The prevalence of cerebral palsy is rising in the UK because of increased survival of extremely low birth weight (ELBW) preterm infants. About 10% of all babies delivered in the UK spend time in special care neonatal units, and the annual number of recorded days of care is >1 million days (ONS 2014). Neonatal seizures are the most common neurological emergency and are associated with high mortality and morbidity and thus even small improvements in care have the potential to be highly significant over the life course. The incidence of neonatal seizures in term infants is 0.5-3 per 1000 live births, and most epidemiological studies only report clinical seizures but rarely sub-clinical seizure states. Thus, a conservative prediction is that there are about 2,000 cases per annum (PA) in the UK.
The primary objectives of this Consortium scheme, ‘The NeuralNET,’ are to develop systems for Early Detection and Stratified Medicine for neonatal seizures as the basis for novel methodological, technical and interventional research and to create a National Platform to support outreach, patient and industry engagement, promote clinical trials and training of young investigators.
Our objectives are:
- To demonstrate that stratification of neonatal seizures using magnetic resonance imaging (MRI), EEG and whole genome sequencing (WGS) is feasible (industry collaboration with Illumina UK, Cambridge,UK);
- To develop, with Illumina, a rapid turn around pipeline for WGS and informatics taking a minimal (1ml) blood volume from babies with report back of “actionable” information to clinicians within 2 weeks;
- To use an inter-regional approach to identify large cohorts of stratified patients in the NICU, creating a unique opportunity to study interventions in an early, potentially enhanced therapeutic window;
- To create a new paradigm for stratified medicine in paediatrics coupled to assessment of long-term outcomes using the electronic medical record, which captures a unique and inherent strength of the NHS organization for population research studies (industry collaboration with Clevermed, Edinburgh,UK).
- To enable targeted clinical trials and encourage industry input through open innovation, the provision of stratified cohorts and data, and through provision of a feasible stratification toolkit;
- To support planning for a clinical trial for Glut1syndrome (industry link with Ultragenyx, Novato, CA, USA);
- To develop clinically and test machine learning tools for MRI and EEG interpretation to improve clinician and cotside recognition of brain injury and sub-clinical seizures for treatment;
- To prospectively identify and treat NICU patients with KCNQ2 encephalopathy (~100cases/PA in the UK) with the repurposing drug carbamazepine to control seizures and assess long term outcomes of this cohort using the electronic medical record to determine the effects of early treatment:
- NeuralNET as a National Platform:
- To provide a novel platform for industry-sponsoredclinical trials (which will otherwise not proceed)without a coordinated national approach;
- To prospectively establish incidence of genetic disordersfor trials of diagnostics and rare disease treatments (industrylinks: Roche, Basel, SZ and Healx, Cambridge, UK);
- To create a national bioresource and database of cases for future studies and encourage future contribution to and use of this valuable resource for mechanistic studies (link: NIHR Rare Disease BioResource);
- In consultation with NICE, consortium findings and cost-effectiveness studies would directly influence care pathway management recommendat ions in the UK.
The NeuralNET will recruit 600 babies from England and Scotland; we expect to stratify the 600 subjects into the following categories; (i) Injury (incl. HIE, Stroke, Infection)=400; (ii) Rare including KCNQ2 benign and severe, KCNT1, SCN2A and other genetic=80; (iii) Metabolic (incl. hypoglycaemia)=60-including transient metabolic and in born errors of metabolism; (iv) Malformations=60.
These numbers are estimates based on historical data.