An international survey on clinicians' perspectives on the diagnosis and management of chronic intestinal pseudo‐obstruction and enteric dysmotility

Chronic intestinal pseudo‐obstruction (CIPO) and enteric dysmotility (ED) are small intestinal motility disorders defined by radiological and manometric criteria. In the absence of consensus guidelines, we surveyed opinions on the diagnosis and management of CIPO and ED among experts from different countries.


| INTRODUC TI ON
Recent international studies have confirmed that small intestinal motility disorders represent a common cause of chronic intestinal failure requiring long-term parenteral feeding, accounting for up to 18% of adult patients requiring long-term parenteral nutrition (PN). 1,2 Moreover, in recent years, it has been suggested that there may be an upward trend in the number of newly diagnosed patients with motility disorders requiring long-term PN. 3,4 Despite this increase, in the absence of universally agreed national or international guidelines criteria, treatment of small intestinal dysmotility may be delayed, contributing adversely to chronicity of symptoms, nutritional status, quality of life, morbidity, mortality, and reported exposure to inappropriate surgeries. 5,6 Based on findings from radiological and motility tests, small intestinal dysmotility can be sub-classified into chronic intestinal pseudo-obstruction (CIPO) and enteric dysmotility (ED). 6-10 CIPO is defined as chronic/recurrent obstructive type symptoms with radiological features of dilated intestine with air/fluid levels in the absence of any lumen-occluding lesion. 7,9 By contrast, ED refers to patients with objective evidence of small bowel dysmotility on antroduodenal manometry (ADM), but without radiological features of a dilated intestine. 10,11 There is some evidence that outcomes are significantly worse in patients with CIPO compared to ED, with a higher requirement for long-term PN dependency, higher mortality, and complications including small intestinal bacterial overgrowth and the need for surgical interventions. 6,12 However, there remains considerable debate among clinicians on the merits of sub-classifying small intestinal dysmotility into CIPO and ED.
The debate predominantly relates to the limitations of ADM as a diagnostic test, due to its invasiveness, which often results in poor tolerance, variability in results, poor correlation with symptoms and histopathology, apparent limited impact on patient management, and lack of availability. 5,7,11,13,14 Another contentious issue in the diagnosis and classification is the role of full thickness biopsies. While patients with small intestinal dysmotility have been shown to have a high incidence of gastrointestinal neuromuscular disorders (GINMD), 12,15 the diagnostic utility and the risk: benefit ratio of performing a full thickness small bowel biopsy remains unclear, 8 despite publication of international consensus guidelines for histopathological diagnosis of GINMD. 16,17 Therefore, in the absence of well-defined national or international clinical practice guidelines, we hypothesized that there would be a variation in opinions and clinical practice between experts across Europe in diagnosing and managing CIPO and ED.
The aim of this survey was therefore to evaluate current opinions on the diagnosis and management of CIPO and ED among international clinical practitioners. An electronic, web-based survey tool (select survey.net, version 4; Class Apps Inc.) was used to generate the survey questionnaire and collect data. The study questionnaire is available in Data S1.

| Questionnaire structure
Following detailed discussions and review within the ESPEN specialist interest group, the study questionnaire was structured into 5. participant's opinions on managing intestinal failure secondary to CIPO and ED, including their experience of long-term PN and caseload in this cohort of patients, their opinions of PN outcomes in CIPO and ED sub-types, and opinions on the role of intestinal transplant.
This study was designed to survey the practices and opinions of clinicians with an interest in CIPO and ED, primarily targeting those in advanced clinical nutrition roles/intestinal failure teams or luminal gastroenterologists with a sub-speciality interest in neurogastroenterology and motility. Participants were provided with definitions of CIPO and ED within the questionnaire, as an aide-memoire for the questions that followed about the two subtypes (Page 3 Data S1).
It was agreed that sections 1-4 (above) would be applicable to all participants. However, it was recognized that section 5 was a specific set of questions only applicable to participants working in a

| Questionnaire distribution
An invitation to participate with a weblink to the questionnaire created by the survey software was circulated electronically via newsletters published for members of the following international societies; ESPEN, ESNM, and United European Gastroenterology.
Clinicians identified by the international study team who have an interest and expertise in GID were also invited to participate in the survey via email. Survey data were collected from March 2018 to October 2018. No patient-related clinical data were collected, so ethical approval was not required for this study.

| Statistical analysis
Survey data were analyzed using counts and proportions.
Comparative analyses were performed using a commercially available software package (Stats Direct v3.1.1, UK).

| Responder demographics
Overall, 154 participants, (UK 40%, Europe 43%, and Non-European Countries 17%) completed sufficient questions to be included in the study.
Most responders were gastroenterologists (66%), a further 16% were sub-specialists in neurogastroenterology and motility, 12% were gastrointestinal surgeons, and 6% were intestinal transplant clinicians. Overall, 56% had a sub-specialty interest in intestinal failure and 85% were consultants/attending clinicians or clinical academics/ professors.

| Incidence of CIPO and ED in the participant's clinical practice
The majority of responders (93%) agreed that CIPO and ED should be recognized as separate entities. The majority of responders see
Of referrals seen with suspected CIPO or ED, 60% of participants reported that only up to a quarter of cases meet clinical and radiological criteria for CIPO (Table 1). Moreover, 65% reported noticing a recent change in the proportion of small intestinal dysmotility referrals with CIPO and ED. More than half (51%) reported observing an increase in the incidence of ED alone, whereas fewer felt there has been an increase in CIPO alone (7%) or both sub-types (15%). In many clinicians' experience, diagnoses of both CIPO and ED are often delayed by 1-5 years ( Table 2). Many participants also reported that a TA B L E 2 Clinicians' estimate of time between symptom onset to GID diagnosis
When reviewing a list of secondary causes of CIPO and ED, they re-

ported that the largest increase in referrals has been in patients with
Ehlers-Danlos syndrome/joint hypermobility (

| Participant's practice and opinions on diagnostic approaches in suspected CIPO/ED
Most participants agreed that CIPO/ED diagnoses are difficult to make, and only 5% found them straightforward. In particular, the majority of participants (56%) found ED to be a difficult diagnosis, while only 10% reported that CIPO is a more difficult diagnosis. The reasons that participants most frequently selected for difficulties and diagnostic delays in >50% of cases included non-specific symptoms (70%), lack of awareness of CIPO/ED among non-specialists (70%), limitations of diagnostic tests (63%), psychological co-morbidity (58%), and difficulty eliminating opioids as the cause (47%).
Clinicians reported that they request a variety of tests to establish a diagnosis of CIPO or ED. While gastric emptying and x-ray colonic transit tests are the most popular investigations, ADM is rarely performed (Figure 1). Clinicians were also surveyed regarding their practice of requesting full thickness biopsies. Referral patterns for full thickness biopsy did not differ between specialists with an in- The general consensus among participants was that full thickness biopsies seldom change management and outcomes. Interestingly  (Table 4).

| Opinions on the efficacy of various management options for CIPO and ED
While very few options appear to benefit the majority of cases, clinicians reported that the most effective options were neuropathic analgesia, antibiotics for small intestinal bacterial overgrowth,  The survey data strongly support the importance of recognizing CIPO as a separate clinical entity, and this would be consistent with clinical data which have shown that the CIPO sub-type is associated with a significantly worse prognosis. 6,12 The trends in referrals seen by those surveyed suggest that there is an increase in referrals with the ED sub-type, with CIPO often making up less than 25% of referrals. While there were no major changes reported in the referral rates of primary and secondary CIPO/ED, there was a notable reported increase in referrals with CIPO and ED secondary to hypermobile Ehlers-Danlos syndrome. However, when compared to respondents from other countries, the majority of clinicians who noted this trend were from the UK. The associations between functional gastrointestinal disorders and hypermobile Ehlers-Danlos are increasingly recognized, 19 and recent data from a UK population have shown a very high prevalence of

functional gastrointestinal disorders in patients with hypermobile
Ehlers-Danlos syndrome, with 84% meeting the diagnostic criteria for functional disorders in multiple gut regions. 20 The reasons for this trend being specific to UK participants are unclear, but may stem from an awareness being higher due to most of the studies to date emanating from the UK. It would seem unlikely that increased awareness alone, however, would drive an increase in severe clinical presentations requiring nutrition support. Further international collaborative epidemiological research on the prevalence of hypermobile Ehlers-Danlos syndrome related dysmotility would therefore be required to investigate this further.
Interestingly, the survey data show that clinicians are more confident in making a diagnosis of CIPO compared to ED. The exact reasons for this difference remain unclear, but the ease of interpretation and availability of radiological investigations to achieve a CIPO diagnosis are a clear advantage when compared to using ADM to diagnose ED. ADM is not widely available, is difficult to interpret, often poorly tolerated, and in this, survey was surprisingly rarely used in establishing diagnoses. The survey data show that clinicians are, instead, using a variety of segmental motility and imaging modalities to characterize the pattern of dysmotility and are using pragmatic approaches including intolerance of small bowel feeding in many cases, even when referring patients with suspected functional and motility disorders for parenteral feeding.
The survey data therefore highlight the need for better diagnos- Diagnostic delays appear to be fairly common in CIPO and ED. 12,26 The survey data suggest a lack of awareness of this group of disorders among non-specialists. This is clearly important as diagnostic delays and lack of knowledge may explain the high incidence of inappropriate surgical interventions that have not only been identified in this survey, but also in several clinical studies. 12,14,27 Delayed diagnosis may also significantly impact the patients' psychological well-being 28 and have been shown in other functional gastrointestinal disorders to be associated with stigmatization. 29 Therefore, there is a clear need to raise awareness of CIPO and ED with appropriate educational strategies among the wider clinical community including gastroenterologists and associated specialists such as surgeons and dieticians in order to prevent diagnostic delays, potentially hazardous surgical interventions, and improve clinical outcomes.
In addition to difficulty with diagnosis, respondents also further highlighted the lack of efficacy of many of the established therapies for CIPO and ED. Strategies which ranked best included treatment of bacterial overgrowth, clinical psychology, the pan-enteric prokinetic prucalopride, PN, and neuropathic analgesia. When considering the latter, it is noteworthy that patients with ED in particular often exhibit severe neuropathic/centrally mediated abdominal pain, which responds very poorly to opioids. Indeed opioids can be detrimental in this setting due to their antimotility effects, worsen pain due opioid induced hyperalgesia, 30 and potentially increase infection risk, 31 which is particularly important when considering HPN. 32 The current survey data are thus in accordance with an increasing body of evidence 33 and recently published clinical guidelines to support use of centrally acting gut-brain neuromodulators rather than the standard use of opioid medications to target this type of neuropathic pain. 34,35 Notably, respondents highlighted the importance of the multidisciplinary care including clinical psychology. Since no single treatment was reported to be highly efficacious, it is vital that care is holistic and that the psychological impact of a dysmotility diagnosis is not neglected. 28 Unfortunately, due to the nature of this study, there was a need to consider maximizing response rates among potential participants.
It was therefore important to limit the complexity of the questionnaire and the amount time that would be required for participant completion. Within these constraints, respondents were asked for their impressions, estimates and opinions on the prevalence, incidence and management, rather than provide actual figures from their clinical practice. Another limitation of the study is that participants were not asked to report separately on the efficacy of all the specific treatments between sub-types. It is therefore not possible to determine whether there were any perceived differences in the efficacy of the various medical and non-medical treatment options listed between the CIPO and ED sub-types.
When considering intestinal failure in CIPO and ED, PN was reported to have a role in treating dehydration, metabolic impairment, and some effect on quality of life in many patients.

ACK N OWLED G M ENTS
The authors would like to acknowledge the partner societies which supported this study including ESPEN, United European Gastroenterology, ESNM, and the neurogastroenterology and motility section of the BSG. The authors would also like to acknowledge the following participants: Tim Vanuytsel (Belgium), Greger Lindberg