EAGLET: EEG vs aEEG to Improve the Diagnosis of neonataL Seizures and Epilepsy (EAGLET)

The EAGLET Project: EEG vs aEEG to Improve the Diagnosis of neonataL Seizures and Epilepsy - a Randomised Trial

The current project undertakes a prospective multicentre randomised controlled trial to evaluate whether full or continuous electroencephalography (cEEG) is superior to amplitude-integrated electroencephalography (aEEG) in the real time evaluation and diagnosis of neonatal seizures and in reducing time to treatment. At-risk new-born infants will be recruited on the participating neonatal intensive care units (NICUs) by trained specialist staff and will have 24 hours of EEG monitoring.

Study Overview

• Status: Recruiting
• Conditions: Neonatal Seizures
• Intervention / Treatment: Diagnostic test: Group B: aEEG with concurrent multichannel (full) continuous cEEG review by clinical neurophysiology

Detailed Description

Seizures are the most common neurological emergency in the neonatal period, affecting over 2000 infants per year in the UK. Although neonatal seizures usually result from acute brain insults, about 10-15% represent genetic forms of epilepsy which are often diagnosed late, thus limiting the timely use of targeted therapies. Lack or delayed initiation of treatment results in a high seizure burden which is independently associated with worse clinical outcomes.

Diagnosing neonatal seizures is challenging because most have only subtle or no clinical manifestation. The gold standard for seizure detection is continuous electroencephalography (cEEG). cEEG can assist with establish the aetiology of seizures, and their management. However, this capability is lacking in most neonatal intensive care units (NICU) due to lack of on-site specialist support. The more common amplitude-integrated EEG (aEEG) uses a limited number of electrodes and is easier to apply and interpret but has been shown to miss a significant number of seizures. It is unclear how often seizure treatment is missed or delayed due to lack of cEEG access. Although studies have compared the diagnostic value of aEEG and cEEG retrospectively, the measured sensitivity of aEEG ranges widely (25-85%), likely due to poor design (retrospective, lack of adequate control group, no power calculations).

The current project undertakes a prospective multicentre randomised controlled trial to evaluate whether cEEG is superior to aEEG in the real time evaluation and diagnosis of neonatal seizures and in reducing time to treatment. At-risk neonates will be recruited on the NICU by trained specialist staff and will have 24 hours of EEG monitoring.

• Study Type: Interventional
• Enrollment (Estimated): 140
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ronit M Pressler, Phd MD MRCPCH; Phone Number: +44 07737333607; Email: r.pressler@ucl.ac.uk
• Study Contact Backup: Name: Topun Austin, MD MRCP MRCPCH PhD; Phone Number: +44 01223217677; Email: topun.austin@addenbrookes.nhs.uk

Study Locations

• United Kingdom
  • Cambridge, United Kingdom
    • Recruiting
    • Cambridge University Hospitals NHS Foundation Trust
    • Contact: Topun Austin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Term or preterm neonate, born at post-menstrual age (PMA) 32-44 weeks;

2. And at least one of the following:

   (2.1) Neonate with any clinical event suspicious of seizures (2.2) Neonate at high-risk of seizures with confirmed or suspected: (2.2.1) Hypoxic ischaemic encephalopathy (moderate to severe, or deemed eligible for therapeutic hypothermia) (2.2.2) Cerebral vascular insult (e.g., perinatal arterial ischaemic stroke, cerebral venous sinus thrombus) (2.2.3) Meningitis / encephalitis - Inflammatory (2.2.4) Inborn error of metabolism (2.2.5) Brain malformation (2.2.6) Large intraventricular haemorrhage (III-IV)

3. Infant is up to 28 days of age
4. Written informed parental consent can be obtained.

Exclusion Criteria:

1. No parental consent
2. Poor prognosis of immediate survival
3. Any contraindication to perform EEG (e.g. structural pathologies interfering with EEG electrode placement, such as cephalohematoma or subgaleal haemorrhage).
4. Infants born at less than 31+6 weeks PMA and infants who are or are suspected to be experiencing or are at high-risk of seizures when aged 29 days or older.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group A is a control group with aEEG monitoring only, and with retrospective cEEG review	Diagnostic test: Group B: aEEG with concurrent multichannel (full) continuous cEEG review by clinical neurophysiology; In group B, the standart-care equivalent aEEG review is undertaken by NICU staff via a 2-channel display. In addition to the standard care, concurrent full EEG is reviewed remotely with regular feedback by a specialist trained clinical neurophysiologist. The clinical neurophysiology reports only on seizure burden, no information or direction is provided regarding clinical management.
Experimental: Group B is undergoing aEEG monitoring with concurrent full EEG review	Diagnostic test: Group B: aEEG with concurrent multichannel (full) continuous cEEG review by clinical neurophysiology; In group B, the standart-care equivalent aEEG review is undertaken by NICU staff via a 2-channel display. In addition to the standard care, concurrent full EEG is reviewed remotely with regular feedback by a specialist trained clinical neurophysiologist. The clinical neurophysiology reports only on seizure burden, no information or direction is provided regarding clinical management.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Seizure detection yield of aEEG compared to full EEG	The primary outcome measure for the study is the difference in the number of correctly identified seizures by NICU staff in real time with (full EEG) or without (aEEG only) the support of clinical neurophysiology.	Each participant will be assessed in Group A (aEEG review only) or Group B (a+cEEG) for 24 hours.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time from first recorded seizure to first recognised seizure and to treatment.	Their time to treatment and time to discharge will also be noted.	Each participant's seizure burden, treatment and discharge timelines will be recorded up until their discharge from the hospital, or for up to 6 months, whichever came first.
Number of false positive seizure detections clinically and/or by aEEG		Followed until their discharge from hospital, or for up to 6 months, whichever came first.
Off-line seizure burden (min/hr) detected by aEEG vs detected by cEEG		Followed until their discharge from hospital, or for up to 6 months, whichever came first.
Parental and staff acceptance of EEG monitoring (combined cohort) using questionnaire.		Parents may fill in the questionnaire online after their infant's discharge from hospital, the questionnaire will take a maximum of 10 minutes to complete.

Collaborators and Investigators

• Sponsor: Cambridge University Hospitals NHS Foundation Trust
• Collaborators: Norfolk and Norwich University Hospitals NHS Foundation Trust; Luton and Dunstable Hospital NHS Foundation Trust; Infant, University College Cork, Ireland; Guy's and St Thomas' NHS Foundation Trust; University Hospital Southampton NHS Foundation Trust

Publications and helpful links

General Publications

• Pinchefsky EF, Hahn CD. Outcomes following electrographic seizures and electrographic status epilepticus in the pediatric and neonatal ICUs. Curr Opin Neurol. 2017 Apr;30(2):156-164. doi: 10.1097/WCO.0000000000000425.
• Malone A, Ryan CA, Fitzgerald A, Burgoyne L, Connolly S, Boylan GB. Interobserver agreement in neonatal seizure identification. Epilepsia. 2009 Sep;50(9):2097-101. doi: 10.1111/j.1528-1167.2009.02132.x. Epub 2009 Jun 1.
• Boylan GB, Kharoshankaya L, Mathieson SR. Diagnosis of seizures and encephalopathy using conventional EEG and amplitude integrated EEG. Handb Clin Neurol. 2019;162:363-400. doi: 10.1016/B978-0-444-64029-1.00018-7.
• Pellegrin S, Munoz FM, Padula M, Heath PT, Meller L, Top K, Wilmshurst J, Wiznitzer M, Das MK, Hahn CD, Kucuku M, Oleske J, Vinayan KP, Yozawitz E, Aneja S, Bhat N, Boylan G, Sesay S, Shrestha A, Soul JS, Tagbo B, Joshi J, Soe A, Maltezou HC, Gidudu J, Kochhar S, Pressler RM; Brighton Collaboration Neonatal Seizures Working Group. Neonatal seizures: Case definition & guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2019 Dec 10;37(52):7596-7609. doi: 10.1016/j.vaccine.2019.05.031. No abstract available.
• Gossling L, Alix JJP, Stavroulakis T, Hart AR. Investigating and managing neonatal seizures in the UK: an explanatory sequential mixed methods approach. BMC Pediatr. 2020 Jan 28;20(1):36. doi: 10.1186/s12887-020-1918-4.
• Rakshasbhuvankar A, Paul S, Nagarajan L, Ghosh S, Rao S. Amplitude-integrated EEG for detection of neonatal seizures: a systematic review. Seizure. 2015 Dec;33:90-8. doi: 10.1016/j.seizure.2015.09.014. Epub 2015 Sep 26.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2023
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: September 13, 2021
• First Submitted That Met QC Criteria: October 13, 2021
• First Posted (Actual): October 15, 2021

Study Record Updates

• Last Update Posted (Actual): August 14, 2023
• Last Update Submitted That Met QC Criteria: August 9, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Epilepsy; Neonatal Seizures; cEEG; aEEG
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Epilepsy; Seizures
• Other Study ID Numbers: A 096043

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No