Linking central sensitization to multisystemic manifestations in hypermobile Ehlers-Danlos syndrome

Hypermobile Ehlers-Danlos Syndrome (hEDS) and Hypermobility Spectrum Disorders (HSD) are complex multisystemic conditions frequently associated with chronic pain. Central Sensitization (CS)-a state of neural amplification and hyperexcitability-is hypothesized to be a unifying mechanism underlying the heterogeneous symptoms in chronic pain patients. Our aim was to investigate the association between central sensitization and multisystemic symptom burden in patients with hEDS/HSD while identifying independent clinical predictors of CS. We prospectively enrolled 150 adults diagnosed with hEDS/HSD at a specialized joint hypermobility clinic. Participants were evaluated using the Central Sensitization Inventory (CSI) and the SPIDER questionnaire. Clinical CS was defined as a CSI score > 40. Statistical analyses included univariate correlations and multivariable logistic regression. Centrally sensitized patients (n = 76) were significantly younger and predominantly female compared to the non-CS group. While CSI scores correlated strongly with all eight SPIDER domains (p < 0.001), a multivariable logistic regression model (AUC 0.98) identified only three independent predictors of CS: fatigue (OR 1.089), pain (OR 1.067), and cardiac dysautonomia (OR 1.057). Central sensitization in hEDS/HSD is independently associated with a triad of fatigue, pain, and cardiac dysautonomia. Clinical management should shift toward multidisciplinary strategies to effectively address the sensitized state in this population.