Discussion

Current advances in the diagnosis, surgical management, and post-operative care of children with HCHD have allowed the vast majority of them to reach adulthood. ^{Reference Marelli, Miller, Marino, Jefferson and Newburger1} Regrettably, however, in parallel to survival HCHD children are at high risk and typically suffer from neurodevelopmental disorders such as inattention, cognitive performance, and executive functions. ^{Reference Dimitropoulos, McQuillen and Sethi5,Reference González, Pliego, Rodríguez, Mendieta and Otero24, Reference Lim, Kingdom and Saini25} Due to the underlying and pervasive condition of hypoxia, brain injuries continue developing with survival. Another observation made among HCHD newborns is that of a reduction in brain size. Taking the negative neurodevelopmental outcomes altogether, all of them have been strongly correlated to the condition of chronic and persistent hypoxia with this last condition resulting from a wide array of simple and complex cardiovascular pathologies. Among those, the foetal and post-natal systemic alterations are key in this respect. ^{Reference Sun, Macgowan and Sled6,Reference Limperopoulos, Tworetzky and McElhinney10,Reference Rudolph14,Reference Kim, Turkington, Kushmerick and Kim26} The reduced body tissue oxygenation fundamentally alters basal metabolism concurrently leading to a general reduction of metabolic energy production. Following this argument, myelination as an end result of lipid synthesis is a biochemical event fundamentally dependent on the existence of adequate metabolic energy reserves. Thus, it is highly likely that the neurotransmission defects determined in this work among HCHD children in essence are the consequence of hypoxia ^{Reference Kim, Turkington, Kushmerick and Kim26} and the manifestation of altered myelination. In this respect, white matter injury is a common issue among preterm neonates and children stricken by HCHD. Histopathologically, in both instances, the lesions are strongly reminiscent of periventricular leukomalacia. ^{Reference Peyvandi, De Santiago and Chakkarapani17,Reference Guo, Duerden and Adams27} Using brainstem auditory-evoked responses as a clinical evaluation tool among children with hypoxic-ischaemic encephalopathy, Romero ^{Reference Romero28} assessed their neurodevelopmental status and neurophysiological profile at the ages of 6 months and later at 2 years. The brainstem auditory-evoked responses of those children showed extended latencies and decrements in amplitude indicating the presence of more extended neurological damage when comparing their results to ours. Jiang et al. ^{Reference Jiang, Liu, Shi, Lin, Bu and Wilkinson29} inform about evident brainstem auditory-evoked response abnormalities in 15 (40.5%) out of 37 children with neurodevelopmental deficits resulting from perinatal asphyxia. Both works ^{Reference Romero28,Reference Jiang, Liu, Shi, Lin, Bu and Wilkinson29} are in agreement in relation to the usefulness of brainstem auditory-evoked responses as a prognostic instrument of the neurodevelopmental outcome.

In the work presented here, the risk posed to cerebral functional integrity by HCHD was assessed through brainstem auditory-evoked responses. The children studied were compromised by a wide variety of severe cardiovascular conditions with all of them showing in common a severe reduction of blood oxygen saturation. There are different kinds of electrophysiological techniques based on the determination of evoked-response potentials and as brainstem auditory-evoked responses themselves; all of them are non-invasive instruments of great value in the assessment of sensory and neural function under normal or pathological conditions. ^{Reference Lauffer and Wenzel30} For instance, brainstem auditory-evoked responses have proved to be a valuable tool in the assessment not only of auditory function integrity but also in the prognosis of neurodevelopmental outcome after perinatal asphyxia, ^{Reference Jiang, Liu, Shi, Lin, Bu and Wilkinson29} also as a successful diagnostic and prognostic method in medical instances as dissimilar as the study of metabolic anomalies, ^{Reference Liu, Li, Chen, Sang and Zhao31} type-2 diabetes mellitus, ^{Reference Sushil, Muneshwar and Afroz32} multiple sclerosis, ^{Reference Leocani, Rovaris and Boneschi33} and others.

Brain stem myelination disturbances were determined among children who either died at birth or in the course of the first three years of life from severe chronic diseases, including congenital heart failure. ^{Reference Dambska and Lauer-Kamionowska34} Among them, the rate of brain stem myelination indicated a disturbed process of maturation. Among those patients with CHD, it is highly likely that chronic hypoxia led to an altered synthesis of myelin sheaths, an event considered to arise independently of neuronal loss or damage. In the study presented here, the results and our point of view are in coincidence with those observations. That is, brainstem auditory-evoked responses of HCHD children showed significantly longer wave latencies and interpeak intervals compared to the control group indicative of altered electrical conduction in the auditory pathway between relay nuclei. As no significant differences in wave amplitudes were determined, this strongly suggests a considerable degree of neuronal cell body preservation. From an electrophysiological point of view, HCHD children present alterations of nerve conductance but not of signal processing; that is, there are defects along the auditory transmission pathway without evidence of gross damage in nuclei relay points, a fact strongly indicative of myelination defects. It is also well-known that neuronal integrity importantly depends on the trophic relationships between neurons and oligodendroglia, therefore if in parallel there is axonal damage this is highly likely to arise in parallel to myelin-forming cell impairment. ^{Reference Dambska and Lauer-Kamionowska34–Reference Fünfschilling, Supplie and Mahad37}

Okutan and colleagues ^{Reference Okutan, Demirkaya, Lenk, Hamamcioğlu, Unay, Vural and Gökçay38} investigated through brainstem auditory-evoked responses the impact of HCHD on brainstem maturation among 23 hypoxic and 22 non-hypoxic children of ages 2 months to 15 years and determined that neural activity was not altered among hypoxic patients compared to their healthy peers. In contrast, hypoxic patients under one year of age had a prolonged I–V interpeak latency, confirming that adequate oxygenation is critical for optimal development. At no other age did they find differences between groups; this is in contrast to our work. In the study presented here, HCHD children presenting severe hypoxia (median blood oxygen saturation, 76%) showed longer latencies of waves I, III, and V, and also longer intervals I-V and III-V at all ages. Sunaga et al. ^{Reference Sunaga, Sone, Nagashima and Kuroume39} reported similar findings working with hypoxic children of ages 1 to 4 years old. The works of Okutan et al., ^{Reference Okutan, Demirkaya, Lenk, Hamamcioğlu, Unay, Vural and Gökçay38} Sunaga et al., ^{Reference Sunaga, Sone, Nagashima and Kuroume39} and this one all determined a statistically significant negative correlation between blood oxygen saturation average level with wave intervals and interpeak latencies (Table 3). In conclusion, chronic hypoxaemia among infants is a leading cause of brainstem alterations most likely related to a progressively altered process of myelination. This leads us to hypothesise that under generalised chronic hypoxia, the detrimental conditions may prevail in areas of the brain where an active post-natal development and myelination are taking place, for instance, in the cerebellum. ^{Reference Altman40}