Review for 10.1186/s12876-022-02572-8 (2022)

Title: Anorectal Manometry for the Diagnosis of Pelvic Floor Disorders in Patients with
Hypermobility Spectrum Disorders and Hypermobile Ehlers-Danlos Syndrome
Version: 2 Date: 18 Jul 2022
Reviewer's report:
The authors performed a large retrospective case control study comparing anorectal physiology
(HRAM, balloon expulsion test and sensitivity testing) and MR defecography in 72 patients
with hEDS and impaired rectal evacuation and in 72 age and sex matched controls with similar
symptoms. This was the second largest study looking at these physiological parameters in
hEDS/HSD patients but had the advantage of reporting on results of balloon expulsion test
(BET) and MR defecography which had not previously been compared in patients with and
without hEDS/HSD. There was no difference in the prevalence of an abnormal BET, but it
appeared that in hEDS/HSD this was predicted by increased anal tone and maximum volume
tolerated compared to in non hEDS/HSD where it was predicted by rectoanal pressure gradient.
There was no difference in the prevalence of structural abnormalities which echoes the findings
in a recently published paper (Choudhary A, Vollebregt PF, Aziz Q, Scott SM, Fikree A.
Rectal hyposensitivity: A common pathophysiological finding in patients with constipation and
associated hypermobile Ehlers-Danlos syndrome. Aliment Pharmacol Ther. 2022 Jun 27. doi:
10.1111/apt.17104. Epub ahead of print. PMID: 35758859.) The discussion is confusing at times
and seems to veer into a discussion  of  the predictors of hEDS which is not the aim of the study,
nor can this be answered by the study design. It also makes some sweeping statements which
are unfounded based on the present study. However on the whole the paper is well written and
there is good discussion of the limitations.
The manuscript can be improved by addressing and clarifying the following points:
1. Please can you clarify methods of assessment for hEDS – you mention Beighton score and
assessment of musculoskeletal symptoms. What criteria did you use to assess this?
2. Apart from the MR defecography did all patients undergo the remaining tests? If not then
it would be useful to know how many patients underwent each test. It would also be useful to
know if patients were asked to stop opiates before the test
3. It is commendable that you included both men and women however the demographics are
skewed towards the females with a huge majority of 96%. Was there a sex difference in the
findings? Will this confound your results?
4.  97% hEDS and 84% controls reported constipation under GI symptoms – why was this not
100% if all patients were being investigated for constipation. If they were not all constipated
does this not introduce some heterogeneity in the clinical presentation of the patients?
5. You describe negative recto-anal pressure gradients and you allude to functional defecation
disorders and dyssynergic defecation but you do not directly report the proportion of patients in
each group would be diagnosed with dyssynergic defecation/functional defecatory abnormalities
and whether there was a difference in the groups.
6. Similarly when reporting rectal sensation, what proportion of patients had rectal
hyposensitivity and how do your findings compare to those in the aforementioned paper
(Choudhary et al) whereby patients with hEDS/HSD had significantly increased rectal
hyponsensitivity
7. Please can you clarify if the results in table 2 are medians or means
8. In Figure 1 I cannot see any annotation on the figure supplied
9. In Table 4  - it would be helpful if you could present the OR, CI and p value for all the
variables used in the regression analysis , in the 3 groups  - all patients, hEDS/HSD patients
and non hEDS patients. It would be useful to translate those parameters into something more
clinically meaningful to make it more relevant to the majority of clinicians who deal more
with pathophysiologies eg megarectum/rectal hyposensitivity/functional defecation disorder/
structural defecation disorder than with parameters of anorectal physiology tests eg higher anal
sphincter pressures/maximum tolerated volume
10. Higher tolerated volumes were associated with abnormal BET in hEDS/HSD. How do you
interpret that? Is it suggestive of a larger diameter rectum or rectal hyposensitivity? Is there a
correlation between higher volumes tolerated and size of rectum on MR defecography? IS there
an association between abnormal BET and rectal hyposensitivity?
11. I am not sure I understand the rationale for predicting hEDS from the logistic regression
analysis. In your study the outcome (dependant variable) is abnormal BET and the independent
variables are presence of hEDS/HSD, comorbidities, symptoms etc. The study is not designed
to look at what predicts hEDS – this seems to be the wrong way round. It may just be your
choice of wording but it seems to be that the following variables (dyspepsia, fibromyalgia, sleep
disorders, and history of vaginal delivery) were independently associated with a diagnosis of
hEDS/HSD. However this is not the point of the study and so I am not sure it is worth devoting
so much of the results and discussion section to this, particularly as hEDS/HSD can more easily
be diagnosed by using the 2017 diagnostic classification
12. In the discussion it would be useful to discuss how your findings compare to that in the
perviously mentioned study of 139 patients with hEDS/HSD - Choudhary A, Vollebregt PF,
Aziz Q, Scott SM, Fikree A. Rectal hyposensitivity: A common pathophysiological finding
in patients with constipation and associated hypermobile Ehlers-Danlos syndrome. Aliment
Pharmacol Ther. 2022 Jun 27. doi: 10.1111/apt.17104. Epub ahead of print. PMID: 35758859
13. In the Discussion you allude to the  multifactorial pathophysiology in pelvic floor but you
do not clarify what these pathophysiologies are
14. The following sentences in the discussion are  unclear–
a. ‘ Mohammed et al reported higher anatomical abnormalities on defecography in HSD/hEDS
patients compared to non HSD/hEDS patients (86% vs 64%, p=0.001). Higher prevalence of
structural abnormalities likely explains our findings of higher rates of incomplete evacuation
on defecography in patients with HSD/hEDS (20% vs 41%, p=0.004) [5]’ . The paper did not
look at hEDS/HSD – it used a screening questionnaire which screened for patients with joint
hypermobility trait  rather than joint hypermobility disorder. Furthermore you allude to how a
higher prevalence of structural abnormalities explains the higher rates on incomplete defecation
– this is confusing as you did not find a higher rate of incomplete defecation on BET, nor did
you find a higher prevalence of structural abnormalities. I wonder whether you need to clarify
the point you are trying to make.
b. –‘, symptom perception can also be affected by confounding psychosomatic disorders.’. I
do not think you have shown this in your study. You have demonstrated only that hEDS is
associated with somatic symptoms but not that symptoms of constipation are.
c.  ‘HR-ARM can provide valuable information about pelvic floor motor and sensory function in
patients with HSD/hEDS’ I am not aware of how HRARM can provide information on sensory
function.