Small fibre damage and neuropathic pain in Ehlers Danlos Syndrome.

Background and aims: Hypermobile Ehlers-Danlos Syndrome (hEDS) frequently presents with chronic pain and autonomic symptoms, often accompanied by suspected Small Fiber Neuropathy (SFN) and overlapping fibromyalgia. The contribution of SFN to pain characteristics and autonomic dysfunction in hEDS remains unclear. This study aimed to evaluate the prevalence of SFN in hEDS patients with chronic pain and autonomic symptoms, determine the frequency of fibromyalgia and compare pain and autonomic symptoms between patients with secondary hEDS-associated fibromyalgia and those with primary fibromyalgia. Methods: We enrolled 23 hEDS patients (21 females) with painful symptoms. Data from 41 patients with primary fibromyalgia were retrieved from a previous study using the same methodology. Pain and autonomic symptoms were assessed using the Neuropathic Pain Symptom Inventory (NPSI) and the COMPosite Autonomic Symptom Score-31 (COMPASS-31) questionnaire, respectively. Diagnostic assessments included Nerve Conduction Studies (NCS), pain somatotopic maps and Quantitative Sensory Testing (QST). Intraepidermal nerve fiber density (IENFD) was measured by using a skin biopsy, while Dinamic Sweat Test (DST) was employed to measure sudomotor function. Results: Among the hEDS patients, 22 (96%) experienced widespread pain. SFN was diagnosed in 7 (30%) patients, who showed reduced IENFD in both distal and proximal sites in a non-lengthdependent pattern, along with impaired cold detection thresholds. No significant differences in NPSI or COMPASS-31 scores were observed between patients with and without SFN. Twenty out of 23 (87%) hEDS patients met the criteria for fibromyalgia. Patients with secondary hEDSassociated fibromyalgia reported lower pain and autonomic symptom scores compared to those with primary fibromyalgia Discussion: SFN is moderately prevalent among hEDS patients with painful symptoms, suggesting it may represent a specific neuropathic component of hEDS. Most hEDS patients with pain fulfill diagnostic criteria for fibromyalgia. Secondary hEDS-related fibromyalgia presents with less severe 3 neuropathic pain and autonomic symptoms than primary fibromyalgia, indicating they might represent distinct entities. Comprehensive, multidisciplinary approaches are warranted to improve diagnosis and management of pain and autonomic symptoms in hEDS patients.