Neuroendocrine Response in Pediatric Febrile Seizures

Febrile Seizures in Children: Association of Thyroxine (T4), Epinephrine, and Norepinephrine Levels With Seizure Characteristics and Hospital Outcomes-A Prospective Controlled Observational Study

Febrile seizures are the most common seizure type in early childhood and usually occur during febrile illnesses. Although most febrile seizures are benign, the biological stress response during seizures is not fully understood. In particular, changes in thyroid hormones and stress-related hormones released by the sympathetic nervous system may play a role in seizure characteristics and clinical outcomes.

This prospective observational study aims to evaluate the neuroendocrine response in children presenting with febrile seizures by measuring serum thyroxine (T4), epinephrine, and norepinephrine levels. These measurements will be obtained during the acute phase after seizure cessation and compared with levels measured at recovery and with febrile children without seizures.

The study will examine the relationship between neuroendocrine marker levels and seizure characteristics such as seizure duration and recurrence, as well as clinical outcomes including length of hospital stay and need for pediatric intensive care unit admission.

By improving understanding of the hormonal stress response associated with febrile seizures, this study aims to contribute to the knowledge of seizure pathophysiology in childhood and may help identify biological factors associated with more severe clinical courses.

Study Overview

• Status: Not yet recruiting
• Conditions: Fever; Febrile Convulsion; Neuroendocrine Stress Response

Detailed Description

Febrile seizures represent a common pediatric neurological emergency and are triggered by fever-related systemic stress rather than primary epileptic pathology. Acute febrile seizures are accompanied by activation of the hypothalamic-pituitary-thyroid axis and the sympathetic-adrenal system, resulting in measurable changes in circulating thyroid hormones and catecholamines. However, the magnitude and clinical relevance of this neuroendocrine response remain incompletely characterized.

This study is designed as a prospective, observational, case-control investigation conducted in a pediatric emergency department setting. Children aged 6 months to 5 years presenting with febrile seizures will be enrolled as the case group. An age-matched control group will consist of febrile children without seizures. Participants will not be assigned to any intervention, and all clinical management will follow standard care practices.

In the febrile seizure group, blood samples for measurement of serum thyroxine (T4), epinephrine, and norepinephrine will be obtained within 30 minutes after seizure cessation to capture the acute neuroendocrine stress response. Additional samples will be collected prior to hospital discharge to assess recovery-phase hormone levels. In the control group, blood samples will be collected during the febrile episode at the time of clinical evaluation. All laboratory analyses will be performed using validated methods under standardized conditions.

Clinical data collected will include demographic characteristics, fever features, seizure type and duration, recurrence during hospitalization, treatment administered, length of hospital stay, and requirement for pediatric intensive care unit admission. The primary objective is to evaluate associations between acute-phase neuroendocrine marker levels and seizure characteristics, particularly seizure duration and recurrence. Secondary objectives include comparisons between febrile seizure patients and febrile controls, as well as associations between hormone levels and clinical outcomes.

Statistical analyses will include descriptive methods, group comparisons using parametric or nonparametric tests as appropriate, correlation analyses, and multivariable regression models adjusting for relevant confounders such as age, sex, peak temperature, seizure type, and treatment exposure. The study aims to provide mechanistic insight into the neuroendocrine stress response associated with febrile seizures and to explore its potential relationship with disease severity and short-term outcomes.

• Study Type: Observational
• Enrollment (Estimated): 120

Contacts and Locations

• Study Contact: Name: Aykut Çağlar, MD; Phone Number: +905303337877; Email: aykutcaglar@adu.edu.tr

Study Locations

• Turkey (Türkiye)
  • Aydın
    • Aydin, Aydın, Turkey (Türkiye), 09010
      • Aydin Adnan Menderes University Hospital
      • Contact: Aykut Çağlar, MD; Phone Number: +905303337877; Email: aykut.caglar@adu.edu.tr
      • Sub-Investigator: Murat Ayar, MD
      • Sub-Investigator: Şule Demir, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study population includes children aged 6 months to 5 years presenting with febrile seizures and an age-matched febrile control group without seizures, enrolled prospectively in a pediatric emergency department. The study evaluates differences in acute neuroendocrine hormone levels (thyroxine [T4], epinephrine, and norepinephrine) and their associations with seizure characteristics and short-term hospital outcomes.

Description

Inclusion Criteria:

• Children aged 6 months to 5 years presenting to the pediatric emergency department with fever (documented at presentation or reported by caregiver within the preceding 24 hours).
• Case group: febrile seizure occurring in the context of a febrile illness.
• Control group: febrile illness without seizure, selected to be age-matched to cases (e.g., within ±6 months).
• Written informed consent obtained from a parent or legal guardian.

Exclusion Criteria:

• Suspected or confirmed central nervous system infection (e.g., meningitis, encephalitis).
• Prior diagnosis of epilepsy or history of afebrile seizures.
• Seizures attributable to acute metabolic derangements at presentation (e.g., significant hypoglycemia, clinically relevant electrolyte disturbances).
• Known thyroid disease or use of thyroid hormone/antithyroid medications.
• Known adrenal disorders or use of systemic catecholamine infusions at enrollment.
• Major chronic neurologic disorders or acute head trauma.
• Inability to obtain blood samples within protocol-defined time windows.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Febrile Seizure Patients; Children aged 6 months to 5 years presenting with febrile seizures who are enrolled prospectively. Blood samples are obtained within 30 minutes after seizure cessation to assess acute neuroendocrine response, including thyroxine (T4), epinephrine, and norepinephrine levels. Additional samples are collected prior to hospital discharge. Clinical data including seizure characteristics, recurrence, length of hospital stay, and need for pediatric intensive care unit admission are recorded. No experimental intervention is administered.
Febrile Controls; Age-matched febrile children without seizures enrolled as the control cohort. Blood samples are obtained during the febrile episode to measure thyroxine (T4), epinephrine, and norepinephrine levels. Clinical data related to fever characteristics are collected for comparison with the febrile seizure cohort. No experimental intervention is administered.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in acute neuroendocrine hormone levels between febrile seizure patients and febrile controls	The difference in serum thyroxine (T4), epinephrine, and norepinephrine levels measured during the acute phase between children presenting with febrile seizures and age-matched febrile children without seizures.	Baseline (during the emergency department presentation)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Association between neuroendocrine hormone levels and seizure duration	The association between acute-phase serum thyroxine (T4), epinephrine, and norepinephrine levels and seizure duration (in minutes) in children presenting with febrile seizures.	Baseline (during the index febrile seizure event)
Association between neuroendocrine hormone levels and hospital length of stay	The association between acute-phase serum thyroxine (T4), epinephrine, and norepinephrine levels and total hospital length of stay in children presenting with febrile seizures.	From hospital admission through discharge (up to 7 days)
Association between neuroendocrine hormone levels and pediatric intensive care unit admission	The association between acute-phase serum thyroxine (T4), epinephrine, and norepinephrine levels and the requirement for pediatric intensive care unit (PICU) admission in children presenting with febrile seizures.	During the index hospitalization (up to 7 days)

Collaborators and Investigators

• Sponsor: Aydin Adnan Menderes University

Publications and helpful links

General Publications

• Asami T, Sasagawa F, Kyo S, Asami K, Uchiyama M. Incidence of febrile convulsions in children with congenital hypothyroidism. Acta Paediatr. 1998 Jun;87(6):623-6. doi: 10.1080/080352598750014003.
• Thebault-Dagher F, Lafontaine MP, Knoth IS, Deguire F, Sheppard E, Cook R, Lagace M, Gravel J, Lupien S, Lippe S. Febrile seizures and increased stress sensitivity in children: How it relates to seizure characteristics. Epilepsy Behav. 2019 Jun;95:154-160. doi: 10.1016/j.yebeh.2019.03.022. Epub 2019 May 3.
• Ladd JM, Sabsabi B, von Oettingen JE. Thyroid Storm in a Toddler Presenting as a Febrile Seizure. Pediatrics. 2020 Feb;145(2):e20191920. doi: 10.1542/peds.2019-1920.
• Han JY, Lee IG, Shin S, Park J. Seizure duration may increase thyroid-stimulating hormone levels in children experiencing a seizure. J Int Med Res. 2020 May;48(5):300060519888401. doi: 10.1177/0300060519888401. Epub 2019 Nov 27.

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2026
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: March 2, 2026
• First Submitted That Met QC Criteria: March 5, 2026
• First Posted (Actual): March 11, 2026

Study Record Updates

• Last Update Posted (Actual): March 11, 2026
• Last Update Submitted That Met QC Criteria: March 5, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Child; Fever; Norepinephrine; Epinephrine; Thyroxine; Neuroendocrine response; Pediatric emergency; Febrile seizure
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Body Temperature Changes; Seizures; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Fever; Seizures, Febrile
• Other Study ID Numbers: ADUPEDFSTEN

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