Skin biopsy reveals generalized small fibre neuropathy in hypermobile Ehlers-Danlos syndromes

Denver Igharo; Joana C Thiel; Roman Rolke; Merve Akkaya; Joachim Weis; Istvan Katona; Jörg B Schulz; Andrea Maier

doi:10.1111/ene.15649

Skin biopsy reveals generalized small fibre neuropathy in hypermobile Ehlers-Danlos syndromes

Eur J Neurol. 2023 Mar;30(3):719-728. doi: 10.1111/ene.15649. Epub 2022 Dec 13.

Authors

Denver Igharo¹, Joana C Thiel¹, Roman Rolke², Merve Akkaya¹, Joachim Weis³, Istvan Katona³, Jörg B Schulz^{1

4}, Andrea Maier¹

Affiliations

¹ Department of Neurology, Medical Faculty RWTH Aachen University, Aachen, Germany.
² Department of Palliative Medicine, Medical Faculty RWTH Aachen University, Aachen, Germany.
³ Institute of Neuropathology, Medical Faculty RWTH Aachen University, Aachen, Germany.
⁴ JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and Medical Faculty RWTH Aachen University, Aachen, Germany.

PMID: 36437696
DOI: 10.1111/ene.15649

Abstract

Background and purpose: Ehlers-Danlos syndromes are hereditary disorders of connective tissue that are characterized by joint hypermobility, skin hyperextensibility and tissue fragility. The most common subtype is the hypermobile type. In addition to symptoms of small fibre neuropathy (SFN) due to damage to the small peripheral nerve fibres, with degeneration of the distal nerve endings, autonomic disorders such as postural tachycardia syndrome (PoTS) are frequently reported features in patients with hypermobile Ehlers-Danlos syndrome (hEDS). To date, the underlying pathophysiological mechanisms are still not completely understood.

Study purpose: To better understand pathophysiological mechanisms of small fiber neuropathy and autonomic neuropathy in hypermobile Ehlers-Danlos Syndromes.

Methods: We prospectively investigated 31 patients with hEDS compared to 31 healthy controls by using skin biopsy, quantitative sensory testing, tilt-table testing, the painDetect, Small Fibre Neuropathy Screening List and the COMPASS-31 (Composite Autonomic Symptom Score 31) questionnaire.

Results: Nineteen (61%) patients with hEDS were diagnosed with SFN, and 10 (32%) fulfilled the criteria for PoTS. Patients with hEDS had significantly higher heart rates than controls. According to quantitative sensory testing, these patients had generalized thermal and tactile hypesthesia. Skin biopsy revealed significantly reduced intraepithelial nerve fibre density proximally (thigh) and distally (lower leg) in patients compared to controls. This was consistent with various complaints of pain and sensory disturbances in both the proximal and distal body regions.

Conclusion: These results confirm histologically proven SFN as a common feature in patients with hEDS, revealing a generalized distribution of nerve fibre loss. Regarding the frequently reported autonomic and neuropathic dysfunctions, the findings support SFN as an important, but not the only, underlying pathomechanism.

Trial registration: ClinicalTrials.gov NCT04310644.

Keywords: Ehlers-Danlos syndrome; Small Fibre Neuropathy Screening List; autonomic small fibre neuropathy; neuropathic pain; postural tachycardia syndrome; skin biopsy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biopsy
Ehlers-Danlos Syndrome* / complications
Ehlers-Danlos Syndrome* / diagnosis
Ehlers-Danlos Syndrome* / pathology
Humans
Skin / pathology
Small Fiber Neuropathy* / etiology

Supplementary concepts

Ehlers-Danlos syndrome type 3

Associated data

ClinicalTrials.gov/NCT04310644