Kim Annink

104 Chapter 5 hippocampal volumes (6,8,26). For example, Gadian and colleagues examined a smaller group of children and found that severe acute hypoxia was associated with reduced hippocampal volumes and memory problems. This was reported in six school-aged children with memory problems that had experienced hypoxia at, or shortly after, birth and showed bilateral reduction of hippocampal volumes of approximately 40% (6,8). Using MR spectroscopy, Mañeru et al. found lower N-acetyl aspartate concentrations and N-acetyl aspartate/choline ratios in the anterior hippocampus of adolescents following HIE, indicating biochemical damage (7). Furthermore, they also confirmed that infants with moderate HIE have bilateral hippocampal atrophy (26). The trend of decreased hippocampal volumes in mild HIE has not been published previously. This finding might explain that several studies found decreased cognitive and memory functions after even mild HIE compared to controls (12). Besides perinatal asphyxia, other conditions leading to neonatal hypoxia, namely acute respiratory distress (ARD) (27), prematurity (28) and congenital heart disease (29), have been associated with decreased hippocampal volumes later in life. Furthermore, smaller hippocampal volumes were found in 12-year-old extracorporeal membrane oxygenation (ECMO) survivors compared to controls (30). The underlying mechanism explaining the vulnerability of the hippocampus to hypoxia is unknown. It has been hypothesized that the high expression and potentiation of N-methyl-D-aspartate (NMDA) receptors in the hippocampus lead to this higher vulnerability (31–34). During hypoxia there is an excessive release of glutamate, leading to NMDA activation (31). NMDA activation causes an influx of calcium into the cell, resulting in neuronal death by the induction of apoptosis and necrosis (31). Furthermore, NMDA activation induces astrogliosis and microglial reactions, leading to impaired recovery of neurons (32). The children reported in this cohort were part of a larger study population whose neuropsychological performance has been published previously (10). In the current subgroup of children who underwent MRI, a significantly impaired IQ and long-term episodic memory in the moderate HIE group was found compared to controls. This is in line with the previously reported data , although we now had smaller subgroups (10). Also, a trend of impaired memory functioning in mild HIE was found for some long-term episodic memory subtests. With a mean of 112, IQ scores in controls were significantly higher than in children with HIE and significantly higher than