Neurologic Complications of Congenital Heart Disease and Cardiac Surgery in Children

Delayed Brain Development

Quantitative and qualitative magnetic resonance imaging (MRI) studies demonstrate that brain development is delayed in the context of CHD beginning in fetal life and persisting into childhood. Fetal brain MRI shows progressive impairment of brain volume during the third trimester in fetuses with complex CHD, particularly those with left-sided obstructive cardiac lesions. In addition, fetuses with CHD have significant delays in brain metabolism, specifically the normal increase of brain N -acetyl-aspartate to choline ratios measured by magnetic resonance spectroscopy (MRS); these delays have been shown to be most prominent in fetuses with no antegrade flow in the aortic arch. Brain maturation is delayed by approximately 4 to 6 weeks in full-term newborns with complex CHD such as HLHS or TGA when compared to normal term infants in studies using brain MRI with diffusion-weighted imaging (DWI) and spectroscopy. Morphometry studies have revealed lower total and regional brain volumes in newborns as well as adolescents with CHD compared to controls.

Aberrant cardiac physiology and abnormal blood flow in children with complex CHD is thought to result in delayed brain maturation beginning in the fetal period. Human cardiac development is largely completed by gestational week seven, while human brain development extends over a much longer period of time. In utero brain growth, myelination, and development of neuronal networks are dependent upon nutrients and oxygen pumped by the heart. To support rapid fetal brain maturation, blood flow to the brain increases throughout fetal life. By the third trimester, the brain is estimated to receive one-quarter of the total ventricular output, demonstrating the critical relationship between the heart and the brain. In the normal fetus, oxygenated blood from the placenta flows through the ductus venosus and preferentially streams across the foramen ovale to the left atrium and ventricle, providing highly oxygenated blood to the brain. In fetuses with TGA, the aorta and pulmonary artery are transposed and the highly oxygenated blood flows preferentially to the pulmonary vasculature rather than the cerebral vasculature. Similarly, in HLHS, inadequate left heart structures lead to reversal of blood flow through the foramen ovale with mixing of oxygenated and deoxygenated blood in the right ventricle and, in cases of aortic atresia, retrograde flow in the ascending aorta. This abnormal physiology results in decreased nutrient and oxygen delivery to the brain during critical fetal development.

Combined brain and cardiac MRI to measure fetal blood flow and oxygen saturation can be used to study the relationship between fetal hemodynamics and brain maturation. Fetuses with complex CHD demonstrate significantly lower cerebral oxygenation consumption and reduced brain volume compared with fetuses without CHD, supporting a link between brain hypoxia and impaired brain maturation. A previous investigation found that delayed surgery beyond 2 weeks of age in infants with TGA is associated with impaired brain growth on MRI and slower language development at 18 months of age compared to surgery before 2 weeks of age. Prolonged periods of cyanosis and pulmonary overcirculation in children without early surgical repair may have adverse effects on brain growth and subsequent neurodevelopment.

Co-existing Genetic Disorders and Brain Malformations

Most congenital heart defects are thought to have a genetic basis, and the presence of a genetic condition is an independent risk factor for adverse neurodevelopmental outcome. Currently however, a genetic etiology is identified in only one-third of children with CHD. A few well-described chromosomal disorders (e.g., trisomies 21, 18, and 13), microdeletions (e.g., 22q11), and specific mutations (e.g., Noonan syndrome) account for a minority of patients with CHD and are associated with cognitive impairment. Nonsyndromic genetic abnormalities have also been associated with neurodevelopmental outcome. For example, in infants with complex CHD, the Apolipoprotein E ε2 allele is associated with worse early neurodevelopmental outcome, particularly motor development, independent of patient and operative factors. Currently unknown genetic and epigenetic factors may play an important additional role, as identified patient risk factors account for only about 30 percent of the expected variation in neurodevelopmental outcomes in children with CHD. In a recent study, pathogenic copy number variants were identified in greater than 10 percent of children with single ventricle lesions, only a minority of whom were noted to be dysmorphic on examination by a clinical geneticist. Genetic testing is now considered a part of standard care for all children with complex CHD.

In addition to delayed maturation, many children with CHD have structural brain malformations that may affect neurodevelopment. The prevalence of brain dysgenesis in children with CHD approaches 30 percent in some fetal MRI and autopsy studies, and varies according to the severity of CHD and the specific underlying cardiac lesion. Infants with HLHS may be at particular risk of developmental brain lesions including microcephaly, focal cortical dysplasia, agenesis of the corpus callosum, and holoprosencephaly. Brain and cardiac anomalies may occur together as a result of genetic and environmental factors, although in many children the specific genes or combination of genes that influence early anomalous development are not identified.

“Silent” Brain Injury in the Neonate

Neonates with complex CHD are at risk for acquired brain injury both pre- and postoperatively. The most common brain injuries observed in newborns with CHD are focal white matter injury (WMI) and small focal infarcts (defined as <1/3 of the arterial distribution), which are often missed by screening cranial ultrasound and more reliably detected with conventional MRI ( Fig. 4-1 ). This type of brain injury typically occurs in the absence of neurologic signs and symptoms (i.e., “clinically silent”). Several large prospective studies using pre- and postoperative brain MRI to identify acquired brain injury in newborns with CHD have shown that up to 60 percent demonstrate evidence of injury. Those with cyanotic heart disease are at the greatest risk.

WMI in term neonates with CHD is characterized by punctate periventricular lesions associated with T1 hyperintensity with or without DWI lesions suggesting acute injury. This pattern of injury is similar to that seen in premature infants termed “periventricular leukomalacia.” The mechanism of brain injury in premature infants is thought to be due mainly to brain immaturity; oligodendrocytes during the third trimester are selectively vulnerable to hypoxia-ischemia, and therefore premature infants have a white matter-predominant pattern of injury. This mechanism of injury likely plays a key role in neonates with CHD who have preoperative brain injury. Qualitative MRI measurements of maturity have suggested that brain immaturity is a risk factor for both pre- and postoperative brain injury. Quantitative MRI techniques (e.g., diffusion tensor imaging and MRS), however, have demonstrated an association between brain immaturity and the risk of preoperative, but not postoperative, brain injury. Given that WMI impacts neurodevelopmental outcomes, there remains a need for in utero strategies to improve brain development.

Estimates of the prevalence of preoperative brain injury in neonates with CHD requiring surgery range from 25 to 50 percent. Reported risk factors for preoperative brain injury include hypoxemia and time to surgery, preoperative base deficit, cardiac arrest, male sex, and the presence of aortic atresia (e.g., lack of antegrade flow in the aorta). Balloon atrial septostomy in neonates with TGA has been associated with preoperative AIS in some studies. Worse severity of preoperative injury has been shown to be significantly associated with higher neonatal illness severity scores, lower preoperative oxygen saturation, hypotension, and septostomy. The clinically “silent” brain injuries identified preoperatively in neonates with CHD have a low risk of progression with surgery and cardiopulmonary bypass, and in most cases should not delay clinically necessary cardiac surgery, though expert multidisciplinary discussion is required for each case.

New postoperative WMI is common, and several intra- and postoperative risk factors have been identified. Some, but not all, studies have identified circulatory arrest as a risk factor for new postoperative WMI on MRI. Other reported intraoperative risk factors include the method of blood pH management (alpha stat versus pH stat), hematocrit level, and maintaining regional cerebral perfusion during aortic arch reconstruction. In the postoperative period, overall hemodynamic stability plays an important role in mitigating the risk of new brain injury. Hypotension and hypoxemia related to low cardiac output syndrome increase the risk of brain injury. Patients with single ventricle heart disease in particular carry a higher risk of postoperative hemodynamic instability, correlating with higher risks for both postoperative brain injury as well as overall morbidity and mortality.

The “clinically silent” descriptor is misleading because these brain injuries influence later neurodevelopmental outcomes. A recent prospective longitudinal cohort study enrolled full-term newborns with single ventricle physiology or TGA, obtained pre- and postoperative MRI, and then conducted neurodevelopmental testing at 12 and 30 months of age. Children with moderate to severe WMI in the neonatal period were found to have significant motor impairments at 30 months of age. However, no association was seen between small focal infarcts and outcome. Others have found that moderate-to-severe WMI is associated with reduced short-term cognitive scores and lower full-scale IQ during early childhood compared to the scores of those who have no or mild WMI.