosis. Note large right cortical and subcortical cystic infarct with white matter atrophy, characteristic of a remote embolic event involving a branch of the right middle cerebral artery.
24
Fig 6. Adolescent aged 15 years, who underwent cardiopulmonary bypass with hypothermic circulatory arrest at age 9 years, has a normal neurological examination result, and an IQ of 111. Axial Tl-weighted scan shows wedge-shaped low signal intensity involving gray and white matter of right parietal lobe consistent with focal infarction (arrow).
Fig 7. Incidental developmental malformation in a 4-monthold male infant with meconium aspiration syndrome, severe lung disease with ventilator dependency, tracheomalacia, bronchomalacia, and a VSD. Close inspection of the angle of the lateral ventricle indicates nodular ectopic gray matter (arrows). The brain also showed decreased brain weight for age, recent hypoxic/ischemic injury of neurons, and microscopic hemorrhages.
MILLER AND VOGEL
Fig 8. Child aged 9 years with mild truncal ataxia and hyperreflexia and no dysmorphic features who underwent hypothermic low flow cardiopulmonary bypass for 40 minutes at age 5 years. Axial T2-weighted image shows unsuspected heterotopic gray matter.
and leukocyte aggregates, or from material aspirated by a cardiotomy sucker or torn from surfaces of the perfusion system.4~Despite careful de-airing procedures, cerebral air emboli often occur, especially during redistribution of blood from the bypass machine to the patient when the heart is again beginning to beat actively.41,42 It is an established observation that acute brain damage secondary to hypoxia-ischemia is prevented or reduced by prior hypothermia.43 This protection lessens after 45 minutes of profound hypothermic circulatory arrest, particularly in neonates. 1,2,44-46The possible neurological sequelae of this loss of protection include cerebral palsy and cognitive dysfunction,2 and neuroimaging may demonstrate basal ganglia change, diffuse white matter loss with cortical thinning (Fig 3), and focal cortical infarcts (Fig 4). The longer the duration of hypothermic circulatory arrest the more likely the presence of abnormal diffuse MRI change. 3 One recent study reported that brain magnetic resonance imaging (MRI) on children who undergo cardiopulmonary bypass with profound hypothermia can be
NEUROPATHOLOGY OF CONGENITAL HEART DISEASE
a useful prognostic instrument. 3 In this study it was shown that those with a normal MRI following surgery also had a normal IQ and neurological examination; focal infarction without diffuse change may be clinically silent (Figs 5 and 6); and that unsuspected cerebral dysgenesis may be revealed and provide an explanation for an accompanying neurodevelopmental deficit (Figs 7 and 8). Neuroimaging may also supply evidence for preoperative brain insult or morphological change. McConnell et al47 performed brain MRI on 15 children aged 17 days to 9 years before cardiopulmonary bypass surgery and 5 days to 4 weeks after operation. In a third of their study patients they found preoperative ventriculomegaly, generous subarachnoid spaces, and in one patient evidence of infarction. It may not
25
be feasible clinically to perform preoperative MRI, or even computed tomography, on extremely medically fragile infants. However, if the anterior fontanel is patent, cranial ultrasonography is a useful technique. In a prospective study on full-term infants with CHD, 1 cranial ultrasonography was performed before, and on more than one occasion, after open heart surgery. The results revealed abnormalities in 27%, and in more than half of these abnormal findings were present before operation. Preoperative abnormal findings included branching thalamic echodensities, multiple periventricular cystic change, and ventriculomegaly. Postoperative findings included an increase in ventricular size, and changes consistent with focal hemorrhage and infarction.
REFERENCES 1. Miller G, Eggli KD, Contant C, et al: Postoperative neurologic complications after open heart surgery on young infants. Arch Pediatr Adolesc Med 149:764-768, 1995 2. Miller G, Tesman JR, Ramer JC, et al: Outcome after open-heart surgery in infants and children. J Child Neurol 11:49-53, 1996 3. Miller G, Mamourian AC, Tesman JR, et al: Long-term MRI changes in brain after pediatric open heart surgery. J Child Neurol 9:390-397, 1994 4. Murugasa B, Yip WCL, Tay JSH, et al: Sonographic screening for renal tract anomalies associated with congenital heart disease. J Clin Ultrasound 18:79-83, 1990 5. Glauser TA, Rorke LB, Weinberg PM, et al: Congenital brain anomalies associated with the hypoplastic left heart syndrome. Pediatrics 85:984-990, 1990 6. Rosenthal GL, Wilson PD, Permutt T, et al: Birth weight and cardiovascular malformations: A population-based study. Am J Epidemiol 133:1273-1281, 1991 7. Jones M: Anomalies of the brain and congenital heart disease: A study of 52 necropsy cases. Ped Pathol 11:721-736, 1991 8. Greenwood RD, Rosenthal A, Parisi L, et al: Extracardiac abnormalities in infants with congenital heart disease. Pediatrics 55:485-492, 1975 9. Ramer JC: Trisomy 21, in Miller G, Ramer JC (eds): Static Encephalopathies of Infancy and Childhood. New York, Raven Press, 1992, pp 143-159 10. Williams T, Zardawi I, Quaife R, et al: Complex cardiac malformation in case of trisomy 9. J Med Genet 22:230-233, 1985 11. Milnick RJ, Bello JA, Shprintzen RJ: Brain anomalies in velo-cardio-facial syndrome. Am J Med Genet 54:100-106, 1994 12. MacKenzie-Stepner K, Witzel MA, Stringer DA, et al: Abnormal carotid arteries in the velocardiofacial syndrome: Report of three cases. Plast Reconstr Surg 80:347-351, 1987 13. Galaburda AM, Wang PR Bellugi U, et al: Cytoarchitec-
tonic anomalies in a genetically based disorder: Williams syndrome. Neuroreport 5:753-757, 1994 14. Ramer JC, Miller G: Other multiple congenital anomaly syndromes, in Miller G, Ramer JC (eds): Static Encephalopathies of Infancy and Childhood. New York, Raven Press, 1992, pp 197-218 15. Salonen R, Herva R: Hydrolethalus syndrome. J Med Genet 27:756-760, 1990 16. Jones KL: Smith's Recognizable Patterns of Human Malformation. Philadelphia, WB Saunders, 1997 17. Frieden IJ, Reese V, Cohen D: PHACE syndrome: The association of posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. Arch Dermatol 132:307-311, 1996 18. Orstavik KI-I, Bechensteen AG, Fugelseth D, et al: Sibs with Ritscher-Schinzel syndrome and anal malformations. Am J Med Genet 75:300-303, 1998 19. Nothen MM, Knopfle G, Fodisch HJ, et al: Steinfeld syndrome: Report of a second family and further delineation of a rare autosomal dominant disorder. Am I Med Genet 46:467-470, 1993 20. Schinzel A: The acrocallosal syndrome in first cousins: Widening of the spectrum of clinical features and further support for autosomal recessive inheritance. J Med Genet 25:332-336, 1988 21. Sabatino G, VerrottiA, Domizio S, et al: The cardio-faciocutaneous syndrome: A long-term follow up of two patients, with special reference to the neurological features. Childs Nerv Syst 13:238-241, 1997 22. Zangwill KM, Boal DK, Ladda RL: Dandy-Walker malformation in Ellis van Creveld syndrome. Am J Med Genet 31:123-129, 1988 23. Herbert AA, Esterly NB, Holbrook KA, et al: The CHILD syndrome: Histologic and ultrastructural studies. Arch Dermato123:503-509, 1987 24. Ramer JC, Mowrey PN, Robins DB, et at" Five children with del(2)(q31q33) and one individual with dup(2)(q31q33)
26
from a single family: Review of brain, cardiac, and limb malformations. Am J Med Genet 37:392-400, 1990 25. Thies U, Back E, Wolff G, et al: Clinical, cytogenetic and molecular investigations in three patients with Wolf-Hirschhorn syndrome. Clin Genet 42:201-205, 1992 26. Schroeder HW, Forbes S, Mack L, et al: Recombination aneusomy of chromosome 5 associated with severe congenital malformations. Clin Genet 30:285-292, 1986 27. Ramas-Fuentes FJ, Nicholson L, Scott CI: Phenotypic variability in the Baller-Gerold syndrome: Report of a mildly affected patient and review of the literature. Eur J Pediatr 153:483-487, 1994 28. Payne RM, Johnson MC, Grant JW, et ah Toward a molecular understanding of congenital heart disease. Circulation 91:494-504, 1995 29. Ewart AK, Morris CA, Atldnson D, et al: Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat Genet 5:11-16, 1993 30. Glover TW: CATCHing a break on 22. Nat Genet 10:257-258, 1995 31. Thomas JA, Graham JM: Chromosome 22qll deletion syndrome: An update and review for the primary pediatrician. Clin Pediatr 5:253-286, 1997 32. Terplan KL: Patterns of brain damage in infants and children with congenital heart disease. Am J Dis Child 125:175188, 1973 33. Tyler HR, Clark DB: Incidence of neurological complications in congenital heart disease. Arch Neurol Psychiatr 77:1722, 1957 34. Newburger JW, Silbert AR, Buckley LP, et al: Cognitive function and age at repair of transposition of the great arteries in children. N Engl J Med 310:1495-1499, 1984 35. O'Dougherty M, Wright FS, Loewenson RB, et al: Cerebral dysfunction after chronic hypoxia in children. Neurology 53:42-46, 1985 36. Niazi SA, Lewis FJ: Profound hypothermia: Report of a case. Ann Surg 147:264-266, 1957
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37. Hoffman JI: Congenital heart disease: Incidence and inheritance. Pediatr Clin North Am 37:25-43, 1990 38. Ferry PC: Neurologic sequelae of open heart surgery. Am J Dis Child 144:369-373, 1990 39. Moody DM, Bell MA, Challa VR, et al: Brain microemboll during cardiac surgery or aortography. Ann Neurol 28:4748, 1990 40. Stephenson LW, Edmunds LH: Cardiopulmonary bypass for open heart surgery, in Bauer AE, Geh AS, Hammond GL, et al (eds): Glenn's Thoracic and Cardiovascular Surgery. Norwalk, CT, Appleton & Lange, 1991, pp 1397-1411 41. Van der Linden J, Casamir-Ahn H: When do cerebral emboli appear during open heart operations? A transcranial Doppler study. Ann Thorac Surg 51:237-241,1991 42. Padayachee TS, Parsons S, Theobald R, et al: The detection of microemboli in the middle cerebral artery during cardiopulmonary bypass: A transcranial Doppler ultrasound investigation using membrane and bubble oxygenators. Ann Thorac Surg 44:298-302, 1987 43. Hickey PR, Anderson NP: Deep hypothermic circulatory arrest: A review of pathophysiology and clinical experience as a basis for anesthetic management. J Cardiothorac Anesth 1:137155, 1987 44. Wells FC, Coghill S, Caplan HL, et al: Duration of circulatory arrest does influence the psychological development of children after cardiac operation in early life. J Thorac Cardiovasc Surg 86:823-831, 1983 45. O'Dougherty M, Wright FS, Garmezy N, et al: Later competence and adaptation in infants who survive severe heart defects. Child Dev 54:1129-1142, 1983 46. Miller G, Rodichok LD, Baylen BG, et al: EEG changes during open heart surgery on infants aged 6 months or less: Relationship to early neurologic morbidity. Pediatr Neurol 10:124-130, 1994 47. McConnell JR, Fleming WH, Chu K, et al: Magnetic resonance imaging of the brain in infants and children before and after cardiac surgery. Am J Dis Child 144:374-378, 1990
LTHOUGH GREAT advances have been made in the reduction of mortality and morbidity in children with congenital heart disease (CHD), there remains an association with a significant incidence of neurological and developmental disorders. These include seizures, cerebral palsy, chorea, cognitive dysfunction and learning, and neuropsychiatric disorders.l,2 The causes of these neurodevelopmental disorders are complex and are related to multiple factors, such as the cause of the CHD itself; neurological consequences of CHD before any surgery; and complications that occur during and after surgical management. Evidence of this brain involvement may be found from neuroimaging and neuropathological studies. 3 This evidence includes developmental malformations, embolism and hemorrhage, hypoxic-ischemic injury, infection, venous thrombosis, and poor brain growth (Fig 1). It is clear that the immature brain is especially dependent on normal cardiovascular function, and CHD poses a number of significant risks to normal development. Structural abnormalities of the brain may result as part of a spectrum of other congenital malformations including CHD, and through a host of acquired phenomena in both the natural course of CHD or its surgical management. The significance of either phenomenon lies in the fact that
A
From the Departments of Pediatrics and Pathology, Baylor College of Medicine, Houston, TX. Address reprint requests" to Geoffrey Miller, MD, Pediatric Neurology Section, Texas Children ~ Hospital, 6621 Fannin St, MC 3-3311, Houston, TX 77030. Copyright 9 1999 by W.B. Saunders Company 1071-9091/99/0601-0004510.00/0 20
neurological disease represents the single most important determinant of extra cardiac morbidity and mortality in CHD. Any assessment of the occurrence of neuropathological sequelae in children with CHD most likely will fall short of the actual incidence. Neurological manifestations of either congenital or acquired lesions may be clinically apparent or over-shadowed by serious complications, often multisystemic, of CHD and of its surgical management. Furthermore, in our experience, there are a disproportionately high incidence of autopsies limited to the chest or heart only, preventing a fuller understanding of both gross and subtle neuropathological findings in CHD. CONGENITAL CAUSES OF BRAIN DISORDER Many children with CHD have a genetic defect and even in those without a demonstrable chromosomal, single gene, or contiguous gene defect, extracardiac anomalies are more frequent than in the general population. Central nervous system (CNS) dysfunction is more common in patients with both cardiac and extracardiac anomalies. 4-8 Certain syndromes predictably involve the heart and CNS. Many of these are associated with chromosomal and gene defects, some of which are listed in the Table 1. The most common association is found in children with trisomy 21. The gross structural changes of the brain in Down's syndrome consist of a narrow superior temporal gyrus, a disproportionately small cerebellum and brainstem, and other morphological abnormalities imposed by the altered bony structure of the cranial cavity. None of these changes account for the mental Seminars in Pediatric Neurology, Vol 6, No 1 (March), 1999: pp 20-26
NEUROPATHOLOGY OF CONGENITAL HEART DISEASE
21
myotonic muscular dystrophy, and some mitochondrial disorders and defects of beta oxidation of fatty acids. It is probable that adverse teratogenic events occurring during early pregnancy may also affect the development of both the brain and heart. However, the exact relationship between this occurrence and specific teratogens remains unclear. An exception to this is the viral teratogen rubella, which causes an embryopathy characterized by CHD, such as patent ductus arteriosus, atrial and ventricular septal defects, and pulmonary artery stenosis, in addition to varying levels of cognitive dysfunction often associated with microcephaly. Fig 1. Intrauterineand postnatallyacquired neuropathological changes in CHD. Coronal section of brain from a 2-monthold infant born at 38 weeks' gestation, with intrauterine growth retardation who underwent repair of esophageal atresia and tracheoesophageal fistula, coarctation of aorta, VSD repair, and closure of PFO. Then the infant developed superior vena cava (SVC) syndrome and underwent thrombectomy from SVC and right atrium followed by eventual renal failure. Autopsy revealed systemic CMV infection. Brain examination showed micrencephaly. Note enlargement of the lateral ventricles bilaterally and the third ventricle, attesting to possible intrauterine damage to developing white matter, and severe periventricular leukomalacia (arrow) and superimposed superior sagittal sinus thrombosis.
retardation found in Down's syndrome, which is thought to be due to abnormalities in dendritic morphology and function. 9 Many cases of CHD with or without congenital brain involvement do not necessarily have a multifactorial cause. Velocardiofacial, DiGeorge, and the CATCH 22 syndromes are due to deletions of chromosome 22q11. 28 Dominantly inherited supravalvar aortic stenosis and sporadic Williams syndrome are due to gene deletion at the elastin gene locus on chromosome 7. 29 It has been reported that deletions of 22qll may be involved in 5% of all newborns with heart defects. 3~ Microcephaly occurs in 40% of individuals with a 22ql 1 deletion and learning difficulties occur in essentially 100%, with mild to moderate mental retardation in 40% to 50%. 31 Psychiatric disorders develop in 10% to 22%. Brain anomalies are also common and include a small vermis and posterior fossa, cysts adjacent to the anterior horns, dysgenesis of the corpus callosum, focal white matter hyperintensities on Tz-weighted magnetic resonance imaging, and anomalies of the internal carotid arteries. 11,12 Other examples of gene defects that affect both brain and heart include the dystrophinopathies,
A C Q U I R E D C A U S E S OF BRAIN D I S O R D E R
Before the use of open heart surgery for the surgical management of CHD in children acquired neurological complications were common, occurring in about 25%. 32,33Severe cyanosis and polycythemia may lead to gradual deterioration of cerebral function and an increased risk of stroke or abscess. However, these neurological risks can be improved by early surgical correction. 34 Without this correction, children with CHD may have significant brain injury from cerebral venous thrombosis, thromboembolism and infarction, abscesses, mycotic aneurysms, and hypoperfusion. 32-35 These risks may still exist regardless of surgery if there is continuing cyanosis, hypoperfusion, right-to-left shunting of blood, and any abnormal cardiac or vascular surface that might provide a thromboembolic source. 3 The advent of increasingly sophisticated surgical techniques has expanded the spectrum of acquired sequelae, at the same time altering the incidence of complications related to the natural history of CHD, which was previously not surgically manageable. Since the technique of profound hypothermia and circulatory arrest was introduced more than 40 years ago, there have been spectacular improvements in the surgical management of CHD, which has enabled correction of complex heart defects early in life. 36,3~ Although most children Who undergo the procedure have an uneventful neurological outcome, there is significant morbidity in some. Factors that affect this outcome include profound hypothermic circulatory arrest for more than 45 to 60 minutes and perioperative embolic cerebrovascular events (Fig 2). Neuropathological studies performed on children who have died
22
MILLER AND VOGEL Table 1. Some Congenital Syndromes That Involve Both Brain and Heart Syndrome
Trisomy 13 Trisomy 18
Trisomy 21
Trisomy 9 and trisomy 9 mosaic 22q 11-deletion syndrome (CATCH 22, Velocardiefacial, DiGeorge)
Williams syndrome
Hydrolethalus syndrome
Miller-Dieker syndrome
PHACE syndrome Ritscher-Schinzel syndrome (craniocerebello-cardiac syndrome, 3C syndrome) VACTERL association with hydrocephalus Steinfeld syndrome Acrocallosal syndrome Cardio-facial-cutaneous syndrome Ellis-van Creveld syndrome
Congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD syndrome) Deletion or duplication of (2) (q31q33)
Heart Defect:
Brain Anomaly
ASD, VSD, coarctation of aorta
Holoprosencephaly, cerebellar heterotopias, microscopic neuronal dysplasias ASD, VSD Gyral and lobar anomalies, hypoplastic pontine gray matter, cerebellar hypoplasia, microscopic neuronal dysplasias Endocardial cushion defects, VSD, ASD, Dendritic abnormalities,9 small superior PDA, aberrant subclavian artery temporal gyrus, small cerebellum and brainstem ASD, VSD, complex malformations Dandy-Walker malformation, agenesis of corpus callosum 10 Conotruncal defects Small vermis, small posterior fossa, cysts adjacent to anterior horns, white matter hyperintensities seen on T2 weighted MRI, anomalies of internal carotid arteries11,12 Supravalvular aortic stenosis, Microcephaly, abnormal neuronal cytoarperipheral pulmonary artery chitecture, cerebrovascular stenoses13,14 stenosis, pulmonary valve stenosis AV canal defects Prenatal onset hydrocephalus, absent corpus callosum and septum pellucidum, abnormal gyration ~5 Tetralogy of Fallot, VSD, pulmonary ste- Lissencephaly, pachygyria, dysgenesis of nosis (these are only occasional corpus callosum ~6 associations) Coarctation of the aorta Dandy-Walker malformation ~7 ASD, VSD Dandy-Walker malformation 18
VSD and other cardiac defects Pentalogy of Fallot ASD, VSD, pulmonary valve abnormalities ASD, pulmonary stenosis Usually ASD of ostium primum or secundum type, single atrium, Ebstein anomaly ASD, VSD, single ventricle, single coronary ostium
Aqueductal stenosis and hydrocephalus16 Holoprosencephaly19 Dysgenesis of corpus callosum, megalencephaly20 Hydrocephalus, cortical atrophy, frontal lobe hypoplasia, small brainstem 2~ Dandy-Walker malformation, heterotopias22
Ipsilatera( hypoplasia of brain, cranial nerves, spinal cord 23
Pulmonary artery stenosis, ASD, Ventriculomegaly, gyral and lobar anomacoarctation of aorta, total anomalous lies, dysgenesis of corpus callosum, optic pulmonary venous return nerve hypoplasia, hydrocephalus, fusion of quadrigeminal bodies24 4p-(Wolf-Hirschhorn syndrome) VSD, ASD Microcephaly, dysgenesis of corpus callosum 2s Recombinant aneusomy of chromosome 5 Tetralogy of Fallot Holoprosencephaly with premaxillary associated with severe congenital malforagenesis26 mations Craniosyostosis-radial aplasia (BallerPolymicrogyria, hydrocephalus27 Subaortic valvular hypetrophy, VSD, Gerold) syndrome Tetralogy of Fallot CHARGE association Tetralogy of Fallot, double outlet right Arhinencephaly, facial palsy, mental retarventricle with common AV canal, dation 16 ASD, VSD, right sided aortic arch Xp21 linked dystrophinopathy Cardiomyopathy Unknown Myotonic dystrophy Cardiomyopathy Ventriculomegaly, abnormal white matter signals seen with MRI Friedreich ataxia Cardiomyopathy Spinal cord atrophy particularly involving posterior columns; occasional cerebellar atrophy
NEUROPATHOLOGY OF CONGENITAL HEART DISEASE
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Fig 2. Neuropathology of small embolic infarctions. Resolving infarction (arrows) in the internal capsule and border of caudate nucleus in a 14-month-old girl with complex congenital heart disease, having undergone repair 2 weeks before death. The infarct is showing early features of organization. Microscopy indicated an age consistent with onset in the perioperative period.
following open heart surgery have reported ischemic lesions and infarcts along arterial border zones and hemorrhage in both gray and white matter. 38 Furthermore, cardiopulmonary bypass in adult humans and dogs is associated with many focal dilatations or small aneurysms in terminal cerebral arteries and capillaries that may be sites of gas bubbles or fat emboli. 39 These microemboli arise from air, fibrin, fat, cellular debris, platelet,
Fig 3. Infant aged 6 months with spastic quadriplegia who underwent prolonged hypothermic circulatory arrest. Coronal Tl-weighted scan at level of basal ganglia shows diffuse widening of cortical sulci and ventriculomegaly. Basal ganglia show high signal intensity (arrows).
Fig 4. Child aged 3 years who underwent prolonged hypothermic circulatory arrest at age 10 days and 28 months and has asymmetric spastic diplegia and an IQ of 68. Axial Tl-weighted image shows asymmetric bilateral low signal intensity in the region of the medial occipital lobe (arrows) and bilateral atrial dilation associated with atrophy.
Fig 5. Large embolic infarction. The patient was a 25-yearold woman with congenital tricuspid atresia who underwent initial repair in infancy, and further repair at age 10 years. Patient died after complications following correction of stenotic and thrombosed anastomosis. Note large right cortical and subcortical cystic infarct with white matter atrophy, characteristic of a remote embolic event involving a branch of the right middle cerebral artery.
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Fig 6. Adolescent aged 15 years, who underwent cardiopulmonary bypass with hypothermic circulatory arrest at age 9 years, has a normal neurological examination result, and an IQ of 111. Axial Tl-weighted scan shows wedge-shaped low signal intensity involving gray and white matter of right parietal lobe consistent with focal infarction (arrow).
Fig 7. Incidental developmental malformation in a 4-monthold male infant with meconium aspiration syndrome, severe lung disease with ventilator dependency, tracheomalacia, bronchomalacia, and a VSD. Close inspection of the angle of the lateral ventricle indicates nodular ectopic gray matter (arrows). The brain also showed decreased brain weight for age, recent hypoxic/ischemic injury of neurons, and microscopic hemorrhages.
MILLER AND VOGEL
Fig 8. Child aged 9 years with mild truncal ataxia and hyperreflexia and no dysmorphic features who underwent hypothermic low flow cardiopulmonary bypass for 40 minutes at age 5 years. Axial T2-weighted image shows unsuspected heterotopic gray matter.
and leukocyte aggregates, or from material aspirated by a cardiotomy sucker or torn from surfaces of the perfusion system.4~Despite careful de-airing procedures, cerebral air emboli often occur, especially during redistribution of blood from the bypass machine to the patient when the heart is again beginning to beat actively.41,42 It is an established observation that acute brain damage secondary to hypoxia-ischemia is prevented or reduced by prior hypothermia.43 This protection lessens after 45 minutes of profound hypothermic circulatory arrest, particularly in neonates. 1,2,44-46The possible neurological sequelae of this loss of protection include cerebral palsy and cognitive dysfunction,2 and neuroimaging may demonstrate basal ganglia change, diffuse white matter loss with cortical thinning (Fig 3), and focal cortical infarcts (Fig 4). The longer the duration of hypothermic circulatory arrest the more likely the presence of abnormal diffuse MRI change. 3 One recent study reported that brain magnetic resonance imaging (MRI) on children who undergo cardiopulmonary bypass with profound hypothermia can be
NEUROPATHOLOGY OF CONGENITAL HEART DISEASE
a useful prognostic instrument. 3 In this study it was shown that those with a normal MRI following surgery also had a normal IQ and neurological examination; focal infarction without diffuse change may be clinically silent (Figs 5 and 6); and that unsuspected cerebral dysgenesis may be revealed and provide an explanation for an accompanying neurodevelopmental deficit (Figs 7 and 8). Neuroimaging may also supply evidence for preoperative brain insult or morphological change. McConnell et al47 performed brain MRI on 15 children aged 17 days to 9 years before cardiopulmonary bypass surgery and 5 days to 4 weeks after operation. In a third of their study patients they found preoperative ventriculomegaly, generous subarachnoid spaces, and in one patient evidence of infarction. It may not
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be feasible clinically to perform preoperative MRI, or even computed tomography, on extremely medically fragile infants. However, if the anterior fontanel is patent, cranial ultrasonography is a useful technique. In a prospective study on full-term infants with CHD, 1 cranial ultrasonography was performed before, and on more than one occasion, after open heart surgery. The results revealed abnormalities in 27%, and in more than half of these abnormal findings were present before operation. Preoperative abnormal findings included branching thalamic echodensities, multiple periventricular cystic change, and ventriculomegaly. Postoperative findings included an increase in ventricular size, and changes consistent with focal hemorrhage and infarction.
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37. Hoffman JI: Congenital heart disease: Incidence and inheritance. Pediatr Clin North Am 37:25-43, 1990 38. Ferry PC: Neurologic sequelae of open heart surgery. Am J Dis Child 144:369-373, 1990 39. Moody DM, Bell MA, Challa VR, et al: Brain microemboll during cardiac surgery or aortography. Ann Neurol 28:4748, 1990 40. Stephenson LW, Edmunds LH: Cardiopulmonary bypass for open heart surgery, in Bauer AE, Geh AS, Hammond GL, et al (eds): Glenn's Thoracic and Cardiovascular Surgery. Norwalk, CT, Appleton & Lange, 1991, pp 1397-1411 41. Van der Linden J, Casamir-Ahn H: When do cerebral emboli appear during open heart operations? A transcranial Doppler study. Ann Thorac Surg 51:237-241,1991 42. Padayachee TS, Parsons S, Theobald R, et al: The detection of microemboli in the middle cerebral artery during cardiopulmonary bypass: A transcranial Doppler ultrasound investigation using membrane and bubble oxygenators. Ann Thorac Surg 44:298-302, 1987 43. Hickey PR, Anderson NP: Deep hypothermic circulatory arrest: A review of pathophysiology and clinical experience as a basis for anesthetic management. J Cardiothorac Anesth 1:137155, 1987 44. Wells FC, Coghill S, Caplan HL, et al: Duration of circulatory arrest does influence the psychological development of children after cardiac operation in early life. J Thorac Cardiovasc Surg 86:823-831, 1983 45. O'Dougherty M, Wright FS, Garmezy N, et al: Later competence and adaptation in infants who survive severe heart defects. Child Dev 54:1129-1142, 1983 46. Miller G, Rodichok LD, Baylen BG, et al: EEG changes during open heart surgery on infants aged 6 months or less: Relationship to early neurologic morbidity. Pediatr Neurol 10:124-130, 1994 47. McConnell JR, Fleming WH, Chu K, et al: Magnetic resonance imaging of the brain in infants and children before and after cardiac surgery. Am J Dis Child 144:374-378, 1990