Letter: Is Enteric Neuropathy Absent in Hypermobility Spectrum Disorders/Hypermobile Ehlers-Danlos Syndrome?

We commend Sweerts et al. for their largest-to-date investigation using antroduodenal manometry (ADM) in 50 patients with hypermobility spectrum disorders (HSD) and hypermobile Ehler-Danlos Syndrome (hEDS) compared to 189 non-HSD/hEDS patients [1]. ADM, a labour-intensive and technically challenging procedure, comes the closest to the gold standard of histopathological evaluation of full-thickness tissue specimens for diagnosing enteric myopathy or neuropathy. Key findings of the study were similar rates of antroduodenal dysmotility and delayed gastric emptying, but less enteric dysmotility in HSD/hEDS patients. As discussed, malnutrition was highly prevalent with 76% of HSD/hEDS patients receiving enteral (62%) or parenteral (13%) support. In contrast, the non-HSD/hEDS comparator group had nearly double the proportion of patients not receiving enteral or parenteral nutrition, suggesting differences in meal tolerability. The ADM protocol employed in this study only allowed a ‘one shot’ assessment of enteric function via a single meal. While logistical and technical challenges exist, 24-h recordings present more opportunities to detect enteric motility between meals, in response to multiple meals, in response to a non-meal stimulus through promotility agents, and diurnal variation [2]. The conclusion of a lower prevalence of enteric dysmotility in the HSD/hEDS cohort based on a single meal challenge in patients with poor meal tolerability during ADM may be premature.

Delayed gastric emptying was present in 85% of the HSD/hEDS cohort. While validated symptom scores for gastroparesis and/or functional dyspepsia were not captured, the corresponding predominant symptom was a cardinal gastroparesis symptom in most patients (nausea/vomiting > 50% and abdominal pain and excessive fullness ~25% of HSD/hEDS group), projected to meet diagnostic criteria for gastroparesis. In gastroparesis overall (i.e., not limited to HSD/hEDS), constipation remains understudied and poorly understood from a pathophysiological standpoint. Fifty-eight percent of patients with gastroparesis have moderate to very severe constipation, and the severity of constipation symptoms correlates with the severity of gastroparesis symptoms [3]. Based on our clinical observations and the lack of use of a prospective stool diary in this study, constipation was probably underreported by HSD/hEDS participants. Underlying rectal evacuation disorders are key drivers of pathophysiology in severe constipation and are present in 60%–75% of patients with HSD/hEDS undergoing anorectal manometry [4, 5].

While the prevalence of enteric dysmotility or neuropathy in HSD/hEDS remains unclear, more than half of HSD/hEDS patients have associated postural orthostatic tachycardia syndrome and dysautonomia [6]. Transauricular vagal nerve stimulation targeting dysautonomia is promising for functional dyspepsia, also highly prevalent in HSD/hEDS, and improves autonomic function with the ability to monitor and adjust settings remotely [7, 8]. Furthermore, radiologically occult tethered cord syndrome can co-occur with cranio-cervical or cervical instability in patients with hEDS, and surgical management may help in select cases [9]. Neuromodulation of thoracic spinal nerves has shown promise in a proof-of-concept study of patients with diabetic gastroparesis, and is undergoing a sham-controlled randomised clinical trial. It may be beneficial in select cases associated with dysautonomia [10].

In conclusion, patients with HSD/hEDS suffer from substantial gastrointestinal symptoms and dysfunction. Further studies into understanding the underlying pathophysiology to drive mechanistic treatments are urgently needed.

Caitlin Green: writing – original draft, writing – review and editing. Anne Maitland: writing – review and editing. Steven A. Kautz: writing – review and editing. Russell Norris: writing – review and editing. Sunil Patel: writing – review and editing. Amol Sharma: writing – original draft, writing – review and editing, supervision, conceptualization, visualization, project administration.

The authors declare no conflicts of interest.

This article is linked to Sweerts et al. papers. To view these articles, visit, https://doi.org/10.1111/apt.18471 and https://doi.org/10.1111/apt.70157.