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Functional defecation disorders in children
Associated comorbidity and advances in management Kuizenga-Wessel, S.Publication date 2017
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Kuizenga-Wessel, S. (2017). Functional defecation disorders in children: Associated comorbidity and advances in management.
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UITNODIGING
Voor het bijwonen van de openbare verdediging van
het proefschrift
Functional
defecation
disorders
in children
associated comorbidity and advances in management op donderdag 2 februari 2017 om 12:00 uur in de Agnietenkapel, Oudezijds Voorburgwal 231 te Amsterdam Receptie na afloop van de promotieS1{ K§zÑga-W%Û¢(
Rhijnvis Feithstraat 56-3 1054VA Amsterdam s.wessel@amc.nl 06-13377360Paranimfen
Claire Wessel clairewessel@gmail.com Nina Steutel n.f.steutel@amc.nl”Ë
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- Nick FredericksonFUNCTIONAL DEFECATION
DISORDERS IN CHILDREN
Associated comorbidity and advances in management
COLOFON
Functional defecation disorders in children - Associated comorbidity and
advances in management, University of Amsterdam, the Netherlands
The financial support for printing this thesis by the following foundations and companies is gratefully acknowledged:
Universiteit van Amsterdam, Coloplast, Hotel Emma te Rotterdam
Book design & illustrations isontwerp.nl ~ Ilse Schrauwers
Printing Gildeprint
ISBN 978-94-92303-10-3
© Sophie Wessel, 2016
All rights are reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without prior permission of the author.
FUNCTIONAL DEFECATION
DISORDERS IN CHILDREN
Associated comorbidity and advances in management
ACADEMISCH PROEFSCHRIFT
ter verkrijging van de graad van doctoraan de Universiteit van Amsterdam op gezag van de Rector Magnificus
prof. dr. ir. K.I.J. Maex
ten overstaan van een door het college voor promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel
op donderdag 2 februari 2017, te 12:00 uur
door
Sophie Wessel
Promotiecommissie
Promotor
Prof. dr. M.A. Benninga, Universiteit van Amsterdam Prof. dr. C. Di Lorenzo, Ohio State University
Overige leden
Dr. D.K. Bosman, Universiteit van Amsterdam Prof. dr. R.H.J. Houwen, Universiteit van Utrecht Prof. dr. R.J.L. Lindauer, Universiteit van Amsterdam Prof. dr. L.W.E. van Heurn, Universiteit van Amsterdam Prof. dr. R.R. van Rijn, Universiteit van Amsterdam Prof. dr. A.J.P.M. Smout, Universiteit van Amsterdam Faculteit der Geneeskunde
TABLE OF CONTENTS
Chapter i
General introduction & outline of this thesis
9Outline thesis 26
PART I Associated problems
Chapter 1 Screening for autism identifies behavioral disorders 37
in children with functional defecation disorders
Chapter 2 ADHD and functional defecation disorders in children 55
Chapter 3 Functional defecation disorders and excessive body 73
weight: a systematic review
PART II Outcome measures
Chapter 4 Reporting outcome measures of functional constipation 97
in children from 0 to 4 years of age
Chapter 5 Reporting on outcome measures of functional constipation 117 in children – a systematic review
Chapter 6 Development of a core outcome set for clinical trials in 135
childhood constipation
PART III Diagnostics
Chapter 7 Characterizing colonic motility in children with chronic 157
intractable constipation: a look beyond high-amplitude propgating sequences
PART IV Treatment
Chapter 8 Transanal irrigation in the treatment of children with 185
intractable functional constipation
Chapter 9 Lack of agreement on how to use antegrade enemas 197
in children
Chapter 10 Surgical decision-making in the management of children 215
with intractable functional constipation: what are we doing and are we doing it right?
Chapter 11 Surgical management for children with functional 237
constipation
Chapter s
Summary, discussion & future perspectives
259Samenvatting, discussie en toekomstperspectieven 267
Chapter a
Appendix
277 Contributing authors 278 List of publications 282 PhD Portfolio 284 Dankwoord 287 Curriculum Vitae 288Chapt%r <
GENERAL
INTRODUCTION &
OUTLINE OF THE THESIS
Parts of this introduction have been published as:
Chapter 8: Diagnostic testing of defecation disorders. S. Kuizenga-Wessel, M.A. Benninga.
Núñez R. and Fabbro M.A. (ed)
Constipation in Children: Diagnosis and treatment, 2013. Nova Science Publisher Inc.
Surgical approaches: cecostomy/appendicostomy for constipation. S. Kuizenga-Wessel, C. Di Lorenzo.
Constipation: Current & Emerging Treatments, 2013. Future Medicine Ltd.
Chapter 11: Functional constipation and incontinence S. Kuizenga-Wessel, M.A. Benninga,
Wyllie R., Hyams J.S., Kay, M. (ed),
Pediatric Gastrointestinal and Liver Disease, 5th edition. 2016. Elsevier Inc.
INTRODUCTION
Constipation and fecal incontinence represent common problems in children. Beyond the neonatal period, only a minority of children has an organic cause for constipation and the etiology remains not well understood. Approximately 3-10% of visits to general pediatric clinics and up to 25% of referrals to
pedi-atric gastroenterologists are related to defecation problems1. Constipation rarely
leads to life threatening complications, but can cause emotional and physical distress and concerns for children and their families, ultimately impairing health
related quality of life2. The main characteristics of constipation are infrequent
painful defecation and fecal incontinence often accompanied by abdominal pain. In less than 15% of cases, children have fecal incontinence without a history and physical examination that indicates underlying constipation. These latter children are classified as functional nonretentive fecal incontinence (FNRFI).
Definition of constipation
For many years, patients, parents, but also healthcare professionals have used different definitions for constipation. The Rome II criteria, developed in 1999, attempted to provide a symptom-based definition of functional constipation, mostly based on expert opinion. Such criteria were sub sequently found to be too restrictive and were revised, between 2004 and 2006, in the Rome III version of pediatric functional gastrointestinal disorders. Different studies have shown that the Rome III criteria are less restrictive than the Rome II criteria
in diagnosing func tional defecation disorders3. Burgers et al. retrospectively
evaluated patients referred for functional defecation disorders, comparing the Rome II and Rome III criteria. They demonstrated that by using the Rome III criteria, functional constipation is diagnosed more frequently compared with
the Rome II criteria (87% and 34%, respectively)4. Recently, the Rome IV criteria
have been published5. To fulfill the Rome IV criteria for func tional
constipa-tion, children should have two or more of symptoms described in Table 1. The Rome III Commit tee suggested different diagnostic criteria for constipation in infants and toddlers up to 4 years of age and for child hood constipation in older children and adolescents.
Definition of fecal incontinence
Fecal incontinence is defined as the involuntary loss of stool into the underwear
in a child older than the age of 4 years5. It represents an upsetting and
psycho-logically distressing problem in children6. Functional fecal incon tinence can be
i In tro du ct io n
and FNRFI. More than 80% of the children with functional fecal incontinence
have retentive fecal incontinence7. These findings were also observed in a Sri
Lankan epidemiologic survey showing that indeed retentive fecal incontinence
is 4.5 times more common than FNRFI8. It is important to differentiate between
retentive and nonretentive fecal incontinence because these two condi tions differ in etiology and management. The diagnostic criteria for FNRFI according to the Rome IV criteria are listed in Table 2.
Epidemiology
The worldwide prevalence of constipation varies from 0.7% to 29.6%1. The lack
of consensus in diagnostic criteria and differences in cultural beliefs about normal bowel habits may have contributed to the worldwide variation in the
prevalence9.
Constipation may occur at any age, but children appear most vulnerable in one of three phases: (1) infancy, with the introduction of cereals and other solids and weaning of (breast) milk; (2) toddlers, at the time of toilet training;
and (3) older children, who avoid bathrooms at school10.
The estimated prevalence of fecal incontinence is between 0.8% and 7.8%.
The prevalence is higher among younger children11, and it is significantly more
common among boys, with a male to female ratio ranging from 3:1 to 6:112.
Pathogenesis
The pathophysiology of constipation in children is mul tifactorial and remains incompletely understood. In a small subset of patients, constipation is secondary to a known organic disorder. In more than 90% of children present ing with constipation, no obvious organic cause is found and thus classified as
func-tional13. In the majority of children, constipation results from purposely or
subconscious stool withholding after the passage of a hard, painful, or fright-ening bowel move ment. Fear of defecation leads to withholding of stool, called retentive posturing. Children often stiffen their legs, grunt, or rise on their toes and rock back and forth. In many cases, this behavior is misinterpreted by parents as an extreme effort to pass stool. Loening-Baucke reported that 45%
of the constipated infants and toddlers exhibited stool-withholding behavior14.
A child may also refuse defeca tion as part of a control and independence struggle with parents during toilet training. A significant number of school-aged children refuse to use school toilets, often citing poorly maintained and unhygienic facilities. As a consequence of withholding, whatever the cause is, the rectal mucosa absorbs water from the fecal mass and the retained stools become progressively more difficult to evacuate. This process leads to a
vicious circle of stool retention. When stool retention remains untreated for a long period, the rectal wall becomes stretched and a megarectum develops. This can result in overflow fecal incontinence, loss of rectal sensation and,
ulti-mately, loss of normal urge to defecate13.
Slow transit constipation
In a subgroup of children with constipation, a delay in total and segmental
colonic transit time has been described15–17. Slow transit constipation (STC) is
characterized by delayed passage of fecal matter through the proximal colon whereas functional fecal retention describes delayed transit in the rectosigmoid
region only18. This form of constipation may comprise up to half of patients who
have chronic, treatment-resistant constipation17.
The delay in CTT might be due to dysfunctional muscles of the colon, resulting in non-powerful contractions, or to dysfunction of the enteric nervous system,
resulting in non-coordinated motor activity19.
In a number of studies it has been shown that the number of antegrade pressure waves in the colon was significantly decreased in children with STC compared
with normal controls20. However, the amplitude of the pressure waves was the
same as in normal controls, suggesting that there was no intrinsic myopathic process involving colonic muscles. These studies suggested that the underlying
abnormality was in neural coordination of contractile activity within the colon16.
A reduction in the numbers and delayed maturation of interstitial cells of Cajal (ICCs) have also been suggested to contribute to the pathophysiology of STC in children, since the ICCs function as pacemaker cells that generate gut
peri-stalsis21,22. However, it is still unknown if ICC changes are primary or secondary to
constipation, and little is known about ICC numbers in healthy children.
Quality of life
Although constipation is not a life-threatening condition, it can cause emotional and physical distress for the affected child and family. Multiple studies showed that constipation can result in impaired health-related quality of life (HRQoL). In the United States, children with constipation had lower mean self-reported HRQoL scores than healthy controls and children with inflammatory bowel
disease and gastroesophageal reflux disease23. Parents of constipated
chil-dren reported lower perceived emotional and social scores for their chilchil-dren compared to parents of healthy children. Similar observations have been described in Australia and Brazil; constipation negatively affected both
phys-ical and psychologphys-ical HRQoL scores24,25. A study from China showed that
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Table 1 Rome III criteria for pediatric functional constipation
Infants up to 4 years of age
Diagnostic criteria must include:
- Two or more criteria for at least month in infants up to 4 years of age 1 Two or fewer defecations per week
2 History of excessive stool retention
3 History of painful or hard bowel movements 4 History of large diameter stools
5 Presence of a large fecal mass in the rectum
In toilet-trained children, the following additional criteria may be used:
- At least 1 episode/week of incontinence after the acquisition of toileting skills - History of large-diameter stools that may obstruct the toilet
Children of at least 4 years
Diagnostic criteria must include:
- Two or more criteria for at least once per week for a minimum of 1 months in infants of at least 4 years
- With insufficient criteria for a diagnosis of irritable bowel syndrome
1 Two or fewer defecations in the toilet per week in a child of a developmental age of at least 4 years
2 At least one episode of fecal incontinence per week
3 History of retentive posturing or excessive volitional stool retention 4 History of painful or hard bowel movements
5 Presence of a large fecal mass in the rectum
6 History of large diameter stool that can obstruct the toilet
After appropriate evaluation, the symptoms cannot be fully explained by another medical condition
Table 2 Rome III criteria for pediatric functional nonretentive fecal
incontinence
Diagnostic criteria must include at least a 1-month history of the following symptoms in a child with a developmental age older than 4 years
1 Defecation into places inappropriate to the socio-cultural context 2 No evidence of fecal retention
After appropriate medical evaluation, the fecal incontinence cannot be explained by another medical condition
families, as well as their family function2. Fecal incontinence even more
nega-tively affects the quality of life of these children and their families26. Children
with incontinence were found to have higher rates of psychosocial problems compared to children without fecal incontinence. Furthermore, when constipa-tion continues into adulthood, affected individuals report difficulties with social
contact and intimacy of up to 20%27. It is important to address these issues
during clinical evaluation to understand the impact of constipation on the lives of affected children.
Associated factors
Behavior problems
Behavior problems are frequently reported in children with functional
defeca-tion disorders28. Likewise, gastrointestinal problems like constipation,
abdom-inal discomfort and reflux seem to be particularly common in children with behavioral and developmental disorders, such as attention deficit
hyperac-tivity disorder (ADHD) and autism spectrum disorders (ASD)29,30. The
associ-ation between behavioral factors and functional defecassoci-ation disorders has increasingly been studies, but the question whether behavior problems result in constipation or vice versa is still not answered yet. It can be hypothesized that behavior problems may result in a complicated period of toilet training, which is known as a possible critical phase in the development of FDD. On the other hand, FDDs might give rise to a considerable level of stress for the child and family, which may lead to behavioral changes.
Obesity
Obesity and functional constipation seem to share a common biopsychosocial model of causation. A relationship between constipation and an increasing
body mass index in children has been reported several times31–33. Lifestyle
factors such as diet and physical activity are assumed to play an important
role in the pathophysiology of both functional constipation and overweight34.
Other possible shard etiological factors are a disordered eating pattern, low fiber intake, hormonal dysfunction, gut microbiota, genetic predisposition, and
psychological and socioeconomic factors31,35,36.
Clinical evaluation and diagnostic testing
The clinical presentation of constipation in children is obvious in the majority but may be subtle and nonspecific in a subset of children. The physician should be aware of symptoms and signs of organic causes or red flag symptoms.
i In tro du ct io n Medical history
The medical history should include questions about the time of the first bowel movement after birth, to discriminate functional constipation from Hirschsprung’s disease. Other important questions include the age of onset; frequency, consis-tency, and size of stools; whether the child experiences pain during defecation or exhibits retentive posturing; and whether blood is present on the toilet paper. Large caliber stools, which may be large enough to clog the toilet, may cause anal fissures, commonly manifested as blood on the toilet paper. Information about the incontinence frequency and day and/or nighttime soiling must be obtained. An assessment of stool pattern, using a defecation diary in combi-nation with the Amsterdam Infant Stool Scale (AISS) or Bristol Stool Scale (BSS),
can be used to estimate the severity of constipation37,38. The AISS is developed
for use in infants and children who are not yet toilet trained. In the AISS, the stool consistency, the amount, and color of stools are described. The BSS, on the other hand, is not age specific and only describes stool consistency. Physicians should ask about the presence of abdominal pain or distention, loss of appetite, fever, nausea, vomiting, weight loss or poor weight gain, problems with neuromuscular development, and psychological or behavior problems. Furthermore, urinary incontinence and urinary tract infections are reported in
a considerable number of children with constipation39. Dietary history and the
history of previous treatment strategies for constipation should be investigated. Finally, it is essential to ask about important life events that might contribute to the development of retentive behavior such as death in family, birth of a
sibling, school problems, and sexual abuse1.
Physical examination
A thorough physical examination should be performed in all children. Physical examination should start with measurement of weight and height. Abdominal examination gives valuable information concerning the accumulation of gas or feces. A palpable fecal mass is present in 50% of children with chronic
consti-pation40. Evaluation of the perianal region provides valuable information about
the position of the anus, evidence of fecal incontinence, skin irritation, eczema, fissures, hemorrhoids, and signs of possible sexual abuse. The anorectal digital examination assesses the perianal sensation, anal tone, size of the rectum and the contraction and relaxation of the anal sphincter. The lumbosacral area should be inspected for the presence of a sacral dimple, a tuft of hair or asymmetry of the buttocks, which may indicate spina bifida occulta.
Laboratory investigations
The European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) formulated in their recommendations that routine laboratory testing to screen for hypothyroidism, celiac disease and hypercalcemia is not recommended in children with constipation in the
absence of alarm symptoms41.
These recommendations are in line with a recent study showing that only a minority of the children with constipation who undergo routine laboratory testing are diagnosed with an organic disease. Only 1.7% of the children was diag-nosed with celiac disease, only 0.6% with hypothyroidism and none with hyper-calcemia. The likelihood of finding patients with an organic cause decreases
even further in children who present with constipation as their only symptom42.
Radiological investigations
Abdominal radiography, including colonic transit time (CTT) measurement and abdominal ultrasound are frequently used to diagnose childhood constipa-tion. Nevertheless, a systematic review evaluating the additional value of these investigations found insufficient evidence for a diagnostic association between clinical symptoms of constipation and fecal loading on abdominal
radio-graphs, CTT and rectal diameter on ultrasound scanning in children 41,43.
Abdominal radiography
The sensitivity and specificity of abdominal radiography in diagnosing
child-hood constipation ranges from 60-80% and from 43-90%, respectively44. Based
on the currently available evidence, the National Institute for Health and Clinical Excellence guideline and the new ESPGHAN/NASPGHAN constipa-tion guideline concluded that abdominal radiography should not be recom-mended as an additional test for constipation in children and therefore has
no role to diagnose functional constipation41,45. Radiography is only useful
to determine the presence of a fecal rectal mass when there is uncertainty as whether the patient is constipated and rectal examination is not possible because of obesity, refusal or psychological factors (sexual abuse) that make
a rectal examination to traumatic13.
Colonic transit time (CTT)
One of the underlying mechanisms of idiopathic constipation is thought to be a disturbance of intestinal motility. Consequently, colonic transit time is assumed delayed in children with idiopathic constipation in comparison to healthy children.
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Colonic transit time can be measured with the following non-invasive techniques:
radiopaque sitz (plastic) markers46, scintigraphy (transit of radioisotopes)47, and by
tracking the movement of a pressure, pH, temperature capsule (Wireless Motility
Capsule)48. Three different patterns of colonic transit time can be described on
colonic transit studies. These include normal colonic transit, colonic inertia (also known as slow-transit constipation with slow propagation throughout all colonic segments), and outlet obstruction (delay is mainly in the rectosigmoidal region). Outlet obstruction is the most commonly encountered form in pediatric func-tional constipation. However, a colonic transit study is not recommended to diag-nose constipation, but may only be useful to discriminate between functional
constipation and FNRFI and in situations in which the diagnosis is not clear41.
Furthermore it is important to emphasize that CTT may be normal in up to 50%
of children with constipation and in 90% of the children with FNRFI49. De Lorijn et
al showed that a bowel diary is sufficient to diagnose constipation. A low defe-cation frequency and/or a high fecal incontinence frequency recorded with a
bowel diary correlated with total CTT, measured with radio-opaque markers50.
Defecography
Fluoroscopic defecography is a dynamic radiological test performed during voluntary defecation of the rectum, to assess the anorectal function at rest and
during defecation51–54. The strength of defecography is that it allows assessment
of the rectal functional with the patient in sitting position during the
proce-dure, to achieve a more physiological defecation.54 Since the introduction by
Wallden in 195255, the technique has been further improved and simplified,
but currently consensus regarding the optimal examination technique is still lacking. Recently, it has been shown that defecography can be a useful tool in understanding the pathophysiology of defecation disorders and it may provide information that impacts the management of children with intractable
defeca-tion disorders54.
Ultrasonography
Based on the assumption that fecal retention is one of the main features of constipation, assessment of stool retention and size of rectum and colon can be measured using abdominal ultrasonography. A rectal diameter larger than 30 mm is considered as enlarged and some studies demonstrated that the diameter of the rectum is significantly larger among constipated
chil-dren compared to healthy chilchil-dren56,57. Although this test is considered to be
a simple, non-invasive technique to demonstrate fecal retention, there is insuf-ficient evidence that the transverse diameter can be used as a predictor of
constipation and fecal impaction43. On the other hand transabdominal
ultra-sound has been shown a reliable alternative to assess the rectal filling state, and might replace digital rectal examination in the evaluation of fearful
chil-dren with constipation39.
Manometry
Anorectal manometry
Anorectal manometry measures pressures in the anorectal region and provides a way to quantify the function of the internal and external anal sphincters. Anorectal manometry is only indicated to demonstrate the presence of the recto-anal inhibitory reflex, which is absent in children with anal achalasia or in children with Hirschsprung’s disease (HD). When the recto-anal inhibi-tory reflex is absent, the diagnosis of HD has to be confirmed by histochem-ical evaluation of the rectum. Anorectal manometry can be useful in differen-tiating between constipation associated fecal incontinence and FNRFI. It has been shown that children with constipation associated fecal incontinence have
higher thresholds for rectal sensation than those with FNRFI49.
Colonic manometry
Colonic manometry is a diagnostic test only performed in specialized motility centers to differentiate between normal colonic motor function and colonic neuromuscular disorders in the evaluation of children with intractable consti-pation. Colonic manometry may be useful in children with long-standing and intractable constipation if a gastrointestinal motility disorder is suspected. This test is used in clinical practice in children with severe constipation when medical therapy fails, to identify children who may benefit from surgery, such as the creation of an antegrade continence enema. In this select patient group, colonic manometry leads to recommendations to change therapy
(mostly surgery) in 93% of patients58,59.
Several studies have used low-resolution colonic manometry to record contrac-tile activity in children with constipation, commonly reporting a reduced frequency of high amplitude propagating contractions (HAPCs) and an absent
or diminished meal response58,60. Such findings indicate that a potential colonic
neuropathy may exist. More recently, studies using high-resolution colonic manometry have emerged. One of the advantages of high-resolution manom-etry is that we are now able to characterize many more propagating motor
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Magnetic resonance imaging (MRI)
To date evidence does not support the use of MRI of the spine in patients with
intractable constipation without other neurological abnormalities41. A recent
study involving children with defecation disorders (constipation, constipation associated FI and FNRFI) reported spinal cord abnormalities (such as an intra-dural lipoma or tethered cord) only in 3% of affected children. Imaging of the spinal cord is therefore only recommended in children presenting with neuro-logic complaints or physical symptoms, such as gluteal cleft deviation,
sugges-tive of spinal cord abnormalities62. Rosen et al. reported improvement in
consti-pation after the spinal cord abnormalities were surgically corrected63.
Treatment
The lack of randomized controlled studies in children has made the treat-ment of constipation largely based on clinical experience rather than on
evidence based controlled clinical trials41,64. The recently published ESPGHAN/
NASPGHAN guideline includes 4 important phases in the treatment of chronic constipation: 1) education, 2) disimpaction, 3) prevention of re-accumulation of
feces and 4) follow-up41.
Education
The treatment starts with education and includes explanation to parents and child of the anatomy and physiology of defecation and its associated disor-ders, explanation of the prevalence of constipation and fecal incontinence, and discussion of the related shame, embarrassment, and social issues. The physician must explain that constipation leads often to a vicious cycle that results in stool withholding, fecal retention and eventually fecal incontinence. It is important to clarify to the family that fecal incontinence is due to rectal impaction and beyond the child’s control. It should also be stressed that the timing of successful treatment is often unpredictable and 50% of treated patients experience a relapse within 1 year while the duration of maintenance
therapy usually takes 6-24 months65. In most cases, a detailed plan
elimi-nates parents’ and the children’s frustration and improves compliance for the prolonged treatment necessary. Without this compliance, the recommended therapy will not be successful.
Disimpaction
Fecal impaction is defined as a large hard mass palpable in the lower abdomen or on digital rectal examination that is unlikely to be spontaneously
maintenance therapy is started, are more likely to improve with treatment
compared to those who do not67. Therefore, disimpaction, or removal of the
fecal impaction, is recommended prior to maintenance therapy41.
Fecal disimpaction can be accomplished with oral, nasal or rectal agents. Orally administration of laxatives is less invasive and is more cost effective than
rectal enemas or manual disimpaction68. Parents however should be informed
that in contrast to rectal enemas their child will experience an increase in fecal incontinence episodes during the first week of treatment. After successful disim-paction the number of fecal incontinence episodes decreases significantly and the same laxative, but in a lower dose, should be continued.
Rectal enemas and suppositories have been widely used to treat fecal impac-tion for many years as well. Although the onset of acimpac-tion is faster than oral therapy, the method of delivery is more invasive.
Maintenance therapy
After disimpaction has been accomplished, the next step of treatment focuses on the prevention of recurrence. This can be achieved through a combination of dietary changes, behavioral interventions and medication.
Dietary interventions Fiber & fluid
A common recommendation to parents is to increase the amount of their child’s daily fluid intake. Conflicting evidence can be found regarding the association between a low dietary fiber intake and constipation. Some studies demonstrated low fiber intake in constipated children compared to healthy
controls, but others did not support this finding69–71. Literature further shows
that current recommendations for dietary fiber intake in children vary
substan-tially among organizations72. A well-balanced diet rich in whole grains, fruits
and vegetables remains the most reasonable advice to parents and children41.
Behavioral interventions
Parents should be encouraged to be positive and supportive throughout the treatment. This can be helpful in reducing the child’s defecation anxiety and
toileting avoidance73. The child is encouraged to do toilet training, in which
the child is encouraged to sit on the toilet up to 5 minutes, three times a day following meals to take advantage of the gastrocolic reflex. A daily dairy to keep record of bowel movements, fecal and urinary incontinence, and medi-cation is helpful to monitor progress and compliance. Sometimes positive rein-forcements or rewards for compliant behavior using stickers or small gifts can
i In tro du ct io n
further encourage children74. The presence of coexisting behavioral problems
often is associated with poor treatment outcome. Psychological referral is indi-cated in children with severe emotional problems who fail intensive medical treatment.
Biofeedback training is a technique that can be used to teach children how to control their perianal muscles in order to pass bowel movement more effi-ciently. It is based on making a physiological mechanism of which patients are unaware of noticeable and measurable to them. A systematic review, however showed that biofeedback when used together with laxative therapy does not add any long-term benefit in children with non-organic fecal incontinence and
constipation75,76.
Oral laxatives
Oral daily laxative therapy should be started immediately after disimpaction. The laxative dose should be adjusted as needed to reach the desired stool consistency and frequency.
Osmotic laxatives
Osmotic laxatives (lactulose, magnesium hydroxide, polyethylene glycol) soften the stools by retaining water within the colon through osmosis. PEG-based
laxa-tives are the most commonly used laxalaxa-tives worldwide77, possibly due to its ease
of administration and palatability. Two randomized controlled trials showed that PEG 3350 was more effective than placebo in increasing stool frequency
and reducing the number of hard stool and pain during defecation78,79.
Stimulant laxatives
Stimulant laxatives, like bisacodyl, increase intestinal motility and interfere with epithelial transport of water and electrolytes. Literature is lacking high-quality randomized controlled trials evaluating the use of stimulant laxatives
in childhood constipation80. Stimulant laxatives can cause abdominal
discom-fort and cramping. Despite intensive medical treatment, only 50% of all chil-dren followed for 6–12 months completely recover from constipation and are
successfully taken off laxatives81.
New laxatives
Several new compounds have been evaluated for adults with constipation, including serotonergic enterokinetic compounds and chloride channel activa-tors. Serotonin is involved in regulating gut motility, visceral sensitivity and intes-tinal secretion through serotonin 5-HT4 receptors, which are mainly expressed
by enteric nervous system interneurons. Prucalopride, is a selective, high-affinity 5-HT4 receptor agonist, with enterokinetic properties, and has been shown to be successful for the symptomatic treatment of chronic constipation in adults in whom
laxatives fail to provide adequate relief82,83,84. Prucalopride stimulates colonic
motility by increasing high-amplitude propagated contractions and accelerates colonic transit in healthy volunteers and adult patients with constipation. However, a large multicenter RCT in children with functional constipation showed that
prucalopride, although well tolerated, was not more effective than placebo85.
The first chloride channel activator, lubiprostone, stimulates intestinal fluid secretion without increasing serum electrolyte levels. This compound showed a significant improvement in bowel habits compared to placebo in several
studies in adults with constipation86–88. The main reported side effect was
nausea. Currently, only one open label study exists in children of different ages with constipation. This study showed that lubiprostone was efficacious and well tolerated in 127 children and adolescents with constipation, with minor side
effects as nausea and vomiting89. A large randomized placebo controlled trials
is currently conducted in Europa and United States in children with functional constipation.
Retrograde enemas
Little is known about the role of retrograde enemas in the maintenance phase of childhood constipation. One randomized controlled trial compared the clin-ical effectiveness of additional treatment with rectal enemas to conventional treatment alone in 100 children aged 8-18 years with at least 2 years symptoms of functional constipation. After 1 year of treatment, the overall success rate was 47.1% in the enema group versus 36.1% in the conventional control group, suggesting there is no additional effect of enemas compared with oral
laxa-tives alone as maintenance therapy for severely constipated children90.
Transanal irrigation
Transanal irrigation with Peristeen® is a relatively new rectal irrigation system that can be used at home in children with constipation and fecal inconti-nence. After inserting the rectal catheter, a balloon attached to the catheter is inflated with air to secure the position of the catheter in the rectum. Then, after infusion of the irrigation fluids into the colon, the balloon is deflated and both stools and irrigation water are evacuated from the rectum. By irrigating the colon, accumulation of large quantities of stools is prevented which conse-quently results in a decrease in the number of fecal incontinence episodes,
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Surgical management
Although conventional therapy usually successfully treats children with functional constipation, a small group continues to have intractable symptoms. Surgical interventions may benefit this minority. Surgery is generally performed in a step-up approach, beginning with the least invasive procedure and proceeding to more invasive treatment options only after failure of the previous step.
Sacral nerve modulation
Sacral nerve modulation (SNM) is a promising new treatment option for patients with intractable functional constipation. SNM involves percutaneous placement of an electrode in the third sacral foramen and implantation of a stimulating
device under the skin in the buttocks92. Clinical results for SNM in constipation
are mostly limited to adults. In literature success rates vary between 47-90% in
adults with constipation or fecal incontinence93. A study by van Wunnick et al
92 demonstrated that constipation symptoms in 13 patients between 10-18 years
of age improved after SNM. Minor complications include pain after implan-tation, displacements of the leads and infection. Recently, a study in children with chronic constipation refractory to conservative treatment, showed that SNM has beneficial effects on defecation frequency and abdominal pain over prolonged period of time, as improvement of symptoms sustained during a
median follow-up of 22.1 months in 42.9% of patients94. Neuromodulation of the
bowel to treat constipation has also been achieved using methods of
stimu-lation across the skin known as transcutaneous electrical stimustimu-lation (TES)95. A
randomized control trial examining the effect of TES, (delivered by physiother-apists three times per week for one month) and sham stimulation on 40 slow transit constipation children improved intestinal transit measured by
scintig-raphy and improved quality of life96,97. Surprisingly, there was no change in the
number of spontaneous bowel movements. Improvement lasted for more than
2 years in 30% of the patients98. The level of evidence, however for
neuromod-ulation of pediatric constipation is low with a clear need for well-designed studies with larger numbers of patients and longer follow up.
Antegrade continence enemas
The use of antegrade continence enema (ACE) has been reported as a successful therapeutic option for children with constipation when maximal conventional therapy is not successful. The antegrade delivery of enemas enables the patient to evacuate the colon at regular intervals, avoiding impac-tion of feces and reducing fecal incontinence. Since its introducimpac-tion in 1990 by
trend towards more minimally invasive procedures100. The use of ACE in
chil-dren with functional constipation has proven to be effective, but success rates
vary among different studies101. A wide variety of enema solutions can be
used, including saline and PEG. Complications include skin lacerations, stoma stenosis, granulation tissue, leakage of enema solution and tube dislodgement.
Colonic resections and ostomies
There is a lack of evidence for surgical treatment of childhood constipation. Currently, the choice for surgery is generally based on severity of symptoms, lack of response to intensive (non)pharmacological treatment and results of diagnostic investigations. Since there are no guidelines for surgery in children with intractable FC, the choice of surgical intervention is challenging and the approach differs among centers.
Temporary or permanent ileostomies and colostomies have been described in
children with functional constipation102. The rationale for diversion is to relieve
symptoms and to decompress the colon, giving the diverted colonic segment time to recover. Several studies have shown that diversion of a dysmotile colonic
segment can lead to improvement of colonic motility in that segment103,104.
Segmental and total colonic resections have also been described in this
setting102. Although outcomes of colon resections and anastomosis were
consid-ered largely successful in 84% of patients with a failure rate of 16%, the included studies in this systematic review were all retrospective case series with
a small number of patients102.
Before surgical interventions are considered in patients with intractable func-tional constipation, families should be counseled by an experienced multi-dis-ciplinary team, including a pediatric gastroenterologist, a pediatric surgeon, a stoma nurse, child psychologist and a social worker.
Other surgical interventions
Long term follow up has shown that anal dilatation does not benefit
chil-dren with functional constipation105. Another treatment option for intractable
constipation is an intrasphincteric injection of Botulinum toxin (BoTox). BoTox reduces the contraction of muscles locally in a temporary manner. The injec-tion of BoTox serves both as a diagnostic test that indicates if the internal anal sphincter hypertonia is what is producing the obstructive symptoms, and as a
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Treatment of fecal incontinence
The treatment of nonretentive fecal incontinence has not been well defined107.
The treatment consists of education, keeping a bowel diary and toilet training 4 times a day following meals and immediately after coming home from school. To date, there are no clinical trials evaluating dietary changes in FNRFI. As described above, the main aim of medical treatment for constipation asso-ciated fecal incontinence is to empty the impacted rectum and to maintain
soft stools during follow-up. In contrast, FNRFI responds poorly to laxatives108.
The softened stools even may worsen symptoms of fecal incontinence. Some-times antidiarrheal drugs, like loperamide, are prescribed for children with fecal
incontinence to reduce the fecal output109. In contrast to adults, experience with
loperamide childhood fecal incontinence is limited11.
Behavioral therapy, toilet training in combination with a reward system, is the most important step in the management of FNRFI. One long-term follow-up study described that after two years of intensive medical and behavioral treatment only 29% of the children were successfully treated. Children should be motivated to adhere to an intensive toilet training program. Keeping record completed
toilet training and bowel movements in a dairy can enhance motivation110.
Currently, surgical interventions have no place in the treatment of children with FNRFI.
Follow-up
It is a misconception that constipation is self-limiting. Most children treated for constipation are eventually cured, although the time required varies and relapses are not uncommon. Therefore it is important to provide support and encouragement through regularly scheduled office visits. Progress should be assessed and, if necessary, dosage adjustments need to be made. After regular bowel habits are established, the medication dosage is gradually decreased. A systematic review found that only half of all children with constipation followed for 6-12 months after therapy were doing well without laxatives. Treatment needs to resume if constipation or fecal incontinence recurs. Early age of onset
of constipation and family history were predictive of persistence of symptoms111.
There is little evidence about the long-term outcome in children with FNRFI. In one study children with FNRFI were followed for 10 years. Only 29% of chil-dren were having less than one episode of fecal incontinence in 2 weeks after 2 years of medical and behavioral therapy. At the age of 18 years, 85% of patients with FNRFI were symptom free. However, this indicates that 15% of chil-dren progress to adulthood with fecal incontinence. No prognostic factors for
OUTLINE OF THE THESIS
The majority of children with functional defecation disorders respond well to conservative treatment, such as laxatives and behavior therapy. Challenging is the small subgroup of patients who are not responsive to conventional treat-ment and continue to have symptoms. Part I of this thesis discusses which outcome measures should be measured in trials regarding functional consti-pation. Part II focuses on new diagnostic tests and Part III on therapeutic strategies for pediatric functional defecation disorders. In Part IV associated (behavior) problems are discussed.
PART I Associated problems
Behavior problems are frequently reported in children with FDD28. Likewise,
gastrointestinal problems like constipation, seem to be particularly common in children with behavioral and developmental disorders, such as attention
deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD)29,30.
A prior study found that 29% of children with FDD scored positive on ASD
screening-questionnaires29. Whether positive screens correctly identify ASD in
children with FDD is unknown. The aim of Chapter 1 is to prospectively assess whether positive screening-surveys for ASD in children with FDDs accurately identify ASD. In Chapter 2 we prospectively assess the prevalence of ADHD in children presenting with FDDs, and the prevalence of FDDs in children with a known diagnosis of ADHD.
Several studies have suggested that there is an association between FDDs and
overweight and/or obesity in children33,36. To date, no comprehensive
system-atic review has been published to evaluate the potential association between FDDs and overweight/obesity in children. Therefore, the aim of Chapter 3 was to systematically review currently available literature regarding the association between FDDs and overweight/obesity in children.
PART II Outcome measures
In order to compare results from clinical trials, uniform definitions and outcome measures are required. The use of inappropriate outcome measures and/or their definitions can compromise the utility of a trial, by representing misleading information on the relevance of the outcome measures, or by overestimating or underestimating trial results. Moreover, comparison between trials and meta-analysis is not possible if uniform outcome measures are not used. Only
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few studies have been performed to address the choice of outcomes in clinical
trials in children112–114. Therefore, our aim of Chapter 4 and Chapter 5
systemati-cally assess how definitions and outcome measures are defined in therapeutic randomized controlled trials of children with functional constipation.
The inconsistencies and bias mentioned above could be tackled by the devel-opment of agreed standardized sets of outcomes, known as core outcome sets. A core outcome set should be measured and reported as a minimum in all trials for a specific clinical area. In Chapter 6 we will describe the core outcome set that we developed for childhood functional constipation.
PART III Diagnostics
Colonic manometry has increased the knowledge of the pathophysiology of gastrointestinal disorders and changed diagnosis and treatment of chronic
constipation in children58. Several studies have used low-resolution manometry
to record contractile activity in children with constipation, commonly reporting a reduced frequency of high amplitude propagating contractions and an
absent or diminished meal response58,60. More recently, studies utilizing
high-res-olution manometry have emerged and described abnormalities in colonic
motor patterns in adults with slow transit constipation115. Whether or not such
motor pattern abnormalities exist in children with chronic intractable constipa-tion has not yet been established. Therefore in Chapter 7, our aim is to quan-tify the colonic motor patterns in such children utilizing high resolution colonic manometry.
Recently cine-magnetic resonance imaging (MRI) was introduced as imaging technique for visualizing colon motility. A study by Kirchhoff et al, including 10 healthy adult volunteers, showed that cine-MRI allows for visualization and reliable recording of high amplitude propagating contractions (HAPCs) using intraluminal bisacodyl administration compared to colonic manometry.
PART IV Treatment
In tertiary care centers, 50% of children referred to a pediatric gastroenter-ologist are still symptomatic after 5 years, and 20% still struggle with
symp-toms after 10 years41. Symptoms can even persist into adulthood despite
inten-sive laxative treatment116. Children with intractable functional constipation may
eventually require alternative therapeutic interventions including surgery. It is therefore necessary to uncover new and more effective interventions for chil-dren with constipation.
Transanal irrigation is a relatively new treatment modality and has been
Data however, on children with functional constipation are scarce. Therefore we evaluated in Chapter 8 the treatment efficacy of transanal irrigation and parental satisfaction in children with intractable functional constipation treated with Peristeen®.
The use of antegrade continence enemas (ACE) has been reported as a successful therapeutic option for patients with long-lasting constipation when
maximal conventional therapy is not successful101. In Chapter 9 we provide an
overview of the existing literature regarding the outcomes of the ACE proce-dure, and we assessed current practices of physicians worldwide regarding the use of an ACE.
Although children with intractable functional constipation may eventu-ally require surgery, there are no evidence-based guidelines for the surgical management of intractable functional constipation in children. Therefore, our
aim of Chapter 10 was to assess the diagnostic and surgical approach of
pedi-atric surgeons and pedipedi-atric gastroenterologists towards children with intrac-table functional constipation. In Chapter 11 we describe the experience of our tertiary care center with the surgical management of children with intractable functional constipation.
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