Correlation of Clinical Symptoms With Neuromorphological Changes of the Colorectal Wall in Patients With a Bowel Evacuation Disorder
Conditions: Defecation Disorder, Neuropathology, Autoimmune Diseases
Sponsor: Evangelisches Klinikum Köln Weyertal gGmbH

 
 
 
 
 
Neuropathological changes 
in the Wall of the large 
Bowel of Patients with 
functional Bowel Disorders 
STUDY PROTOCOL 
Study Protocol Version 1; 2018-10-18 

  
Study Protocoll 
Version 1 
Date: 2018-10-18
 
 
 
Review of the human subjects protection board 2019-03-18 
Study protocol 
 
To investigate neurohistomorphological changes of the colon and rectal wall 
and their genesis in patients with a bowel evacuation disorder in the sense of 
an intestinal transit and expulsion disorder. 
 
Short title of the study: 
 
Neuropathological achanges of the intestinal wall in patients with bowel 
evacuation disorder. 
 
Head of the clinical trial: 
 
PD Dr. Claudia Rudroff 
Head of the Clinic for General and Visceral Surgery 
Ev. Klinikum Köln Weyertal gGmbH 
Weyertal 76 
50931 Köln 
 
TEL.: +49-221-479-2212 
Fax: +49-221-479-2505 
Email: claudia.rudroff@evk-koeln.de 
 
Summary: 
 
Constipation and defecation disorders affect about 15% of the European population 
and of those up to 30% of the patients over 65 years of age. For those affected, this is 
associated with major restrictions in quality of life and high health care costs . 
The underlying causes of constipation and defecation are complex and only partially 
understood. 
 
Intestinal (full wall) resections taken in clinical practice from these patients when 
conservative therapy has been exhausted show rarefaction of ganglion cell nests in 
the myenteric plexus and submucosal plexus as well as changes in cholinergic 
innervation [Han EC et al 2012, Bassotti G. et al 2007, Wedel T. et al 2002]. 
 
Initial histopathological investigations suggest an inflammatory genesis of this 
rarefaction of ganglion cell nests, which will be further characterised/investigated 
in the context of this study on the basis of further histopathological and 
serological investigations. This may lead to novel therapeutic approaches that can 
causally treat the symptoms of those affected. 

 
 
 
Introduction: 
 
Intestinal transit disorders (constipation/obstipation) and/or defecation disorders 
(expulsion disorders) are widespread symptoms in our culture, which, depending on 
their severity, can become a disease. Epidemiological studies show that up to 30% 
of the population over the age of 65 is affected. The suffering of those affected is 
usually very high. 
 
The patients are usually treated conservatively at first. The focus is on lifestyle 
changes, dietary adjustments and medication to support bowel movements. If the 
symptoms persist despite consistent conservative therapy, additional diagnostics 
such as laboratory tests, sonography and colonoscopy are performed. 
Further diagnostic steps include anal manometry, defecography and colon transit time. 
 
In individual cases, bowel wall biopsies are taken as a further specific diagnostic tool, 
for example before a sacral nerve pacemaker (SNS= sacral neurostimulation) is 
indicated. In a study by Valli et al. it was shown that full-wall biopsies can be taken 
without significant risks for the patients and are very helpful for differentiated 
diagnosis [Valli PV et al. 2018]. In other cases, bowel resection is necessary due to 
mechanically induced causes of bowel dysfunction. 
 
From 2015 onwards, the systematic neuropathological examination of whole-wall 
samples was performed on the bowel specimen of patients who were surgically 
treated in our clinic for defecation disorders. In addition, in individual cases in which 
no bowel resection was indicated, rectal full-wall samples were taken to confirm the 
diagnosis and indication for SNS and examined neuropathologically in the same 
way. The intestinal wall was examined for ganglion cell nests in the myenteric plexus 
and the submucosal plexus in order to identify the pathophysiological cause of the 
transport disorder. 
 
In addition to the described rarefaction of the ganglion cell nests in the myenteric 
plexus and the submucosal plexus, initial results show both a change in the 
cholinergic innervation and changes that suggest a postinfectious reaction. 
Increasing evidence links gastroenteritic germs with chronic intestinal motility 
disorders [Porter CK et al. 2013, Mearin F et al. 2009], so that a Campylobacter or 
Yersinia infection could well be the trigger for the observed neuropathological 
changes. Should such an infection be diagnosed in our patient population, antibiotic 
treatment in the early stages of the disease could possibly prevent the 
neuropathological changes described. 

  
Study Protocoll 
Version 1 
Date: 2018-10-18
 
 
 
Review of the human subjects protection board 2019-03-18 
 
The aim of the study: 
 
The aim of the study is to illuminate the pathomechanism of chronic intestinal 
emptying disorders. In addition to the identification of histopathological features on 
intestinal wall specimen, possible causes are to be clarified on the basis of 
serological investigations. If the further investigations confirm our hypothesis, novel 
therapeutic/preventive approaches could be generated. 
 
Type of trial, study design/methodology: 
 
Clinical observational study, prospective 
 
Method: 
 
Currently, patients found to have rarefaction of ganglion cell nests in the myenteric 
and submucosal plexus in whole wall specimens receive prokinetics (e.g. Resolor) 
or sacral neurostimulation if conservative therapy is exhausted. Those in whom this 
therapy fails and/or in whom bowel evacuation can be attributed to morphological 
changes of the bowel such as massive kinking or stenosis in the imaging programs 
performed (MR defecography, colon KE, CT if necessary, colon transit time 
measurement (Hinton test)) are candidates for bowel resection. 
 
The following additional steps are to be taken to carry out the planned studies: 
 
- The intestinal preparations (n=58) already taken for diagnostic purposes (rectal full-
wall biopsy) or in the course of an intestinal resection on the patient's own specimen 
and the future specimens are to be preserved and examined in detail 
histopathologically and, if necessary, molecularly pathogenetically. 
 
- In addition, EDTA blood (10ml) should be taken and stored anonymously at -20 
degrees Celsius for later serological examinations for a maximum of 10 years. 
 
- Furthermore, the clinical data will be completed with the help of a systematic 
questioning of the patients beyond the scope of a medical history. In addition, scores 
regarding their health and psychological well-being (PHQ-9), quality of life (SF-36) 
and their bowel habits (Wexnerscore and Longoscore) are collected. 
 
The neuropathological examinations planned within the framework of this study will be 
carried out at the Institute for Neuropathology of the University of

  
Study Protocoll 
Version 1 
Date: 2018-10-18
 
 
 
Review of the human subjects protection board 2019-03-18 
Cologne, Josef-Stelzmann-Str., 50931 Cologne. Blood samples for obtaining EDTA 
serum will be taken during the follow-up examination at the Evangelisches Klinikum 
Köln Weyertal (EVK), Weyertal 76, 50931 Cologne. The EDTA serum is centrifuged 
at the Institute of Neuropathology of the University of Cologne, Josef- Stelzmann-Str., 
50931 Cologne, stored and examined in the laboratory there. 
 
The sample preservation of the intestinal wall for the extended neuropathological and 
molecular pathological processing, the clinical follow-up examinations (questioning 
and scores) as well as the blood samples (optional) are only taken within the 
framework of this study after prior information and written consent of the patient. 
 
Patient numbers: 
 
58 so far (ongoing study) 
 
Inclusion criterion: 
 
Patients with severe defecation disorders, both in terms of colonic transit disorder 
and obstructive defecation disorder, and combinations of both, who have been 
managed conservatively and require a full-wall bowel biopsy or bowel resection for 
medical indication. 
 
Exclusion criteria: 
 
Lack of consent 
 
Ethical conduct of the clinical trial: 
 
The present study protocol was written in accordance with the Declaration of Helsinki 
in the currently valid version. 
These principles include, but are not limited to, ethics committee procedures, 
patient education and informed consent, protocol adherence, administrative 
documents, data collection, patient record (source documents). 
A patient may only be enrolled in the study if he or she has given consent to do so 
after being informed orally and in writing by an investigator about the nature, 
significance and scope of the study in an appropriate and comprehensible manner. It 
must be clear to him/her that he/she can withdraw his/her consent at any time and 
without giving reasons, without incurring any disadvantages. The original of the 
written consent is kept in the study folder of the study centre. The patient will be 
given a copy of the written informed consent form. In addition, a copy of both 
documents will be enclosed in the patient's file. 

  
Study Protocoll 
Version 1 
Date: 2018-10-18
 
 
 
Review of the human subjects protection board 2019-03-18 
 
Patient information and consent form as well as all other documents received by the 
participants will be submitted to the responsible ethics committee for approval before 
use. Within the framework of monitoring, it is checked whether the respective current 
consent was signed by the patient concerned. 
 
Data protection: 
 
The provisions of the data protection laws are observed. It is ensured that all research 
materials and data are adequately pseudo-anonymized in accordance with data 
protection regulations prior to scientific utilization. People who do not consent to the 
disclosure will not be included in the study. 
 
Literature: 
 
Han EC, Oh HK, Ha HK, Choe EK, Moon SH, Ryoo SB, Park KJ. Favorable 
surgical treatment outcomes for chronic constipation with features of colonic 
pseudoobstruction. World J Gastroenterol. 2012 Aug 28;18(32):4441-6. 
 
Bassotti G, Villanacci V, Nascimbeni R, Asteria CR, Fisogni S, Nesi G, Legrenzi L, 
Mariano M, Tonelli F, Morelli A, Salerni B. Colonic neuropathological aspects in 
patients with intractable constipation due to obstructed defecation. Mod Pathol. 
2007 Mar;20(3):367-74. Epub 2007 Feb 2. 
 
Wedel T, Roblick UJ, Ott V, Eggers R, Schiedeck TH, Krammer HJ, Bruch HP. 
Oligoneuronal hypoganglionosis in patients with idiopathic slow-transit constipation. 
Dis Colon Rectum. 
2002 Jan;45(1):54-62. 
 
Valli PV, Pohl D, Fried M, Caduff R, Bauerfeind P. Diagnostic use of endoscopic full- 
thickness wall resection (eFTR)-a novel minimally invasive technique for colonic 
tissue sampling in patients with severe gastrointestinal motility 
disorders.Neurogastroenterol Motil. 2018 Jan;30(1). doi: 10.1111/nmo.13153. Epub 
2017 Jul 6. 
 
Do MY, Myung SJ, Park HJ, Chung JW, Kim IW, Lee SM, Yu CS, Lee HK, Lee JK, 
Park YS, et al. Novel classification and pathogenetic analysis of hypoganglionosis 
and adult-onset Hirschsprung’s disease. Dig Dis Sci. 2011;56:1818–1827. 
 
Porter CK, Choi D, Cash B, Pimentel M, Murray J, May L, Riddle MS. Pathogen-
specific risk of chronic gastrointestinal disorders following bacterial causes of 
foodborne illness. BMC Gastroenterol. 2013 Mar 8;13:46. 
 
Mearin F, Perello A, Balboa A, Perona M, Sans M, Salas A, Angulo S, Lloreta J, 
Benasayag R, Garcia-Gonzalez MA. Pathogenic mechanisms of postinfectious 
functional gastrointestinal disorders: results 3 years after gastroenteritis. Scand J 
Gastroenterol. 2009;44(10):1173– 1185.