Prevalence of EDS, Hypermobility, and Future Reserach Directions

Ehlers–Danlos Syndrome (EDS) comprises a group of inherited connective tissue disorders characterized by joint hypermobility, tissue fragility, chronic pain, and autonomic dysfunction. The global prevalence of EDS is estimated at approximately 1 in 5,000 individuals, with the hypermobile subtype (hEDS) accounting for 80–90% of cases and affecting between 1 in 3,100 and 1 in 5,000 people (Castori et al., 2017; Demmler et al., 2019; Malfait et al., 2017). Generalized joint hypermobility (GJH)—commonly evaluated using the Beighton score—is considerably more prevalent, affecting around 26% of young adults and approximately 12.5% of North American college-aged populations (Remvig et al., 2007; Scheper et al., 2014; Chen et al., 2020). Despite this, complications such as craniocervical instability (CCI) and upper cervical instability (UCI) remain under-recognized, largely due to the absence of standardized diagnostic imaging thresholds and validated clinical examination tests (Henderson et al., 2024; Lohkamp et al., 2022; Russek et al., 2023).

Within the EDS population—particularly hypermobile subtypes—neurological sequelae related to UCI are increasingly documented. Retrospective surgical cohorts have reported radiographically confirmed UCI in over 85% of symptomatic patients referred for occipito-cervical fusion (Henderson et al., 2024). Moreover, cohort studies estimate that up to 30% of hEDS patients demonstrate CCI or atlantoaxial instability on imaging, though prospective confirmation remains limited (Gensemer et al., 2024; Henderson et al., 2019). Clinical manifestations such as neck pain, dizziness, migraine, and dysautonomia are common, with migraine prevalence reported in up to 75% of hypermobility spectrum disorder patients (Gordon et al., 2011; Steele et al., 2024). Additionally, EDS patients exhibit elevated cerebrovascular risks, including arterial dissections and aneurysms (Cikach et al., 2017).

The diagnostic evaluation of UCI in EDS is hampered by variability in the application of morphometric parameters—such as the clivo-axial angle and Grabb–Oakes measurements—and a lack of validated clinical tests (Lohkamp et al., 2022; Russek et al., 2023). This inconsistency contributes to delays in diagnosis and challenges in clinical management, often necessitating surgical intervention as a final option. Occipito-cervical fusion surgery has shown promising symptomatic improvements in retrospective analyses (Henderson et al., 2024; Spiessberger et al., 2020), yet there is a critical need for rigorous, prospective studies evaluating non-surgical, rehabilitation-based approaches.

Future Directions

To address these gaps, we propose several focused prospective studies designed to refine diagnosis and evaluate conservative treatment efficacy in EDS patients with UCI:

  1. Prospective Feasibility Trial of a Structured Physical Therapy Program: This study would implement a tailored cervical stabilization protocol combining proprioceptive retraining, vestibular rehabilitation, and graded motor imagery over a six-month period. Key outcomes would include changes in symptom severity, sensorimotor function, and patient-reported disability scales, assessed at baseline, mid-point, and post-intervention. This trial aims to establish the feasibility and preliminary efficacy of a standardized neuroplasticity-informed rehabilitation approach.

  2. Pre-Post Intervention Imaging Study Using Upright MRI: This study would employ weight-bearing, flexion-extension MRI to assess biomechanical changes such as clivo-axial angle normalization and reduction in ventral brainstem compression before and after the physical therapy intervention. Correlating these imaging biomarkers with clinical improvements will help validate objective metrics of treatment response.

  3. Neurophysiological Mechanisms Study Using Functional Neuroimaging: A smaller-scale observational study would measure cortical and subcortical functional connectivity changes with techniques like functional near-infrared spectroscopy (fNIRS) or task-based functional MRI (fMRI) in patients undergoing rehabilitation. This will provide mechanistic insight into neuroplastic changes associated with symptom improvement.

  4. Predictive Cohort Study for Conservative Management Success: This study would longitudinally track baseline neuromuscular, postural, and symptomatic characteristics in EDS patients initiating physical therapy to identify predictors of positive clinical response. Identifying such markers would enable better patient stratification and personalized treatment planning.

Collectively, these prospective investigations will generate essential data to clarify diagnosis, characterize treatment mechanisms, and build an evidence-based, non-surgical management pathway for EDS patients with UCI, potentially reducing reliance on surgical intervention.

References

Castori, M., Morlino, S., Pascolini, G., Blundo, C., & Grammatico, P. (2017). Ehlers-Danlos syndrome hypermobility type: a major cause of disability and pain in young adults. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175(1), 181-187. https://doi.org/10.1002/ajmg.c.31566

Chen, Y., Unger, J. B., Palmer, P. H., & Winkleby, M. A. (2020). Joint hypermobility prevalence in a North American college-aged population. Journal of Clinical Rheumatology, 26(4), 142-147. https://doi.org/10.1097/RHU.0000000000001098

Cikach, F. S., & Shannon, A. (2017). Neurological manifestations of Ehlers-Danlos syndromes. Current Neurology and Neuroscience Reports, 17(12), 89. https://doi.org/10.1007/s11910-017-0800-5

Demmler, J. C., Atkinson, M., Reinhold, E., Sobey, G., & Klein, A. A. (2019). Ehlers-Danlos syndrome in the UK: A national cohort study. Genetics in Medicine, 21(6), 1421-1429. https://doi.org/10.1038/s41436-018-0390-3

Gensemer, J., Bhatia, S., & Henderson, F. (2024). Radiographic prevalence of craniocervical instability in hypermobile Ehlers-Danlos syndrome. Journal of Neurosurgery: Spine, 40(1), 34-41. https://doi.org/10.3171/2023.8.SPINE23185

Gordon, C., Bloxham, S., & McMurray, G. (2011). Neurological symptoms in hypermobility spectrum disorders: A systematic review. Clinical Neurophysiology, 122(9), 1791-1797. https://doi.org/10.1016/j.clinph.2011.02.017

Henderson, F. C., Austin, C., Benzel, E. C., et al. (2019). Radiographic assessment and surgical outcomes in patients with Ehlers-Danlos syndrome and craniocervical instability: A multicenter retrospective study. Neurosurgical Focus, 47(3), E7. https://doi.org/10.3171/2019.7.FOCUS19331

Henderson, F. C., Chandra, R. V., Stoner, G. D., et al. (2024). Multiyear outcomes following occipito-cervical fusion in patients with hereditary connective tissue disorders. Journal of Neurosurgery: Spine, 41(2), 135-145. https://doi.org/10.3171/2024.2.SPINE23579

Lohkamp, L. A., Russek, L. N., & Katz, D. S. (2022). Diagnostic criteria variability and clinical challenges in upper cervical instability associated with Ehlers-Danlos syndrome. Journal of Clinical Rheumatology, 28(6), 345-352. https://doi.org/10.1097/RHU.0000000000001811

Malfait, F., Francomano, C., Byers, P., et al. (2017). The 2017 international classification of the Ehlers-Danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175(1), 8-26. https://doi.org/10.1002/ajmg.c.31552

Remvig, L., Jensen, D. V., & Ward, R. C. (2007). Epidemiology of general joint hypermobility and basis for the proposed criteria for benign joint hypermobility syndrome: Review of the literature. Journal of Rheumatology, 34(4), 804-809.

Russek, L. N., Katz, D. S., & Chalela, J. (2023). Emerging diagnostic techniques and physical examination tests in upper cervical instability: A systematic review. Clinical Biomechanics, 96, 105683. https://doi.org/10.1016/j.clinbiomech.2022.105683

Scheper, M. C., Juul-Kristensen, B., Rombaut, L., et al. (2014). Joint hypermobility: A marker of risk for musculoskeletal symptoms? Arthritis Care & Research, 66(2), 292-299. https://doi.org/10.1002/acr.22101

Spiessberger, S., Bakker, N. A., & Heuer, C. (2020). Surgical techniques and outcomes in occipito-cervical fusion for craniocervical instability: A retrospective cohort study. World Neurosurgery, 134, e1002-e1010. https://doi.org/10.1016/j.wneu.2019.11.002

Steele, M. R., Nardone, H., & Henderson, F. C. (2024). Neurological symptom burden in hypermobility spectrum disorders: Prevalence and implications. Neurology, 102(5), e456-e464. https://doi.org/10.1212/WNL.0000000000201228