Congenital heart disease (CHD) accounts for approximately 5-8% of all live births each year and is the most common congenital anomaly and an important cause of death in children with CHD. While the survival rate of children with CHD has increased over the past decades with improvements in cardiac surgical techniques and related perioperative management, the functional status of the nervous system in some children is not negligible, with nearly half of the pediatric survivors having extensive neurological developmental deficits.
Although these defects are often attributed to surgical brain injury, previous studies have shown that more than half of infants with CHD already have neurological abnormalities prior to neonatal surgery, and the causes of these abnormalities are multifactorial and may be related to genetic abnormalities, hypoxic injury, or embolism. Therefore, this paper provides a review of the effects of CHD on the brain development of children with CHD during the fetal period as well as during infancy, including intrauterine brain development disorders, cerebral blood flow abnormalities, genetic abnormalities, congenital abnormalities of neurological function and tissue structure in infants and children, and acquired brain injury.
1.Fetal cerebral blood flow abnormalities in CHD
Cardiac malformations cause alterations in intracardiac blood circulation, which are responsible for abnormal cerebral blood flow. The principles are complex and may be related to the oxygen content of cerebral blood flow, cardiac function, and cardiac output. Cardiac malformations may cause inadequate blood and oxygen supply to the fetal brain. If the compensatory mechanisms of fetal circulatory self-protection are not effectively compensated, the cerebral vasculature will self-regulate, and its self-regulatory mechanisms are considered to be a precursor of abnormal neurological development. Because cerebral vasodilation appears before fetal oxygenation is involved, it can be a timely response to fetal high risk as well as fetal circulatory abnormalities. However, in other words, the protective mechanism is not sufficient for with maintaining normal brain development.
Donofrio et al. applied Doppler ultrasound techniques to measure the resistance and pulsatility indices of the fetal cerebral vasculature [1], and it has been suggested that these indices are lower than normal and are associated with fetal growth retardation and abnormal neurodevelopment [2-6]. The ratio of these indices of cerebral artery/umbilical artery is used to evaluate the autoregulatory capacity of cerebral vessels and is a better predictor of intrauterine growth retardation and poor neurological prognosis than any single index.Arbeille et al [4] found that the resistance of cerebral and umbilical arteries decreased linearly after 15 weeks of gestation in normal fetuses, but the resistance of cerebral artery was always higher than that of umbilical artery. The cerebral artery/umbilical artery resistance ratio was >1 in 97% of normal fetuses in this study and <1.0 in 88% of developmentally delayed fetuses.
Cerebral artery resistance and cerebral artery/umbilical artery resistance ratios were lower in CHD fetuses compared to normal fetuses. The highest prevalence of abnormal cerebral artery/umbilical artery resistance ratio was found in fetuses with left and right heart dysplasia syndrome (58%, 60%), followed by TOF and TGA (45%, 25%).Gramellini et al [5] found that a cerebral artery/umbilical artery pulsatility index ratio <1.08 in fetuses after 30 weeks of high-risk pregnancy was accurate for the diagnosis of intrauterine growth retardation 70% and 90% for the prediction of poor perinatal fetal prognosis.
Guorong et al [7] found that a normal cerebral artery pulsatility index and an increased umbilical artery/cerebral artery pulsatility index ratio in CHD fetuses suggested a greater redistribution of blood in favor of the brain, whereas a decreased cerebral artery pulsatility index in CHD fetuses with congestive heart failure suggested a decrease in cardiac function can lead to cerebral vasodilation.
In addition, the application of Doppler ultrasound techniques to detect diastolic retrograde flow in the fetal aortic isthmus can also indirectly predict fetal neurological dysplasia in high-risk pregnancies. In fetal life, diastolic aortic isthmus blood flow is directed toward the descending aorta. Diastolic reverse flow in the aortic isthmus may be attributed to placental disease and/or reactive dilation of the cerebral vasculature due to cerebral hypoxia from various causes, including CHD, resulting in an altered cerebral/placental vascular resistance ratio [8-10].
2. genetic abnormalities associated with children with CHD
In known genetic chromosomal disorders such as Down’s syndrome, DiGeorge’s syndrome, Turner’s syndrome, William’s syndrome, velocardiofacial (VCFS) syndrome, etc. are usually associated with varying degrees of cardiovascular malformations and developmental delays [11]. Children with Down syndrome all have varying degrees of neurodevelopmental impairment and the prevalence of cardiovascular malformations is approximately 40%, with endocardial cushion defects and ventricular septal defects being the most common. Children with Turner’s syndrome have reduced IQ associated with aortic valve malformation and aortic stenosis. branch stenosis. In addition, Gaynor et al [12] found that genetic polymorphisms in apolipoprotein E can affect the ability to repair the nervous system after central nervous system injury. carriers of the APOEe2 allele had significantly lower psychomotor development scores, suggesting a genetic sensitivity to brain injury.
3. Congenital abnormalities of neurological function in children with CHD
Limperopolous et al [13-14] prospectively examined preoperative neurological function in children with CHD and found abnormalities in 50% of newborns and 38% of infants. chock et al [15] reported a preoperative incidence of severe neurological abnormalities (e.g. epilepsy, abnormal tone, choreoathetosis) in CHD children of about 17%. glaucer et al [16] performed a neurological examination in children with hypoplastic left heart syndrome (HLHS) and found neurological abnormalities or epilepsy in 38% of the children. In neonates, neurological abnormalities included hypotonia, hypertonia, hypersensitivity, motor incoordination, and inattention.
Sixty-two percent of newborns have impaired emotional self-regulation, 34% have feeding difficulties, and 5% have epilepsy. In infancy, neurological abnormalities include hypotonia, drifting head, lethargy, fidgeting, irritability, motor incoordination, feeding difficulties, and often autism.Limperoupoulos et al [17] performed preoperative neurological function and EEG in 60 infants with CHD and found epileptiform manifestations in 19%. In children with CHD, although most of their intellectual development is within the normal range, they often lag behind healthy children of the same age, and children with cyanotic CHD are often born with more severe intellectual impairment than non-cyanotic children due to chronic hypoxia and malnutrition, and may also have language dysfunction and learning disabilities or even mental retardation. Bjarnason-Wehrens et al [18] used a physical coordination test to assess the development of the motor system in 194 children with CHD, aged (10.0 ± 2.7) years, and 455 healthy controls, aged (9.6 ± 2.17) years, and found that 26.8% of the CHD group had mild motor system disorders and 31.9% had severe motor system disorders, compared with 16.5% and 5.5% of the healthy controls, respectively. The CHD group significantly lagged behind the healthy control group (P<0.01).
4. Congenital abnormalities in the organization of the nervous system in children with CHD
The prevalence of central nervous system abnormalities is also high in children with CHD without a clear genetic syndrome, which may be associated with brain malformations, brain damage and delayed brain development due to unspecified genetic abnormalities and hemodynamic abnormalities [19-20]. Autopsy of children with HLHS revealed a high prevalence of CNS abnormalities in this disease, with 27% having significant microcephaly, 27% having abnormal cortical formation, and 10% having severe CNS malformations (e.g., hypoplasia of the corpus callosum as well as anencephaly of the forebrain) [20]. The presence of structural CNS abnormalities can be detected preoperatively by physical as well as neuroimaging methods in children with CHD in vivo. CNS abnormalities that can be detected by transcranial Doppler ultrasound include brain atrophy [21], calcification of the basal ganglia [21-22], and dilatation of the ventricles and subarachnoid space [15,19,22]. And new MRI techniques, such as magnetic resonance spectroscopy (MRS) with diffusion tensor imaging (DTI), provide a new window for the study of brain development in living neonates.
MRI has a high detection rate of brain developmental abnormalities in children with preoperative CHD. Licht [23] et al. used MRI in 25 children with CHD and found brain damage in 53%, including microcephaly (24%), incomplete closure of fontanelle (16%), and periventricular leukomalacia (PVL) (28%). Microcephaly is more prevalent in cyanotic neonates with oxygen saturation less than 85%. Whereas white matter damage is characteristic of brain damage in preterm infants [24] and is seen in CHD term infants, it has been suggested that the abnormality may begin in embryo with reduced cerebral oxygen transport, a theory further supported by studies of intrauterine cerebral blood flow in CHD fetuses. In addition, Licht et al [25] used MRI to measure head circumference and the maturation score of the brain (including four parameters: myelin formation, intracortical folding, degeneration of the migrating zone of neurokeratinocytes, and the presence of germinal matrix tissue) in HLHS and TGA term newborns and found that the head circumference of the affected children was smaller than that of the control group by one standard deviation, and the total brain maturation score was significantly smaller than that of the control group.This study suggests that term newborns with CHD This study suggests that maturation is delayed by about one month in full-term newborns with CHD compared with normal children in the control group.
MRS and DTI allow the study of microstructural and metabolic abnormalities in the brain, and found that the ratio of N-acetylaspartate to choline increases with brain maturation, while the ratio of lactate-to-choline will decrease with brain maturation, the mean diffusion value will also decrease with brain development, and the various anisotropic scores of white matter pathways increase with brain development. brain development in CHD term infants is delayed, and more than half of CHD More than half of children with CHD have preoperative neurological abnormalities. Miller et al [26] compared 41 full-term CHD neonates (29 with transposition of the great arteries and 12 with VSD) with 16 control infants born at a similar time and found that 13 CHD infants had white matter damage, while control neonates did not; CHD infants had a 10% decrease in N-acetylaspartate to choline ratio, a 28% increase in lactate-to-choline ratio, a 4% increase in mean diffusion value There was no significant correlation between preoperative brain damage on MRI and MRS or DTI findings, because microstructural and metabolic abnormalities in the brain are not seen on conventional MRI.
In addition, MRI and MRS can be used to detect abnormal brain development during fetal life. CHD fetuses had smaller whole brain volume and cranial cavity volume and slower increase in N -acetylaspartate/choline ratio than control fetuses. Multifactorial analysis concluded that whole-brain volume was independently associated with cardiac malformations as well as through cardiac output, and that N -acetylaspartate/choline ratio and lactate levels predicted cardiac malformations with reduced aortic arch collateral blood flow. Also, this study suggests that late pregnancy CHD fetuses, especially in the presence of reduced cardiac output, generally show evidence of delayed brain development, metabolic impairment, and reduced whole brain volume by imaging.
5. Acquired brain damage in children with preoperative CHD
In addition to congenital neurological retardation, hemodynamic changes in children with CHD, either hypoxic or non-hypoxic, can lead to acquired brain damage. 45% of children with HLHS (half without surgical treatment) were found to have cerebral ischemic-hypoxic injury and/or intracranial hemorrhage by Glauser et al. Cerebral ischemic-hypoxic injury includes: cerebral necrosis, periventricular leukomalacia, and brainstem necrosis. These injuries can be detected by transcranial Doppler ultrasound studies, which show ventricular hemorrhage, cerebral atrophy, neurobasal ganglia calcification, ventricular and subarachnoid dilatation, and ischemic changes.Licht et al [23] found PVL in 28% of children with CHD on preoperative MRI.
Mahle et al [28] similarly found that 25% of children with CHD had significant ischemic injury on preoperative MRI, including PVL or cerebral infarction; the presence of cerebral ischemia was further demonstrated by the finding of persistent elevated lactate on MRS in 50% of children. More recently, McQuillen et al [29], using neuroimaging evidence, found that in 39% of children with brain injury, the stroke was secondary to white matter injury. This study suggests a high prevalence of cerebral white matter injury, especially PVL, and that other causes of neonatal ischemia and hypoxia should be noted; some of the acquired brain damage in children with CHD may be related to malformations of the cerebrovascular bed and/or abnormal brain development; it may also be due to the susceptibility of the affected children to damage of cerebral white matter cells, similar to the cellular fragility of preterm infants.
In addition, in addition to neuroimaging evidence, various serum biological indicators can also detect acquired brain damage in children with CHD. It has been shown that high levels of serum lactate are a marker of overall perfusion deficit and that this indicator is consistently elevated in children with preoperative CHD [30]. Glial-derived protein S100B is associated with cerebral ischemia, and S100B levels are elevated in children with preoperative CHD [31-33], with HLHS being the highest and negatively correlated with the internal diameter of the ascending aorta, and the results of this study further suggest that the amount of aortic collateral blood in fetuses and infants with HLHS directly affects cerebral perfusion as well as contributes to preoperative ischemic brain injury [33]. In addition, children with CHD also have persistently elevated preoperative pro-inflammatory cytokines IL-6 and persistently decreased IL-10 [34].
Conclusion
Infants with CHD often have neurological abnormalities before undergoing surgery in the neonatal period, and this abnormality is the result of early intrauterine developmental impairment due to CHD, as well as further damage later in life, for reasons that are thought to be multifactorial and related to genetic abnormalities, hypoxic brain damage or embolism. Research in this area has been conducted abroad and has yielded some results, but in China, most studies still focus on post-surgical neurological damage, with less attention paid to preoperative neurological abnormalities. It is hoped that the study of preoperative neurological abnormalities in children with CHD will provide a theoretical basis for future research on early intervention in fetuses with special cardiac anomalies to improve early neurological development by altering their hemodynamics and increasing cerebral oxygen supply.