Expanding neurologic phenotypes in Ehlers-Danlos syndromes: a narrative review

Background Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, tissue fragility, and variable multisystem involvement. Although musculoskeletal and cardiovascular features are well recognized, neurologic manifestations are common, clinically significant, and frequently underrecognized. These manifestations range from dysautonomia and small fiber neuropathy (SFN) to cervical instability, epilepsy, and cerebrovascular complications. Emerging evidence further implicates autonomic dysfunction, altered connective tissue biomechanics, and neuroimmune interactions in gastrointestinal dysmotility and related gut-brain axis disturbances in EDS. This review highlights these emerging connections alongside the broader neurologic spectrum of EDS. Objective To summarize the major neurologic manifestations of EDS, with emphasis on nonvascular neurologic complications, diagnostic approaches, and management considerations relevant to clinical practice. Methods A literature search was performed using PubMed/MEDLINE. Studies published in English within the last 10 years were screened for eligibility. Eligible studies included human studies evaluating neurologic manifestations in patients with diagnosed EDS. Review articles, cohort studies, observational studies, and clinically relevant case series were included. Results Postural orthostatic tachycardia syndrome and other autonomic symptoms are frequently reported in hypermobile EDS (hEDS) and hypermobility spectrum disorders (HSD). Autonomic dysfunction is also associated with gastrointestinal symptoms and dysmotility, although its causal contribution remains incompletely defined. SFN has been demonstrated in multiple hEDS/HSD cohorts and may contribute to neuropathic pain and autonomic symptoms. Structural neurologic complications including Chiari I malformation, cervical instability, atlantoaxial instability, and tethered cord syndrome are increasingly recognized. Migraine and orthostatic headache are common, while epilepsy and congenital structural brain abnormalities are associated with rarer subtypes. Vascular neurologic complications, especially in vascular EDS, include cervical artery dissection, aneurysmal subarachnoid hemorrhage, and stroke. Conclusion Neurologic manifestations of EDS are diverse and often multisystemic. Earlier recognition improves diagnostic accuracy, reduces unnecessary morbidity, and facilitates multidisciplinary management. Greater prospective data and subtype-specific neurologic characterization are needed.