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2. Runyan DK, Wattam C, Ikeda R, Hassan F, Ramiro L. Child abuse and neglect by parents and other caretakers. In: Krug E, Dahlberg L, Mercy J, Zwi A, Lozano R, eds. World report on violence and health. Geneva: World Health Organization; 2002. 3. Pinhiero P. World report on violence against children. New York: United Nations; 2006. 4. Lansford JE, Pe~ na Alampay L, Al-Hassan S, Bacchini D, Silvia Bombi A, Bornstein M, et al. Corporal punishment of children in nine countries as a function of child gender and parent gender. Int J Pediatr. Article ID 672780, 12 pages, http://dx.doi.org/10.1155/2010/672780; 2010. Epub 2010 Sep 23. 5. Runyan DK, Shankar V, Hassan F, Hunter W, Jain D, Paula C, et al. International variations in harsh child discipline. Pediatrics 2010;126:e701-11.
Vol. 164, No. 5 6. Theodore A, Chang JJ, Runyan DK, Hunter WM, Bangdiwala SI, Agans R. The epidemiology of the physical and sexual maltreatment of children in the Carolinas. Pediatrics 2005;126:e331-7. 7. Zolotor AJ, Robinson TW, Runyan DK, Barr RG, Murphy RA. The emergence of spanking among a representative sample of children under two years of age in North Carolina. Front Child Neurodevelop Psychiatry 2011;2:36. 8. Survey USA. Results of Survey USA News Poll #13013. Available at: http:// www.surveyusa.com/client/PollReport.aspx?g=edef1e43-54b6-4ec2-b2bca916b0fc6740. Accessed February 4, 2014. 9. Zolotor AJ, Theodore A, Chang JJ, Berkoff MC, Runyan DK. Speak softly and forget the stick: corporal punishment and child physical abuse. Am J Prevent Med 2008;35:364-9.
Encephalopathy of Congenital Heart Disease– Destructive and Developmental Effects Intertwined
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emarkable improvements in cardiac surgical techniques development were noted in 21% of one large series.8 Thus, for newborns and very young infants with complex overall, conventional neuropathology principally shows a congenital heart disease (CHD) have led to pronounced particular predominance of cerebral WMI, frequently with increases in survival; however, neurologic sequelae are still accompanying neuronal injury in multiple nuclear structures. common and generally range from 25% to 50%.1,2 In recent MRI studies of infants with complex CHD have confirmed the prominence of WMI, but notably also years, a large literature has begun to define See related article, p 1121 suggest an admixture of important disturthe anatomic features of the brain disturbances in later brain development. Thus, depending somewhat bance with CHD, the underlying neurobiological mechanisms, on the severity and nature of the cardiac lesion and the timing and the relationship with later neurologic consequences. As of surgery, approximately 20%-50% exhibit MRI features of discussed later, there appears to be a remarkable similarity beovert WMI.6,7,9-11 (Because the focal necrotic lesions of PVL tween certain aspects of the brain disturbance in CHD and those recently delineated in more detail in preterm infants. are usually microscopic in size, these conventional MRI assessInsight into the anatomic features of the brain disturbance ments likely underestimate the full extent of WMI.) In addition in CHD has been provided by conventional neuropathologto WMI, however, advanced MRI techniques, including diffuical studies postmortem and by magnetic resonance imaging sion tensor, volumetric, and spectroscopic methods, have pro(MRI) analyses in vivo. Neuropathological studies indicate vided findings consistent with cerebral white matter that the brain disturbance in CHD before surgery is domi“immaturity.”12-15 Overall diffusion and anisotropic diffusion nated by cerebral white matter injury (WMI), generally commeasures in newborns with CHD are similar to those seen in parable with periventricular leukomalacia (PVL) as described infants approximately 4 weeks less mature. Disturbances in in preterm infants.3-5 The incidence of such injury at postanisotropic diffusion involve primarily radial diffusivity, consistent with a disturbance of premyelinating oligodendromortem examination ranges from 50% to 100%. Neuronal cyte (pre-OL) ensheathment of axons in preparation for myeloss and gliosis in the cerebral cortex, thalamus, basal ganglia, lination, which occurs postterm in the human cerebrum.16,17 and brainstem/cerebellum are less marked but relatively frequent (approximately 50%). Cerebral infarcts, multifocal The advanced MRI techniques also show that brain abnormalparenchymal hemorrhage, and watershed injury are less comities in newborns with CHD involve cerebral cortical and deep mon accompaniments.3,4 These various destructive lesions nuclear structures, with well documented decreases in cortical surface area and cortical folding/gyral development.18 Indeed, are accentuated after cardiac surgery and cardiopulmonary 2,6,7 bypass. such abnormalities have been identified by fetal MRI.19 In this Overt disturbances in early brain development 8 do occur but are unusual (10%), whereas abnormalities issue of The Journal, Owen et al20 describe impaired volumetric referable to later developmental events (20-40 weeks gestadevelopment of the thalamus and basal ganglia. In addition, tion) are somewhat more common; impairments of gyral fetal MRI studies have documented impaired brain volumetric development, with apparent onset at approximately 28 weeks gestation.21 Chronic hypoxia-ischemia appears to be the primary initiating pathogenetic factor.1 Thus, considered CHD Congenital heart disease GABA MRI pre-OL PVL WMI
g-Aminobutyric acid Magnetic resonance imaging Premyelinating oligodendrocyte Periventricular leukomalacia White matter injury
The author declares no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.01.002
962
May 2014 together, the conventional neuropathological studies and the advanced MRI data suggest that the brain abnormality in infants with CHD is a complex mixture of destructive and developmental disturbances. Insight into the neurobiological mechanisms likely operative in infants with CHD is provided by recent work with preterm infants demonstrating that the brain abnormality originates and evolves over a similar maturational period (the last trimester of gestation), is caused particularly by hypoxia-ischemia, is primarily chronic, and involves a complex amalgam of destructive and developmental disturbances, affecting particularly white matter but also multiple neuronal/axonal structures.16 The details of this amalgam have been elucidated in greater detail in preterm infants and likely are highly relevant to infants with CHD as well. In preterm infants, advanced neuropathological studies point to abnormalities of specific cerebral white matter constituents (ie, pre-OLs, axons, subplate neurons, and latemigrating g-aminobutyric acid [GABA]-ergic neurons), as well as cerebral cortex and deep nuclear structures, especially the thalamus.16 Pre-OLs are by far the most dominant cells of oligodendroglial lineage in human preterm white matter, accounting for 90% of the lineage at 28 weeks gestation and 50% near term.22 Not until the postterm period do mature myelin-producing oligodendrocytes start to gain prominence. Pre-OLs are exquisitely vulnerable to hypoxia-ischemia and are injured by a cascade involving excitotoxicity, microglial activation, and generation of free radicals.17 The pre-OL injury initially includes cell death or survival with loss of cell processes, followed by proliferation of progenitors and replenishment of the vulnerable pre-OL pool (with propensity to repeat hypoxic-ischemic injury) but, ultimately, failure of maturation of these pre-OLs after termination of the hypoxic-ischemic insults, with resulting impaired myelination.17,23-25 Importantly, an essentially identical scenario has been shown recently in an experimental model of hypothermia, circulatory arrest, and cardiopulmonary bypass.26 This scenario with replenishment but maturational failure of preOLs may explain the MRI findings of white matter immaturity in newborns with CHD. Also of potential relevance to infants with CHD, advanced neuropathological studies of preterm infants with PVL have elucidated effects on other developing white matter components, including axons, subplate neurons, and latemigrating GABAergic neurons. Axons are in a state of very active development in the third trimester,27 and in preterm infants with PVL, many axons undergo degeneration.28 This degeneration could lead to impaired development of the cerebral cortex and thalamus by anterograde and retrograde mechanisms, consistent with recently reported MRI and neuropathological data in preterm infants.16 Developing axons were shown to be particularly susceptible to hypoxicischemic injury in a neonatal rat model.29 Subplate neurons are a transient population of neurons beneath the cortical plate in the third trimester in the human brain30; these cells are critical as sites of transient synaptic
EDITORIALS contact for thalamocortical, corticocortical, and commissural cortical fibers that are rapidly developing during this period.31,32 Subplate neurons also have been shown to be vulnerable to hypoxia-ischemia in a neonatal rat model.33 Recent studies in preterm infants demonstrated diminished subplate neurons in association with PVL.34 Based on experimental studies, the consequences of subplate neuron loss are impaired cortical and thalamic development, as detected by MRI in living preterm infants.16 Late-migrating GABAergic neurons, destined for superficial layers of the cerebral cortex and thalamus, also are abundant in cerebral white matter in the third trimester human brain.35 Injury to these neurons results in impaired cerebral cortical development, along with such functional deficits as heightened excitability and disturbed specification of cognitive critical periods. A neuropathological study of preterm infants with PVL detected a loss of these migrating neurons.36 The advanced neuropathological studies that revealed these effects on white matter neuronal/axonal structures in preterm infants have not yet been applied to infants with CHD. Nevertheless, the MRI findings described earlier in infants with CHD suggest that these effects likely occur. In addition to the aforementioned cerebral white matter neuronal/axonal components, cerebral cortical neurons, actively differentiating in the third trimester, are affected in preterm infants with WMI.37 The MRI data raise the possibility of this effect in infants with CHD as well. The disturbance in development may be related either directly to hypoxiaischemia or secondarily to axonal or subplate neuron disturbances. A recent study in an experimental model of chronic hypoxia and WMI clearly showed impaired cortical differentiation.38 Finally, a detailed neuropathological study found affects on the thalamus in at least 60% of preterm infants with PVL.39,40 Similarly, thalamic neuronal loss and gliosis were identified in approximately 50% of infants with CHD studied neuropathologically.4 Whether these affects on the thalamus reflect primary hypoxic-ischemic injury (because of the high metabolism and concentration of excitatory amino acid receptors in thalamus) or secondary anterograde and retrograde effects related to white matter axonal and subplate neuron disturbance is unclear, but it is likely that at least one of these phenomena accounts for the decreased thalamic volume documented by MRI in living infants with CHD.20 Clearly, advanced neuropathological studies of the brain in infants with CHD are needed to determine conclusively whether these infants sustain the same changes in the white matter and nuclear structures described in preterm infants. Nevertheless, in view of the similarities in terms of timing and nature of insults, prominence of WMI, and MRI data showing cortical and thalamic underdevelopment, it seems likely that the brain abnormality in infants with CHD will prove to be a complex amalgam of destructive and developmental disturbances, as we have described in preterm infants.16 Indeed, the term coined for the combination of white matter and neuronal/axonal abnormalities in premature infants, the “encephalopathy of prematurity,”16 perhaps could be appropriately modified in this context to the “encephalopathy of CHD.” 963
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Neurodevelopmental deficits are common in infants and children with complex CHD. Preoperative neurologic abnormalities are apparent in approximately 40%-50% during the neonatal period.1,41 The most notable later disturbances in children involve cognition. IQ is generally below that of controls, albeit within the average range.1,42 More notably, a variety of cognitive functions are specifically impaired. The anatomic correlates of the cognitive deficits are not entirely understood, but the work of Owen et al in this issue of The Journal20 provides important new insights. Studying 35 infants with complex CHD before surgery by volumetric MRI, the authors identified tissue-specific volumetric disturbances, particularly increased cerebrospinal fluid volume (perhaps secondary to cerebral white matter disturbance) and diminished subcortical gray matter volume (thalamus/ basal ganglia). Importantly, careful neonatal and subsequent neurobehavioral studies identified correlations between the volumetric deficits and specific neurobehavioral measures. Because of the small number of subjects, as the authors suggest, the clinical–anatomic correlations should be considered hypothesis-generating rather than established. Nevertheless, the authors’ work is exciting, detecting volumetric changes in a critical gray matter structure (ie, thalamus) during the neonatal period, perhaps secondary to a combination of destructive and developmental disturbances described earlier, and it demonstrates potentially great value for neonatal MRI screening to identify infants in particular need of early intervention to improve neurologic outcome. The later anatomic correlates of the long-term neurocognitive disturbances in infants and children with CHD are unclear. Follow-up studies of infants with CHD by conventional imaging have shown predominately white matter abnormalities and volume loss43 or apparent “resolution” of earlier detected WMI.7 The small size of the initial focal necrotic lesions of PVL and the subsequent glial scarring and condensation of such lesions likely underlie the later invisibility on MRI. More importantly, however, a recent study of 49 adolescents with transposition of the great arteries by advanced MRI microstructural analysis showed widespread cerebral white matter microstructural abnormalities.44 Thus, despite scant evidence of overt white matter abnormalities on conventional MRI, widespread reductions in fractional anisotropy in cerebral white matter have been demonstrated. The structures most affected (superior and inferior longitudinal fasciculi, inferior occipitofrontal fasciculus, and uncinate fasciculus) are corticocortical tracts that develop rapidly in the third trimester,16 the time of evolution of brain abnormalities in the fetus with CHD. These tracts play critical roles in the specific neurocognitive deficits identified in children with CHD.44 The microstructural MRI findings suggest abnormal development of axons and myelin and are consistent with the mechanisms identified in preterm infants. Thus, the concept of early destructive influences leading to permanent developmental deficits is supported in infants with CHD, as in preterm infants. The possibility that the subsequent anatomic deficits in CHD are related in considerable part to disturbances in brain development, especially connectivity and circuitry, has impli964
Vol. 164, No. 5 cations for interventions. Thus, therapies that can help shape circuitry and enhance plasticity could be especially important in infants and children with CHD. Although discussed appropriately elsewhere,45 intervention programs directed at cognitive, behavioral, and attentional functions seem to be critical. The sophisticated MRI techniques described earlier may allow selection in the neonatal period for such interventions and perhaps in the future for specific pharmacologic and even cellular therapies directed at improving neuronal, axonal, and myelin development. n Joseph J. Volpe, MD Bronson Crothers Distinguished Professor of Neurology Harvard Medical School Boston Children’s Hospital Boston, Massachusetts *Reprint requests: Joseph J. Volpe, MD, Boston Children’s Hospital, 3 Blackfan Circle, CLS 13070, Boston, MA 02115. E-mail: joseph.volpe@childrens. harvard.edu
References 1. Donofrio MT, Duplessis AJ, Limperopoulos C. Impact of congenital heart disease on fetal brain development and injury. Curr Opin Pediatr 2011;23:502-11. 2. McQuillen PS, Miller SP. Congenital heart disease and brain development. Ann NY Acad Sci 2010;1184:68-86. 3. Glauser TA, Rorke LB, Weinberg PM, Clancy RR. Acquired neuropathologic lesions associated with the hypoplastic left heart syndrome. Pediatrics 1990;85:991-1000. 4. Kinney HC, Panigrahy A, Newburger JW, Jonas RA, Sleeper LA. Hypoxic-ischemic brain injury in infants with congenital heart disease dying after cardiac surgery. Acta Neuropathol (Berl) 2005;110:563-78. 5. Hinton RB, Andelfinger G, Sekar P, Hinton AC, Gendron RL, Michelfelder EC, et al. Prenatal head growth and white matter injury in hypoplastic left heart syndrome. Pediatr Res 2008;64:364-9. 6. Beca J, Gunn JK, Coleman L, Hope A, Reed PW, Hunt RW, et al. New white matter brain injury after infant heart surgery is associated with diagnostic group and the use of circulatory arrest. Circulation 2013; 127:971-9. 7. Mahle WT, Tavani F, Zimmerman RA, Nicolson SC, Galli KK, Gaynor JW, et al. An MRI study of neurological injury before and after congenital heart surgery. Circulation 2002;106(12 Suppl 1):I109-14. 8. Glauser TA, Rorke LB, Weinberg PM, Clancy RR. Congenital brain anomalies associated with the hypoplastic left heart syndrome. Pediatrics 1990;85:984-90. 9. Galli KK, Zimmerman RA, Jarvik GP, Wernovsky G, Kuypers MK, Clancy RR, et al. Periventricular leukomalacia is common after neonatal cardiac surgery. J Thorac Cardiovasc Surg 2004;127:692-704. 10. Petit CJ, Rome JJ, Wernovsky G, Mason SE, Shera DM, Nicolson SC, et al. Preoperative brain injury in transposition of the great arteries is associated with oxygenation and time to surgery, not balloon atrial septostomy. Circulation 2009;119:709-16. 11. Ortinau C, Beca J, Lambeth J, Ferdman B, Alexopoulos D, Shimony JS, et al. Regional alterations in cerebral growth exist preoperatively in infants with congenital heart disease. J Thorac Cardiovasc Surg 2012; 143:1264-70. 12. Miller SP, McQuillen PS, Hamrick SE, Xu D, Glidden DV, Charlton NN, et al. Abnormal brain development in newborns with congenital heart disease. N Engl J Med 2007;357:1928-38. 13. Licht DJ, Shera DM, Clancy RR, Wernovsky G, Montenegro LM, Nicolson SC, et al. Brain maturation is delayed in infants with complex congenital heart defects. J Thorac Cardiovasc Surg 2009;137:529-36.
May 2014 14. Dimitropoulos A, McQuillen PS, Sethi V, Moosa A, Chau V, Xu D, et al. Brain injury and development in newborns with critical congenital heart disease. Neurology 2013;81:241-8. 15. Sethi V, Tabbutt S, Dimitropoulos A, Harris KC, Chau V, Poskitt K, et al. Single-ventricle anatomy predicts delayed microstructural brain development. Pediatr Res 2013;73:661-7. 16. Volpe JJ. Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol 2009;8: 110-24. 17. Volpe JJ, Kinney HC, Jensen FE, Rosenberg PA. The developing oligodendrocyte: key cellular target in brain injury in the premature infant. Int J Dev Neurosci 2011;29:423-40. 18. Ortinau C, Alexopoulos D, Dierker D, Van Essen D, Beca J, Inder T. Cortical folding is altered before surgery in infants with congenital heart disease. J Pediatr 2013;163:1507-10. 19. Clouchoux C, du Plessis AJ, Bouyssi-Kobar M, Tworetzky W, McElhinney DB, Brown DW, et al. Delayed cortical development in fetuses with complex congenital heart disease. Cereb Cortex 2012;23: 2932-43. 20. Owen M, Shevell M, Donofrio MT, Majnemer A, McCarter R, Vezina G, et al. Brain volume and neurobehaviour in newborns with complex congenital heart defects. J Pediatrics 2014;164:1121-7. 21. Limperopoulos C, Tworetzky W, McElhinney DB, Newburger JW, Brown DW, Robertson RL Jr, et al. Brain volume and metabolism in fetuses with congenital heart disease: evaluation with quantitative magnetic resonance imaging and spectroscopy. Circulation 2010;121:26-33. 22. Back SA, Luo NL, Borenstein NS, Levine JM, Volpe JJ, Kinney HC. Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury. J Neurosci 2001;21:1302-12. 23. Buser JR, Maire J, Riddle A, Gong X, Nguyen T, Nelson K, et al. Arrested preoligodendrocyte maturation contributes to myelination failure in premature infants. Ann Neurol 2012;71:93-109. 24. Back SA, Luo NL, Mallinson RA, O’Malley JP, Wallen LD, Frei B, et al. Selective vulnerability of preterm white matter to oxidative damage defined by F(2)-isoprostanes. Ann Neurol 2005;58:108-20. 25. Billiards SS, Haynes RL, Folkerth RD, Borenstein NS, Trachtenberg FL, Rowitch DH, et al. Myelin abnormalities without oligodendrocyte loss in periventricular leukomalacia. Brain Pathol 2008;18:153-63. 26. Ishibashi N, Scafidi J, Murata A, Korotocova L, Zurakowski D, Gallo V, et al. White matter protection in congenital heart surgery. Circulation 2012;125:859-71. 27. Haynes RL, Borenstein NS, DeSilva TM, Folkerth RD, Liu LG, Volpe JJ, et al. Axonal development in the cerebral white matter of the human fetus and infant. J Comp Neurol 2005;484:156-67. 28. Haynes RL, Billiards SS, Borenstein NS, Volpe JJ, Kinney HC. Diffuse axonal injury in periventricular leukomalacia as determined by apoptotic marker fractin. Pediatr Res 2008;63:656-61. 29. Alix JJ, Zammit C, Riddle A, Meshul CK, Back SA, Valentino M, et al. Central axons preparing to myelinate are highly sensitivity to ischemic injury. Ann Neurol 2012;72:936-51. 30. Kostovic I, Judas M. The development of the subplate and thalamocortical connections in the human foetal brain. Acta Paediatr 2010; 99:1119-27.
EDITORIALS 31. Vasung L, Huang H, Jovanov-Milosevic N, Pletikos M, Mori S, Kostovic I. Development of axonal pathways in the human fetal fronto-limbic brain: histochemical characterization and diffusion tensor imaging. J Anat 2010;217:400-17. 32. Bystron I, Blakemore C, Rakic P. Development of the human cerebral cortex: Boulder Committee revisited. Nat Rev Neurosci 2008;9:110-22. 33. McQuillen PS, Sheldon RA, Shatz CJ, Ferriero DM. Selective vulnerability of subplate neurons after early neonatal hypoxia-ischemia. J Neurosci 2003;23:3308-15. 34. Kinney HC, Haynes RL, Xu G, Andiman SE, Folkerth RD, Sleeper LA, et al. Neuron deficit in the white matter and subplate in periventricular leukomalacia. Ann Neurol 2012;71:397-406. 35. Xu G, Broadbelt KG, Haynes RL, Folkerth RD, Borenstein NS, Belliveau RA, et al. Late development of the GABAergic system in the human cerebral cortex and white matter. J Neuropathol Exp Neurol 2011;70:841-58. 36. Robinson S, Li Q, Dechant A, Cohen ML. Neonatal loss of gammaaminobutyric acid pathway expression after human perinatal brain injury. J Neurosurg 2006;104(6 Suppl):396-408. 37. Andiman SE, Haynes RL, Trachtenberg FL, Billiards SS, Folkerth RD, Volpe JJ, et al. The cerebral cortex overlying periventricular leukomalacia: analysis of pyramidal neurons. Brain Pathol 2010;20:803-14. 38. Dean JM, McClendon E, Hansen K, Azimi-Zonooz A, Chen K, Riddle A, et al. Prenatal cerebral ischemia disrupts MRI-defined cortical microstructure through disturbances in neuronal arborization. Sci Transl Med 2013;5:168ra7. 39. Pierson CR, Folkerth RD, Billards SS, Trachtenberg FL, Drinkwater ME, Volpe JJ, et al. Gray matter injury associated with periventricular leukomalacia in the premature infant. Acta Neuropathol 2007;114:619-31. 40. Ligam P, Haynes RL, Folkerth RD, Liu L, Yang M, Volpe JJ, et al. Thalamic damage in periventricular leukomalacia: novel pathologic observations relevant to cognitive deficits in survivors of prematurity. Pediatr Res 2009;65:524-9. 41. Majnemer A, Limperopoulos C, Shevell MI, Rohlicek C, Rosenblatt B, Tchervenkov C. A new look at outcomes of infants with congenital heart disease. Pediatr Neurol 2009;40:197-204. 42. Bellinger DC, Wypij D, Rivkin MJ, DeMaso DR, Robertson RL Jr, Dunbar-Masterson C, et al. Adolescents with d-transposition of the great arteries corrected with the arterial switch procedure: neuropsychological assessment and structural brain imaging. Circulation 2011; 124:1361-9. 43. von Rhein M, Scheer I, Loenneker T, Huber R, Knirsch W, Latal B. Structural brain lesions in adolescents with congenital heart disease. J Pediatr 2011;158:984-9. 44. Rivkin MJ, Watson CG, Scoppettuolo LA, Wypij D, Vajapeyam S, Bellinger DC, et al. Adolescents with D-transposition of the great arteries repaired in early infancy demonstrate reduced white matter microstructure associated with clinical risk factors. J Thorac Cardiovasc Surg 2013; 146:543-549 e1. 45. Marino BS. New concepts in predicting, evaluating, and managing neurodevelopmental outcomes in children with congenital heart disease. Curr Opin Pediatr 2013;25:574-84.
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www.jpeds.com
2. Runyan DK, Wattam C, Ikeda R, Hassan F, Ramiro L. Child abuse and neglect by parents and other caretakers. In: Krug E, Dahlberg L, Mercy J, Zwi A, Lozano R, eds. World report on violence and health. Geneva: World Health Organization; 2002. 3. Pinhiero P. World report on violence against children. New York: United Nations; 2006. 4. Lansford JE, Pe~ na Alampay L, Al-Hassan S, Bacchini D, Silvia Bombi A, Bornstein M, et al. Corporal punishment of children in nine countries as a function of child gender and parent gender. Int J Pediatr. Article ID 672780, 12 pages, http://dx.doi.org/10.1155/2010/672780; 2010. Epub 2010 Sep 23. 5. Runyan DK, Shankar V, Hassan F, Hunter W, Jain D, Paula C, et al. International variations in harsh child discipline. Pediatrics 2010;126:e701-11.
Vol. 164, No. 5 6. Theodore A, Chang JJ, Runyan DK, Hunter WM, Bangdiwala SI, Agans R. The epidemiology of the physical and sexual maltreatment of children in the Carolinas. Pediatrics 2005;126:e331-7. 7. Zolotor AJ, Robinson TW, Runyan DK, Barr RG, Murphy RA. The emergence of spanking among a representative sample of children under two years of age in North Carolina. Front Child Neurodevelop Psychiatry 2011;2:36. 8. Survey USA. Results of Survey USA News Poll #13013. Available at: http:// www.surveyusa.com/client/PollReport.aspx?g=edef1e43-54b6-4ec2-b2bca916b0fc6740. Accessed February 4, 2014. 9. Zolotor AJ, Theodore A, Chang JJ, Berkoff MC, Runyan DK. Speak softly and forget the stick: corporal punishment and child physical abuse. Am J Prevent Med 2008;35:364-9.
Encephalopathy of Congenital Heart Disease– Destructive and Developmental Effects Intertwined
R
emarkable improvements in cardiac surgical techniques development were noted in 21% of one large series.8 Thus, for newborns and very young infants with complex overall, conventional neuropathology principally shows a congenital heart disease (CHD) have led to pronounced particular predominance of cerebral WMI, frequently with increases in survival; however, neurologic sequelae are still accompanying neuronal injury in multiple nuclear structures. common and generally range from 25% to 50%.1,2 In recent MRI studies of infants with complex CHD have confirmed the prominence of WMI, but notably also years, a large literature has begun to define See related article, p 1121 suggest an admixture of important disturthe anatomic features of the brain disturbances in later brain development. Thus, depending somewhat bance with CHD, the underlying neurobiological mechanisms, on the severity and nature of the cardiac lesion and the timing and the relationship with later neurologic consequences. As of surgery, approximately 20%-50% exhibit MRI features of discussed later, there appears to be a remarkable similarity beovert WMI.6,7,9-11 (Because the focal necrotic lesions of PVL tween certain aspects of the brain disturbance in CHD and those recently delineated in more detail in preterm infants. are usually microscopic in size, these conventional MRI assessInsight into the anatomic features of the brain disturbance ments likely underestimate the full extent of WMI.) In addition in CHD has been provided by conventional neuropathologto WMI, however, advanced MRI techniques, including diffuical studies postmortem and by magnetic resonance imaging sion tensor, volumetric, and spectroscopic methods, have pro(MRI) analyses in vivo. Neuropathological studies indicate vided findings consistent with cerebral white matter that the brain disturbance in CHD before surgery is domi“immaturity.”12-15 Overall diffusion and anisotropic diffusion nated by cerebral white matter injury (WMI), generally commeasures in newborns with CHD are similar to those seen in parable with periventricular leukomalacia (PVL) as described infants approximately 4 weeks less mature. Disturbances in in preterm infants.3-5 The incidence of such injury at postanisotropic diffusion involve primarily radial diffusivity, consistent with a disturbance of premyelinating oligodendromortem examination ranges from 50% to 100%. Neuronal cyte (pre-OL) ensheathment of axons in preparation for myeloss and gliosis in the cerebral cortex, thalamus, basal ganglia, lination, which occurs postterm in the human cerebrum.16,17 and brainstem/cerebellum are less marked but relatively frequent (approximately 50%). Cerebral infarcts, multifocal The advanced MRI techniques also show that brain abnormalparenchymal hemorrhage, and watershed injury are less comities in newborns with CHD involve cerebral cortical and deep mon accompaniments.3,4 These various destructive lesions nuclear structures, with well documented decreases in cortical surface area and cortical folding/gyral development.18 Indeed, are accentuated after cardiac surgery and cardiopulmonary 2,6,7 bypass. such abnormalities have been identified by fetal MRI.19 In this Overt disturbances in early brain development 8 do occur but are unusual (10%), whereas abnormalities issue of The Journal, Owen et al20 describe impaired volumetric referable to later developmental events (20-40 weeks gestadevelopment of the thalamus and basal ganglia. In addition, tion) are somewhat more common; impairments of gyral fetal MRI studies have documented impaired brain volumetric development, with apparent onset at approximately 28 weeks gestation.21 Chronic hypoxia-ischemia appears to be the primary initiating pathogenetic factor.1 Thus, considered CHD Congenital heart disease GABA MRI pre-OL PVL WMI
g-Aminobutyric acid Magnetic resonance imaging Premyelinating oligodendrocyte Periventricular leukomalacia White matter injury
The author declares no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.01.002
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May 2014 together, the conventional neuropathological studies and the advanced MRI data suggest that the brain abnormality in infants with CHD is a complex mixture of destructive and developmental disturbances. Insight into the neurobiological mechanisms likely operative in infants with CHD is provided by recent work with preterm infants demonstrating that the brain abnormality originates and evolves over a similar maturational period (the last trimester of gestation), is caused particularly by hypoxia-ischemia, is primarily chronic, and involves a complex amalgam of destructive and developmental disturbances, affecting particularly white matter but also multiple neuronal/axonal structures.16 The details of this amalgam have been elucidated in greater detail in preterm infants and likely are highly relevant to infants with CHD as well. In preterm infants, advanced neuropathological studies point to abnormalities of specific cerebral white matter constituents (ie, pre-OLs, axons, subplate neurons, and latemigrating g-aminobutyric acid [GABA]-ergic neurons), as well as cerebral cortex and deep nuclear structures, especially the thalamus.16 Pre-OLs are by far the most dominant cells of oligodendroglial lineage in human preterm white matter, accounting for 90% of the lineage at 28 weeks gestation and 50% near term.22 Not until the postterm period do mature myelin-producing oligodendrocytes start to gain prominence. Pre-OLs are exquisitely vulnerable to hypoxia-ischemia and are injured by a cascade involving excitotoxicity, microglial activation, and generation of free radicals.17 The pre-OL injury initially includes cell death or survival with loss of cell processes, followed by proliferation of progenitors and replenishment of the vulnerable pre-OL pool (with propensity to repeat hypoxic-ischemic injury) but, ultimately, failure of maturation of these pre-OLs after termination of the hypoxic-ischemic insults, with resulting impaired myelination.17,23-25 Importantly, an essentially identical scenario has been shown recently in an experimental model of hypothermia, circulatory arrest, and cardiopulmonary bypass.26 This scenario with replenishment but maturational failure of preOLs may explain the MRI findings of white matter immaturity in newborns with CHD. Also of potential relevance to infants with CHD, advanced neuropathological studies of preterm infants with PVL have elucidated effects on other developing white matter components, including axons, subplate neurons, and latemigrating GABAergic neurons. Axons are in a state of very active development in the third trimester,27 and in preterm infants with PVL, many axons undergo degeneration.28 This degeneration could lead to impaired development of the cerebral cortex and thalamus by anterograde and retrograde mechanisms, consistent with recently reported MRI and neuropathological data in preterm infants.16 Developing axons were shown to be particularly susceptible to hypoxicischemic injury in a neonatal rat model.29 Subplate neurons are a transient population of neurons beneath the cortical plate in the third trimester in the human brain30; these cells are critical as sites of transient synaptic
EDITORIALS contact for thalamocortical, corticocortical, and commissural cortical fibers that are rapidly developing during this period.31,32 Subplate neurons also have been shown to be vulnerable to hypoxia-ischemia in a neonatal rat model.33 Recent studies in preterm infants demonstrated diminished subplate neurons in association with PVL.34 Based on experimental studies, the consequences of subplate neuron loss are impaired cortical and thalamic development, as detected by MRI in living preterm infants.16 Late-migrating GABAergic neurons, destined for superficial layers of the cerebral cortex and thalamus, also are abundant in cerebral white matter in the third trimester human brain.35 Injury to these neurons results in impaired cerebral cortical development, along with such functional deficits as heightened excitability and disturbed specification of cognitive critical periods. A neuropathological study of preterm infants with PVL detected a loss of these migrating neurons.36 The advanced neuropathological studies that revealed these effects on white matter neuronal/axonal structures in preterm infants have not yet been applied to infants with CHD. Nevertheless, the MRI findings described earlier in infants with CHD suggest that these effects likely occur. In addition to the aforementioned cerebral white matter neuronal/axonal components, cerebral cortical neurons, actively differentiating in the third trimester, are affected in preterm infants with WMI.37 The MRI data raise the possibility of this effect in infants with CHD as well. The disturbance in development may be related either directly to hypoxiaischemia or secondarily to axonal or subplate neuron disturbances. A recent study in an experimental model of chronic hypoxia and WMI clearly showed impaired cortical differentiation.38 Finally, a detailed neuropathological study found affects on the thalamus in at least 60% of preterm infants with PVL.39,40 Similarly, thalamic neuronal loss and gliosis were identified in approximately 50% of infants with CHD studied neuropathologically.4 Whether these affects on the thalamus reflect primary hypoxic-ischemic injury (because of the high metabolism and concentration of excitatory amino acid receptors in thalamus) or secondary anterograde and retrograde effects related to white matter axonal and subplate neuron disturbance is unclear, but it is likely that at least one of these phenomena accounts for the decreased thalamic volume documented by MRI in living infants with CHD.20 Clearly, advanced neuropathological studies of the brain in infants with CHD are needed to determine conclusively whether these infants sustain the same changes in the white matter and nuclear structures described in preterm infants. Nevertheless, in view of the similarities in terms of timing and nature of insults, prominence of WMI, and MRI data showing cortical and thalamic underdevelopment, it seems likely that the brain abnormality in infants with CHD will prove to be a complex amalgam of destructive and developmental disturbances, as we have described in preterm infants.16 Indeed, the term coined for the combination of white matter and neuronal/axonal abnormalities in premature infants, the “encephalopathy of prematurity,”16 perhaps could be appropriately modified in this context to the “encephalopathy of CHD.” 963
THE JOURNAL OF PEDIATRICS
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Neurodevelopmental deficits are common in infants and children with complex CHD. Preoperative neurologic abnormalities are apparent in approximately 40%-50% during the neonatal period.1,41 The most notable later disturbances in children involve cognition. IQ is generally below that of controls, albeit within the average range.1,42 More notably, a variety of cognitive functions are specifically impaired. The anatomic correlates of the cognitive deficits are not entirely understood, but the work of Owen et al in this issue of The Journal20 provides important new insights. Studying 35 infants with complex CHD before surgery by volumetric MRI, the authors identified tissue-specific volumetric disturbances, particularly increased cerebrospinal fluid volume (perhaps secondary to cerebral white matter disturbance) and diminished subcortical gray matter volume (thalamus/ basal ganglia). Importantly, careful neonatal and subsequent neurobehavioral studies identified correlations between the volumetric deficits and specific neurobehavioral measures. Because of the small number of subjects, as the authors suggest, the clinical–anatomic correlations should be considered hypothesis-generating rather than established. Nevertheless, the authors’ work is exciting, detecting volumetric changes in a critical gray matter structure (ie, thalamus) during the neonatal period, perhaps secondary to a combination of destructive and developmental disturbances described earlier, and it demonstrates potentially great value for neonatal MRI screening to identify infants in particular need of early intervention to improve neurologic outcome. The later anatomic correlates of the long-term neurocognitive disturbances in infants and children with CHD are unclear. Follow-up studies of infants with CHD by conventional imaging have shown predominately white matter abnormalities and volume loss43 or apparent “resolution” of earlier detected WMI.7 The small size of the initial focal necrotic lesions of PVL and the subsequent glial scarring and condensation of such lesions likely underlie the later invisibility on MRI. More importantly, however, a recent study of 49 adolescents with transposition of the great arteries by advanced MRI microstructural analysis showed widespread cerebral white matter microstructural abnormalities.44 Thus, despite scant evidence of overt white matter abnormalities on conventional MRI, widespread reductions in fractional anisotropy in cerebral white matter have been demonstrated. The structures most affected (superior and inferior longitudinal fasciculi, inferior occipitofrontal fasciculus, and uncinate fasciculus) are corticocortical tracts that develop rapidly in the third trimester,16 the time of evolution of brain abnormalities in the fetus with CHD. These tracts play critical roles in the specific neurocognitive deficits identified in children with CHD.44 The microstructural MRI findings suggest abnormal development of axons and myelin and are consistent with the mechanisms identified in preterm infants. Thus, the concept of early destructive influences leading to permanent developmental deficits is supported in infants with CHD, as in preterm infants. The possibility that the subsequent anatomic deficits in CHD are related in considerable part to disturbances in brain development, especially connectivity and circuitry, has impli964
Vol. 164, No. 5 cations for interventions. Thus, therapies that can help shape circuitry and enhance plasticity could be especially important in infants and children with CHD. Although discussed appropriately elsewhere,45 intervention programs directed at cognitive, behavioral, and attentional functions seem to be critical. The sophisticated MRI techniques described earlier may allow selection in the neonatal period for such interventions and perhaps in the future for specific pharmacologic and even cellular therapies directed at improving neuronal, axonal, and myelin development. n Joseph J. Volpe, MD Bronson Crothers Distinguished Professor of Neurology Harvard Medical School Boston Children’s Hospital Boston, Massachusetts *Reprint requests: Joseph J. Volpe, MD, Boston Children’s Hospital, 3 Blackfan Circle, CLS 13070, Boston, MA 02115. E-mail: joseph.volpe@childrens. harvard.edu
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