Trauma and onset of symptoms in Ehlers Danlos Syndrome

Trauma as a Catalyst: Symptom Onset in Previously Asymptomatic Ehlers-Danlos Syndrome Patients

Abstract

Ehlers-Danlos Syndrome (EDS) is a group of heritable connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. While some individuals remain asymptomatic, trauma can unmask the underlying pathology, leading to significant disability. This review explores the scientific basis for trauma-induced symptom emergence in EDS, highlights imaging findings, clinical case series, and discusses the pathophysiological mechanisms and diagnostic considerations.

Introduction:
Ehlers-Danlos Syndrome (EDS) encompasses a heterogeneous group of connective tissue disorders caused by mutations affecting collagen and collagen-modifying proteins. Although the clinical spectrum is broad, individuals with hypermobile EDS (hEDS) or classical EDS may remain asymptomatic into adulthood. However, trauma—ranging from motor vehicle accidents to surgical interventions—can precipitate the onset of symptoms such as chronic pain, joint instability, and autonomic dysfunction. Recognition of trauma as a potential unmasking factor is essential for timely diagnosis and appropriate care.

Pathophysiological Mechanisms Linking Trauma and Symptom Onset in EDS:

1. Collagen Fragility and Microtrauma Accumulation
   EDS is characterized by defects in type I, III, or V collagen (depending on subtype), which compromises tissue integrity and repair mechanisms. Even minor trauma can lead to subclinical joint injury, ligament laxity, or soft tissue damage, particularly in joints already predisposed to hypermobility [1,2].

2. Loss of Compensatory Mechanisms
   Asymptomatic individuals may rely on muscular compensation or proprioceptive adaptation. Trauma can overwhelm these compensatory mechanisms, leading to musculoskeletal decompensation and persistent pain or dysfunction [3].

3. Neurogenic Inflammation and Central Sensitization
   Traumatic injury can trigger neurogenic inflammation and central sensitization, phenomena particularly evident in EDS patients predisposed to chronic pain syndromes like CRPS and fibromyalgia [4]. This may explain why a previously tolerable joint instability becomes painful and disabling after trauma.
4. Autonomic Dysregulation and Mast Cell Activation
   Physical trauma can activate downstream dysregulation of the autonomic nervous system and mast cells, potentially unmasking comorbidities such as POTS or MCAS, commonly seen in hEDS patients [5,6].

Clinical Evidence:

• Case Series and Observational Data:
  Multiple case reports and series describe the delayed onset of symptomatic EDS following trauma:
  • Henderson et al. documented patients with cervical instability and cerebrospinal fluid leaks manifesting post-whiplash in individuals later diagnosed with hEDS [7].
  • Castori et al. described how trauma frequently marked the beginning of disabling symptoms in previously undiagnosed hEDS patients [8].
• Surgical and Postpartum Triggers:
  Invasive procedures and childbirth are also recognized as triggers in susceptible individuals. Women with hEDS often experience worsening of symptoms postpartum, attributed to both mechanical stress and hormonal changes [9].
• Pediatric to Adult Transition Studies:
  A longitudinal study by Rombaut et al. showed an increase in musculoskeletal pain and fatigue in hEDS patients over time, with physical stressors accelerating this progression [10].

Implications for Diagnosis and Management:

• Post-Trauma Assessment:

Patients presenting with disproportionate pain, instability, or delayed recovery after trauma should be assessed for connective tissue disorders, especially if they exhibit hypermobility or family history of EDS.

• Early Rehabilitation and Joint Protection:

Management should emphasize proprioceptive training, stabilization exercises, and avoidance of further mechanical overload. Multidisciplinary care is often needed.

• Pre-Trauma Identification:

Screening for joint hypermobility (e.g., Beighton score) in children and young adults, especially athletes, may help preempt severe outcomes.

Imaging Findings in Post-Traumatic Symptomatic EDS

Imaging plays a pivotal role in evaluating newly symptomatic individuals with EDS, particularly after trauma. While connective tissue disorders are primarily clinical diagnoses, radiological studies help identify structural sequelae and guide management. Key modalities and findings include:

1.     Dynamic Cervical Spine MRI and CT

In patients with post-traumatic neck pain, headaches, or neurological symptoms, dynamic flexion-extension MRI can reveal:
- Cranio-cervical instability (CCI)
- Atlantoaxial instability (AAI)
- Brainstem compression or cervicomedullary kinking
- Retroflexed odontoid process
Henderson et al. showed CCI in hEDS patients post-whiplash with abnormal clivo-axial angles and C1-C2 translation.

2.     High-Resolution MRI of the Spine

May reveal tethered cord syndrome, Chiari malformations, or meningeal cysts in patients with new symptoms after trauma. CSF leaks may be confirmed via gadolinium-enhanced myelography or radioisotope cisternography.

3. Whole-Body Kinetic MRI (in research settings)

Functional MRI techniques assess ligamentous tension and microinstability, especially in the cervical spine.

4. Dural Ectasia

Seen on sacral MRIs, may become symptomatic after trauma, manifesting as pelvic pain or bowel/bladder dysfunction.

Discussion

The use of advanced imaging techniques has enhanced the recognition of trauma-related complications in EDS, particularly those not detectable on routine imaging. This supports the theory that EDS patients possess latent biomechanical vulnerabilities that may decompensate when exposed to physical trauma. Imaging findings not only confirm symptom etiology but also help distinguish between central sensitization and structural pathology—guiding both conservative and surgical interventions.

Conclusion:
Trauma may serve as a key triggering event for the onset of clinical symptoms in individuals with undiagnosed or subclinical Ehlers-Danlos Syndrome. Understanding this relationship is crucial for early diagnosis, effective management, and the development of preventive strategies.

References

1. Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers–Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):8–26. doi:10.1002/ajmg.c.31552
2. Rombaut L, Malfait F, Cools A, et al. Musculoskeletal complaints, physical activity and health-related quality of life among patients with the Ehlers-Danlos syndrome hypermobility type. Disabil Rehabil. 2010;32(16):1339–1345.
3. Chopra P, Tinkle B, Hamonet C, et al. Pain management in the Ehlers–Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):212–219.
4. Hakim AJ, O'Callaghan C, Pocinki A, et al. Cardiovascular autonomic dysfunction in Ehlers-Danlos syndrome–hypermobility type. Am J Med Genet C Semin Med Genet. 2017;175(1):168–174.
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7. Castori M, Morlino S, Pascolini G, et al. Pain in Ehlers-Danlos syndromes: manifestations, therapeutic strategies and future perspectives. Expert Opin Orphan Drugs. 2016;4(11):1145–1158.
8. Volkov NM, Vrooman L, Gazit Y, et al. Pregnancy and delivery in women with Ehlers-Danlos syndrome. Am J Perinatol. 2020;37(13):1342–1349.
9. Rombaut L, De Wandele I, Malfait F, et al. Medication, surgery, and physiotherapy among patients with the Ehlers-Danlos syndromes: a survey study. Disabil Rehabil. 2011;33(9):731–737.
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11. 1. Henderson FC, Francomano CA, Koby M, et al. Craniocervical instability in patients with Ehlers-Danlos syndrome. Neurosurg Rev. 2020;43(4):1091–1104. doi:10.1007/s10143-019-01171-8
    2. Schievink WI, Maya MM, Louy C, Moser FG, Tourje J. Cranial MRI findings in spontaneous intracranial hypotension: significance and relation to underlying cause. AJNR Am J Neuroradiol. 2008;29(5):853–857.
    3. Castori M, Celletti C, Camerota F. Evaluation of kinesiological and functional patterns in EDS patients using ultrasound and motion analysis. Clin Rheumatol. 2013;32(5):649–656.
    4. Kranz PG, Tanpitukpongse TP, Choudhury KR, Amrhein TJ, Gray L. CSF venous fistula in spontaneous intracranial hypotension: imaging characteristics and outcomes. AJNR Am J Neuroradiol. 2016;37(7):1374–1379.

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1. Henderson FC, Francomano CA, Koby M, et al. Craniocervical instability in patients with Ehlers-Danlos syndrome. Neurosurg Rev. 2020;43(4):1091–1104. doi:10.1007/s10143-019-01171-8
2. Schievink WI, Maya MM, Louy C, Moser FG, Tourje J. Cranial MRI findings in spontaneous intracranial hypotension: significance and relation to underlying cause. AJNR Am J Neuroradiol. 2008;29(5):853–857.
3. Castori M, Celletti C, Camerota F. Evaluation of kinesiological and functional patterns in EDS patients using ultrasound and motion analysis. Clin Rheumatol. 2013;32(5):649–656.
4. Kranz PG, Tanpitukpongse TP, Choudhury KR, Amrhein TJ, Gray L. CSF venous fistula in spontaneous intracranial hypotension: imaging characteristics and outcomes. AJNR Am J Neuroradiol. 2016;37(7):1374–1379.

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