Evaluating the Role of Inflammation in Neonatal Epileptogenesis (NSR-RISE)

Neonatal Seizure Registry: The Role of Inflammation After Neonatal Seizures and Later Development of Epilepsy

The purpose of this study evaluate the relationship between inflammation and epilepsy in neonates with seizures after birth.

Study Overview

• Status: Active, not recruiting
• Conditions: Epilepsy; Inflammatory Response; Seizures; Neonatal Seizure
• Intervention / Treatment: Diagnostic test: Blood draw; Other: Survey

Detailed Description

Seizures are a common symptom of neurologic dysfunction in the neonatal period, affecting more than 16,000 newborns in the United States per year. Over 25% of neonates with acute symptomatic seizures develop post- neonatal epilepsy (PNE), which is often resistant to medical therapies. There is a critical need to identify those patients most at risk for PNE and understand the mechanisms by which early seizures increase the propensity for recurrent seizures, in hopes of identifying novel therapeutic targets in this population. There is increasing evidence for the role of neuro-inflammation in the development of epilepsy. Levels of cytokines and micro-RNA (miRNA) may serve as markers of disease severity and have been implicated in epileptogenesis in animal models. The purpose of this study is to evaluate plasma cytokine and miRNA levels after neonatal-onset acute symptomatic seizures and determine their association with acute seizure severity and PNE.

• Study Type: Observational
• Enrollment (Estimated): 87

Contacts and Locations

Study Locations

• United States
  • California
    • Oakland, California, United States, 94609
      • UCSF Benioff Children's Hospital Oakland
    • San Francisco, California, United States, 94158
      • University of California, San Francisco
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48103
      • University of Michigan, Mott Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 4 days (Child)
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Newborns who are admitted at one of the participating children's hospitals

Description

For participants in the acute symptomatic seizure group:

Inclusion Criteria:

• Neonates <44 weeks corrected age at seizure onset
• Seizures due to acute brain injury
• Parent(s) who are English or Spanish literate (with assistance of interpreter)

Exclusion Criteria:

• Neonates at risk for adverse outcome independent of seizures and underlying brain injury
• Neonates with mild, temporary causes for seizures
• Newborns with neonatal-onset epilepsy syndromes
• Neonates who do not survive the initial hospital admission
• Neonates will not be excluded based on race, ethnicity, gender or gestational age

For participants in the control group:

Inclusion Criteria:

• Neonates that are born > 37 weeks and <44 weeks postmenstrual age at enrollment
• Consultation by the pediatric neurology inpatient service due neonatal paroxysmal events, with normal neurologic examination and ultimate diagnosis of non-epileptic spells on continuous video-EEG (ordered for clinical purposes, not for research) OR consultation for hypoxic ischemic encephalopathy in neonates undergoing therapeutic hypothermia, with early exit from therapy owing to normal neurologic examination, normal continuous video-EEG and uncertain diagnosis of encephalopathy.
• Neonates requiring neurologic consultation for mild hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia, with normal examination, cEEG, and neuroimaging upon rewarming.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Acute symptomatic seizures; This is a cohort of 72 participants who will be enrolled into this study from the neonatal intensive care unit (NICU) after being diagnosed with seizures. They will be asked to contribute a blood specimen obtained ideally 48-96 hours (though blood collection allowed 24-120 hours) after seizures are diagnosed, to participate in an optional blood draw at 2-4 months of age, and to complete surveys at 12 & 24 months of age.	Diagnostic test: Blood draw; Evaluation of plasma inflammatory markers including cytokines and micro-RNA.; Other: Survey; Regarding epilepsy and development.
Control; This is a cohort of 15 participants who will be enrolled into this study from the neonatal intensive care unit (NICU) after having an EEG for possible seizures, but found to have a normal EEG. They will be asked to contribute a blood specimen obtained ideally 48-96 hours (though blood collection allowed 24-120 hours) after birth.	Diagnostic test: Blood draw; Evaluation of plasma inflammatory markers including cytokines and micro-RNA.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Seizure burden	Investigators will evaluate the seizure burden from the initial diagnostic electroencephalogram (EEG) after birth by determining the average number of seizures per hour.	At study entry
Percentage of participants diagnosed with epilepsy	The investigators will determine the proportion of participants who develop clinical and or electrographic seizures.	24 months of age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of participants diagnosed with epilepsy	The investigators will determine the proportion of participants who develop clinical and or electrographic seizures.	12 months of age
Epilepsy Severity	The investigators will administer an investigator-developed questionnaire designed to define the frequency of seizures (monthly, weekly, daily, or greater than daily).	12 months of age
Epilepsy Severity	The investigators will administer an investigator-developed questionnaire designed to define the frequency of seizures (monthly, weekly, daily, or greater than daily).	24 months of age
Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS)	The Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) will be assessed at 12 months of age. The score ranges from 50 to 200 with higher scores associated with normal development.	Assessment takes up to 15 minutes and will be conducted at 12 months of age
Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS)	The Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) will be assessed at 24 months of age. The score ranges from 50 to 200 with higher scores associated with normal development.	Assessment takes up to 15 minutes and will be conducted at 24 months of age

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS); University of Michigan; Boston Children's Hospital; UCSF Benioff Children's Hospital Oakland
• Investigators: Principal Investigator: Adam L Numis, MD, University of California, San Francisco

Publications and helpful links

General Publications

• Numis AL, Foster-Barber A, Deng X, Rogers EE, Barkovich AJ, Ferriero DM, Glass HC. Early changes in pro-inflammatory cytokine levels in neonates with encephalopathy are associated with remote epilepsy. Pediatr Res. 2019 Nov;86(5):616-621. doi: 10.1038/s41390-019-0473-x. Epub 2019 Jun 24.

Study record dates

Study Major Dates

• Study Start (Actual): December 15, 2018
• Primary Completion (Estimated): November 30, 2024
• Study Completion (Estimated): November 30, 2024

Study Registration Dates

• First Submitted: February 4, 2020
• First Submitted That Met QC Criteria: February 4, 2020
• First Posted (Actual): February 6, 2020

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; Inflammation; EEG; Cytokine; Neonatal seizure; Micro-RNA
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Epilepsy; Inflammation; Seizures
• Other Study ID Numbers: K23NS105918 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No