Neurodevelopmental Impairment in Specific Neonatal Disorders

Introduction

Neurodevelopmental impairment (NDI) is an important long-term complication for neonatal intensive care unit (NICU) graduates. Neonates admitted to the NICU are undergoing a critical period of neurologic development, and any insult to the brain could lead to detrimental neurodevelopmental outcomes. The improvement in high-risk neonates’ survival rates due to neonatal care advancements has highlighted the importance of studying long-term neurologic prognosis. NDI can occur in cognitive, motor, vision, hearing, or language domains and can seriously impair the child's social, academic, and behavioral functioning. To optimize outcomes, there should be a obligation to follow-up and ameliorate the neurodevelopmental outcomes of the NICU survivors.

This chapter discusses the epidemiology and pathophysiology of NDI in the context of five conditions frequently seen in the NICU. These are hypoxic-ischemic encephalopathy (HIE), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), and sepsis. This review includes evidence from our own quality-improvement studies and an extensive literature review of the PubMed, Embase, and Scopus databases. To avoid bias in identifying studies, keywords were short-listed a priori from anecdotal experience and PubMed's Medical Subject Heading thesaurus. In this review, considerable overlap is demonstrated in the neurodevelopmental manifestations and neurologic abnormalities among neonatal conditions, which indicates multifactorial pathogenesis of NDI.

Pathophysiology

The underlying mechanism of NDI in preterm NICU infants could be related to anatomic and physiologic vascular abnormalities associated with the relative immaturity of the brain ( Fig. 96.1 ). Cerebral white matter is especially susceptible to prematurity-related vascular insults. Periventricular white matter injury (PWMI) such as that seen in the lesions in Figs. 96.2 and 96.3 is a leading cause of long-term NDI. ^, These lesions frequently lead to motor impairment. PWMI is attributed to cerebral white matter blood flow interference because of the immature vasculature; ischemic white matter is vulnerable to free radical–mediated injury to the oligodendrocyte progenitors. The severity of white matter abnormality in neonatal sepsis depends on the timing (postmenstrual age) of diagnosis, with more severe pathology in infants developing sepsis before 28 weeks. Figs. 96.4 and 96.5 show the evolution of white matter lesions over longer periods of time.

Oligodendrocyte progenitors are particularly susceptible to ischemia and inflammation in the process of preterm encephalopathy. The loss of lineage-specific progenitors and the consequent reduction in the number of mature oligodendrocytes can impair cerebral myelination. In animal models, cerebral hypoperfusion and hypoxia-ischemia have shown abnormalities in oligodendrocyte progenitor cells, periventricular white matter, and cortical gray matter. Along similar lines, excessive glutamate release during neonatal stress in the NICU could lead to excitotoxic damage to the oligodendrocyte progenitors and cause PWMI. In addition, cerebral maturation is impeded in NEC, as evidenced by a lower rate of increase of the N-acetyl cysteine–choline ratio in affected infants than in unaffected controls. Periventricular injuries could also be a consequence of moderate-severe IVH.

Intestinal inflammation could directly affect the severity of neuroinflammation ( Fig. 96.6 ). Immunogenic systemic inflammatory reaction with an increase in cytokines such as tumor necrosis factor might contribute to the pathogenesis of PWMI. Elevated plasma and cerebrospinal fluid interleukin-1 beta and tumor necrosis factor-alpha increase the risk for white matter injury in preterm neonates with early-onset sepsis. Biouss et al. reported that neonatal mice with NEC had reduced cortical girth, abnormal cell apoptosis, a decreased population of mature neurons and oligodendrocytes, and defective development of neural progenitor cells. Two other experimental models showed that animal neonates with NEC develop neuroinflammation associated with altered hippocampal gene expression, abnormal myelination, and cognitive deficits due to activation of microglial cells. ^,

Furthermore, Niño et al. explained that inflamed intestinal tissue in NEC releases toll-like receptor 4 activators such as lipopolysaccharides that propagate neuroinflammation and promote oxidative stress; this, as a result, leads to reduced myelination in the hippocampus, midbrain, and corpus callosum. Haynes et al. hypothesized that free-radical oxidative and nitrative (due to nitric oxide) damage to oligodendrocyte progenitor cells contributes to PWMI. The studies described above indicate that early surgical removal of necrotic intestinal tissue in NEC could lower the severity of neuroinflammatory response in the brain, supporting a dose-related effect.

Other potential pathogenic mechanisms contribute to NDI development in NICU infants; poor nutrition and decreased growth associated with a prolonged stay in a NICU and exposure to surgery and anesthetics could contribute to abnormal neurologic development. Ehrenkranz et al. demonstrated that growth velocity during NICU admission was inversely associated with cerebral palsy (CP) and NDI incidence in extremely low birth weight (ELBW) infants. Besides, poor nutrition and inadequate caloric intake in preterm infants can lead to poor head growth, representing poor neurologic development. It is important to note that antenatal steroids reduce the risk of NDI in extremely preterm infants partially by reducing the incidence of IVH and cystic periventricular leukomalacia. A summary of the most frequently seen magnetic resonance imaging (MRI) prognostic biomarkers is shown in Tables 96.1 and 96.2 .

Hypoxic-Ischemic Encephalopathy