Reference Values of Intraepidermal Nerve Fiber Density in Children and Small Fiber Neuropathy in Neurometabolic and Neurodevelopmental Disorders in Children (SFN_children)

Reference Values of Intraepidermal Nerve Fiber Density in Children and Small Fiber Neuropathy in Children With Acquired and Genetic Neurodevelopmental Disorders - An Unrecognized Cause of Pain and Window Into Brain Pathology ? -

Background: Small-Fiber-Neuropathy describes the degeneration of mildly or unmyelinated nerve fibers and causes neuropathic pain and autonomic dysfunction. Gold standard for the diagnosis is a small skin punch biopsy from the lower leg and the histological quantification of the intraepidermal nerve fiber density (IENFD). In children, the normal IENFD has not been systematically assessed and normal reference values are needed. In Parkinson´s disease, the neurodegeneration also affects the peripheral nerves and SFN is present already in the early stages. Whether neurodevelopmental disorders (NDDs) in childhood are likewise associated with SFN is largely unknown. The IENFD is age-dependent and declines with age.

Aims: In this study, we are establishing the reference values for the physiological IENFD in children from 0-18 years. Moreover, we are investigating if children with NDDs have a reduced IENFD and if SNF is a clinically relevant cause of pain and autonomic dysfunction.

Study Overview

• Status: Recruiting
• Conditions: Cerebral Palsy; Mitochondrial Diseases; Small Fiber Neuropathy; Developmental Delay Disorder
• Intervention / Treatment: Diagnostic test: Skin biopsy

• Study Type: Observational
• Enrollment (Anticipated): 240

Contacts and Locations

Study Locations

• Germany
  • Düsseldorf, Germany, 40225
    • Recruiting
    • University Hospital Düsseldord, Department of General Pediatrics, Neonatology and Pediatric Cardiology
    • Contact: Luisa Averdunk, MD; Phone Number: +492118117675; Email: luisa.aver@gmail.com
    • Contact: Felix Distelmaier, MD; Email: felix.distelmaier@med.uni-duesseldorf.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

1. Control (no underlying neurological disorder) individuals
2. Neurodevelopmental disorder_Genetic cause known
3. Neurodevelopmental disorder_Acquired (cause known, for example perinatal asphyxia or intracranial bleeding)
4. Neurodevelopmental disorder_Cause unknown

Description

control patients

Inclusion Criteria:

• Elective surgical intervention from lower leg
• Interest to participate in the study, informed consent
• Unremarkable neurological development

Exclusion Criteria:

• Clinical signs of polyneuropathy, autonomic dysfunction
• Skin inflammation, scar, skin disease, other known chronic diseases that can cause small fiber pathology

Neurodevelopmental patients

Inclusion Criteria:

• Neurodevelopmental problems (developmental delay, muscular hypotonia, seizures, ataxia,...) with age of onset before the age of 18 years
• Interest to participate in the study, informed consent

Exclusion Criteria:

• Known polyneuropathy
• Skin inflammation, scar, skin disease, other known chronic diseases that can cause small fiber pathology

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Control (no underlying neurological disorder)	Diagnostic test: Skin biopsy; Control skin biopsies from children without a chronic underlying disease are drawn from surgical crop margins during elective orthopedic surgery of the lower leg (n<80). Skin punch biopsies from children with acquired (n<80) or genetic NDD (n<80) or unknown etiology (N<80) are drawn in the setting of elective interventions during sedation or after local anesthesia. IENFD is quantified by immunohistochemistry and compared between the control and NDD group.
Neurodevelopmental disorder_Genetic cause known	Diagnostic test: Skin biopsy; Control skin biopsies from children without a chronic underlying disease are drawn from surgical crop margins during elective orthopedic surgery of the lower leg (n<80). Skin punch biopsies from children with acquired (n<80) or genetic NDD (n<80) or unknown etiology (N<80) are drawn in the setting of elective interventions during sedation or after local anesthesia. IENFD is quantified by immunohistochemistry and compared between the control and NDD group.
Neurodevelopmental disorder_Acquird (cause known)	Diagnostic test: Skin biopsy; Control skin biopsies from children without a chronic underlying disease are drawn from surgical crop margins during elective orthopedic surgery of the lower leg (n<80). Skin punch biopsies from children with acquired (n<80) or genetic NDD (n<80) or unknown etiology (N<80) are drawn in the setting of elective interventions during sedation or after local anesthesia. IENFD is quantified by immunohistochemistry and compared between the control and NDD group.
Neurodevelopmental disorder_Cause unknown	Diagnostic test: Skin biopsy; Control skin biopsies from children without a chronic underlying disease are drawn from surgical crop margins during elective orthopedic surgery of the lower leg (n<80). Skin punch biopsies from children with acquired (n<80) or genetic NDD (n<80) or unknown etiology (N<80) are drawn in the setting of elective interventions during sedation or after local anesthesia. IENFD is quantified by immunohistochemistry and compared between the control and NDD group.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Intraepidermal nerve fiber density	2 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Pathological protein deposits, morphological alterations of cell organells	2 years

Collaborators and Investigators

• Sponsor: Heinrich-Heine University, Duesseldorf

Publications and helpful links

General Publications

• Lauria G, Bakkers M, Schmitz C, Lombardi R, Penza P, Devigili G, Smith AG, Hsieh ST, Mellgren SI, Umapathi T, Ziegler D, Faber CG, Merkies IS. Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. J Peripher Nerv Syst. 2010 Sep;15(3):202-7. doi: 10.1111/j.1529-8027.2010.00271.x.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2022
• Primary Completion (Anticipated): December 30, 2023
• Study Completion (Anticipated): December 30, 2024

Study Registration Dates

• First Submitted: November 30, 2022
• First Submitted That Met QC Criteria: November 30, 2022
• First Posted (Estimate): December 12, 2022

Study Record Updates

• Last Update Posted (Estimate): December 12, 2022
• Last Update Submitted That Met QC Criteria: November 30, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Damage, Chronic; Neuromuscular Diseases; Peripheral Nervous System Diseases; Cerebral Palsy; Mitochondrial Diseases; Developmental Disabilities; Neurodevelopmental Disorders; Small Fiber Neuropathy
• Other Study ID Numbers: SFN children; 2021-1556 (Other Identifier: Ethical review board - Medical faculty, Heinrich-Heine University, University Hospital Düsseldorf)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: All IPD that underlie results in a publication
• IPD Sharing Time Frame: After publication
• IPD Sharing Access Criteria: Email to principal investigators explaining why it might be helpful to share the data.
• IPD Sharing Supporting Information Type: Study Protocol; Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

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