Background: Neonatal seizures remain a significant cause of morbidity and mortality worldwide. The past decade has resulted in substantial progress in seizure detection and understanding the impact seizures have on the developing brain. Optical monitoring such as cerebral near-infrared spectroscopy (NIRS) and broadband NIRS can provide non-invasive continuous real-time monitoring of the changes in brain metabolism and haemodynamics. Aim: To perform a systematic review of optical biomarkers to identify changes in cerebral haemodynamics and metabolism during the pre-ictal, ictal, and post-ictal phases of neonatal seizures. Method: A systematic search was performed in eight databases. The search combined the three broad categories: (neonates) AND (NIRS) AND (seizures) using the stepwise approach following PRISMA guidance. Results: Fifteen papers described the haemodynamic and/or metabolic changes observed with NIRS during neonatal seizures. No randomised controlled trials were identified during the search. Studies reported various changes occurring in the pre-ictal, ictal, and post-ictal phases of seizures. Conclusion: Clear changes in cerebral haemodynamics and metabolism were noted during the pre-ictal, ictal, and post-ictal phases of seizures in neonates. Further studies are necessary to determine whether NIRS-based methods can be used at the cot-side to provide clear pathophysiological data in real-time during neonatal seizures.

Neonatal seizures are commonly associated with acute perinatal brain injury, while understanding regarding the downstream molecular pathways related to seizures remains unclear. Furthermore, effective treatment and reliable biomarkers are still lacking. Post-translational modifications can contribute to changes in protein function, and post-translational citrullination, which is caused by modification of arginine to citrulline via the calcium-mediated activation of the peptidylarginine deiminase (PAD) enzyme family, is being increasingly linked to neurological injury. Extracellular vesicles (EVs) are lipid-bilayer structures released from cells; they can be isolated from most body fluids and act as potential liquid biomarkers for disease conditions and response to treatment. As EVs carry a range of genetic and protein cargo that can be characteristic of pathological processes, the current study assessed modified citrullinated protein cargo in EVs isolated from plasma and CSF in a piglet neonatal seizure model, also following phenobarbitone treatment. Our findings provide novel insights into roles for PAD-mediated changes on EV signatures in neonatal seizures and highlight the potential of plasma- and CSF-EVs to monitor responses to treatment.

Brain tissue temperature is a dynamic balance between heat generation from metabolism, passive loss of energy to the environment, and thermoregulatory processes such as perfusion. Perinatal brain injuries, particularly neonatal encephalopathy, and seizures, have a significant impact on the metabolic and haemodynamic state of the developing brain, and thereby likely induce changes in brain temperature. In healthy newborn brains, brain temperature is higher than the core temperature. Magnetic resonance spectroscopy (MRS) has been used as a viable, non-invasive tool to measure temperature in the newborn brain with a reported accuracy of up to 0.2 degrees Celcius and a precision of 0.3 degrees Celcius. This measurement is based on the separation of chemical shifts between the temperature-sensitive water peaks and temperature-insensitive singlet metabolite peaks. MRS thermometry requires transport to an MRI scanner and a lengthy single-point measurement. Optical monitoring, using near infrared spectroscopy (NIRS), offers an alternative which overcomes this limitation in its ability to monitor newborn brain tissue temperature continuously at the cot side in real-time. Near infrared spectroscopy uses linear temperature-dependent changes in water absorption spectra in the near infrared range to estimate the tissue temperature. This review focuses on the currently available methodologies and their viability for accurate measurement, the potential benefits of monitoring newborn brain temperature in the neonatal intensive care unit, and the important challenges that still need to be addressed.