Kim Annink

267 General discussion / Conclusions & clinical implications / Future directions Long-term follow-up Atrophy of the Papez circuit, including the hippocampus, mammillary bodies and fornix, was in our studies associated with school-age cognitive and memory problems in both children treated with and without therapeutic hypothermia. It would be interesting to assess atrophy of the Papez Circuit in children with HIE included in one of the randomized controlled trials for therapeutic hypothermia and compare the atrophy between hypothermia treated infants and controls. Preclinical studies can also help to investigate the effect of therapeutic hypothermia and other add-on therapies on the circuit of Papez. In the Netherlands, infants with HIE are currently followed in the outpatient clinics until 5.5 years of age. As shown in this thesis and by others, some deficits, such as memory problems or behavioral problems, only become evident at school-age (1,30–32,66,67). Longer follow-up in the outpatient clinic can be useful to screen for these deficits, but this can also be done by other institutions such as school, the rehabilitation center, the local child health care center or the family doctor. Knowledge about these deficits can create awareness that enables earlier detection of problems and earlier therapy or rehabilitation. More research is needed to establish the best therapies to improve memory and executive functioning in these children. In clinical trials, the primary outcome is often death, neurodevelopmental outcome at two years of age or epilepsy. These are important outcomes, but might not reveal the overall neuroprotective effect of interventions. To assess the actual effect of new interventions, follow-up of patients into school-age (or even up to adulthood) is recommended including a full neuropsychological assessment including memory, executive functioning and behavior. Also the impact on the family might be worthwhile to investigate. Furthermore, there are no follow-up studies of infants with HIE into adulthood, investigating the presence of psychiatric disorders, career opportunities and social functioning. Infants that were born extremely preterm and term infants with a very low birth weight are known to have an increased risk for developing psychiatric disorders (68). In the future, when the first patients with HIE that were treated with therapeutic hypothermia have reached adulthood, it is important to look further into their adulthood outcome. 12