Abstract
Ehlers-Danlos syndromes (EDS) encompass a group of genetic connective tissue disorders that affect the structure and function of proteins and enzymes that provide stability to the body. The hypermobile subtype of EDS (hEDS) is the most common and is characterized by joint hypermobility, skin hyperextensibility, and widespread musculoskeletal pain. Neuropathic symptoms, including pain, numbness, tingling, and weakness, are increasingly recognized in this population. This paper proposes a study to test the hypothesis that hEDS individuals will have a higher prevalence of positive Tinel signs compared to controls, indicating heightened sensitivity to nerve irritation or compression in hEDS that can guide better diagnosis and treatment.
Introduction
Ehlers-Danlos syndromes (EDS) are a group of inherited connective tissue disorders primarily affecting the structure and function of collagen and related proteins (, ). Among these, the hypermobile subtype (hEDS) is the most prevalent and is characterized by joint hypermobility, skin hyperextensibility, and chronic musculoskeletal pain (). In addition to these hallmark features, individuals with hEDS frequently report neuropathic symptoms such as pain, numbness, tingling, and weakness ().
The structural fragility inherent in hEDS, resulting from collagen dysfunction, may predispose individuals to peripheral nerve irritation or entrapment. Connective tissue laxity contributes to joint instability and recurrent subluxations, potentially increasing mechanical stress on adjacent nerves (). Although each subtype of EDS, with the exception of hEDS, has an identified molecular basis, all share features that may contribute to increased nerve vulnerability (, ). These biomechanical factors suggest a plausible link between hEDS and heightened susceptibility to nerve-related symptoms.
Tinel's sign—a clinical marker characterized by tingling sensations elicited by percussion over a nerve—is commonly used to assess nerve irritation or regeneration (, ). It is frequently positive in nerve entrapment syndromes such as carpal tunnel and cubital tunnel syndromes. Given the propensity for joint instability and mechanical strain in hEDS, it is hypothesized that individuals with this condition will demonstrate a higher prevalence of positive Tinel signs, reflecting increased nerve sensitivity or chronic irritation.
Prior studies have documented an association between EDS and peripheral neuropathies, including entrapment syndromes like thoracic outlet syndrome, carpal tunnel syndrome, and others (–). However, no systematic investigation has evaluated the prevalence of Tinel's sign in the hEDS population. This study seeks to address this gap by assessing the frequency and distribution of positive Tinel signs in individuals with hEDS, thereby contributing to a deeper understanding of the neuropathic manifestations associated with this condition.
Hypothesis
Individuals with hypermobile Ehlers-Danlos syndrome (hEDS) will exhibit a significantly higher prevalence of positive Tinel's signs compared to the general population due to increased susceptibility to nerve irritation and compression.
Proposed mechanism
The underlying mechanism of Tinel signs in hEDS individuals is possibly multifactorial. This may include increased joint laxity and subluxation as frequent joint instability and subluxation may subject peripheral nerves to increased mechanical stress, leading to irritation and subsequent positive Tinel's signs. Previous reports have raised concern for brachial plexopathies playing a role in the pathogenesis of neuropathy in patients with EDS type III (hEDS), in the absence of outright trauma (). Microtrauma to nerves: in hEDS individuals, the lack of sufficient support from connective tissues may allow minor, repetitive trauma to nerves, causing micro-injuries that manifest as nerve hypersensitivity. Inflammatory response and neuropathic changes: chronic mechanical stress on nerves may trigger local inflammation, further exacerbating nerve irritation and contributing to a positive Tinel's response. While the direct pathophysiology is still unclear, previous retrospective and prospective research has shown that nerve fiber loss and neuropathy—evidenced by biopsy and sensory testing—occurs more often in patients with hEDS compared to controls (, ). Increased vulnerability of the nerves to stress and compression: joint instability may predispose to malalignment of the nerve pathway leading compression or focal neuropathic lesion. This has been revealed in similar scenarios and case reports of postural causes of neuropathy ().
Proposed study
A prospective cross-sectional study is proposed for the study design. Two groups will be assessed—a cohort of individuals diagnosed with hEDS and a control group from the general population with no history of connective tissue disorders or joint hypermobility. The inclusion criteria for the hEDS group will consist of individuals meeting the 2017 International Classification criteria for hypermobile EDS (). The control group will be matched for age and sex. Small fiber neuropathy individuals will be in a separate subgroup. The exclusion criteria will be the presence of confounding causes of neuropathy, such as thyroid disease, amputation, and stroke.
Regarding the assessment for Tinel sign, the presence of a Tinel sign will be determined on physical exam as previously described in the literature (). In the lower extremity, with palpation at the anatomic entrapment site, tingling, shock-like, or electrical sensations radiating along the nerve's distribution will be equivalent to a positive Tinel sign. For example, a positive Tinel Sign will be noted if the patient experiences pain and tingling with palpation at the fibular neck (i.e., common peroneal nerve compression). The presence of neuropathy will be determined by the score of the Michigan Neuropathy Symptom Index patient version test, with the presence of neuropathy being defined as a score of 4 or greater (). Tinel sign will be assessed bilaterally at multiple common sites of nerve compression, sensory, and motor neurological examination on the innervation field of each nerve including but not limited to locations in Table 1.
Table 1
| Nerve | Tunnel/Region | Percussion site | Positive response |
|---|---|---|---|
| Brachial plexus | Supraclavicular | Above clavicle, lateral to neck | Tingling in entire arm or C5–T1 dermatomes |
| Axillary nerve | Quadrangular space | Posterior shoulder, below glenohumeral joint | Tingling in deltoid and lateral upper arm |
| Dorsal scapular nerve | Scapular tunnel | Medial scapular border | Deep aching or tingling in scapular region |
| Radial nerve | Radial tunnel | 4–5 cm distal to lateral epicondyle | Tingling in dorsal forearm or radial hand |
| Median nerve | Proximal forearm (Pronator) | Between heads of pronator teres | Tingling in thumb, index, middle, 1/2 ring finger |
| Median nerve | Carpal tunnel | Volar wrist, over flexor retinaculum | Same as above |
| Ulnar nerve | Cubital tunnel | Posterior to medial epicondyle | Tingling in ring and little fingers, ulnar forearm |
| Sciatic nerve | Piriformis | Midpoint between greater trochanter & ischial tuberosity | Tingling down posterior thigh/leg/foot |
| Femoral nerve | Inguinal tunnel | Below inguinal ligament, lateral to femoral artery | Tingling in anterior thigh, medial leg |
| Lateral femoral cutaneous | ASIS tunnel | Just inferior/medial to ASIS | Tingling in anterolateral thigh |
| Common peroneal nerve | Fibular tunnel | At fibular neck | Tingling in lateral leg and dorsum of foot |
| Superficial peroneal nerve | Lower leg tunnel | Lateral mid-leg | Tingling in anterolateral leg, dorsum of foot |
| Deep peroneal nerve | Ankle tunnel | Lateral to EHL tendon at ankle | Tingling in first web space |
| Tibial nerve | Popliteal tunnel | Midline of popliteal fossa | Tingling in plantar foot, posterior calf |
| Posterior tibial nerve | Tarsal tunnel | Posterior to medial malleolus | Tingling in sole of foot and toes |
Tinel signs criteria by tunnel syndrome.
Sensory and motor nerve conduction velocity (NCV) studies across the potential entrapment sites above will be completed on at least four selected nerves which can most easily be examined, to include: median nerve at the wrist, ulnar nerve at the elbow, fibular nerve at the fibular head segment and tibial nerve at the ankle. NCV testing will be performed with surface stimulation and recording. An electrode pair will be put over the skin on the given peripheral nerve site to apply supramaximal stimulation. Recording electrodes will be placed over the muscles innervated by the given nerve (motor NCV), as well as those recorded over the nerve trunks (sensory or mixed NCV) (). Stimulation and recording points for each nerve to be examined are listed in Table 2.
Table 2
| Nerve | Stimulation site(s) | Electrode placement (Recording site) |
|---|---|---|
| Median (APB) | S1: 8 cm proximal to active electrode, over median nerve at wrist S2: forearm at antecubital fossa | Active: Thenar eminence, midpoint of wrist crease to 1st MCP joint |
| Median sensory | Over median nerve at the wrist | 2nd digit of hand, active at prox phalanx, reference 2 cm distal |
| Ulnar (ADM) | S1: 8 cm proximal to active electrode, over ulnar nerve at wrist. S2: Below elbow. S3: Above elbow | Active: Over abductor digiti minimi on hypothenar eminence |
| Ulnar sensory | Over the ulnar nerve at wrist | 5th digit of hand, active at prox phalanx, reference 2cm distal |
| Radial (EDC) | S1: Antecubital fossa lateral to biceps tendon; S2: Proximal to the spiral groove | Active: Over extensor digitorum communis, distal to elbow |
| Radial sensory | Over radial nerve at the wrist | Distal ¼ point of forearm |
| Peroneal (EDB) | S1: Ankle over peroneal nerve; S2: Below fibular head; S3: Popliteal fossa | Active: Over extensor digitorum brevis on dorsum of foot |
| Tibial (AH) | Ankle and popliteal fossa | Active: Over abductor hallucis on medial foot |
| Sural | Mid-calf | Bar electrode posterior to lateral malleolus |
| Superficial peroneal | Mid-lateral leg | Bar electrode anterior ankle |
Electrode placement and recording points for nerve conduction studies.
Muscle abbreviations: APB, abductor pollicis brevis; ADM, abductor digiti minimi; EDC, extensor digitorum communis; EDB, extensor digitorum brevis; AH, abductor hallucis.
For data collection, the prevalence of positive Tinel signs at each anatomical site will be recorded for both groups, and the total number of sites per individual with positive Tinel sign will also be analyzed. The prevalence of positive Tinel signs in the hEDS group will be compared by statistical analysis to the control group using chi-square tests for categorical data. Logistic regression models will be employed to adjust for potential confounders such as age, gender, and occupation.
Discussion
Principal findings
This study is expected to demonstrate that individuals with hEDS exhibit a significantly higher prevalence of positive Tinel signs across multiple anatomical sites compared to controls. In addition, individuals with hEDS may display positive Tinel signs at atypical locations not commonly associated with entrapment syndromes in the general population. Subgroup analyses may also identify a correlation between the degree of joint hypermobility and features of small fiber neuropathy, which may or may not coincide with a positive Tinel sign.
Clinical implications
If confirmed, these findings would offer a new perspective on the neuropathic symptoms frequently reported in individuals with hEDS (). A higher prevalence of Tinel positivity may reflect a greater susceptibility to peripheral nerve irritation or compression due to underlying connective tissue fragility. Clinically, this underscores the importance of thorough and systematic peripheral nerve assessments in hEDS populations. Early recognition of nerve entrapment syndromes could lead to earlier intervention and potentially mitigate the progression of chronic neuropathic pain. These results may also inform the development of more targeted management strategies for neuropathic symptoms in this group.
Strengths and limitations
A key strength of this study is its systematic approach to evaluating Tinel's sign across multiple anatomical sites in a clinically relevant population. The anatomical mapping of nerve irritation may yield novel insights into the distribution and pathophysiological patterns of nerve involvement in hEDS.
However, several limitations should be noted. Tinel's sign is a subjective clinical test with potential for inter-examiner variability. Its presence may be influenced by patient sensitivity, examiner technique, and lacks specificity for underlying pathology. Additionally, as a cross-sectional study, causal relationships between hypermobility, nerve irritation, and neuropathic symptoms cannot be established. The absence of confirmatory diagnostic tools such as nerve conduction studies, skin biopsies, or quantitative sensory testing may also limit the interpretability of findings. Future studies incorporating objective assessments of nerve function and longitudinal follow-up will be critical to validating and expanding upon these results.
Future directions
To build on these findings, future research should incorporate objective neurophysiological and histopathological assessments, such as nerve conduction studies, corneal confocal microscopy, or intraepidermal nerve fiber density analysis. Longitudinal studies may also help to determine whether the presence of Tinel signs in hEDS is predictive of worsening neuropathic symptoms or long-term nerve dysfunction. Ultimately, a better understanding of peripheral nerve involvement in hEDS could contribute to earlier diagnosis, more effective interventions, and improved quality of life for affected individuals.
Conclusion
Testing the hypothesis that hEDS individuals will have a higher prevalence of positive Tinel sign could provide insight into the neuropathic manifestations of the disorder, potentially guiding future diagnostic and treatment strategies. Further research is required to explore the clinical significance of this relationship and how it might influence patient care for hEDS.
Statements
Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Author contributions
SH: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. DK: Formal analysis, Funding acquisition, Methodology, Resources, Writing – review & editing.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. Financial support for publication was provided by the UVA Health EDS Center.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that Gen AI was used in the creation of this manuscript. Generative AI was used in the initial draft of the manuscript; however, the author(s) authenticated each section in subsequent drafts.
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Summary
Keywords
Tinel sign, hypermobile Ehlers-Danlos syndromes, cubital tunnel syndrome, carpal tunnel syndrome, neuralgia, neuropathy
Citation
Hashemi SS and Knight DRT (2025) Hypothesis paper: high prevalence of Tinel sign in hypermobile Ehlers-Danlos syndrome. Front. Neurol. 16:1508176. doi: 10.3389/fneur.2025.1508176
Received
08 October 2024
Accepted
15 August 2025
Published
31 October 2025
Volume
16 - 2025
Edited by
Ovidiu Constantin Baltatu, Anhembi Morumbi University, Brazil
Reviewed by
A. Emre Öge, Istanbul University, Türkiye
William Ericson, Ericson Hand and Nerve Center, United States
Updates
Copyright
© 2025 Hashemi and Knight.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Shahreyar Shar Hashemi shashemi@nerveboneandjoint.comDacre R. T. Knight ths4er@uvahealth.org
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.