Background/Purpose: Chronic pain is one of the most common complaints of individuals with Ehlers-Danlos syndrome (EDS) and the effects of the existing therapeutical modalities are at best only partially effective. The etiology and mechanisms of pain in EDS have barely been studied, and the current understanding of the underlying neural, molecular and cellular pathways is minimal. Classical EDS (cEDS) is caused by heterozygous alterations in the COL5A1 or COL5A2 gene, encoding type V collagen. Moreover, with an estimated prevalence of 1:20,000, cEDS is the most common molecularly explained EDS type. Our group previously demonstrated an increased sensitivity to mechanical stimuli (mechanical allodynia) and disorganization of the nociceptive innervation in a mouse model for cEDS due to Col5a1 haploinsufficiency. This makes cEDS a highly interesting and suitable EDS type to study pain processing mechanisms.

Methods: Molecularly confirmed cEDS patients (n=20) and age and sex matched healthy controls (n=20) were recruited. Subjective pain was measured using Visual Analogue Scales and symptoms possibly indicating neuropathic pain were evaluated using the PainDETECT and DN4 questionnaires. Forebrain processes that are known to influence pain were studied using several questionnaires (TAMPA scale for kinesiophobia, Hospital Anxiety and Depression scale, Pain Vigilance and Awareness scale, Central Sensitization Inventory and SF-36). Clinical sensitivity to (in)noxious stimuli was studied by measuring pain thresholds for electrical, thermal, vibration, touch, and pressure stimuli. Central pain inhibition was studied using a central pain modulation protocol (CPM) with immersion of one hand in hot water and parallel measurement of pain pressure thresholds.

Results: Individuals with cEDS suffer from significant pain, but no positive scores were found for possible neuropathic pain. The TAMPA scale for Kinesiophobia showed significant kinesiophobia in cEDS. The hospital anxiety and depression scale did not differ between controls and individuals with cEDS, and the SF-36 questionnaire indicated that individuals with cEDS suffer from significant limitations due to physical health but no limitations due do emotional problems. The Pain Vigilance and Awareness questionnaire showed no significant differences compared to controls.Lower pain thresholds were found for pressure and temperature indicating possible hyperalgesia in cEDS. Interestingly, we also found a possible sensory/neurological deficit as individuals with cEDS had higher detection thresholds (for thermal, electrical, mechanical and vibration stimuli), and a significantly higher number of paradoxical heat sensations (errors in distinguishing between warmth or cold sensations) were present upon thermal stimulation. The CPM protocol did show signs of dysfunctional central pain inhibition in individuals with cEDS as the pain pressure thresholds did not differ significantly before, during and after immersion of the hand (as was the case in the control subjects).

Conclusion: cEDS individuals show presence of significant pain, hyperalgesia, a sensory deficit, and deficient central pain inhibition compared to controls.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identifying-a-pain-signature-in-classical-ehlers-danlos-syndrome-preliminary-results-from-questionnaires-and-experimental-pain-testing/