Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers–Danlos syndrome

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Abstract

Objectives

Many non-musculoskeletal complaints in EDS-HT may be related to dysautonomia. This study therefore aims to investigate whether dysautonomia is present and to explore the underlying mechanisms.

Methods

A total of 39 females with EDS-HT and 35 age-matched controls underwent autonomic function testing. Resting autonomic tone was assessed using heart rate variability (frequency domain) and baroreflex sensitivity analysis (cross correlation). Autonomic reactivity was assessed using the Autonomic Reflex Screen test battery. Factors suspected to contribute to dysautonomia, e.g., neuropathy, medication use, decreased physical activity, depression, pain-induced sympathetic arousal, and connective tissue laxity, were quantified using validated questionnaires, the Beighton score, and measurement of skin extensibility.

Results

The EDS-HT group showed autonomic deregulation with increased sympathetic activity at rest and reduced sympathetic reactivity to stimuli. Increased resting activity was indicated by a higher LF/HF ratio compared to controls (1.7 ± 1.23 vs 0.9 ± 0.75, p = 0.002); decreased reactivity by a greater BP fall during valsalva (−19 ± 12 vs −8 ± 10, p < 0.001), and a smaller initial diastolic BP increase during tilt (7% vs 14%, p = 0.032). Orthostatic intolerance was significantly more prevalent in EDS-HT than controls (74% vs 34%) and was most frequently expressed as postural orthostatic tachycardia. Lowered QSART responses suggest that sympathetic neurogenic dysfunction is common in patients (p < 0.013), which may explain the dysautonomia in EDS-HT. Further, connective tissue laxity and vasoactive medication use were identified as important factors in aggravating dysautonomia (p < 0.035).

Conclusion

Dysautonomia consisting of cardiovascular and sudomotor dysfunction is present in EDS-HT. Neuropathy, connective tissue laxity, and vasoactive medication probably play a role in its development.

Introduction

The Ehlers–Danlos syndrome (EDS) is a heritable connective tissue disorder characterized by generalized joint hypermobility, skin hyperextensibility, and tissue fragility. Patients are classified into 6 subtypes based on the Villefranche Nosology [1]. The hypermobility type (EDS-HT) is considered one of the largest subgroups, with prevalence of 1 in 5000–20,000 births [2]. As a consequence of hypermobility, patients experience recurrent joint dislocations, musculotendinous lesions, and chronic pain [3].

Besides these overt musculoskeletal symptoms, patients with EDS-HT also suffer from a large variety of non-musculoskeletal complaints, among which are palpitations, syncope, diarrhea, constipation, and thermoregulatory complaints [4]. Although EDS-HT is often perceived as a locomotor disorder, a recent study has shown that the non-musculoskeletal symptoms sometimes dominate the symptom profile and are related to significant impairment in daily life [5]. In fibromyalgia (FM), chronic fatigue syndrome (CFS), and joint hypermobility syndrome (JHS), which all show a large clinical overlap with EDS-HT, many of the non-musculoskeletal complaints have been attributed to an underlying dysautonomia [6], [7], [8], [9].

In EDS-HT, autonomic function has not yet been investigated, although dysautonomia is suspected on a clinical basis and would explain many of the non-musculoskeletal complaints in this population as well. Detection is of importance, because autonomic dysfunction has been related to a poor disease prognosis, decreased quality of life, and increased cardiac morbidity and mortality in other pathologies [10], [11], [12], [13], [14]. Individuals with autonomic dysfunction often have an unstable blood pressure, increasing the risk of cardiac complications under general anesthesia [15], [16]. If dysautonomia is present in EDS-HT, this risk should be considered, as these patients often undergo surgery in order to treat musculoskeletal and gastrointestinal problems [17].

Although dysautonomia has been demonstrated in JHS and is strongly suspected in EDS-HT, the exact cause is unclear. Several authors have suggested peripheral neuropathy, connective tissue abnormalities, and deconditioning as the possible pathomechanisms in hypermobile patients on a theoretical basis [6], [18], [19], but evidence supporting these hypotheses is lacking [19]. Identification of the underlying and aggravating factors, however, is necessary to provide an adequate treatment.

Therefore, this study aims to evaluate whether dysautonomia is present in EDS-HT, to determine its severity and distribution, and to explore possible underlying mechanisms. Consequently, testing of autonomic function was performed, consisting of cardiac testing (vagal and adrenergic function) and peripheral testing (sudomotor and adrenergic function). In addition, we explored whether neuropathy, medication use, physical activity, depression, pain-induced sympathetic arousal, and parameters of connective tissue laxity were related to autonomic dysfunction.

Section snippets

Subjects

A total of 39 female patients with EDS-HT (age 38.7 ± 10.14 years) and 35 age- and sex-matched healthy controls (age 39.5 ± 9.43 years) participated. As more than 90% of the EDS-HT patients are female [1], this study included only women. Patients were diagnosed at the Centre for Medical Genetics in Ghent University Hospital using the revised Villefranche Nosology [1]. Exclusion criteria were pregnancy in the current or past year, acute infection, structural heart disease or a disease known to

Resting autonomic activity (Table 1)

The resting systolic and diastolic BP was significantly higher in the patient group. Further, the higher HR in patients compared to controls, in combination with a higher LF/HF ratio and a higher normalized LF power, strongly suggests that resting cardiac sympathetic activity is increased in patients. Concerning resting cardiac parasympathetic activity, the results are inconclusive. Patients had a significantly lower normalized HF power, but the absolute HF power, which is a better marker of

Discussion

This study aimed to evaluate whether dysautonomia is present in EDS-HT, to determine its severity and distribution, and to explore the underlying mechanisms. Until today, autonomic function has only been tested in JHS and has been limited to testing the reactivity of the cardiovascular system [6]. Information regarding resting cardiovascular activity and the sudomotor system was added by this study. The results demonstrate that dysautonomia is indeed present in the EDS-HT population, that it is

Role of the funding source

This work was supported by the Methusalem Grant BOF08/01M01108 from the Flemish Government and Ghent University to Anne De Paepe. This did not influence the study design, collection, analysis, or the interpretation of data.

Acknowledgments

We would like to express our gratitude towards all patients participating in the study. Further, we want to thank Dr. Wim Peersman for his advice on statistical analysis, Dr. Johan Ryckaert for the technical help in QSART testing, and Elke Derynck for her work in the data analysis.

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