The predictive role of therapeutic hypothermia in epilepsy and neuromotor development in hypoxic–ischemic encephalopathy

Objective: The aim of this study was to evaluate the predictive effect of therapeutic hypothermia on long–term epileptic seizure development and neuromotor outcomes in newborns diagnosed with hypoxic–ischemic encephalopathy (HIE). Materials and Methods: This ambidirectional observational study included 110 patients diagnosed with stage II–III HIE, admitted to the Neonatal Intensive Care Unit of Inönü University Turgut Özal Medical Center between 2013 and 2023, who received or not receive therapeutic hypothermia. Clinical, laboratory, imaging, and electroencephalogram (EEG)/amplitude–integrated electroencephalogram (aEEG) findings from the neonatal period were reviewed retrospectively. Subsequently, patients were re–evaluated at the pediatric neurology outpatient clinic, where neurological examinations, seizure history, and developmental milestones were assessed. Neurodevelopmental status was measured using the Denver II Developmental Screening Test. Results: The average age of patients assessed in the pediatric neurology clinic was 79.52 ± 30.28 months. Neurological findings such as microcephaly, positive Babinski sign, hypertonia, hyperactive deep tendon reflexes (DTR), quadriplegia (p<0,001), dystonia (p=0,001), and positive clonus reflex (p=0,003) were significantly more common in patients who did not receive hypothermia treatment. According to the logistic regression analysis, patients with abnormal neurological examination findings during the neonatal period had a 22.5-fold higher risk of having abnormal neurological examination findings in the pediatric neurology outpatient clinic (OR: 22.512; 95% CI: 2.905–174.451; p=0.003). Additionally, this risk increased 9.05-fold in patients who did not receive hypothermia treatment (OR: 9.052; 95% CI: 3.029–27.048; p<0.001). Epileptic seizures developed in 65% of the patients who did not receive hypothermia treatment. 83,3% Of the patients who experienced multiple seizures per day did not receive therapeutic hypothermia. Of the patients whose epileptic seizures persisted since the neonatal period, 57.2% had not received hypothermia treatment (p<0,001). The prevalence of epileptic seizures was found to be significantly lower in patients who received hypothermia treatment (p<0,001). The majority of patients who experienced more than one epileptic seizure per day were found not to have received hypothermia treatment (p<0,001). Among 21 patients who had seizures during the neonatal period but did not experience recurrence during follow–up, 95.2% had received hypothermia treatment. According to the logistic regression analysis, the risk of epileptic seizures observed in the pediatric neurology outpatient clinic was 15.61 times higher in patients who did not receive hypothermia treatment (OR: 15.619; 95% CI: 4.903–49.759; p<0.001). In patients with abnormal neurological examination findings during the neonatal period, this risk increased 8.88 times (OR: 8.880; 95% CI: 1.952–40.408; p=0.005). Furthermore, significant developmental delays were noted in early milestones, including head control (p<0,001), unsupported sitting (p<0,001), ambulation (p<0,001), first words (p<0,001), and two–word sentence formation (p<0,001). According to the Denver II test, 63.2% of patients who did not receive hypothermia therapy exhibited severe developmental delays in both personal-social and gross motor domains (p<0,001). Conclusion: The findings suggest that therapeutic hypothermia affects a significant role in reducing epileptic seizure development and improving long–term neurodevelopmental outcomes in patients with HIE. Those who did not receive hypothermia treatment exhibited a higher incidence of epilepsy and substantial delays in neuromotor development. Thus, initiating hypothermia therapy promptly in eligible HIE cases may substantially improve neurological prognosis and decreasing the risk of epilepsy. Keywords: Hypoxic-ischemic encephalopathy, Therapeutic hypothermia, Epilepsy, Neurodevelopment, Newborn, Denver II test.