Welcome to the 9th EAPS Congress Programme Scheduling

Abstract Body

Despite treatment with therapeutic hypothermia (HT) in developed countries, only ~50% of babies with moderate-severe neonatal encephalopathy (NE) survive without without cerebral palsy or neurocognitive impairment. Novel, safe and effective adjunct therapies are needed. Teatment needs to target each phase of the evolving injury.

In the last 2 years twe have learned much. In 2021, the HELIX trial suggested that HT is not safe and effective in LMIC, where the main burden (>96%) of NE occurs. In 2022, the results of the HEAL trial, using Epo as an adjunct with cooling in a large Phase III RCT, suggested that Epo does not augment HT protection. There is increased understanding around sex dimorphism and the different cell death pathways in males and females; will neuroprotection be different according to sex?

There are several ongoing neonatal neuroportection trials in high income settings. In my talk I will focus on two main neuroprotective therapies to be used as adjuncts with HT: Melatonin and Mesenchymal Stem Cells (MSC). Melatonin is a powerful antioxidant with robust protection at pharmamcological levels in preclinical models as a single agent and combined with HT. I will discuss the translational pathway and plans for Phase I/II RCTs. I will also discuss our large animal studies with human umbilical MSC given intranasally as an adjunct with HT. I will discuss promising therapeutic agents for use in LMIC as single or combined therapies, in particular Azithromycin.

Where will be be in 5 years? I will discuss steps we need to take to optimize neuroprotection over the next 5-10years. Factors that need to be considered include: (i) timing of therapy (early or late or both); (ii) adequate therapeutic levels and importance of PK studies; (iii) sex specific therapies; (iv) cooling or no cooling.

Abstract Body

Neonatal brain injury is frequently encountered in the setting of the neonatal intensive care unit. In the term born infant, hypoxic ischemic injury is the most common type of brain injury. This may occur following perinatal asphyxia, but can also be observed in infants with congenital heart disease. Such brain injury may significntaly affect neurodevelopmental outcome, includingmemory function. The aim of this presentation is to provide an overview of memory function following common patterns of neonatal brain injury in term infants and review how memory function is correlated with neonatal MRI and MRI in childhood.

Background and Aims

Decreased complexity of brain near infrared spectroscopy signals have been associated with poor outcome both for intraventricular haemorrhage in preterm infants and in traumatic brain injury in adults. This study aims to evaluate the complexity of broadband near infrared spectroscopy (BNIRS) signals in relation to outcome following neonatal encephalopathy (NE). BNIRS is a novel brain monitoring and imaging technique developed recently to monitor cerebral mitochondrial oxidative metabolism along with cerebral oxygenation and haemodynamics.

Methods

Data were collected from 22 term neonates (36-44 weeks) who underwent hypothermia after neonatal encephalopathy. BNIRS monitoring performed at 48 hours of life. Multiscale system entropy (MSE) was adopted to assess the complexity of five BNIRS signals: oxy- and deoxy- haemoglobin (HbO₂ and HHb), haemoglobin total (THb), Haemoglobin difference (HbD) and cytochrome c oxidase (oxCCO) over one hour of recordings for each infant.

Thalamic Lac/NAA on proton magnetic resonance spectroscopy was used as the outcome biomarker with a cut off 0.39. Group analyses were performed using Wilcoxon matched pair test.

Results

Thirteen infants had good outcome (Lac/NAA <0.39), nine had poor outcome (Lac/NAA>=0.39). Higher signal complexities were noted with better outcome for all brain signals (figure 1). Sample entropy was significantly different between the two outcome groups following NE (two tailed P value <0.0001 for HbO₂, HHb and HbD, 0.04 for oxCCO).

Conclusions

Loss of BNIRS signal complexity following NE was significantly correlated with poor outcome following NE. Complexity analysis of brain signals can be a useful tool for early assessment of injury severity and predict outcome following NE.

Background and Aims

Neonatal encephalopathy caused by hypoxia ischemia (HI) is a leading cause of childhood mortality and disability. Stem cell-based therapies seem promising to prevent long-term neurological deficits. Previous work in neonatal HI revealed unexpected risks of mesenchymal stromal cell (MSC) therapy due to interaction with the brains’ microenvironment. However, MSCs are supposed to mediate their therapeutic effects in a paracrine mode via extracellular vesicles (EV).

Methods

Nine-day-old C57BL/6 mice were exposed to HI through ligation of the right common carotid artery followed by 1 hour hypoxia (10% oxygen). MSC-EVs were administered at day 1, 3 and 5 after HI via intraperitoneal (i.p.) and intranasal (i.n.) application followed by analyses of brain tissues at day 7. Due to a limited lifespan of MSCs, we also investigated therapeutic effects of EVs derived from immortalized and clonally expanded MSCs (ciMSCs).

Results

Both, i.p. and i.n. administration of MSC-EVs reduced HI-induced brain injury with a significant advantage of i.n. over i.p. administration. Therapeutic efficacy of ciMSC-EVs was comparable to EVs from corresponding primary MSCs, resulting in reduced HI-induced striatal brain injury. Intranasal delivery of ciMSC-EVs decreased neuronal loss, reduced micro- and astroglia activation and promoted oligodendrocyte maturation.

Conclusions

Our data suggest that i.n. administration of MSC-EVs is a promising therapy for neonatal HI. The possibility of using ciMSC-EVs opens up new avenues for the standardized manufacturing of clinical grade EV products, an important prerequisite for routine clinical application and scale up production to industrial levels, circumventing problems associated with MSC-EV heterogeneity.

Background and Aims

Perinatal brain injury is a major contributor to neonatal morbidity, mortality and long-term adverse neurodevelopment outcomes. Umbilical Cord Blood (UCB)-derived cell therapy, which involves the use of multipotent stem cells isolated from UCB, is showing promise in pre-clinical models, and early-phase clinical trials are now underway.

We aimed to systematically review and analyse the evidence for UCB-derived cell therapy for perinatal brain injury from preclinical studies.

Methods

A combined search strategy was used to search for eligible studies in MEDLINE, PubMed and other databases. Two authors independently screened studies, performed risk of bias assessment and completed data extraction. A meta-analysis of different brain related outcomes was then conducted according to grey matter (GM) and white matter (WM) structures. Data was synthesised using Review Manager (5.4.1) software and expressed as standardised mean difference (SMD) with 95% confidence intervals (CI), using a random effects model.

Results

Systematic search of literature yielded a total of 1150 citations and after review, 50 studies (7 large, 43 small animal) were included. Administration of UCB-derived cells in animal models of perinatal brain injury significantly improved brain outcomes across several domains including: apoptosis (GM, SMD 1.14 (0.48,1.81), P=0.0008), (WM, 1.74 (0.86, 2.62), P=0.0001), astrogliosis (GM, 0.76 (0.26,1.26), P=0.003), (WM, 1.14 (0.45, 1.82), P=0.001), long-term motor function (0.73 (0.26,1.21), P=0.003), neuroinflammation, neurogenesis, oligodendrocyte number and infarct volume.

Conclusions

Systematic review and meta-analysis of pre-clinical litterature demonstrates that UCB-derived cell therapy is an efficacious treatment in animal models of perinatal brain injury, with benefits seen across a range of domains.