Clinical practice guidelines for Allied Disorders of Hirschsprung’s
Disease –Practical version“Establishment of guideline including transition in pediatric intractable gastrointestinal disease” (TheMinistry of Health, Labour and Welfare of Japan, Health Labour Sciences Research Grant in fiscal years
2014-2016: Tomoaki Taguchi’s group).
Issue date of the first edition: June 4, 2017

Table of contents
I.

Introduction ........................................................................................................................................ 3

II.

Guideline Summary ........................................................................................................................... 5

III.

List of terminology and abbreviations ............................................................................................ 9IV.

Development organization and policy........................................................................................... 11
1. Development body .............................................................................................................................. 111) Guideline steering committee .......................................................................................................... 112) Guideline development group ............................................................................................................ 113) Systematic review team ...................................................................................................................... 12
4) External evaluation committee member ........................................................................................... 125) Administration office for the guideline development ....................................................................... 12

2. Development process .............................................................................................................................. 13
1) Policy .................................................................................................................................................... 13
2) Precautions .......................................................................................................................................... 143) Conflict of interest ............................................................................................................................... 14
4) Funding for the development ............................................................................................................. 14V.

SCOPE .............................................................................................................................................. 15
1. Basic characteristics of allied disorders of Hirschsprung's disease .................................................... 151) Clinical characteristics of allied disorders of Hirschsprung's disease ............................................ 15
2) Epidemiological characteristics of allied disorders of Hirschsprung's disease............................... 163) Overall flow of clinical practice for each allied disorders of Hirschsprung's disease ........................... 16
2. Coverage of the clinical practice guideline ............................................................................................ 40
1) Within the scope of this guideline ...................................................................................................... 40
2) Outside of the scope of this guideline ................................................................................................ 40
3. CQ and systematic review ...................................................................................................................... 40
1) Setting of CQ ....................................................................................................................................... 40
2) Systematic review ............................................................................................................................... 40
4. Determination of recommendations to finalization and implementation policy ................................ 421) Determination of recommendations .................................................................................................. 422) Finalization.......................................................................................................................................... 433) Implementation ................................................................................................................................... 43

VI.

Recommendation .............................................................................................................................. 49

1.CQ1: How are isolated hypoganglionosis, MMIHS, CIIP diagnosed? ....................................................... 49
2.CQ2: What kind of drug therapy is recommended for the treatment of isolated hypoganglionosis, MMIHS,
and CIIP? ...................................................................................................................................................... 57
3.CQ3: Is gastrointestinal decompression therapy recommended for the treatment of isolated
hypoganglionosis, MMIHS, and CIIP? ......................................................................................................... 64

1

4.CQ4: Is nutrition therapy recommended for isolated hypoganglionosis, MMIHS, and CIIP? .................. 69
5.CQ5: Is radical surgical treatment recommended for the treatment of isolated hypoganglionosis, MMIHS,
and CIIP? ...................................................................................................................................................... 75
6.CQ6: Is small bowel transplantation recommended for the treatment of isolated hypoganglionosis, MMIHS,
and CIIP? ...................................................................................................................................................... 78

7.CQ7: What is the prognosis of isolated hypoganglionosis, MMIHS, and CIIP? .................................. 84
VII.

Planning after public release .......................................................................................................... 87

1. Organization after public release .......................................................................................................... 87
2. Introduction ............................................................................................................................................. 87
3. Evaluation of effectiveness ..................................................................................................................... 87
4. Revision.................................................................................................................................................... 882

I. Introduction
Despite the presence of ganglion cells in the rectum, some cases showing symptoms and findings similar
to those of Hirschsprung's disease have been recognized among pediatric surgeons. Since Ravitch
described such cases as “pseudo Hirschsprung's disease” in the Annals of Surgery in 1958, various
descriptions have been used, such as Hirschsprung’s disease-related disorders, variant Hirschsprung’s
disease, allied disorders of Hirchsprung’s disease, and Hirschsprung’s disease-related neuromusculardisorders of the intestine. However, the disease concepts and the individual diseases included in the
disease group have changed gradually over time. In Japan, this group of disease was initially described as“aganglionosis-related disease” in Neonate Surgery in 1978, and in 1988, a survey report of
Pseudo-Hirschsprung's Disease and Related Disorders was released in the Journal of the JapaneseSociety of Pediatric Surgeons (Akihiro Toyosaka). In 1993, a national survey was conducted by a researchgroup on allied Hirschsprung's diseases (Eizo Okamoto).
The development of a clinical practice guideline for allied disorders of Hirschsprung's diseases was
triggered by a nationwide survey included in the “Nation-wide survey and Proposal of guideline in
Hirschsprung’ disease allied disorders” project supported by the Ministry of Health, Labour and Welfareof Japan (Tomoaki Taguchi's group), in fiscal year 2011. The disease concept, classification, diagnostic
criteria, and classification of severity were determined by the“Comprehensive investigation andestablishment of guideline in pediatric intractable hepato-gastrointestinal disease” (Tomoaki Taguchi'sgroup) in 2012-2013. The development of a clinical practice guideline for allied disorders ofHirschsprung's disease was continued by the “Establishment of guideline including transition in pediatricintractable gastrointestinal disease” (Tomoaki Taguchi's group) in 2014-2016, and the guideline has now
been released. Pediatric surgeons, pediatricians, pathologists, and others repeatedly discussed thedisease concept, classification, and how to treat chronic idiopathic intestinal pseudo-obstruction. With theparticipation of Dr. Atsushi Nakajima from the adult domain of the research group for chronic idiopathic
intestinal pseudo-obstruction, guidelines spanning such diseases from childhood to adulthood weresuccessfully released.
With the cooperation of many people, three of the seven known allied disorders of Hirschsprung's
disease isolated hypoganglionosis, megacystis-microcolon-intestinal hypoperistalsis syndrome, andchronic idiopathic intestinal pseudo-obstruction were officially certified as intractable diseases by the
Ministry of Health, Labor and Welfare of Japan. We have had to employ unique methods to develop theseclinical practice guideline, as high quality evidence is limited for these intractable diseases due to the few
cases available for evaluation, the unknown etiology, and the lack of any established treatments.
Fortunately, the doctors in Medical Information Network Distribution System (Minds) understood thesituation and kindly provided careful guidance throughout the project. I sincerely appreciate the great
support and efforts made by the systematic review team, who examined hundreds of domestic andinternational articles in detail in a short period of time, creating the evidence tables and Systematic
Review reports by organizing the findings corresponding to each Clinical Question. This evidence table is3now the core of this guideline, and I hope it will serve as a useful document for clinical and research
practice. Experts in the guideline development team created the recommendations in a short period oftime. These efforts by the research members are greatly appreciated and were thoroughly vetted inexternal evaluation by Dr. Toshio Morizane. I hope that this clinical practice guideline will prove usefulfor both daily clinical practice as well as future studies.
I would like to pay my respect and show my gratitude to Dr. Tomoaki Taguchi for his strong leadership
throughout this research project.

June 4, 2017
Japanese Study Group of Allied Disorders of Hirschsprung’s Disease
Guideline development group

Hiroshi Matsufuji4II. Guideline Summary
CQ1: How are isolated hypoganglionosis, MMIHS, and CIIP diagnosed?
CQ1-1

How is isolated hypoganglionosis diagnosed?

Recommendation

A full-thickness biopsy of the gastrointestinal tract (especially the small intestineand sigmoid colon) is recommended for the definitive diagnosis of isolated
hypoganglionosis. [1C]

CQ1-2

How is megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS)
diagnosed?

Recommendation

For cases in which symptoms of bowel obstruction, such as abdominal distension
and vomiting, are present during the neonatal period and no organic obstruction isobserved, a gastrointestinal series is recommended. When a microcolon is observed
and megalocystis is simultaneously confirmed by cystography or computed
tomography (CT)/ultrasonography, MMIHS is strongly suspected. An intestinal
full-thickness biopsy is recommended for the definitive diagnosis to differentiate itfrom other allied Hirschsprung's diseases. [1C]

CQ1-3

How is chronic idiopathic intestinal pseudo-obstruction (CIIP) diagnosed?

Recommendation

The duration of symptoms and the bowel obstruction conditions are determinedfrom the clinical history and physical examination findings. The presence ofintestinal dilatation, air-fluid level formation, and the absence of mechanicalobstruction are confirmed by diagnostic imaging. For children, an intestinal
full-thickness biopsy is recommended for the definitive diagnosis to differentiate itother allied Hirschsprung's diseases. For adults, it is important to differentiate
true mechanical obstruction and secondary intestinal pseudo-obstruction, and afull-thickness biopsy is not conducted as it is for children. [1D]

CQ2: What kind of drug therapy is recommended for the treatment of isolated hypoganglionosis,
MMIHS, and CIIP?
What kind of drug therapy is recommended for the treatment of isolated
CQ2-1
hypoganglionosis?
Recommendation

CQ2-2
Recommendation

CQ2-3
Recommendation

No drug therapy is recommended for isolated hypoganglionosis at this point. [D]What kind of drug therapy is recommended for the treatment of
megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS)?
Although the usefulness of Chinese medicines (Daikenchuto) or probiotics has beenreported as drug therapy for MMIHS, evidence is insufficient to recommend these
therapies at present. [D]What kind of drug therapy is recommended for the treatment of chronic idiopathic
intestinal pseudo-obstruction (CIIP)?
As drug therapies for CIIP, prucalopride, cisapride, Chinese medicines(Daikenchuto), probiotics, and antibiotic (erythromycin) are sometimes used, andsome reports have shown the usefulness of those agents for functional
5

gastrointestinal disorder or abdominal symptoms. However, evidence is insufficient
to recommend these therapies at present. [D]CQ3: Is gastrointestinal decompression therapy recommended for the treatment of isolated
hypoganglionosis, MMIHS, and CIIP?
CQ3-1

Is gastrointestinal decompression therapy recommended for the treatment ofisolated hypoganglionosis?

Recommendation

Upper jejunostomy is proposed for isolated hypoganglionosis. Ileostomy may beeffective in some cases, but the efficacy of enterostomy at any other part of theintestinal tract is unknown. [2C]CQ3-2

Is gastrointestinal decompression therapy useful for the treatment
megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS)?

Recommendation

No evidence supports thedecompression for MMIHS. [D]CQ3-3

Is gastrointestinal decompression useful for the treatment of chronic idiopathic
intestinal pseudo-obstruction (CIIP)?

Recommendation

Intermittent decompression via enteric tube may be effective in some CIIP cases,
and enterostomy may be effective in other cases. The appropriate approach should
be considered on a case-by-case basis. [2D]

positiverecommendationofofgastrointestinal

CQ4: Is nutritional therapy recommended for isolated hypoganglionosis, MMIHS, and CIIP?
CQ4-1

Are enteral nutrition and parenteral nutrition useful as nutritional therapies for
isolated hypoganglionosis?

Recommendation

Enteral nutrition and parenteral nutrition are recommended as nutritional
therapies for isolated hypoganglionosis. [1D]CQ4-2

Are enteral nutrition and parenteral nutrition useful as nutritional therapies formegacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS)?

Recommendation

Enteral nutrition and parenteral nutrition are recommended as nutritional
therapies for MMIHS. [1D]CQ4-3

Are enteral nutrition and parenteral nutrition useful as nutritional therapies forchronic idiopathic intestinal pseudo-obstruction (CIIP)?

Recommendation

Enteral nutrition and parenteral nutrition are recommended as nutritional
therapies for CIIP. [1D]

CQ5: Is radical surgical treatment recommended for the treatment of isolated hypoganglionosis,
MMIHS, and CIIP?
CQ5-1

Is radical surgical treatment (other than stoma construction) recommended for thetreatment of isolated hypoganglionosis?

Recommendation

Avoiding radical surgical treatment is proposed. [2C]6

CQ5-2Is radical surgical treatment (other than stoma construction) recommended for thetreatment of megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS)?

Recommendation

Resection of dilated intestines does not improve ileus symptoms in MMIHS, so
avoiding radical surgical treatment is proposed. [2D]

CQ5-3

Recommendation

Is radical surgical treatment (other than stoma construction) recommended for thetreatment of chronic idiopathic intestinal pseudo-obstruction (CIIP)?
Concomitant use of antegrade continence enema and antidromic enema is proposed
for the treatment of CIIP to improve defecation. [2D]
In cases with duodenal dilatation, duodenojejunostomy is proposed to improve theintestinal transit. It may relieve the pseudo-obstructive symptoms to some extent.
[2D]
Intestinal resection dose not improve the pseudo-obstructive symptoms, so avoiding
radical surgical treatment is proposed. [2D]

CQ6: Is small bowel transplantation recommended for the treatment of isolated hypoganglionosis,
MMIHS, and CIIP?
CQ6-1

Is small bowel
hypoganglionosis?

transplantation

usefulfor

the

Recommendation

Small bowel transplantation is proposed for the treatment of isolated
hypoganglionosis, as it may be useful for the following cases: patients in whom
discontinuing parenteral nutrition (PN) is difficult even after the maximum use of
the native intestinal tract under intestinal rehabilitation; patients in whom thenumber of central venous access routes is lacking; patients with repeated episodesof sepsis; and patients with progressive hepatopathy. [2D]

CQ6-2

Is
small
bowel
transplantation
usefulforthetreatment
megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS)?

Recommendation

Isolated small bowel transplantation is proposed for cases not complicated withliver or renal failure. [2D]Multiple organ transplantation is proposed for cases complicated with liver or renal
failure. [2D]CQ6-3

Is small bowel transplantation useful for the treatment of chronic idiopathic
intestinal pseudo-obstruction (CIIP)?

Recommendation

Small bowel transplantation for the treatment of CIIP is proposed, as it may be
useful for the following cases: patients whose symptoms remain intolerable evenwith adequate parenteral nutrition, enteral nutrition, and gastrointestinal
decompression therapy; patients in whom the number of central venous accessroutes is lacking; and patients with repeated episodes of sepsis. The possible
impairment of the native gastric outlet function needs to be considered when small
bowel transplantation is planned and performed. [2D]

CQ7: What is the prognosis of isolated hypoganglionosis, MMIHS, and CIIP?
CQ7⁻1

What is the prognosis of isolated hypoganglionosis?

7

treatmentofisolatedofRecommendation

Long-term survival can be expected with appropriate treatment. In many cases,
adequate nutritional support and intestinal stoma care are required for a long
period of time. [C]

CQ7-2

What is the prognosis
syndrome (MMIHS)?

Recommendation

Patients with MMIHS have a poor prognosis in comparison to healthy children;
however, long-term survival can be expected with appropriate treatment. In manycases, adequate nutritional support and intestinal stoma care are required, and thefunctional prognosis is poorer than that of healthy children. [C]

CQ7-3

What is the prognosis of chronic idiopathic intestinal pseudo-obstruction (CIIP)?

Recommendation

The actual prognosis of CIIP developed in childhood is not poor; however, adequate
nutritional support and intestinal stoma care are required for a long period inmany cases. The functional prognosis of CIIP is poor. [C]ofmegacystis-microcolon-intestinal

8

hypoperistalsis

III.

List of terminology and abbreviations
Abbreviation

Terminology
Hypoganglionosis
Acetylcholinesterase
staining
Transitional segment/
transitional zone

AchE staining

Pseudo-obstruction
Air-fluid level / niveau

Megacystis-microcolonintestinal
hypoperistalsis
syndrome
Clinical question

MMIHS

CQ

Enteral nutrition

Systematic review

SR

Atresia of small
bowel/small
intestinal atresia
Intestinal
decompression
Manometry/intestinal
manometric study

Peristalsis

Microcolon

ganglion
ganglion

neuronal

Clinically asked questions concerning various aspects of a disease, such as thecondition, evaluation, treatment, risk, and prophylaxis.
Organized by formulation with four elements (Patient, Intervention, Comparison,
Outcome; PICO) to facilitate literature searches.
A method of injecting liquid food and nourishing diet into the stomach or small
intestine directly when food cannot be taken orally. Injected through a tube,
gastrostomy, or enterostomy.
A review using systematic and explicit methods to select and analyze collected datafrom high-quality studies, such as randomized controlled trials (RCTs).
An intestinal blockage caused by a reduced blood supply due to volvulus or
intussusception in the fetal stage.

Nerve cells present in the intestinal tract. Multiple nerve (ganglion) cells form anintestinal neural ganglion (plexus).

Isolatedhypoganglionosis

Intestinal
dysplasia

A state of having a small number of intestinal ganglion cells. In Europe and the US, it
may refer to the transitional zone of Hirschsprung's disease.
An enzymatic staining method. In the aganglionic intestine of Hirschsprung's disease,
positive nerve fibers can be seen to be growing with such staining.
Site between the aganglionic intestinal segment of Hirschsprung's disease and thenormal intestine. The number of ganglion cells is not sufficient in this zone. It may bedescribed as “Hypoganglionosis”.
A state of bowel obstruction without mechanical obstruction of the intestinal lumen.
An image seen with bowel obstruction, presented as a sharp flat horizontal line
representing the interface between gas density above and fluid density below in theintestinal tract.
An allied Hirschsprung's disease.

To drainage the gastrointestinal contents via enterostomy, gastrostomy, naso-gastrictube, long tube, or trans-anal tube in order to relieve intragastrointestinal pressure.
An examination to evaluate the presence of a normal pattern of intestinal motility bymeasuring the intragastrointestinal pressure. The object of the examination is toperceive the disease and its pathology and evaluate the motility function before andafter surgical treatment.
A technique providing nutrition intravenously. Intravenous nutrients are injected
into a peripheral vein, higher-concentrated nutrients are directly infused into thecentral vein near the heart.
A thick node where peripheral nerve cells and nerve fibers come together. In theintestinal tracts, it consists of multiple nerve cells and glia cells.
An opening in the intestinal tract created on the abdominal wall to excrete stool due
to intestinal tract disease.
Movements of the intestinal tract made by contraction and relaxation of the smoothmuscle. This movement mixes, breaks, and transfers the gastrointestinal contents(food).
Unused colon smaller in diameter and length than the normal colon. It is aconsequence of a reduced colonic capacity due to congenital proximal intestinal
obstruction and is different from structural abnormalies of the colon.

Parental nutrition,
intravenous
alimentation
Neuralganglion/neural plexus
Stoma/intestinal stoma

Intestinal
cell/entericcell

Description

An allied Hirschsprung's disease. In such cases, the number of intestinal ganglion
cells is small. To distinguish this disease from the transitional segment of
Hirschsprung's disease (hypoganglionosis), it is described as isolated
hypoganglionosis.
IND

An allied Hirschsprung's disease.

Segmental dilatation ofintestine

An allied Hirschsprung's disease.

Bowel obstruction

A state that consists of mechanical blockage of the intestinal lumen and functional
blockage of the bowel stream (paralytic ileus) due to reduced peristalsis.

Recto-anal inhibitoryreflex/recto
anal
reflex/recto
internal
anal
sphincter
inhibitory reflex

RAR/ RAIR

A reflex response of relaxation of the internal anal sphincter followed by distention
stimulation of the rectum. Patients with Hirschsprung's disease lack the response.

9

Rectal mucosal biopsy

Internal anal sphincter
achalasia

An examination collecting a small part of the rectal mucosa for a pathologicaldiagnosis. Acetylcholinesterase staining is used for the differentiation of
Hirschsprung's disease.
IASA

An allied Hirschsprung's disease. The recto internal anal sphincter reflex is lacking,but ganglion cells exist in the rectum.

Aganglionosis

Used synonymously with Hirschsprung's disease. A state of lacking ganglion cells in
the intestinal tract.

Bacterial translocation

A state in which enteric bacteria or bacterial products move across the intestinal
membrane and emerge either in the lymphatics or the visceral circulation, causing
infection. Sometimes observed when the intestinal mucosal defense system is ruined,
when systemic and/or local immunity is compromised, or when intestinal bacterial
overgrowth is present with motility disorder.

Hirschsprung's
disease,congenital
megacolon

HIRS/H disease/HD

Peristaltic disorders, bowel obstruction, and constipation are caused by the congenital
absence of intestinal ganglion cells at the distal side of the intestinal tract. It is also
called congenital megacolon, as the normal colon at the oral side of the aganglionicsegment is dilated secondarily.

Allied disorders ofHirschsprung's disease

A group of diseases with conditions similar to Hirschsprung's diseases despite thepresence of intestinal ganglion cells.

Immaturity of ganglia

An allied Hirschsprung's disease. Bowel obstructive symptom is evoked due toimmature intestinal ganglion cells.

Chronic
intestinal
pseudo-obstruction

CIPO/CIP

A generic term of pseudo-obstruction resulting in chronic course. It is categorized into
"primary", which has a cause in the intestinal tract itself, "secondary", which isrelated to systemic illness or drugs, and "idiopathic" with an unknown etiology.

Chronic
idiopathic
intestinal
pseudo-obstruction

CIIP

Idiopathic (cryptogenic) type of chronic intestinal pseudo-obstruction. An allied
Hirschsprung's disease.

10IV. Development organization and policy
1. Development body
“Establishment of guideline including transition in pediatric intractable gastrointestinal disease” (The Ministry of Health,Labour and Welfare of Japan, Health Labour Sciences Research Grant in fiscal years 2014-2016: Tomoaki Taguchi’sgroup)
Japanese Study Group of Allied Disorders of Hirschsprung’s Disease

1) Guideline steering committee
Tomoaki Taguchi
Takeshi Tomomasa
Masaki Nio
Hiroshi Tamai
Masanori Tamura

Haruhiko Sago

Akira Toki
Shunsuke Nosaka
Tatsuo Kuroda
Masahiro Yoshida

Department of Pediatric Surgery, Reproductive and Developmental Medicine,
Graduate School of Medical Sciences, Kyushu University
PAL Children’s Clinic
Department of Pediatric Surgery, Tohoku University Graduate School of
Medicine
Department of Pediatrics, Osaka Medical College
Department of Pediatrics, Center for Maternal, Fetal and Neonatal Medicine,
Saitama Medical Center, Saitama Medical University
Department of Perinatal Medicine and Maternal Care, National Center forChild Health and Development
Division of Pediatric Surgery, Department of Surgery, Showa University
School of Medicine
Department of Radiology, National Center for Child Health and Development
Department of (Pediatric) Surgery, Keio University School of Medicine
Chemotherapy Research institute, KAKEN Hospital2) Guideline development group
Hiroshi MatsufujiAtsushi Nakajima
Hiroyuki Kobayashi
Hideki Sou
Kouji Masumoto
Yoshio Watanabe
Yutaka Kanamori
Yoshinori Hamada

Department of Pediatric Surgery, St Luke's International Hospital
Department of Gastroenterology and Hepatology, Yokohama City University
School of Medicine
Department of Hospital Administration, Juntendo University
Department of Pediatric Surgery, Osaka Women’s and Children’s Hospital
Departments of Pediatric Surgery, Faculty of Medicine, University ofTsukuba
Department of Pediatric Surgery, Aichi Children's Health and Medical Center
Division of Surgery, Department of Surgical Specialties, National Center forChild Health and Development
Division of Pediatric Surgery, Department of Surgery, Kansai Medical
11

University
Department of Pediatric General and Urogenital Surgery, Juntendo

Atsuyuki Yamataka

University School of Medicine

Naoki Shimojima

Department of Surgery, Tokyo Metropolitan Children's Medical Center

Takeshi Tomomasa

PAL Children’s Clinic

Akio Kubota

Second Department of Surgery, Wakayama Medical University
Department of Pediatrics and Child Health, Kurume University School of

Kosuke Ushijima

Medicine
General Internal medicine 2, General Medical Center, Kawasaki Medical

Ken Haruma

SchoolDepartment of Behavioral Medicine, Tohoku University Graduate School of

Shin Fukudo

Medicine

3) Systematic review team
Yuko Araki

Department of Pediatric Surgery, St Luke's International Hospital

Takahiro Kudo

Department of Pediatrics, Juntendo University Faculty of Medicine

Satoshi ObataDe Department of Pediatric Surgery, Reproductive and Developmental Medicine,
Graduate School of Medical Sciences, Kyushu University
Department of Advanced Medicine & Innovative Technique, Kyushu
University Hospital

Wataru Sumida
Toshihiko Watanabe

Department of Pediatric Surgery, Aichi Children's Health and Medical Center
Division of Surgery, Department of Surgical Specialties, National Center forChild Health and Development

Suguru Fukahori

Department of Pediatric Surgery, Kurume University School of Medicine

Yoshimitsu Fujii

Division of Pediatrics, Tohoku Medical and Pharmaceutical University

Yoshiyuki Yamada

Division of Allergy and Immunology, Gunma Children's Medical Center

Keisuke Jimbo

Department of Pediatrics, Juntendo University Faculty of Medicine

Fujimi Kawai

St.Luke’s International University Library

Tomoya Fukuoka

Shinsuke Onuma

Department of Pediatric Gastroenterology, Nutrition and Endocrinology,
Osaka Women’s and Children’s Hospital
Department of Pediatric Gastroenterology, Nutrition and Endocrinology,
Osaka Women’s and Children’s Hospital4) External evaluation committee member
Toshio Morizane

Chief Visiting Researcher, Japan Council for Quality Health Care

5) Administration office for the guideline development
Satoshi Ieiri

Department of Pediatric Surgery, Kagoshima University
12Department of Pediatric Surgery, Reproductive and Developmental Medicine,
Genshiro Esumi

Graduate School of Medical Sciences, Kyushu University
Perinatal Maternal Center, Kyushu University Hospital
Department of Pediatric Surgery, Reproductive and Developmental Medicine,

Takahiro Jimbo

Graduate School of Medical Sciences, Kyushu University
Department of Pediatric Surgery, Tsuchiura Kyodo General Hospital
Department of Pediatric Surgery, Reproductive and Developmental Medicine,

Satoshi Obata

Graduate School of Medical Sciences, Kyushu University
Department of Advanced Medicine & Innovative Technique, Kyushu
University Hospital

Tomoko Yamasaki

Department of Pediatric Surgery, Reproductive and Developmental Medicine,
Graduate School of Medical Sciences, Kyushu University

2. Development process

1) Policy
Allied disorders of Hirschsprung's disease consist of the following seven diseases: (1) immaturity ofganglia,(2)

isolatedhypoganglionosis,(3)

intestinal

neuronal

dysplasia(IND),(4)

megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), (5) segmental dilatation ofintestine, (6) internal anal sphincter achalasia (IASA), and (7) chronic idiopathic intestinal
pseudo-obstruction (CIIP). The guideline development committee members, as specialists in eachdisease, explained the basic characteristics of allied disorders of Hirschsprung's disease overall anddescribed each disease in detail. Since the pathological diagnosis plays the most important role indetermining the clinical practice policy for allied disorders of Hirschsprung's disease, a segment on
pathological approach was created.
Four allied disorders of Hirschsprun’s disease immaturity of ganglia, IND, segmental dilatation ofintestine, and IASA show a good clinical course and are extremely rare; as such, these diseases arelikely to rarely cause confusion when making therapeutic decisions in clinical practice.

Although the other three diseases isolated hypoganglionosis, MMIHS, and CIIP are also rarediseases, quite a few cases have been documented, and their clinical course is serious. These threediseases may therefore require the consideration of evidence and fair opinions from specialists when
making decisions on their treatment in clinical practice. For these reasons, these three diseases wereselected as targets of the clinical questions (CQs) of this guideline.

This guideline was developed using the methodologies in the "Minds Handbook for Clinical Practice
Guideline Development 2014" and the "Minds Manual for Clinical Practice Guideline Development."
However, as we expected difficulty in obtaining high-quality evidence on each disease, a uniqueapproach was used for the systematic review. As the scope of the CQ includes intractable diseases, the13opinions from the guideline development committee members, as specialists, are extremely important.
The committee members therefore held protracted discussions in order to prevent them from relying
too heavily on their individual experiences, thereby helping them to build up a consensus.

2) Precautions
No clinical practice guideline for this group of diseases has yet been drafted. As many of the diseases inthis group develop in childhood, clinical practice among pediatric patients was the focus in compilingthis guideline. However, an increasing number of cases are enjoying a long-term survival due to recent
progress in medicine; therefore, clinical practice for the transitional period from childhood to adulthood
was also considered. Regarding clinical practice for CIIP that develops in adulthood, the “Clinicalpractice guideline for adults with chronic idiopathic intestinal pseudo-obstruction” (Research Project on
Measures for Intractable Diseases, Health Labour Sciences Research Grant in 2011 fiscal year:
Nakajima’s group) should be referenced.

3) Conflict of interest
There are no conflicts of interest to disclose among the stakeholders related to the development of thisguideline.

4) Funding for the development
This guideline development was funded by the following research projects:-“Nation-wide survey and Proposal of guideline in Hirschsprung’ disease allied disorders” (TheMinistry of Health, Labour and Welfare of Japan, Health Labour Sciences Research Grant in fiscal
year 2011: Tomoaki Taguchi’s group)-“Comprehensive

investigation

andestablishmentofguidelineinpediatric

intractable

hepato-gastrointestinal disease” (The Ministry of Health, Labour and Welfare of Japan, Health
Labour Sciences Research Grant in fiscal years 2012-2013: Tomoaki Taguchi’s group)-“Establishment of guideline including transition in pediatric intractable gastrointestinal disease”(The Ministry of Health, Labour and Welfare of Japan, Health Labour Sciences Research Grant infiscal years 2014-2016: Tomoaki Taguchi’s group)

14

V. SCOPE
1. Basic characteristics of allied disorders of Hirschsprung's disease

1) Clinical characteristics of allied disorders of Hirschsprung's diseasea. Background
Hirschsprung's disease is characterized by a transit disorder of intestinal content, delayed meconium
excretion, abdominal distention, bilious vomiting, constipation, and intestinal dilatation (megacolon) at
the proximal side, resulting from dysperistalsis and a lack of a recto-anal reflex caused by aganglionosisof the intestinal tract at the distal side. In the field of pediatric surgery, this disease has been widely
recognized, and the condition has been elucidated and appropriate therapy developed.
However, in this clinical and research setting, a group of diseases with similar symptoms andlaboratory findings to Hirschsprung's disease despite the presence of ganglion cells in the rectum has also
been recognized and is termed "allied disorders of Hirschsprung's disease" in Japan. The disease concept
and diseases included in the group have changed over time, and a consensus has yet to be establishedamong specialists.
A nationwide survey on the subject was conducted in the project of “Nation-wide survey and Proposalof guideline in Hirschsprung’ disease allied disorders” (The Ministry of Health, Labour and Welfare ofJapan, Health Labour Sciences Research Grant in fiscal year 2011: Tomoaki Taguchi’s group). In the next
project, “Comprehensive investigation and establishment of guideline in pediatric intractable
hepato-gastrointestinal disease” (The Ministry of Health, Labour and Welfare of Japan, Health Labour
Sciences Research Grant in fiscal years 2012-2013: Tomoaki Taguchi’s group), specialists in pediatricsurgery, pediatric gastrointestinal medicine, and adult gastrointestinal medicine determined the disease
concept, classification, diagnostic criteria, and classification of severity. Subsequently, the development ofa clinical guideline for allied disorders of Hirschsprung's disease was decided in the project of“Establishment of guideline including transition in pediatric intractable gastrointestinal disease” (TheMinistry of Health, Labour and Welfare of Japan, Health Labour Sciences Research Grant in fiscal years
2014-2016: Tomoaki Taguchi’s group).

b. Definition of allied disorders of Hirschsprung's diseases
Allied disorders of Hirschsprung's disease is a disease group characterized by symptoms and signs similar
to those of Hirschsprung's disease, such as bowel obstruction, intestinal dilatation, and chronic
constipation, despite the presence of ganglionic cells in the rectum.

c. Classification of allied disorders of Hirschsprung's disease
The following seven diseases below are defined as allied disorders of Hirschsprung's disease, and areclassified based on the pathological findings of intestinal nerves from hematoxylin and eosin (HE) or
acetylcholinesterase (AchE) staining of the intestinal tract or rectal mucosa samples collected at surgery
or a biopsy.
15

● Diseases with abnormality in the intestinal ganglion cells(1) Immaturity of ganglia(2) Isolated hypoganglionosis(3) Intestinal neuronal dysplasia (IND)● Diseases without abnormality in the intestinal ganglion cells (HE or AchE staining)(4) Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS)(5) Segmental dilatation of itestine(6) Internal anal sphincter achalasia (IASA)(7) Chronic idiopathic intestinal pseudo-obstruction (CIIP)

2) Epidemiological characteristics of allied disorders of Hirschsprung's disease
The table below shows the numbers of cases with allied Hirschsprung's diseases and the 10-year survival
rates major pediatric medical institutions in Japan. Data were obtained in the project of “Nation-wide
survey and Proposal of guideline in Hirschsprung’ disease allied disorders” (The Ministry of Health,Labour and Welfare of Japan, Health Labour Sciences Research Grant in fiscal year 2011: Tomoaki
Taguchi’s group).
Allied disorders of Hirschsprung's
disease● Abnormal ganglion cell group(1) Immaturity of ganglia(2) Isolated hypoganglionosis(3) Intestinal neuronal dysplasia● Normal ganglion cell group(4) Megacystis-microcolon-intestinal
hypoperistalsis syndrome(5) Segmental dilatation of intestine(6) Internal anal sphincter achalasia(7) Chronic idiopathic intestinal
pseudo-obstruction

Number of cases
for the primary
surveyNumber of cases
for the secondary
surveyNumberdefinitive
cases

of

19
114
17

28
90
11

28
70
11

100%
78%
100%

29

19

10

53%

35

28

27

96%

6
94

2
56

2
56

100%
89%

Survival
rate3) Overall flow of clinical practice for each allied disorders of Hirschsprung's disease
Histopathology of allied disorders of Hirschsprung's disease
This disease group is not associated with aganglionosis, but its clinical symptoms and findings are similar
to Hirschsprung's disease and inclide bowel obstructive symptoms such as abdominal distention,
abdominal pain, bilious emesis, and dilatation of intestinal tracts; delayed meconium excretion; andconstipation. For this reason, a histological evaluation plays an important role in the diagnosis of allied
disorders of Hirschsprung’s disease. The histological evaluation of enteric ganglions, especially inneonates and infants, requires professional knowledge and experience.
The majority of neonatal ileus cases may result in emergent laparotomy, and some diseases in thisgroup requiring a histological evaluation (isolated hypoganglionosis, immaturity of ganglia) must be
distinguished from small bowel atresia and Hirschsprung’s disease (aganglionosis).
Idealy, intestinal full-thickness biopsy samples should be collected at the three points indicated in16the flow chart (Figure 1), with HE staining and immunohistological investigations used for thehistopathological diagnosis (Figures 2–4). Anti-HuC/D antibody has excellent sensitivity and specificity
for identifying immature and small neurocytes of neonates and infants. Sox10 antibody positivity inintestinal glia cell nuclei is useful for differentiating immature neurocytes from intestinal glia cells.
When the neural plexus is normal in size and ganglion cells are normal in number and size in samples
obtained by full-thickness biopsies from the stoma site at the oral side sufficiently far from the caliber
change and from the terminal ileum, Hirschsprung's disease should be diagnosed if hypertrophic
acetylcholinesterase-positive nerve fibers in the lamina propria mucosae is observed in samples obtainedby a rectal mucosal biopsy or if a lack of myenteric ganglion cells and nerve fascicle formations isobserved in a sample obtained by a full-thickness biopsy from the sigmoid colon.
A useful indicator for the diagnosis of isolated hypoganglionosis is the presence of ≤20
HuC/D-positive cells per centimeter within the muscularis propria in a specimen from a resected
intestinal tract, as this is a significantly lower number than that noted in normal intestinal tract.
For the diagnosis of immaturity of ganglia with immature neurocytes but no abnormal numbers,present in normal sized nerve plexus, the final diagnosis should be made based on the absence of any
abnormality in the nerve plexus and neurocytes at the time of stoma closure.

17

Figure 1. Histopathological differentiation of allied disorders of Hirschsprung's disease

Figure 2. Normal Auerbach's myenteric plexus
Several matured ganglion cells are observed in the nerve plexus.

18

Figure 3. Immaturity of ganglia, Auerbach's myenteric plexus
The nerve plexus is normal in size, and ganglion cells are normal in number but small and immature.

Figure 4. Isolated hypoganglionosis, Auerbach's myenteric plexus (arrow)
The nerve plexus is small and, the number of ganglion cells is decreased.

19

(1) Immaturity of ganglia
Disease concept: Neonatal ileus symptoms present with a clinical manifestation similar to meconium
disease. In a barium enema examination, narrowing of the colon is observed (microcolon or small colon).
In the neonatal period, the recto-anal reflex is negative in many cases, but turns positive in infancy. A
rectal mucosal biopsy can differentiate immaturity of ganglia from Hirschsprung's disease based on thelack of hypertrophic AchE-positive nerve fibers. As the lesion may extend to the small bowel, ileostomy isrequired in many cases during the neonatal period. On a pathological examination, the intramural
ganglion cells are sufficient in number but are small and markedly immature. Neurocytes may mature inseveral months, and ileostomy closure can be performed. Both the vital and functional prognoses of thisdisease are good.

Diagnostic criteria
Primary diagnostic criteria
1) Develops during the neonatal period2) Affected bowel may extend to the small bowel3) Caliber change is observed during surgery
Secondary diagnostic criteria
1) Symptoms improve over time2) On diagnostic imaging, microcolon or narrowing of the left hemicolon is present.
Pathological diagnostic criteria (1 and 2 or 1 and 3 need to be met)
1) Immature ganglion cells (small in size)2) Normal number and distribution of ganglion cells3) Ganglion cells mature over time
Isolated hypoganglionosis is diagnosed based on an indispensable pathological examination atenterostomy if two or more primary diagnostic criteria, or if one primary plus two secondary diagnostic
criteria are met.

A nationwide survey followed 28 cases for 10 years from 2001 to 2010. The number of cases with definitive
diagnoses meeting the above criteria (proposed) was 15, and all of them survived.

20

(2) Isolated hypoganglionosis
Disease concept: Isolated hypoganglionosis is a disease that causes serious functional bowel obstruction
during the neonatal period or later, and is a congenital gastrointestinal disease with poor prognosis. In
English, it is expressed as ‘isolated hypoganglionosis’ in order to distinguish it from the site with reduced
neurocytes (transitional zone) observed between the aganglionic and normoganglionic segment in
Hirschsprung's disease.
Most cases require stoma (enterostomy) and parenteral nutrition for life support over a long period oftime, and severe cases are potential candidates for small bowel transplantation. It is difficult todifferentiate isolated hypoganglionosis from Hirschsprung's disease by a barium enema examination oranorectal manometry.
An intestinal pathological examination shows that the intestinal nerve plexus is small with few
ganglion cells. In this respect, it is difficult to differentiate the isolated hypoganglionic tract from thetransition zone of Hirschsprung's disease between the aganglionic and normoganglionic tract. The
individual ganglion cells in the whole intestinal tract are small in size during the neonatal period, butthey grow over time as they mature, although their number will never increase. Isolated
hypoganglionosis can be distinguished from Hirschsprung's disease in that it has no exogenous nerve
fiber growth in the colon and no nerve fiber growth at the distal colon. Laparotomy is required to resolve
bowel obstruction during the neonatal period. A definitive diagnosis can be made by a pathologicalexamination with a full-thickness intestinal biopsy.

Diagnosis criteria
1) Bowel obstruction symptoms present in the early neonatal period
2) The intestinal nerve plexus is hypoplastic and the number of ganglion cells is significantly smaller thannormal on a pathological examination

Note ） In the neonatal period, Hirschsprung's disease can be ruled out using frozen section of
full-thickness intestinal specimens collected from the jejunum or ileum (both if possible) and sigmoid
colon. At the second laparotomy, at two months of age or later, such as when changing a double-barrel
fistula into a Bishop-Koop type fistula, permanent preparations of the entire intestinal circumference
should be created to assess the decrease in ganglionic cell number.

Severity criteria
A severe case is defined as one whose daily life is significantly impaired due to bowel obstruction
symptoms, such as abdominal distension, nausea and vomiting, and abdominal pain, and when at least
one of the following three items is met:
1) Parenteral nutrition is required.
2) Enteral nutrition is required.
21

3) Continuous gastrointestinal decompression is required.Note)
Note) Gastrointestinal decompression refers to the drainage of intestinal contents through enterostomy,
gastrostomy, nasogastric tube, ileus tube, transanal tube, etc.

Basic clinical practice policy is to provide adequate nutrition via central venous parenteral nutrition
and/or enteral nutrition and to perform appropriate decompression surgery in order to prevent congestive
enteritis. Decompression necessarily requires enterostomy. The enterostomy site is important, as the firststoma site is a key factor in determining the treatment outcome of isolated hypoganglionosis. In thenationwide survey conducted in 2001-2010, cases that underwent jejunostomy at the first surgery had
better outcomes than those with ileostomy. Regarding the appropriateness of resection of the functionallydisordered intestinal tract at the anal side from enterostomy, the need for preservation may be suggested
based on the outcome of the experimental treatments. Unfortunately, however, no cohort study has yet
been conducted, so further studies are needed before any conclusions can be made. Severe cases can also
be saved by organ transplantation, and future studies should examine the appropriateness of small boweltransplantation versus multiorgan transplantation for such patients.

22

(3) Intestinal Neuronal Dysplasia (IND)
Disease concept: IND was first decribed by Meier-Ruge in 1971, which he further classified into two types:
Type A and Type B. Type A is very rare, accounting for about 5% of all IND cases, and is associated withbowel obstruction, diarrhea, and bloody stool during the neonatal period. Reduced innervation of theintestinal sympathetic nervous system is also typically observed.
As Type B can account for up to 95% of IND cases, this section will focus on Type B IND. In IND TypeB, blockage of the lower gastrointestinal tract similar to that of Hirschsprung's disease is observed. A
barium enema examination does not provide any characteristic findings of IND except for dilation of therectosigmoid colon. Recto anal reflex examinations display both positive and negative cases of IND. In
terms of pathology, malformation of the intestinal parasympathetic nervous system is present in patientswith IND. AchE staining, displays evidence of submucosal giant ganglia, hyperganglionosis, ectopic
ganglia, and the growth of AchE-positive nerve fibers (Figure 5). These conditions may exist
independently, with anal atresia, or with intestinal segments consisting of normal ganglion cells in
Hirschsprung's disease. Whether these pathological findings are due to congenial change, secondarychange related to growth and development, or due to constipation remains controversial. Conservative
therapies, such as laxatives or use of an enema, can often control conditions related to IND. If these
conditions cannot be improved through conservative methods, resection of the internal anal sphincter isadvised. Intestinal resection may also be required in rare cases. Reports of morbidity rates acrossinstitutions tend to differ due to lack of common diagnostic criteria and pathological investigation
strategies. In order to address this issue, uniform diagnostic criteria and practiced methodologies are
essential and must be shared among institutions.

Diagnostic criteria
The following three items must be met:
1) Symptoms similar toHirschsprung's disease2) Presence of botha) Giant ganglia (≥9 ganglion cells in one ganglia)b) Growth of AchE-positive nerve fibers
3) Neonates and infants are not applicableNote) Neonatal and infant cases that meet criteria 1) and 2) need to be strictly monitored as potential
IND cases.

In a nationwide survey conducted over a 10 year period, from 2001 to 2010, 8 definitive and 9 suspectedcases were enrolled, with 11 cases confirmed as IND. The most common onset time was the neonatal andinfancy period, followed by childhood. There have only been a few reports of IND cases in Japan, whilesome cases may have been diagnosed under chronic functional constipation.

23

Figure 5. Intestinal Neuronal Dysplasia (IND)
Acetylcholinesterase staining (left): Submucosal giant ganglia is observed.
HE staining (right): Many ganglion cells are observed in a large nerve plexus.

24(4) Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS)
Disease concept: A serious disease that presents as bowel obstruction-like symptoms in the neonatal
period and later, resulting in intestinal failure, which is accompanied by megalocystis and microcolon.
Many such cases require gastrointestinal decompression via gastrostomy or intestinal stoma during
neonatal period. In a pathological examination, no abnormality is observed in the intestinal nerve plexus.

Diagnostic criteria
1) Bowel obstruction symptoms such as abdominal distension, vomiting, and abdominal pain present
immediately after birth2) Megacystis present
3) Barium enema reveals microcolon in the neonatal period (Figure 6)4) No mechanical obstructive lesion observed in the gastrointestinal tract
5) No pathological abnormalities observed in the neural plexus of a full-thickness intestinal biopsy
specimen

Severity criteria
A severe case is defined as one whose daily life is significantly impaired due to bowel obstructive
symptoms, such as abdominal distension, nausea, vomiting, and abdominal pain, and when at least oneof the following three items is met:
1) Parenteral nutrition is required2) Enteral nutrition is required3) Continuous gastrointestinal decompression is required Note)
Note) Gastrointestinal decompression refers to the drainage of intestinal contents through enterostomy,
gastrostomy, nasogastric tube, ileus tube, transanal tube, etc.

A nationwide survey conducted over 10 years from 2001 to 2010 enrolled 19 definitive and 5 suspectedcases. Enterostomy was performed for 16 out of the 19 definitive cases for decompression.
Due to intestinal failure, parenteral nutrition or enteral nutrition needs to be used for a long periodof time. Four out of the 19 cases needed total parenteral nutrition, and 12 needed concomitant use ofparenteral nutrition and enteral nutrition. Seven out of the 9 surviving cases required parenteralnutrition. For this reason, serious complications, such as hepatic disorder, catheter-related bloodstream
infection, enteritis, and bacterial translocation, can easily occur with this disease.
Ten out of the 19 cases survived, and 9 cases died, with a 5-year survival rate of 62.8% and 10-year
rate of 56.5%. The main causes of death were hepatic disorder and sepsis.

25

Figure 6 Barium enema image of MMIHS
Microcolon is observed.

26

(5) Segmental Dilatation of Intestine
Disease concept: Segmental dilatation of the intestine is a rare disease that presents with localized
dilatation of intestines without mechanical bowel obstruction and malformation of the intestinal nerve
plexus. Since Swenson and Rathauser reported this disease as a "new entity" in 1959, various causes
have been discussed; however, the clinical manifestation and pathological findings vary, and the disease
concept has never been determined in a simple manner. It may therefore be appropriate to regard it as agroup of diseases that presents with localized intestinal dilatation.

Diagnostic criteria
This disease is diagnosed when the following six items are met:
1) Intestinal tract segmentally (permanently) dilated2) Normal intestinal segment abruptly transitions to a dilated segment
3) No endogenous or exogenous cause of obstruction noted at the anal side of the dilated segment
4) Complete or partial bowel obstruction observed on diagnostic imaging
5) Normal distribution of the nerve plexus on a pathological examination
6) Resection of the lesion improves symptoms

Severity classification: If this disease is not complicated by any other diseases, resection of the lesion
significantly improves the symptoms. The prognosis is good, and severity classification may beunnecessary.
Clinical manifestation: In Japan, although about 50 cases have been reported in the literature, nolarge-scale survey has been conducted in the past. A nationwide survey conducted over 10 years from2001 to 2010 identified 37 cases, including 26 definitive and 9 suspected cases. Based on a secondary
survey of these cases, 28 were determined as definitive cases by adding 2 of the suspected cases, after
discussions at investigation group meetings and general meetings.
Gender: Regarding the 28 cases, 19 (68%) were boys and 9 (32%) were girls. Boys were more likely topresent with this disease than girls.
Gestational week and birth weight: The gestational week was 30.2 weeks on average, with 7 cases (25%)
of preterm deliveries. The average birth weight was 2,319 g. The number of low-birth-weight infants was
9 (32%), including 1 very-low-birth-weight infant and 2 extremely-low-birth-weight infants.
Chromosome aberration: Two cases (7.1%) of trisomy 21 was observed.
Family history: The majority (26 cases) had no family history, while 2 had a history. In one case, four
cousins on the mother's side had segmental dilatation of the colon, and one of them died. The other caseshowed marked constipation.
Combined malformation: Seen in 7 cases out of 28 cases. Two cases had patent ductus arteriosus (PDA),
and the remaining five cases had the following malformations (one each): Fallot's tetralogy, ventricularseptal defect (VSD), cerebral palsy/colpocephaly/mandibular hypoplasia/low-set ears, FG syndrome,27

Fallot's tetralogy/encephalatrophy/scoliosi/cleft lip and palate/low-set ears/horseshoe kidney/righthydronephrosis/hypospadias.
Gastrointestinal tract complications: Four out of 28 cases had complications, including 2 cases (7.1%) ofmalrotation, 1 case (3.5%) of ileal atresia, and 1 case (3.5%) of anal atresia.
Dilatation sites: Ileum was the most common (14 cases, 50%) site, followed by sigmoid colon (5 cases,18%), jejunum (3 cases, 11%), transverse colon (3 cases, 11%), from the cecum to transverse colon (1 case),
cecum (1 case), and duodenum (1 case).
Onset time: The neonatal period (18 cases, 64%) was the most common, and with the frequency
decreasing with increasing age as follows: infancy (6 cases, 21%), childhood (2 cases, 7.1%), and school age
or later (2 cases, 7.1%).
Initial symptom: Abdominal distension (20 cases, 71%), vomiting (13 cases, 46%), abnormality noted on aprenatal diagnosis (7 cases, 25%), chronic constipation (6 cases, 21%), and delayed meconium excretion (4cases, 14%). One case had strangulated ileus due to midgutvolvulus, and another had intestinal
perforation.
Examination findings: Twenty-five cases (89%) showed abnormal dilatation of the intestine on plain
abdominal X-ray. A barium enema examination was performed for 23 cases, of which 12 (52%) werediagnosed with segmental dilatation of intestine. Seven cases (25%) were found to have intestinal
dilatation by ultrasonography or magnetic resonance imaging (MRI) in the prenatal period. The recto
anal reflex was positive in all seven examined cases, and no increase in acetylcholinesterase-positive
nerve fibers was seen in any of the five cases in which a rectal mucosal biopsy were performed.
Diagnosis: Plain abdominal radiography successfully indicated the presence of the lesion in many cases(Figure 7). A preoperative diagnosis also requires confirmation of the segmental intestinal dilatation bycontrast radiography or computerized tomography (CT). When the dilatation site is in the colon, it needs
to be differentiated from Hirschsprung's disease. A caliber change should be observed clearly at the oralside of the dilated segment by barium enema for this disease. If it is not clear, anorectal manometry or arectal mucosal biopsy is required for the differentiation.
Treatment: Resection of the dilated segment (Figure 8) and end-to-end anastomosis of the intestine will
provide a good prognosis. Surgery was performed in 27 cases, and 1 case was waiting for surgery.
Laparotomy was performed for the resection of the dilated segment and intestinal anastomosis in 26
cases out of 27 cases. For 1 case, segmental dilatation of intestine (SD) was detected during the surgery
for malrotation, and the patient was followed up without resection. However, the dilatation persisted, andit was resected after the survey. Out of the 26 cases in which resection of dilated segment and intestinal
anastomosis were performed, enterostomy was created in 4 cases, and gastrostomy was created in 2 cases.
Surgery was performed during the neonatal period in 13 cases (48%), infancy in 4 cases (15%), childhoodin 5 cases (19%), and school-age in 3 cases (11%).
Prognosis: A total of 27 cases are surviving with a good prognosis. One patient died: a 9-year-old boy withcerebral palsy who had segmental dilatation in the cecum. Ileocecal resection was performed, but he died28

of sepsis, hepatic disorder, and catheter infection at 12 years of age. A necrotic change was observed in a
resected specimen.

Figure 7. Plain abdominal X ray of segmental dilatation of intestine
Seven months of age. Marked intestinal dilatation and air-fluid level are observed.

Figure 8. Resected dilated intestinal segment29

(6) Internal Anal Sphincter Achalasia (IASA)
Disease concept: IASA is a disease that shows intractable constipation due to relaxation failure of theinternal anal sphincter despite the presence of ganglion cells in the rectal wall.
This disease has been reported to account for 4.5% of chronic constipation in childhood and may beincorrectly diagnosed as chronic functional constipation. Regarding the treatment, in addition to
medication, resection of the internal anal sphincter and botulinum toxin injection are performed. The
prognosis of this disease is very good.
Diagnostic criteria
1) Refractory constipation present
2) No narrowing of the rectum observed under contrast enema
3) Negative recto anal reflex4) Ganglion cells present in the specimen from a rectal mucosal biopsy(Notes on diagnosis)- The recto anal reflex should be evaluated with definite stimulation of the rectum after emptying therectal contents, and the absence of a relaxation response of the internal anal sphincter should be
confirmed.
- The status of AchE-positive nerve fibers should be checked when possible.
A total of 6 cases, including 3 cases in the primary nationwide survey conducted over 10 years from 2001
to 2010 and an additional 3 cases, were enrolled, and 2 met the above diagnostic criteria.

30(7) Chronic Idiopathic Intestinal Pseudo-obstruction (CIIP)
Disease concept: CIIP is an intractable disease with unknown etiology that presents with prolonged bowel
obstructive symptoms, such as abdominal distension, nausea and vomiting, and abdominal pain. Dilated
bowel and air-fluid levels are shown on radiological examinations.
Chronic intestinal pseudo-obstruction (CIPO) is defined as functional motility disorder, presenting
obstructive symptoms without mechanical obstruction to prevent the transportation of thegastrointestinal contents. CIPO is classified into three types: primary type, caused by gastrointestinal
lesions; secondary type, associated with systemic illness or drugs; and idiopathic type with unknown
etiology.
As the primary type includes Hirschsprung's disease (aganglionosis) and allied disorders ofHirschsprung's disease (except CIIP), a diagnosis of childhood CIIP requires differentiation from these
diseases. In the diagnosis of adult CIIP, it is important to differentiate secondary CIPO. In the adultdomain, this disease remains recognized not only among general clinicians but even by medical
practitioners specializing in the gastrointestine. Inappropriate clinical practices and unrequired
surgeries for the bowel obstructive conditions have been performed. Under these circumstances, “Clinicalpractice guideline for chronic intestinal pseudo-obstruction” (Research Project on Measures for
Intractable Diseases, Health Labour Sciences Research Grant in fiscal year 2011: Nakajima’s group) was
released publicly. In contrast, in the child domain, there are many neonatal-onset cases, and the diseaseis recognized as an allied disorder of Hirschsprung's disease. This chapter mainly describes CIIP thatdevelops in childhood.
Definition: CIIP is an intractable disease with unknown etiology, that presents with bowel obstructive
symptoms, such as abdominal distension, nausea and vomiting, abdominal pain, and intestinal dilatation,
due to gastrointestinal motility disorder despite the absence of anatomical obstruction.

Diagnostic criteria
The following 7 items need to be satisfied:
1) Persistent or repetitive development, over a long period of time, of symptoms of serious bowel
obstruction that may require hospitalization, such as abdominal distension, nausea and vomiting,abdominal pain, etc.
2) Duration of symptoms is ≥2 months for neonatal onset and ≥6 months for onset in infancy or later
3) Gastrointestinal dilatation and air-fluid level noted on diagnostic imagingNote 1)
4) No lesions mechanically blocking the gastrointestinal tract
5) No pathological abnormalities in the nerve plexuses on HE stained full-thickness intestinal biopsy
specimensNote 2)6) Megacystis-microcolon-intestinal hypoperistalsis syndrome and segmental dilatation of intestine
are excluded7) Secondary chronic intestinal pseudo-obstruction is excluded.Note 3)31

Note 1) Confirmation of the air-fluid level on plain abdominal radiography in a standing position is notnecessarily required for neonates.
Note 2) For adults, when an intestinal full-thickness biopsy is unobtainable, a characteristic peristalsis
disorder should be confirmed by manometry or cine MRI.
Note 3) Table 1 shows the secondary chronic intestinal pseudo-obstructions to be excluded.

Severity criteria
Severe case is defined as one whose daily life is significantly impaired due to bowel obstructive
symptoms, such as abdominal distension, nausea and vomiting, and abdominal pain, and when at least
one of the following three items is met:
1) Parenteral nutrition is required.
2) Enteral nutrition is required.
3) Continuous gastrointestinal decompression is required.Note)
Note) Gastrointestinal decompression refers to the drainage of intestinal contents through enterostomy,
gastrostomy, nasogastric tube, ileus tube, transanal tube, etc.

Table 1. Secondary chronic intestinal pseudo-obstruction
1) Gastrointestinal smooth muscle-related diseases
Systemic sclerosis
Dermatomyositis
Multiple myositis
Systemic lupus erythematosus
Mixed connective tissue disease (MCTD)
Ehlers-Danlos syndrome
Muscular dystrophy
Amyloidosis
Small bowel-based lymphoid infiltration
Brown bowel syndrome (Ceroidosis)
Mitochondrial encephalomyopathy2) Gastrointestinal nerves-related diseases
Familial dysautonomia
Primary dysautonomia
Diabetic neuropathy
Myotonic dystrophy
Pseudo-obstruction after infection, such as EB virus, Herpes Zoster virus, and Rota virus
3) Endocrine diseases
Hypothyroidism
Hypoparathyroidism
Phaeochromocytoma
4) Metabolic diseases
UremiaPorphyria
Serious electrolytes abnormality (K+, Ca2+, Mg2+)
32

5) Others
Celiac disease
Kawasaki disease
Eosinophilic enteritis
Paraneoplastic pseudo-obstruction
Mesenteric vein thrombosis
Side reactions to radiotherapy
Angioedema
Intestinal tuberculosis
Crohn's disease
Chagas disease
Paralytic ileus resulting from injury, after gastrointestinal surgery, intraperitoneal inflammation, etc.
Ogilvie syndrome6) Drug-induced diseases
AntidepressantAntianxiety drug
Anthraquinone-based laxative
Phenothiazine drugs
Vinca alkaloid
Anticholinergic drug
OpioidCa channel blocker
Verapamil
Clinical manifestation: In a nationwide survey conducted over 10 years from 2001 to 2010, the numberof primary enrollments of childhood-onset CIPO was 92, of which 90% or more were idiopathic. Amongthese, 56 cases met the diagnostic criteria of CIIP. This disease may sporadically develop, and peristalsis
disorders may occur at any sites or multiple sites of the gastrointestinal tract. Lesion sites (dilated
intestines) are frequently observed in the small bowel and the colon (Figures 9, 10).
Symptoms: The major initial symptoms are abdominal distension and vomiting for neonatal andinfant-onset cases, and abdominal distension, vomiting, constipation, and diarrhea for older children.
Adult cases may often present with abdominal pain. In some cases suffering from long-lasting
pseudo-obstructiove symptoms, gastrointestinal resting may relieve the symptoms. However, in the
majority of cases, remission and exacerbation may be repeated with progressing conditions.
Flow of clinical practices: CIIP is likely to develop in the neonatal period or infancy, with bowel
obstructive symptoms requiring emergent operations for the diagnosis and treatment; older children may
often show gradual progress of their condition. Neonatal and infant-onset cases require differentiationfrom Hirschsprung's disease, isolated hypoganglionosis, megacystis-microcolon-intestinal hypoperistalsis
syndrome (MMIHS), and segmental dilatation of intestine. For this reason, an intestinal full-thickness
biopsy on laparotomy and gastrointestinal decompression with enterostomy are attempted early after the
onset in most cases.
For cases with an onset in older childhood and adulthood, when an intestinal full-thickness biopsy is33

unobtainable, alternatively, a characteristic peristalsis disorder is checked for by cine MRI or manometry(Figures 11, 12). It is also important to differentiate the disease from mechanical bowel obstruction andsecondary intestinal pseudo-obstruction (Table 1). We herein report the diagnostic diagrams for child andadult CIIP (Figures 13, 14).
Many cases progress gradually, with repeating remission and exacerbation. Treatment may startwith conservative treatments, such as drug therapy and intravenous/enteral nutrition, and then shift toinvasive treatments, such as decompression by tubing or enterostomy, as the condition progresses.
Intestinal perforation, necrosis, and severe enteritis indicate surgical treatments. Even after enterostomy
and resection of dilated segments, obstructive symptoms may relapse due to dysfunction in the remaining
intestines in many cases. Thus, multiple surgeries, such as exploratory laparotomy, enterostomy,
intestinal resection, and enterostomy closure may be performed in some cases. In a few cases, small boweltransplantation may be performed when these conservative treatments become ineffective due tocomplications or when patients have suffered from intolerable pain for a long period of time (Figure 15).
Prognosis: Although the prognosis is relatively good, repeated long-term hospitalization is needed. Evenfor outpatient cases, intravenous/enteral nutrition support, and enterostomy managements may
significantly limit their daily life. When gastrointestinal decompression is not effective, intestinal
perforation or enteritis may lead to sepsis, resulting in death.
A total of 53 (94.2%) out of 56 cases that met the diagnostic criteria are surviving for a long-term, butjust a small part of them improved their conditions. The average duration of symptoms is 14.6 years, andthe number of cases transitioning to adulthood CIIP is increasing. Nearly half of cases needgastrointestinal decompression via gastrostomy, enterostomy, or tubing. Furthermore, 74% of cases needsome nutritional support, such as parenteral nutrition and/or enteral nutrition.

34

Figure 9

Plain abdominal X-ray of neonatal-onset CIIP

At day 8 after birth (left) and 4 months of age (right), intestinal dilatation is observed. No air-fluid levels
are observed due to imaging in the prone position.

Figure 10 Plain abdominal X-ray of older childhood-onset CIIP
At 7 years of age (left), intestinal dilatation and air-fluid levels were present. At 17 years of age (right),
the dilatation had progressed, and free air was observed under the diaphragm.

35

Figure 11. Cine MRI of chronic idiopathic intestinal pseudo-obstruction
Peristalsis is evaluated by continuously regenerating 30 images obtained by about 15-second continuous
shooting of the organ. Selecting a specific site (circle) to graphically show the temporal change in the
diameter of the intestine is useful for a peristaltic evaluation. In healthy subjects, the diameter of theintestinal tract changes over time, with repeated contractions observed (a, c). In CIIP patients, thediameter of the intestinal tract hardly changes over time, and contractions are not noted (b, d).

T=0s

T=5s

T=10s

T=15s

a) Healthy subject: No morbid dilatation of the small bowel is observed, and active intestinal peristalsis
is maintained.

Intestinal tract diameter (mm)b) CIIP patient: Morbid dilatation of the small bowel is present with a marked decrease in peristalsis.

Rate of contraction

Contraction cyclec) Healthy casesd) CIIP cases

36Figure 12. Small bowel manometry for chronic idiopathic intestinal pseudo-obstruction
For the accurate evaluation of CIIP, an investigation of the abnormality in the small bowel motility isimportant. After inserting a pressure transducer catheter nasally into the small bowel, the motility ismeasured over 24 h.
Upper: Oral side, Middle: Anal side by 5 cm, Lower: Anal side by 10 cm. Horizontal axis: Time (5-minuteinterval scale), Vertical axis: Pressure (mmHg).
In healthy subjects, the interdigestive small bowel motility and postprandial small bowel motility
can be easily distinguished. Interdigestive small bowel motility consists of phase I with no contractions,
phase II with irregular contractions, and phase III in which 11 to 12 tetanic contractions per minute, andthese phases in this order are repeated periodically. Postprandial small bowel motility is induced witheating and is characterized by irregular contractions. The absence of a normal small bowel motility
pattern was confirmed during the daytime with a CIIP patient shown below (a). Nighttime is suitable for
evaluating the interdigestive small bowel motility, as the interdigestive time is longest between dinnerand breakfast for the typical person, and agitation of the central nervous system may not easily influence
the gastrointestinal tract. Normally, the characteristic phase III that occurs periodically is observed
during the nighttime. However, phase III was not noted, and the absence of a normal small bowel motility
pattern was confirmed while sleeping at night in the CIIP patient shown below (b).

a) CIIP case (Daytime)b) CIIP case (Nighttime)37

Figure 13. Diagnostic flowchart for pediatric chronic idiopathic intestinal pseudo-obstruction

38

Figure 14. Diagnostic flowchart for chronic idiopathic intestinal pseudo-obstruction (for older children
and adults)

Figure 15. Treatment flowchart for chronic idiopathic intestinal pseudo-obstruction39

2. Coverage of the clinical practice guideline

1) Within the scope of this guidelinea. All allied disorders of Hirschsprung's diseaseb. Diagnoses for patients suspected of being in this disease groupc. Clinical history, physical findings, diagnostic imaging, histopathology for this disease group
d. Treatment for patients with a definitive diagnosis of this diseasee. Medications, enteral nutrition, parenteral nutrition, various gastrointestinal decompression
methods, surgical treatment, and transplantation for this disease groupf. Vital and functional prognoses for each disease2) Outside of the scope of this guidelinea. Hirschsprung's disease (aganglionosis)b. Primary intestinal pseudo-obstruction not included in this disease groupc. Secondary intestinal pseudo-obstruction

3. CQ and systematic review

1) Setting of CQ
Four allied disorders of Hirschsprun’s disease—immaturity of ganglia, IND, segmental dilatation ofintestine, and IASA—show a good clinical course and are extremely rare; as such, these diseases arelikely to rarely cause confusion when making therapeutic decisions in clinical practice.
Although the other three diseases—isolated hypoganglionosis, MMIHS, and CIIP—are also rarediseases, quite a few cases have been documented, and their clinical course is serious. These threediseases may therefore require the consideration of evidence and fair opinions from specialists when
making decisions on their treatment clinical practice. For these reasons, these three diseases wereselected as targets of the clinical questions (CQs) of this guideline.
The following seven CQs were created, and the recommendations are posed individually for the threediseases.

2) Systematic review
CQ1: How are isolated hypoganglionosis, MMIHS, and CIIP diagnosed?
CQ2: What kind of drug therapy is recommended for the treatment of isolated
hypoganglionosis, MMIHS, and CIIP?
CQ3: Is gastrointestinal decompression therapy recommended for the treatment ofisolated hypoganglionosis, MMIHS, and CIIP?
CQ4: Is nutritional therapy recommended for the treatment of isolated
hypoganglionosis, MMIHS, and CIIP?
CQ5: Is (radical) surgical treatment recommended for the treatment of isolated
hypoganglionosis, MMIHS, and CIIP?
CQ6: Is small bowel transplantation recommended for the treatment of isolated
hypoganglionosis, MMIHS, and CIIP?
CQ7: What is the prognosis of isolated hypoganglionosis, MMIHS, and CIIP?

40

This guideline was developed using the methodologies in the "Minds Handbook for Clinical Practice
Guideline Development 2014" and the "Minds Manual for Clinical Practice Guideline Development."
However, as we expected difficulty in obtaining high-quality evidence on each disease, a unique approach
was used for the systematic review.
There are only a few reports on the rare diseases in the CQs, so sometimes the three diseases were
duplicated or confused in a single paper. In addition, a scoping search showed that a majority of thearticles were case reports. Many of the case reports have descriptions on the diagnosis, treatment,
prognosis, and complications. For these reasons, we decided that the search would be conducted not by
each CQ but by three diseases collectively, and the outcomes whould then be assigned to each CQ.
The databases used were PubMed and Ichu-Shi Web, the languages in the scope were Japanese andEnglish, and search date was unlimited. A total of 1,477 articles were obtained, and 3 members of ourgroup conducted primary screening, ultimately selecting 396 articles for secondary screening (Tables 2, 3).
Secondary screening by 10 members resulted in dropping 108 articles, and the evidence table wasdeveloped based on the remaining 288 articles.
In the creation of the evidence table, when one article was applicable to two or more CQs, extra rows
were set accordingly, and the applicable outcomes and conclusions were recorded. The completed evidence
table was summarized by each CQ, and a "Summary by CQ" was created. The SR team then madesystematic review reports by each CQ.

(1) Overview of the systematic review

Decisions prior to the literature search
Database used: PubMed and Ichu-Shi Web
Published year of literature in scope: All articles published through 2015
Search conditions of literature: Only humans used as research subjects
Language: Japanese and English
Diseases in scope: Three allied disorders of Hirschsprung's disease (isolated hypoganglionosis, MMIHS,
and CIIP)

Overview of the literature search
Search by: Two members of the SR team (working independently)
Search formula: Refer to the materials (Database search results: Tables 2, 3, Literature searchflowchart: Figure 16).
Number of articles: 1,488 (PubMed: 1,011 + Ichu-Shi Web: 477)

(2) Primary screening
Personnel in charge: Three members of the SR team
Screening method: The above-mentioned 3 members independently checked the titles and abstracts of41

1488 articles. At this stage, articles clearly unrelated to the predetermined CQs were excluded. Articles
for which the contents could not be judged based only on the title and abstract were included for review.
Primary screening result: After comparing the results from the 3 members, 396 out of 1,488 articles
were ultimately selected for secondary screening.

(3) Secondary screening and creation of evidence table
Personnel in charge: 10 members of the SR team.
Screening method: 10 members above shared the screening of 396 articles. Full screening by checking
the full texts determined which articles to choose based on the selection criteria.
Secondary screening result: After the SR team leader's review, 288 out of 396 articles were finallyselected for evidence table creation.
Evidence table creation: From the 288 articles selected, 10 members extracted the details from them fora total of 836 pieces of evidence to create an evidence table. (Contents of the evidence table: bibliographic
information, study design, PICO, conclusion, and CQs applicable)(4) Evaluation and consolidation of evidence (creation of CQ summary)
Personnel in charge: SR team leader
Creation of CQ summary: The CQ summary was created by classifying the 836 pieces of evidence
evtracted by the 10 SR team members by CQ, target disease, and outcome and then summarizing bystudy design.
Significance of CQ summary creation: The applicable studies focused on rare diseases of allied
Hirschsprung's diseases, and the majority of the target articles were case reports and case series. In order
to utilize them without disregarding low-evidence-level studies, we adopted a method of carefully
extracting evidence based on the CQ and target disease from each article and reorganized the findings asa CQ summary. This method visualized the total pieces of evidence and provided a value, which isdifferent from conventional evidence-level, onto accumulated facts empirically obtained in clinicalpractice.

(5) Systematic review report
The contents of the CQ summary were recapitulated to make a systematic review report. For every
comparison of CQs, the outcomes of benefits and harms were listed, and a consolidated document was
created for the judgement of its usefulness.
4. Determination of recommendations regarding the finalization and implementation policy

1) Determination of recommendations
The evidence table, summary by CQ, and systematic review report created by SR team were submitted to
the guideline development group, who created proposed recommendations and commentary based on thesubmitted materials. Since most of the evidence comprised case reports and case series, the strength of42the evidence was almost "D", but recommendations were created for the usefulness in clinical practice.
After a consensus meeting, the recommendations were determined by 13 guideline development
committee members using the Delphi voting method via e-mail (Table 4). Two committee members incharge of clinical practices for the adult domain declined to vote due to their having limited clinicalpractice experience in the child domain. Several other committee members also declined to vote for thedetermination of recommendation on CQ in one’s duty. At the first round of voting, all of therecommendations obtained 90% or greater approval.

2) Finalization
Between December 1 and December 31, 2016, a recommendation draft was posted on the homepages of
the Japanese Society of Pediatric Surgeons; the Japanese Society for Pediatric Gastroenterology,
Hepatology and Nutrition; and the Japanese Society of Neurogastroenterology to solicit public comments.
It was finalized after an external evaluation by epidemiology specialists (Table 5).

3) Implementation
The detailed version was mailed to major medical institutions and, at the same time, published inresearch reports. The practical version was issued as a publication and also posted on the homepages of
the Japanese Society of Pediatric Surgeons and the Japanese Society for Pediatric Gastroenterology,
Hepatology and Nutrition for dissemination.

43

Table 2. Database search result 1

Title

Allied disorders of Hirschsprung's disease

CQ
Database

PubMedDate

2015/2/5

Searched by

FK/YA

#

Search formula(((("chronic intestinal

Number of literature1011

pseudo-obstruction"[TIAB]) OR (("Intestinal
Pseudo-Obstruction"[Mesh]) AND(chronic[TW]))) OR (((((((("Neuronal intestinal
pseudoobstruction"[Supplementary Concept]) OR"Megacystis microcolon intestinal
hypoperistalsis syndrome"[Supplementary
Concept]) OR "intestinal
dysganglionoses"[TIAB]) OR "Megacystis
microcolon intestinal hypoperistalsis
syndrome"[TIAB]) OR MMIHS[TIAB] OR"Neuronal intestinal pseudoobstruction"[TIAB])
OR "Chronic idiopathic intestinal
pseudo-obstruction syndrome "[TIAB]) OR((("Hirschsprung Disease"[Mesh]) OR("Hirschsprung*"[TW])) AND ((allied[TIAB]) OR(variant[TIAB] OR variants[TIAB])))) OR("Congenital idiopathic intestinal
pseudoobstruction"[nm]) OR (("Intestinal
Pseudo-Obstruction"[Mesh]) AND(congenital[TIAB])) OR (immaturity[TIAB] AND
ganglia[TW]) OR hypoganglionosis[TW] OR("segmental dilation"[TIAB] AND intestine[TW])
OR ("internal anal sphincter"[TIAB] ANDachalasia[TW]))) NOT (Animals[MH] NOT
Humans[MH]) AND English[LA])44

Table 3. Database search result 2
Title

Allied disorders of Hirschsprung's disease

CQ
Database

Ichu-Shi Web

Date

2015/1/22

Searched by

FK/YA

#

Search formula((((CIPO/AL or (chronic/AL and (bowel
obstruction-negative/TH or
pseudoobstruction/AL))) or ((((allied
Hirschsprung's disease/AL) or (allied
Hirschsprung's disease/AL) or (Immaturity/AL)or (hypoganglionosis/AL) or (neuronal/AL andintestinal/AL and dysplasia/AL) or((megacystis-microcolon-intestinal
hypoperistalsis syndrome/TH or MMIHS/AL)) or(anal achalasia/TH) or (CIIP/AL) or (chronic
idiopathic intestinal pseudoobstruction/AL))))))and (PT=except for minutes and CK=human))45

Number of literature
477

Table 4. Voting result by guideline development group
Number of votes

Number of approvals

CQ1-1

13

12

92.3

CQ1-2

13

13

100

CQ1-3

13

13

100

CQ2-1

13

13

100

CQ2-2

13

13

100

CQ2-3

13

13

100

CQ3-1

13

13

100

CQ3-2

13

13

100

CQ3-3

13

13

100

CQ4-1

13

13

100

CQ4-2

13

13

100

CQ4-3

13

12

92.3

CQ5-1

12

11

91.7

CQ5-2

12

12

100

CQ5-3

12

11

91.7

CQ6-1

13

13

100

CQ6-2

13

13

100

CQ6-3

13

13

100

CQ7-1

10

10

100

CQ7-2

10

10

100

CQ7-3

10

10

100

46

Ratio (%)

Table 5
Toshio Morizane Chief Visiting Researcher, Japan Council for Quality Health Care
External evaluation of the Clinical Practice Guideline“It is logically summarized and presented with high relevance. This guideline describes the current
issues and is considered to be highly useful in areas with poor evidence in clinical practice”.
number
1

2
3

4

5

6

7

8

9

Evaluated points
The scope to be handled in thewhole medical treatment related
to the target disease/healthproblem is clear (whole or part).
The contents conform to theknowledge level of the target
guideline users.
The magnitude and certainty oftheeffectofintervention(diagnosis, treatment, etc.) on
the patient’s outcomes are
scientifically evaluated based onasystematic
review(qualitative/quantitative).
The benefits and disadvantages(harm, burdens, expenses) ofinterventions are evaluated in
an appropriate manner.
The
strengthoftherecommendation is based on theimportanceofmultipleoutcomes, the magnitude anduncertainty of benefits andharms,
andthecost
effectiveness. It is also based onacomparisonofmultipleinterventions, if necessary.
The
viewpointsofamulti-disciplinary
supporting
team as well as those of thesubjects are reflected in therecommendation.
The
individual
recommendations correspond tothe clinical questions, and thesubjects, including attributes,
are clear.
The description of individualinterventions is concrete andfeasible.
Facilities,
staffs,equipments, etc. are
also
described, if necessary.
Management is done so that the
COI of the guideline creator does
not affect the recommendation.

Evaluation
123 ○
4 *

123 ○
4

Comments
A thorough presentation of the medical
treatmentforAllieddisordersofHirschsprung’s disease (the diagnosis,
medication, surgical therapy, etc.)
Presentation of professional content that
actually corresponds to the medical treatment

123 ○
4

No CQs can be meta-analyzed. The strengh ofevidence is evaluated by the quantative
summarization of evidence related to the CQs
from articles searched comprehensively.

123 ○
4

Whether it is “useful" or "harmful" isevaluated quantitatively.

123 ○
4

Because the diseases mentioned here are
rare, the need for a cost-effectiveness analysis
is considered to be low.

12 ○
3 4

The
provisionofcare
requiring
multi-disciplinary support, such as daily caremanagement and home medical care, should
be considered in a future study.

123 ○
4

Recommendations are presented based oneach diagnosis and the patient’s attributes.

123 ○
4

As the target diseases are rare, it is assumed
that care at facilities capable of advanced
medical treatment including small intestinetransplantation is a prerequisite.

1 2○
3 4

The creator has no COIs to disclose. Details
about the management are unknown.

* Score: 1 Strongly Disagree, 2 Disagree, 3 Agree, 4 Strongly Agree47

Figure 16. Literature search flowchart (allied disorders of Hirschsprung's disease)[4-2. Literature search flowchart] PRISMA statement is modified.

48

VI. Recommendation
1. CQ1: How are isolated hypoganglionosis, MMIHS, CIIP diagnosed?
CQ1-1: How is isolated hypoganglionosis diagnosed?
Recommendation: A full-thickness biopsy of the gastrointestinal tract (especially the small intestine andsigmoid colon) is recommended for the definitive diagnosis of isolated hypoganglionosis.
Strengthof
1 (Strong): Recommend to “perform” or “not to perform”○
recommendation
2 (Weak) : Propose to “perform” or “not to perform”
Evidence

A (Strong)

B (Moderate)

C (Weak)○

D (Very weak)Commentary
Isolated hypoganglionosis (HP) is the most difficult disease to diagnose among the allied disorders ofHirschsprung's disease. This is because the basic concept of HP is not clear, and a definitive method of
diagnosis has not been clearly established. Reported diagnostic methods for HP include 1) plain
abdominal X-ray, 2) gastrointestinal imaging, 3) manometry, 4) a rectal mucosal biopsy, and 5) a
gastrointestinal full-thickness biopsy. Among these, many studies have shown that a full-thickness
gastrointestinal biopsy (especially from the small and large bowels) was useful for diagnosing HP. This isbecause the definitive diagnosis of HP has been based on reduced neurocytes in the myenteric plexus(Auerbach's plexus) in many former reports. Some reports have shown that when it is difficult to assess
the neurocyte distribution by HE staining, histochemical staining (such as AchE, NADPH, SDH, LDH,
silver staining) is useful for the diagnosis.1-33) In particular, a questionnaire survey conducted in 2012 fordomestic pediatric surgery institutions in Japan reported that an intraoperative frozen section diagnosis
had a low accuracy, and a pathological diagnosis by permanent preparation had 94% accuracy.34)
Therefore, a gastrointestinal full-thickness biopsy has been considered useful in the diagnosis of HP. No
complications have been reported in association with full-thickness biopsies.
As for the usefulness of a rectal mucosal biopsy, some reports have recommended a full-thickness
biopsy for the final diagnosis of HP, as the former has low accuracy.18, 19, 34) The reason is that the
submucosal nerve plexus (Meissner's plexus) of HP is normal, and AchE staining is also negative or
normal (i.e. it is useful for excluding Hirschsprung's disease, but not useful for the definitive diagnosis ofHP).

In addition, plain abdominal radiography and gastrointestinal imaging may not be useful for thedefinitive diagnosis of HP. Findings obtained from these imaging examination such as the air-fluid leveland gas-filled intestine on plain abdominal radiography, and intestinal dilatation, intestinal stenosis,
megacolon, microcolon, and caliber change on gastrointestinal imaging are similar to those of other allied
Hirschsprung's diseases. A diagnosis therefore cannot be determined by imaging studies alone. Suchmodalities may also increase unnecessary hazardous X-ray exposure.17, 34-38)

The usefulness of manometry conducted for allied disorders of Hirschsprung's disease is uncertain. It
49may indicate gastrointestinal dysfunction but has low accuracy due to non-constant results in neonatal
population, such as reflex negativity, reflex positivity, or atypical reflex. Some articles have reported onesophageal and duodenal manometry, but irregular peristalsis observed in the upper gastrointestinal
tracts is not specific to HP. Intestinal manometry is not thought to be useful in the diagnosis of HP.18, 21, 23,
24, 34, 37-39)

In conclusion, the most useful examination in the diagnosis of HP is a full-thickness gastrointestinal
biopsy, although a rectal mucosal biopsy can be performed first to rule out Hirschsprung’s disease. Plain
abdominal X-ray, barium enema, and rectal manometry are not useful for the definitive diagnosis of HP
and may even cause harm due to X-ray exposure. However, those examinations may be useful for thedifferential diagnosis of other allied disorders of Hirschsprung's disease.

References
1）Ida S.【Toward Seamless Medical Treatment from Pediatrics to Internal Medicine】 Particular Disease;
Gastrointestinal Disease; Intestinal Failure (Long-term TPN Patient, Allied Hirschsprung disease, CIIP,etc.). Diagnosis and Treatment. 2013; 101: 1867-72. (Article in Japanese)
2）Sashiyama H, Tsujinaka Y, Hamahata Y, et al. A surgical case of colonic Segmental Hypoganglionosis. J
Jpn Soc Coloproctol. 2013; 66: 263-8. (Article in Japanese)3）Watanabe Y, Takasu H, Sumida W. A preliminary report on the significance of excessively long segment
congenital hypoganglionosis management during early infancy. J Pediatr Surg. 2011; 46: 1572-7.
4）Wakatsuki K, Kaneizumi T, Yagura K, et al. A case of hypoganglionosis localized in the small intestine.
J Jpn Surg Assoc. 2007; 68: 878-81. (Article in Japanese)5）Meier-Ruge WA, Bruder E. Pathology of chronic constipation in pediatric and adult coloproctology.
Pathobiology. 2005; 72): 1-102.
6）Tomita R, Munakata K, Howard ER, et al. Histological studies on Hirschsprung's disease and its allied
disorders in childhood. Hepatogastroenterology. 2004; 51: 1042-4.
7）Tomita R, Ikeda T, Fujisaki S, et al. Hirschsprung's disease and its allied disorders in adults'
histological and clinical studies. Hepatogastroenterology. 2003; 50: 1050-3.
8）Kobayashi H, Li Z, Yamataka A, et al. Overexpression of neural cell adhesion molecule (NCAM)
antigens on intestinal smooth muscles in hypoganglionosis: is hypoganglionosis a disorder of theneuromuscular junction? Pediatr Surg Int. 2003; 19: 190-3.
9 ） Kobayashi H, Yamataka A, Lane GJ, et al. Pathophysiology of hypoganglionosis. J Pediatr
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10）Rolle U, Yoneda A, Solari V, et al. Abnormalities of C-Kit-positive cellular network in isolated
hypoganglionosis. J Pediatr Surg. 2002; 37: 709-14.
11）Munakata K, Fukuzawa M, Nemoto N. Histologic criteria for the diagnosis of allied diseases ofHirschsprung's disease in adults. Eur J Pediatr Surg. 2002; 12: 186-91.
5012）Kubota A, Yamauchi K, Yonekura T, et al. Clinicopathologic relationship of hypoganglionosis. J
Pediatr Surg. 2001; 36: 898-900.
13）Nogueira A, Campos M, Soares-Oliveira M, et al. Histochemical and immunohistochemical study ofthe intrinsic innervation in colonic dysganglionosis. Pediatr Surg Int. 2001; 17: 144-51.
14）Meier-Ruge WA, Brunner LA, Engert J, et al. A correlative morphometric and clinical investigation of
hypoganglionosis of the colon in children. Eur J Pediatr Surg. 1999; 9: 67-74.
15）Watanabe Y, Ito F, Ando H, et al. Morphological investigation of the enteric nervous system in
Hirschsprung's disease and hypoganglionosis using whole-mount colon preparation. J Pediatr Surg. 1999;
34: 445-9.
16）Hirobe S, Hayashi A, Kamakata S, et al. 【Total colon and extensive aganglionosis】 Experiences ofadvanced hypoganglionosis, especially on differentiation and association with aganglionosis. Japanese
Journal of Pediatric Surgery. 1998; 30: 527-31. (Article in Japanese)17）Puri P. Variant Hirschsprung's disease. J Pediatr Surg. 1997; 32: 149-57.
18）Tomita R, Munakata T. Transition in clinical practice of Pediatric Surgery - Pathophysiology of Allied
disorders of Hirschsprung’s disease in adults. Japanese Journal of Pediatric Surgery. 1997; 29: 713-21．
(Article in Japanese)19）Tomita R, Munakata T, Kurosu Y. Diagnosis of adulthood Hirschsprung’s disease and Allied diseases
from the histopathological view with rectal biopsy. JJCS. 1996; 21: 975-9．(Article in Japanese)20）Yamataka A, Fujiwara T, Nishiye H, et al. Localization of intestinal pacemaker cells and synapses in
the muscle layers of a patient with colonic hypoganglionosis. J Pediatr Surg. 1996; 31: 584-7.
21）Watanabe Y, Harada T. Measurement of upper gastrointestinal manometry in Allied disorders ofHirschsprung’s disease. Japanese Journal of Pediatric Surgery. 1996; 28: 1062-6．(Article in Japanese)
22）Yamataka A, Fujiwara T, Sunakawa M, et al. Distribution of Peristaltic Pacemaker (C - KIT
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1996; 28: 1058-61．(Article in Japanese)23）Toyosaka A, Seki Y, Miura K, et al. Allied disorders of Hirschsprung’s disease - Especially on
Intramural neurocytosis, Hypoganglionosis. Japanese Journal of Pediatric Surgery. 1996; 28: 1037-47．
(Article in Japanese)24）Taguchi T, Suita S, Nakao M, et al. Temporal changes in the pathology of Allied disorders ofHirschsprung’s disease. Japanese Journal of Pediatric Surgery. 1996; 28: 1029-36．(Article in Japanese)25）Smith VV. Intestinal neuronal density in childhood: a baseline for the objective assessment of hypoand hyperganglionosis. Pediatr Pathol. 1993; 13: 225-37.
26）Yamataka A, Miyano T, Urao M, et al. Distribution of neuromuscular junctions in the bowel affectedby hypoganglionosis. J Pediatr Gastroenterol Nutr. 1993; 16: 165-7.
27）Meier-Ruge W. Epidemiology of congenital innervation defects of the distal colon. Virchows Arch A
Pathol Anat Histopathol. 1992; 420: 171-7.
28 ） Meijers JH, Molenaar JC. Congenital malformation of the enteric nervous system: history,
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5129）Minowa Y, Nakata Y. A Case of allied disorder of Hirschsprung Disease Controlled Gastrostomy andenterostomy for 5 Years. Japanese Journal of Pediatric Surgery. 1990; 22: 280-4．(Article in Japanese)30）Puri P, Fujimoto T. Diagnosis of allied functional bowel disorders using monoclonal antibodies andelectronmicroscopy. J Pediatr Surg. 1988; 23: 546-54.
31）Ariel I, Hershlag A, Lernau OZ, et al. Hypoganglionosis of the myenteric plexus with normal
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32）Munakata K, Okabe I, Morita K. Histologic studies of rectocolic aganglionosis and allied diseases. J
Pediatr Surg. 1978; 13: 67-75.
33）Kadair RG, Sims JE, Critchfield CF. Zonal colonic hypoganglionosis. JAMA. 1977; 238: 1838-40.
34）Watanabe Y, Kanamori Y, Uchida K, et al. Isolated hypoganglionosis: results of a nationwide survey
in Japan. Pediatr Surg Int. 2013; 29: 1127-30.
35）Zhang HY, Feng JX, Huang L, et al. Diagnosis and surgical treatment of isolated hypoganglionosis.
World J Pediatr. 2008; 4: 295-300.
36）Hayakawa K, Hamanaka Y, Suzuki M, et al. Radiological findings in total colon aganglionosis andallied disorders. Radiat Med. 2003; 21: 128-34.
37）Tomita R, Ikeda T, Fujisaki S, et al. Upper gut motility of Hirschsprung's disease and its allied
disorders in adults. Hepatogastroenterology. 2003; 50: 1959-62.
38）Munakata K, Okabe I, Koshinaga T, et al. Diagnosis of Hypoganglionosis with contrast enema
examination. J.J.S.P.R. 1989; 5: 124-5．(Article in Japanese)39）Tomita R, Munakata K, Igarashi S, et al. Pathophysiological investigation of adult Hirschsprung’s
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in Japanese)52

CQ1-2: How is megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) diagnosed?
Recommendation: For cases in which symptoms of bowel obstruction, such as abdominal distension andvomiting, are present during the neonatal period and no organic obstruction is observed, a gastrointestinal
series is recommended. When a microcolon is observed and megalocystis is simultaneously confirmed bycystography or computed tomography (CT)/ultrasonography, MMIHS is strongly suspected. An intestinal
full-thickness biopsy is recommended for the definitive diagnosis to differentiate it from other allied
disorders of Hirschsprung's disease.

Strengthofrecommendation

1 (Strong): Recommend to “perform” or “not to perform”○

Evidence

A (Strong)

2 (Weak): Propose to “perform” or “not to perform”
B (Moderate)

C (Weak)○

D (Very weak)Commentary
Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a serious syndrome with an
unknown etiology. Bowel obstructive symptoms are noted from neonatal period, resulting in intestinal
failure and accompanied by megalocystis and microcolon.

Diagnostic criteria:
1) Bowel obstruction symptoms such as abdominal distension, vomiting, and abdominal pain present
immediately after birth2) Megacystis present
3) Barium enema reveals microcolon in the neonatal period4) No mechanical obstructive lesion observed in the gastrointestinal tract
5) No pathological abnormality observed in the neural plexus in specimen with a full-thickness
intestinal biopsy
All five of these items need to be met.

Although plain abdominal X-ray is indispensable for the diagnosis of bowel obstruction, an extended gas
pattern of the stomach and small bowel are general findings for bowel obstruction in neonates, so thediagnosis can rarely be determined based on X-ray findings alone. However, the observation of a lower
abdominal mass shadow due to megalocystis on abdominal X-ray may be useful for the diagnosis.1, 2)
Enema is useful for the confirmation of microcolon, an indispensable sign of this disease. Note that
ileal atresia and Hirschsprung's disease (entire colon aganglionosis) also present with both
gastrointestinal obstructive symptoms and microcolon during the neonatal period, so these diseases may
be difficult to differentiate by contrast enema.
If megalocystis is indicated with the symptoms of gastrointestinal obstruction, MMIHS should beconsidered. Although cystography can be useful for a clear diagnosis of megalocystis, no further clinicalinformation can be obtained using this modality. Ultrasonography or computed tomography (CT) can bealternative diagnostic imaging methods for the diagnosis of megalocystis.
Due to severe abdominal distension, laparotomy is performed during the neonatal period in manycases. MMIHS is often diagnosed based on the intra-operative findings. A full-thickness intestinal biopsy53

is indispensable during laparotomy, as other allied disorders of Hirschsprung’s disease, such as CIIP andisolated hypoganglionosis, must be differentiated. In addition, extensive Hirschsprung's disease andhypoganglionosis, can be differentiated with a full-thickness biopsy. MMIHS is characterized by theabsence of abnormalities in ganglion cells.3, 4) MMIHS must also be differentiated from CIIP, as neither ofthem have abnormalities in ganglion cells; the former can be distinguished by the presence of
megalocystis and microcolon during the neonatal period. If possible, the ganglion cells should be checkedusing frozen sections and the histology should be confirmed using permanent preparations. No
hypertrophic AcE-positive nerve fibers are seen in the rectal mucosa with a suction biopsy, so
Hirschsprung's disease can be differentiated, but it is difficult to differentiate MMIHS from other allied
disorders of Hirschsprung's disease using a suction biopsy.
Prenatal diagnoses have often been made in recent years based on a dilated intestinal tract andmegalocystis.5–7) Progressive cystectasy, hydroureteronephrosis, and gastrointestinal dilatation arecharacteristic findings in the prenatal period.

References
1）Tomita R, Morita K, Munakata K. On the significance of Peptidergic Nerve in Hirschsprung’s disease
and Hypoganglionosis. Journal of Smooth Muscle Research. 1989; 25: 147-54．(Article in Japanese)2）Kupferman JC, Stewart CL, Schapfel DM, et al. Megacystis-microcolon-intestinal hypoperistalsis
syndrome. Pediatr Nephrol. 1995; 9: 626-7.
3）Piotrowska AP, Rolle U, Chertin B, et al. Alterations in smooth muscle contractile and cytoskeleton
proteins and interstitial cells of Cajal in megacystis microcolon intestinal hypoperistalsis syndrome. J
Pediatr Surg. 2003; 38: 749-55.
4）Gomi A, Okamatsu T, Yatuka M, et al. Allied disorders of Hirschsprung’s disease – Clinical course of
MMIHS. Japanese Journal of Pediatric Surgery. 1996; 28: 1080-5．(Article in Japanese)5）Tuzovic L, Anyane-Yeboa K, Mills A,et al. Megacystis-microcolon-intestinal hypoperistalsis syndrome:case report and review of prenatal ultrasonographic findings. Fetal Diagn Ther. 2014; 36: 74-80.
6）Dewan PA, Brown N, Murthy DP,et al. Hydrometrocolpos and segmental colonic dilatation in a girlwith megacystis-microcolon-intestinal hypoperistalsis syndrome. J Paediatr Child Health. 1995; 31:
479-82.
7）Tanabe M, Takahashi H, Oonuma N, et al. Experience of treatment with Cisapride on Chronic
Idiopathic Intestinal Pseudoobstruction (CIIP). J. Jpn. Soc. Pediatr. Surg. 1991; 27: 48-55. (Article inJapanese)

54

CQ1-3: How is chronic idiopathic intestinal pseudo-obstruction (CIIP) diagnosed?
Recommendation: The duration of symptoms and the bowel obstruction conditions are determined fromthe clinical history and physical examination findings. The presence of intestinal dilatation, air-fluid
level formation, and the absence of mechanical obstruction are confirmed by diagnostic imaging. For
children, an intestinal full-thickness biopsy is recommended for the definitive diagnosis to differentiate
it other allied disorders of Hirschsprung's disease. For adults, it is important to differentiate truemechanical obstruction and secondary intestinal pseudo-obstruction, and a full-thickness biopsy is notconducted as it is for children.
Strengthof
1 (Strong): Recommend to “perform” or “not to perform”○
recommendation
2 (Weak): Propose to “perform” or “not to perform”
Evidence

A (Strong)

B (Moderate)

C (Weak)

D (Very weak)○Commentary
The diagnosis of CIIP requires all of the following 4 items to be met.
1) Chronic bowel obstruction observed2) Intestinal dilatation and air-fluid levels on diagnostic imaging
3) No intramural obstruction of the gastrointestinal tract
4) Other diseases excluded

A duration of symptoms ≥2 months for children and ≥6 months for adults shall be confirmed.
Intestinal dilatation and air-fluid levels are diagnosed by plain abdominal X-ray, CT, MRI, or similar
modalities.1–4) For neonates, radiological examinations in a standing or lateral decubitus position may bedifficult, so the confirmation of air-fluid levels by plain abdominal X-ray is not necessarily required.
In the diagnosis of pediatric intestinal pseudo-obstruction, the location of dilated segments, thedegree of peristaltic disorder, and the presence of non-mechanical obstruction can be detected based on
the gastrointestinal gas pattern on plain abdominal X-ray and gastrointestinal series.1,4) For adults,
luminal obstructions caused by neoplastic lesions, inflammation, and adhesion need to be excluded.
The diagnosis of idiopathy requires the exclusion of other pseudo-obstructions.
For children, diseases classified as primary pseudo-obstructions need to be differentiated. Althoughcongenital aganglionosis (Hirschsprung's disease) can be diagnosed by a suction rectal mucosal biopsy, apathological evaluation by a full-thickness bowel biopsy is indispensable for the differential diagnosis of
isolated hypoganglionosis and immaturity of ganglia.5,6)

In adults, primary intestinal pseudo-obstructions other than CIIP are rare, and the exclusion of
secondary pseudo-obstructions is emphasized in the diagnosis of idiopathy. The secondary
pseudo-obstructions to be differentiated are listed in Table 1.

Cine MRI and intestinal manometry are useful for assessing peristaltic disorders present in CIIP,
and these two examinations are used instead of a full-thickness biopsy in adults.7–11)

55

References
1）Byrne WJ, Cipel L, Ament ME, et al. Chronic idiopathic intestinal pseudo-obstruction syndrome.
Radiologic signs in children with emphasis on differentiation from mechanical obstruction. Diagn
Imaging. 1981; 50: 294-304.
2）Orita T, Harafuji I, Matsumoto M, et al. A case of Chronic idiopathic intestinal pseudo-obstruction
accompanied by Von Recklinghausen 's disease. The Japanese Journal of Gastroenterological Surgery.
1992; 25: 1334-8．(Article in Japanese)3）Munoz-Yague MT, Solis-Munoz P, Salces I, Ballestin C, et al. Chronic intestinal pseudo-obstruction: adiagnosis to be considered. Rev Esp Enferm Dig. 2009; 101(5): 336-42.
4 ） Masuzawa Y, Iwamoto K, Ichida K, et al. A case considered as Chronic idiopathic intestinal
pseudo-obstruction (CIIP) with significant flatulence. Shin - senri hospital Medical Journal. 1996; 7: 72-7.
(Article in Japanese)5）Muto M, Matsufuji H, Tomomasa T, et al. Pediatric chronic intestinal pseudo-obstruction is a rare,
serious, and intractable disease: a report of a nationwide survey in Japan. J Pediatr Surg. 2014; 49(12):1799-803.
6）Munoz-Yague MT, Solis-Munoz P, Salces I, et al. Chronic intestinal pseudo-obstruction: a diagnosis tobe considered. Rev Esp Enferm Dig. 2009; 101(5): 336-42.
7) Tomomasa T. Findings from gastroduodenal manometory in Chronic idiopathic intestinal
pseudo-obstruction - especially on phase 3. Journal of Smooth Muscle Research. 1993; 29: 204-6. (Article
in Japanese)
8）Watanabe Y, Harada T, Murahashi O, et al. A new method of upper gastrointestinal manometry inassessment of pediatric gastrointestinal motility – the usefulness in diagnosis and treatment offunctional ileus. J. Jpn. Soc. Pediatr. Surg. 1992; 28: 1115-20. (Article in Japanese)
9）Tsujikage S. Examination of gastrointestinal and urinary tract abnormalities in adults with chronic
idiopathic intestinal pseudo-obstruction (CIIP). Med. j. Osaka Univ. 1991; 43: 31-43. (Article in Japanese)10）Munoz-Yague MT, Marin JC, Colina F, et al. Chronic primary intestinal pseudo-obstruction fromvisceral myopathy. Rev Esp Enferm Dig. 2006; 98: 292-302.
11 ） Irtan S, Bellaiche M, Brasher C, et al. Stomal prolapse in children with chronic intestinal
pseudoobstruction: a frequent complication? J Pediatr Surg. 2010; 45: 2234-7.

56

2. CQ2: What kind of drug therapy is recommended for the treatment of isolated hypoganglionosis,
MMIHS, and CIIP?
CQ2-1: What kind of drug therapy is recommended for the treatment of isolated hypoganglionosis?
Recommendation: No drug therapy is recommended for isolated hypoganglionosis at this point.
Evidence

A (Strong)

B (Moderate)

C (Weak)

D (Very weak)○Commentary
Drug therapies for isolated hypoganglionosis are performed in various institutions and include prokinetic
agent, probiotics, Japanese herbal medicine (Daikenchuto), antibiotics, enemas, laxatives, andantidiarrheal drugs. However, no randomized controlled trial (RCT) or case series has described theefficacy of these treatments. There is only one case report on probiotics1), and one case report mentioning
on the use of anticholinergic or prostaglandin preparation.2)
As mentioned, the efficacy of the Japanese herbal medicine (Daikenchuto), which is often usedclinically in Japan, is still unknown. Regarding probiotics, a case report1) showed that the administrationof probiotics increased the amount of enteral nutrition and decreased the frequency of enteritis, but noother reports have been found to support its results. Anticholinergic or prostaglandin preparation drugs
may have no effect on improving the gastrointestinal motility in case of isolated hypoganglionosis2), as
only one report exists and the effectiveness is unclear. Note that no adverse events have been reported to
be associated with any of the drugs mentioned above.
At present, based on the available evidence, no drug can be recommended as an effective agent, that
improves gastrointestinal functional disorder or symptoms accompanying isolated hypoganglionosis.

References
1）Kiyohara Y, Nakanaga M, Takahashi T, et al. Usefulness of symbiotics for Allied disorders ofHirschsprung’s disease. The Journal of Japanese Society for Parenteral and Enteral Nutrition. 2010; 25:935-9. (Article in Japanese)
2）Nagoshi R, Onimoto H, Nagata I, et al. A case of Chronic intestinal pseudo-obstruction complicatedwith congenital central hypoventilation syndrome (Ondine's curse). Journal of Saitama Children's
Medical Center. 1991; 8: 51-7. (Article in Japanese)57

CQ2-2: What kind of drug therapy is recommended for megacystis-microcolon-intestinal hypoperistalsis
syndrome (MMIHS)?
Recommendation: Although the usefulness of Japanese herbal medicines (Daikenchuto) or probiotics
has been reported as drug therapy for MMIHS, evidence is insufficient to recommend these therapies atpresent.
Evidence
A (Strong)
B (Moderate)
C (Weak)
D (Very weak)○Commentary
Prokinetic agents (e.g. cisapride, metoclopramide), probiotics, Japanese herbal medicine (Daikenchuto),
antibiotics (e.g. erythromycin), enemas, laxatives, and antidiarrheal drugs are sometimes used to treat
MMIHS. Some case reports have described their efficacies, but there are no RCTs or case series to support
these findings. Prokinetic agents, such as cisapride (no longer marketed in Japan) and metoclopramide
are sometimes used, and their effectiveness was investigated in six case reports.1–6) All of the reports
concluded that these agents are ineffective in improving gastrointestinal motility. For replacement ofcisapride, mosapride, a serotonin receptor agonist is now available in the Japanese market. However, noreports have yet focused on the effect.
The Japanese herbal medicine (Daikenchuto) has been reported to be effective in four casereports.7-10) This agent reportedly induces improvement in the gastrointestinal motility and intestinal
transit time7), an increased amount of enteral nutrition intake8), and improvement in bowel obstruction
symptoms.9, 10) The effects of probiotics have been described in only one case report11), in which probiotics
were administered via lower jejunostomy to prevent enteritis, and enteritis did not develop. The effects ofantibiotics have been described three case reports5, 6, 10), in which the effectiveness of erythromycin wasinvestigated, but the results did not show any effectiveness.

Some case reports have described the administration of pantothenic acid, prostaglandin12), or a
sympathetic blocker13), none of which had any effect to improve the gastrointestinal motility.

In conclusion, no drug therapy can be recommended, but the Japanese herbal medicine Daikenchutoand probiotics may be attempted, as their effectiveness has been described in some case reports. Notethat no adverse events have been reported to be associated with any of the drugs mentioned above.

References1）Al-Alaiyan S, Nazer H. Megacystis-microcolon-intestinal hypoperistalsis syndrome. Ann Saudi Med.
1996; 16: 353-5.
2）Couper RT, Byard RW, Cutz E, et al. Cardiac rhabdomyomata and megacystis-microcolon-intestinal
hypoperistalsis syndrome. J Med Genet. 1991; 28: 274-6.
3）Goldberg M, Pruchniewski D, Beale PG, et al. Megacystis - microcolon-intestinal hypoperistalsis
syndrome. Pediatr Surg Int. 1996; 11: 246-7.
584）Al Harbi A, Tawil K, Crankson SJ. Megacystis-microcolon-intestinal hypoperistalsis syndrome
associated with megaesophagus. Pediatr Surg Int. 1999; 15: 272-4.
5）White SM, Chamberlain P, Hitchcock R, et al. Megacystis-microcolon-intestinal hypoperistalsis
syndrome: the difficulties with antenatal diagnosis. Case report and review of the literature. Prenat
Diagn. 2000; 20: 697-700.
6）Manop J, Chamnanvanakij S, Wattanasarn C. Megacystis microcolon intestinal hypoperistalsis
syndrome (MMIHS): a case report in Thailand. J Med Assoc Thai. 2004; 87: 1385-8.
7）Kubo M, Yanai T. Experience of treatment with Daikenchuto for various cases of ileus. Progress in
Medicine. 1997; 17: 2547-9. (Article in Japanese)8）Kakita H, Ito K, Koide W, et al. A case of Megacystis Microcolon Intestinal Hypoperistalsis Syndrome,in which Daikenchuto was effective. J Jpn Soc Perin Neon Med. 2004; 40: 863-7. (Article in Japanese)9）Iwashita K, Satake M, Kubo M. Problems on management of infants with Allied disorders ofHirschsprung’s Disease. The Journal of Yamanashi Central Hospital. 2000; 27: 19-22. (Article inJapanese)
10) Hirakawa H, Ueno S, Matuda H, et al. Effect of the herbal medicine dai-kenchu-to on gastrointestinal
motility in patients with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) andchronic idiopathic intestinal pseudo-obstruction (CIIP): report of two cases. Tokai J Exp Clin Med. 2009;34(1): 28-33.
11) Shimizu H, Ise K, Yamashita M, et al. A case of megacystis microcolon intestinal hypoperistalsis
syndrome with successful surgical treatment. J. Jpn. Soc. Pediatr. Surg. 2013; 49: 1117-21. (Article inJapanese)12) Kano T, Tateno Y, Anakura M, et al. A case of Megacystis-Microcolon-Intestinal Hypoperistalsis
Syndrome(MMIHS). The Journal of Clinical Pediatrics. 1994; 42: 199-203. (Article in Japanese)
13) Berdon WE, Baker DH, Blanc WA, et al. Megacystis-microcolon-intestinal hypoperistalsis syndrome:a new cause of intestinal obstruction in the newborn. Report of radiologic findings in five newborn girls.
AJR Am J Roentgenol. 1976; 126(5): 957-64.

59

CQ2-3: What kind of drug therapy is recommended for the treatment of chronic idiopathic intestinal
pseudo-obstruction (CIIP)?
Recommendation: As drug therapies for CIIP, prucalopride, cisapride, Japanese herbal medicines(Daikenchuto), probiotics, and antibiotic (erythromycin) are sometimes used, and some reports haveshown the usefulness of those agents for functional gastrointestinal disorder or abdominal symptoms.
However, evidence is insufficient to recommend these therapies at present.
Evidence
A (Strong)
B (Moderate)
C (Weak)
D (Very weak)○Commentary
Some drugs are used to control CIIP, including prokinetic agents (e.g. prucalopride, cisapride), a Japanese
herbal medicine (Daikenchuto), probiotics, antibiotics (e.g. erythromycin, polymyxin B), enema, laxatives,and antidiarrheals. However, there are few RCTs or case series to support the evidence, and most of theavailable articles are case reports.
The efficacy of prokinetic agents, such as prucalopride and cisapride (no longer marketed in Japan),have been reported. Prucalopride is a 5-HT4 receptor agonist and unapproved in Japan. One case series
report1) investigated the effectiveness of prucalopride in seven cases in their protocol, and three of four
who completed the protocol showed improvement of obstructive symptoms. It should be noted that threepatients withdrew from this protocol, but none of them had adverse events. In addition, one
cross-sectional study2) has reported improvement in bowel obstructive symptoms with cisapride.
Furthermore, six case reports showed the usefulness of cisapride, including an increased amount ofenteral nutrients3,4), reduction in the intestinal transit time5), and improvement in bowel obstructive
symptoms.6-8) However, conversely, three case reports9–11) reported that cisapride was ineffective. The
efficacy seems to vary depending on the pathology of individual cases. The effectiveness of mosapride, aserotonin receptor agonist now marketed in Japan to replace cisapride, for CIIP has not yet beenreported.

Two case reports12, 13) described the usefulness of the Japanese herbal medicine, Daikenchuto in
improving gastrointestinal motility and bowel obstructive symptoms. However, one case report14) found it
to be ineffective. The evidence supporting the usefulness is thought to be scarce. Note that no adverse
events have been reported to be associated with Daikenchuto.

Two case reports15, 16) have described the efficacy of probiotics. In these reports, an increased intake ofenteral nutrition and reduced incidence of enteritis were reported. Although there have been reports
describing their ineffectiveness, the evidence supporting their effectiveness is not sufficient. Note that noadverse events have been reported to be associated with probiotics.
Regarding antibiotics, four case reports14,17-19) showed the effectiveness of erythromycin.
Erythromycin was administered with the expectation of enhancing intestinal motility, and most of thesereports described increased enteral nutrition intake and improvement in bowel obstructive symptoms.
60

There have been no reports of ineffectiveness, nor any adverse events. Metronidazole and polymyxin B
are administered to control the intestinal flora. Of the two drugs, only polymyxin B has been reportedwith regard to its efficacy against CIIP. However, findings have been conflicting; one case report20)
described the improvement of symptoms, and two case reports21, 22) indicated ineffectiveness. No adverse
events were reported. Erythromycin may be effective, but the evidence is poor, and the efficacy ofpolymyxin B is considered is unclear.
Regarding other drugs, one case report7) found laxatives to be effective. Improvement in bowel
obstructive symptoms by a cholinergic agent was shown in a case report8), but this effect was denied infour other case reports.10,21-23) The effectiveness of laxatoves is therefore still unknown. Prostaglandin has
also been used, and two case reports20, 22) found that they improved bowel obstructive symptoms, butthree reports3,20,24) showed ineffectiveness. The effect of this drug in improving symptoms is also unknown.
Buprenorphine, a weak opioid, was reported as an agent for relieving abdominal pain.25) Althoughevidence is not sufficient, it may be useful for relieving symptoms of abdominal pain associated with CIIP
as well.
In conclusion, there are no recommended medications, but probiotics and erythromycin may be
attempted, as their effectiveness has been shown in some case reports.

References
1）Munoz-Yague MT, Solis-Munoz P, Salces I, et al. Chronic intestinal pseudo-obstruction: a diagnosis tobe considered. Rev Esp Enferm Dig. 2009; 101(5): 336-42.
2 ） Tanabe M, Takahashi H, Oonuma N, et al. Experience of Chronic Idiopathic Intestinal
Pseudo-obstruction (CIIP) treated with Cisapride. J. Jpn. Soc. Pediatr. Surg. 1991; 27(1): 48-55. (Article
in Japanese)3）Yamamoto M, Arisawa K, Kumon Y, et al. A case of Chronic idiopathic intestinal pseudo-obstruction.
The Journal of the Hyogo Medical Association. 1994; 37: 68-71. (Article in Japanese)4）Horiuchi I, Ito H, Yamashita T, et al. A case of Chronic idiopathic intestinal pseudo-obstruction
developed in neonatal period. J. Jpn. Soc. Pediatr. Surg. 1991; 27:48-55. (Article in Japanese)5）Tanaka M, Matsuhashi N, Arai H, et al. A case of Chronic idiopathic intestinal pseudo-obstruction andrreported cases in Japan. Therapeutics. 1987; 18: 537-40. (Article in Japanese)6）Tomizuka H, Setoguchi Y, Ogura J, et al. A case of Chronic idiopathic intestinal pseudo-obstruction andmedical treatments. J. New Rem. & Clin. 1989; 38: 158-65. (Article in Japanese)7）Miyauchi K, Ooshima Y, Shimizu M, et al. A case of Chronic idiopathic intestinal pseudo-obstruction
and investigation on reported cases in Japan. Journal of Japanese Society of Gastroenterology. 1991; 88:1359-63. (Article in Japanese)
8）Ament ME, Vargas J. Diagnosis and management of chronic intestinal pseudo-obstruction syndromes
in infancy and childhood. Arq Gastroenterol. 1988; 25: 157-65.

619）Suita R, Sai H, Izumi H. An autopsy case of Chronic idiopathic intestinal pseudo-obstruction syndrome(CIIPS)．Japanese Journal of Pediatrics. 1983; 36: 135-42. (Article in Japanese)10）Yahano S, Furuya S, Kadowaki H. Clinical course of 8 - year - old girl with CIIP and problems of long- term TPN support. Japanese Journal of Pediatric Surgery. 1983; 15: 1129-33. (Article in Japanese)
11）Ozawa M, Yamada R, Oohama M. Two cases of Chronic Idiopathic Intestinal Pseudo-obstruction
Syndrome(CIIPS)．Japanese Journal of Pediatric Surgery. 1983; 15: 1139-46 . (Article in Japanese)12）Kubo M, Yanai T. Experiences of treatmet with Daikenchuto for various kinds of ileus. Progress in
Medicine. 1997; 17: 2547-9. (Article in Japanese)13）Kubota A, Kawahara H, Hasegawa T, et al. Surgical intervention for chronic constipation. Japanese
Journal of Pediatric Surgery. 2008; 40: 226-34. (Article in Japanese)
14）Hirakawa H, Ueno S, Matsuda H, et al. Effect of the herbal medicine Daikenchuto on gastrointestinal
motility in patients with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) andchronic idiopathic intestinal pseudo-obstruction (CIIP): report of two cases. Tokai J Exp Clin Med. 2009;34(1): 28-33.
15）Kiyohara Y, Nakanaga M, Takahashi T, et al. The efficacy of symbiotics for allied Hirschsprung’s
disease. J JSPEN. 2010; 25: 935-9. (Article in Japanese)
16）Oonishi S, Wada H, Tamai S, et al. A case of CIPS who was struggling to treat weight gain andintestinal infection. Kinki Shinseiji Kenkyukai Kaishi. 2005; 14:24-8. (Article in Japanese)17） Masuzawa Y, Iwamoto K, Ichida K, et al. A case considered as chronic idiopathic intestinal
pseudo-obstruction (CIIP) with significant flatulence. Shin - senri hospital Medical Journal. 1996; 7: 72-7.
(Article in Japanese)18）Iwashita K, Satake M, Kubo M. Problems on management of Infants with Allied disorders ofHirschsprung’s Disease. The Journal of Yamanashi Central Hospital. 2000; 27: 19-22. (Article inJapanese)
19）Dalgic B, Sari S, Dogan I, et al. Chronic intestinal pseudoobstruction: report of four pediatric patients.
Turk J Gastroenterol. 2005; 16: 93-7.
20 ） Yoshida T, Murai K, Sugimoto S. Two cases considered to be Chronic idiopathic intestinal
pseudo-obstruction. Jpn J Clin Radiol. 1997; 31(2): 335-8. (Article in Japanese)21）Isa T, Muto Y, Hokama A . A case of Chronic idiopathic intestinal pseudo-obstruction (CIIP) withimproved clinical symptoms by hyperbaric oxygen therapy. The Japanese Journal of Clinical andExperimental Medicine. 1989; 66: 2197-200. (Article in Japanese)22）Michiura J, Katsumi M, Kawano N, et al. A case of Chronic idiopathic intestinal pseudo-obstruction
with mitral valve divergence syndrome. The Japanese Journal of Gastroenterological Surgery. 1988; 21:1134-7. (Article in Japanese)23）Nozawa H, Hori T, Kubo K. An older child with Chronic idiopathic intestinal pseudo-obstruction
presenting chronic constipation – Problems on diagnosis. Japanese Journal of Pediatric Surgery. 1983; 15:1135-8. (Article in Japanese)

6224）Tanaka T, Ootani K, Ando G, et al. A case of Chronic idiopatic intestinal pseudo-obstruction, The
Journal of the Tottori Medical Association. 1989; 17: 54-9. (Article in Japanese)25）Munoz-Yague MT, Marin JC, Colina F et al. Chronic primary intestinal pseudo-obstruction fromvisceral myopathy. Rev Esp Enferm Dig. 2006; 98(4): 292-302.

63

3. CQ3: Is gastrointestinal decompression therapy recommended for the treatment of isolated
hypoganglionosis, MMIHS, and CIIP?
CQ3-1: Is gastrointestinal decompression therapy recommended for the treatment of isolated
hypoganglionosis?
Recommendation: Upper jejunostomy is proposed for isolated hypoganglionosis. Ileostomy may beeffective in some cases, but the efficacy of enterostomy at any other part of the intestinal tract is
unknown.
Strengthof
1 (Strong): Recommend to “perform” or “not to perform”
recommendation
2 (Weak): Propose to “perform” or “not to perform”○

Evidence

A (Strong)

B (Moderate)

C (Weak)○

D (Very weak)Commentary
Isolated hypoganglionosis is a disease that requires prolonged fasting and central venous nutrition
management due to enteritis caused by stagnation of intestinal contents, subsequent sepsis, andabdominal pain. Effective gastrointestinal decompression may enable enteral feeding and provide theexpectation of growth and a long-term survival. Enterostomy sites have been discussed in case series andcase reports.
Regarding the type of gastrointestinal decompression, only one case has described gastrostomy withconcomitant decompression via high jejunostomy; this approach enabled enteral nutrition1), andintestinal lavage was empirically performed in the reported case at the time of exacerbation. The
prognosis varies depending on the location of the entertostomy, and effective usage of the enterostomy
may enable enteral feeding in many cases. Compared with ordianary jejunostomy and ileostomy, highjejunostomy is significantly more effective with regard to X-ray findings, the survival rate2), and theincidence of bowel obstruction3), with good outcomes.4, 5) The effectiveness of ileostomy is unclear. There
have been cases requiring ileectomy due to functional failure6), and enterostomy was re-performed at ahigher position3). However, there was also a case of improved bowel obstruction4). There are no reportsof effective colostomy, and additional enterostomy was required in the reported cases.3, 7)

References
1) Minowa Y, Nakata K. A case of allied disorder of Hirschsprung’s disease controlled with gastrostomy
and enterostomy for 5 Years. Japanese Journal of Pediatric Surgery. 1990; 22(3)：280-4．(Article inJapanese)
2) Watanabe Y, Sumida W, Takasu H,et al. Early jejunostomy creation in cases of isolated
hypoganglionosis: verification of our own experience based on a national survey. Surg Today. 2015; 45:1509-12.
3) Watanabe Y, Kanamori Y, Uchida K, et al. Isolated hypoganglionosis: results of a nationwide survey inJapan. Pediatr Surg Int. 2013; 29: 1127-30.
4) Nishijima E, Oono K, Yoshioka T, et al. A case of Hypoganglionosis in 6 - year - old girls, is it possible toclose ileostomy? - Evaluation of peristalsis and defecation of the remaining residual bowel with artificial
64

valves. The Medical Frontline. 1991; 46(12): 2514-5．(Article in Japanese)5）Minowa Y, Nakata K. A case of allied disorder of Hirschsprung’s disease controlled with gastrostomy
and enterostomy for 5 Years. Japanese Journal of Pediatric Surgery. 1990; 22(3)：280-4．(Article inJapanese)
6）Miura H, Ooi R, Sogi N. Allied disorders of Hirschsprung’s diseases – 3D structures of Auerbach plexus
in Hypoganglionosis. Japanese Journal of Pediatric Surgery. 1996; 28：1048-52．(Article in Japanese)
7) Watanabe Y, Harada T. Upper gastrointestinal manometry in allied disorders of Hirschsprung’s
disease. Japanese Journal of Pediatric Surgery. 1996；28: 1062-6．(Article in Japanese)65

CQ3-2: Is gastrointestinal decompression therapy recommended for the treatment of
megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS)?
Recommendation: No evidence supports the positive recommendation of gastrointestinal decompression
for MMIHS.
Evidence
A (Strong)
B (Moderate)
C (Weak)
D (Very weak)○Commentary
MMIHS is a serious disease that requires prolonged fasting and central venous nutrition management
due to enteritis caused by peristaltic disorder, subsequent sepsis, and abdominal pain.
Regarding gastrointestinal decompression therapy for MMIHS, some reports have shown that tube
decompression did not improve the symptoms1), and enteral feeding was not enabled by decompression
via gastrostomy, even with simultaneous enterostomy2), despite its efficacy for isolated hypoganglionosis.
Regarding intestinal lavage, there was a case3) in which switching to antegrade lavage by Malone surgery
after transanal lavage resulted in being able to provide home care to the patient. Regardless of theenterostomy site, enterostomy can only temporarily4) or partially5) relieve symptoms and does notcontribute to prognostic improvement.6) Colostomy is ineffective.4) No side effects or adverse events
accompanying decompression therapy have been reported.

References
1 ） Al Harbi A, Tawil K, Crankson SJ: Megacystis-microcolon-intestinal hypoperistalsis syndrome
associated with megaesophagus. Pediatr Surg Int. 1999; 15: 272-4.
2）Berdon WE, Baker DH, Blanc WA,et al. Megacystis-microcolon-intestinal hypoperistalsis syndrome: a
new cause of intestinal obstruction in the newborn. Report of radiologic findings in five newborn girls.
AJR Am J Roentgenol. 1976; 126: 957-64.
3）Shimizu H, Ise K, Yamashita M, et al. A case of Megacystis-microcolon-intestinal hypoperistalsis
syndrome in which surgical treatment was successful. J. Jpn. Soc. Pediatr. Surg. 2013; 49: 1117-1121.
(Article in Japanese)4）Goldberg M, Pruchniewski D, Beale PG,et al. Megacystis - microcolon - intestinal hypoperistalsis
syndrome. Pediatr Surg Int. 1996; 11: 246-7.
5）Hirakawa H, Ueno S, Matuda H, et al. Effect of the herbal medicine Dai-kenchu-tou on gastrointestinal
motility in patients with Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) and
Chronic idiopathic intestinal pseudo-obstruction (CIIP): report of two cases. Tokai J Exp Clin Med. 2009;34: 28-33.
6 ） Manop J, Chamnanvanakij S, Wattanasarn. Megacystis-microcolon-intestinal hypoperistalsis
syndrome (MMIHS): a case report in Thailand. J Med Assoc Thai. 2004; 87: 1385-8.

66

CQ3-3: Is gastrointestinal decompression effective for chronic idiopathic intestinal pseudo-obstruction(CIIP)?
Recommendation: Intermittent decompression via enteric tube may be effective in some CIIP cases, andenterostomy may be effective in other cases. The appropriate approach should be considered on acase-by-case basis.
Strengthof
1 (Strong): Recommend to “perform” or “not to perform”
recommendation
2 (Weak): Propose to “perfom” or “not to perform”○
Evidence
A (Strong)
B (Moderate)
C (Weak)
D (Very weak)○Commentary
CIIP is a disease that requires repeated, prolonged fasting and central venous nutrition management due
to enteritis caused by stagnation of intestinal contents, subsequent sepsis, and abdominal pain. Effective
gastrointestinal decompression may enable enteral feeding and provide the expectation of growth andlong-term survival. However, which type of gastrointestinal decompression therapy is most effective
depends on each case.
Tube decompression as a gastrointestinal decompression therapy for CIIP reported to be effective insome cases and ineffective in others. One case reported that the bowel obstruction symptoms wereremitted with nasogastric tube and enteral nutrition was enabled, but the bowel obstruction symptoms
relapsed.1) For ileus tube, there was a case of marked improvement in abdominal distension andabdominal pain2); however, there have been some cases of ineffectiveness3) and no improvement in
intestinal dilatation.4) There have been cases in which the oral intake was enabled by intestinal lavage
and continuous decompression through enterostomy5), in which high jejunostomy temporarily improved
bowel obstruction symptoms and enabled a small amount of oral intake6), and in which ileostomy waseffective.4, 6) Nevertheless, the ineffectiveness of enterostomy has also been reported.7) Colostomy has notbeen shown to be effective in any cases and has been reported not to have improved bowel obstruction
symptoms even with simultaneous ileostomy.6) No side effects or adverse events accompanying
decompression therapy have been reported.

References
1) Tachibana M, Nakazawa Y, Sakamoto Y, et al. A case of Chronic idiopathic intestinal
pseudo-obstruction; its complications and problems on long-term management. Gastroenterology. 1987; 6:
421-8．(Article in Japanese)
2）Tanaka M, Matsuhashi N, Arai H, et al. A case of Chronic idiopathic intestinal pseudo-obstruction andcases in Japan. Therapeutics (Chiryo-gaku). 1987; 18: 537-40．(Article in Japanese)3）Michiura H, Katsumi M, Kawano N, et al. A case of Chronic idiopathic intestinal pseudo-obstruction
with mitral valve divergence syndrome. The Japanese Journal of Gastroenterological Surgery. 1988; 21:1134-7．(Article in Japanese)4）Matsuura A, Kikuchi T, Ooshima T, et al. A case of Chronic idiopathic intestinal pseudo-obstruction
with transverse colonic axial torsion. J Abdom Emerg Med. 1996; 16(7): 1321-4．(Article in Japanese)5）Nishijima E, Anpuku M, Higashimoto Y, et al. Treatment experience of Chronic idiopathic intestinal
pseudo-obstruction (CIIPS) - Complications and problems on nutritional management of 8 cases
developed in infancy. JJPEN: The Japanese Journal of Parenteral and Enteral Nutrition.1992; 14:671395-401．(Article in Japanese)6）Kubota A, Okuyama H, Takahashi T, et al. 【Pathology and Treatment of Intestinal Torsion in Children】
A Case Report of CIIPS caused by intestinal malrotation - Consideration on the Difference Between
CIIPS and MMIHS. Japanese Journal of Pediatric Surgery. 2005; 37: 824-31．(Article in Japanese)
7）Hirakawa H, Ueno S, Matuda H, et al. Effect of the herbal medicine dai-kenchu-to on gastrointestinal
motility in patients with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) andchronic idiopathic intestinal pseudo-obstruction (CIIP): report of two cases. Tokai J Exp Clin Med. 2009;34: 28-33.

68

4. CQ4: Is nutrition therapy recommended for isolated hypoganglionosis, MMIHS, and CIIP ?
CQ4-1: Are enteral nutrition and parenteral nutrition effective as nutritional therapies for isolated
hypoganglionosis?
Recommendation: Enteral nutrition and parenteral nutrition are recommended as nutritional therapies
for isolated hypoganglionosis.
Strengthof
1 (Strong): Recommend to “perfom” or “not to perfom”○
recommendation
2 (Weak): Propose to “perform” or “not to perform”
Evidence
A (Strong)
B (Moderate)
C (Weak)
D (Very weak)○Commentary
Aside from a few case reports, few papers have discussed nutritional therapy for isolated
hypoganglionosis.The evidence level is very low. However, for this disease, which can develop during theneonatal period, parenteral nutrition therapy is clinically performed from an early stage in most of thecases, and enteral feeding therapy is combined with it once the disease condition is stabilized after stoma
construction. Recommending parenteral nutrition and enteral nutrition as nutritional treatments is
considered to be appropriate.
For parenteral nutrition, there are reports in which intermittent central venous nutrition was usefulfor preventing hepatic dysfunction1) and in which home total parenteral nutrition using an implanted
central vascular catheter was useful.2) As central venous nutrition may be an indispensable andlong-term nutrition treatment for this disease, its complications need to be well recognized for its safe
implementation. Furthermore, since it is a long-term therapy, a catheter with a cuff or an implanted
central vascular catheter needs to be used for infection prevention, and home total parenteral nutrition
should also be taken into consideration.

Enteral nutrition has never been specifically reported in papers, and the clinical managements
depend on the efforts and ideas of each institution. Because a small intestinal stoma is constructed inmany cases at present, some kind of enteral nutrition may be indispensable. Although breast milk,
adjusted milk, semidigested nutrient, digestive nutrient, and elemental diet have all been appropriately
used as enteral nutrients, the most appropriate nutrient has not yet been determined.
Nutritional therapy should be considered in combination with surgical treatment and medications
for this disease.

References
1）Yamauchi K, Suita S, Sakaguchi T, et al. Investigation of a normalized case of advanced liver
dysfunction due to parenteral nutrition. The Journal of Japanese Society for Parenteral and Enteral
Nutrition. 1993; 8: 72-5．(Article in Japanese)2）Iida N, Ogita K, Kai H. Home parenteral nutrition – treatment for short bowel syndrome. Japanese
Journal of Pediatric Surgery. 2006; 38: 1061-7．(Article in Japanese)69

CQ4-2: Are enteral nutrition and parenteral nutrition useful as nutritional therapies formegacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS)?
Recommendation: Enteral nutrition and parenteral nutrition are recommended as nutritional therapies
for MMIHS.
Strengthofrecommendation

1 (Strong): Recommend to “perform” or “not to perform”○

Evidence

A (Strong)

2 (Weak): Propose to “perform” or “not to perform”
B (Moderate)

C (Weak)

D (Very weak)○CommentaryThis disease is still a disease with a poor prognosis, and peristalsis dysfunction with unknown etiology
develops during the neonatal period. A nationwide survey in Japan showed that total parenteral nutrition(TPN) was needed for 4 cases and a combination of parenteral and enteral nutrition was needed for 12
cases out of 19 definitively diagnosed cases. In 7 out of the 9 surviving cases at present, parenteralnutrition has been required. Based on these survey results and the fact that saving the lives of children
with MMIHS is clinically difficult without enteral and parenteral nutrition support, parenteral andenteral nutrition are deemed appropriate for this disease, although the evidence level is low.
Three articles support the usefulness of parenteral nutrition: one reported on the promotion of
growth hormone secretion with nocturnal cyclic TPN1), another showed its usefulness over a short periodof time2), and another reported on the long-term survival on cyclic TPN.3) However, there have beenreports of associated adverse events, including repeated catheter-related bloodstream infection caused bylong-term central venous nutrition4-7), cholestatic hepatic dysfunction6,8-10), the development of portal
hypertension symptoms11), and copper deficiency.12) When providing parenteral nutrition, clinicians
should be familiar with the risk of those adverse events and perform appropriate preventative measuresand treatments.
The usefulness of enteral nutrition has been reported.13) The effectiveness of combination withparenteral nutrition has also been reported.14, 15) However, these findings have been cited in a limited
number of case reports and the evidence level is low. Regarding enteral nutrition for this disease, effective
methods and appropriate nutrients need to be determined in the future.

References
1）Yokoyama S, Hirakawa H, Soeda J,et al. Twenty-four-hour profile of growth hormone in cyclic
nocturnal total parenteral nutrition. Pediatrics. 1997; 100: 973-6.
2）Shikano T, Tateno Y, Anakura M, et al. A case of Megacystis-Microcolon-Intestinal Hypoperistalsis
Syndrome (MMIHS)．The Journal of Clinical Pediatrics, Sappo. 1994; 42: 199-203．(Article in Japanese)3 ） Yokoyama S, Fujimoto T, Tokuda Y, Mitomi T: Successful nutrition management of
megacystis-microcolon-intestinal hypoperistalsis syndrome - a case report. Nutrition. 1989; 5: 423-6.
4）Nazer H, Rejjal A, Abu-Osba Y,et al. Megacystis-microcolon-intestinal hypoperistalsis syndrome. Saudi
J Gastroenterol. 1995; 1: 180-3.
705）Goldberg M, Pruchniewski D, Beale PG,et al. Megacystis - microcolon - intestinal hypoperistalsis
syndrome. Pediatr Surg Int. 1996; 11: 246-7.
6）Shinkai M. A new treatment for children with intestinal failire – An effect of omega-3 lipid emulsion on
children with intestinal failire associated liver disease. Kanagawa Children's Medical Center Journal.
2011; 40: 316-8．(Article in Japanese)
7）Kaida S, Mizote H, Tanaka Y, et al. Efficacy of Broviac catheter for children with MMIHS requiringlong-term TPN. J. Jpn. Soc. Surg. Infect. 2003; 15: 119-22．(Article in Japanese)8）Lee NC, Tiu CM, Soong WJ, et al. Megacystis-microcolon-intestinal hypoperistalsis syndrome: report ofone case. Acta Paediatr Taiwan. 2003; 44: 238-41.
9 ） Masetti M, Rodriguez MM, Thompson JF, et al. Multivisceral transplantation for megacystis
microcolon intestinal hypoperistalsis syndrome. Transplantation. 1999; 68: 228-32.
10）Iihoshi Y, Okada A. Hepatic disorders in long-term surviver of allied disorders of Hirschsprung’s
disease. Japanese Journal of Pediatric Surgery. 1996; 28: 1104-7. (Article in Japanese)
11 ） Kohler M, Pease PW, Upadhyay V. Megacystis-microcolon-intestinal hypoperistalsis syndrome(MMIHS) in siblings: case report and review of the literature. Eur J Pediatr Surg. 2004; 14: 362-7.
12）Tokuda Y, Yokoyama S, Tsuji M, et al. Copper deficiency in an infant on prolonged total parenteralnutrition. JPEN J Parenter Enteral Nutr. 1986; 10: 242-4.
13）White SM, Chamberlain P, Hitchcock R, et al. Megacystis-microcolon-intestinal hypoperistalsis
syndrome: the difficulties with antenatal diagnosis. Case report and review of the literature. Prenat
Diagn. 2000; 20: 697-700.
14）Gillis DA, Grantmyre EB. Megacystis-microcolon-intestinal hypoperistalsis syndrome: survival of amale infant. J Pediatr Surg. 1985; 20: 279-81.
15）Kaida S, Mizote H, Tanaka Y, et al. Efficacy of Broviac catheter for children with MMIHS requiringlong-term TPN. J. Jpn. Soc. Surg. Infect. 2003; 15: 119-22．(Article in Japanese)71

CQ4-3: Are enteral nutrition and parenteral nutrition effective as nutritional therapies for chronic
idiopathic intestinal pseudo-obstruction (CIIP)?
Recommendation: Enteral nutrition and parenteral nutrition are recommended as nutritional therapies
for CIIP.
Strengthof
1 (Strong): Recommend to “perform” or “not to perform”○
recommendation
2 (Weak): Propose to “perform” or “not to perform”
Evidence
A (Strong)
B (Moderate)
C (Weak)
D (Very weak)○CommentaryThis disease may develop in neonates or older children. In both cases, intestinal peristaltic disorder may
persist over a long period of time, and some kind of nutritional therapy is indispensable.1-3) Thus, therecommendation of nutritional therapy for this disease is deemed appropriate. While the evidence levelmay be weak, as most of the evidence supporting the application of nutritional therapy for this disease isfrom case reports, like for isolated hypoganglionosis and MMIHS the number of reports is slightly higher,
and some reviews have been written.
Nine articles have described the usefulness of parenteral nutrition.4-12) The usefulness reported
includes the effect of fatty acid emulsion on hepatic steatosis, improvement of bowel obstruction
symptoms, and improvement in the quality of life by cyclic TPN using an implanted central vascularcatheter. However, there are some case reports and reviews13-15) regarding adverse events, such as traceelement deficiency, electrolyte disturbance, and sudden death due to trace element deficiency on
long-term central venous nutrition. Since this disease may have a long duration of symptoms, special
attention needs to be paid to the complications related to long-term parenteral nutrition.
The efficacy of enteral nutrition was reported in seven case reports and one review.5,9,12,14,16-19) Its
usefulness has been reported with respect to the use of semidigested nutrients, concomitant use of
semidigested nutrients and a low-residue diet, use of semidigested nutrients and/or digestive nutrients,
and a reduction in the frequency of ileus symptoms with semidigested nutrients. Furthermore, twoarticles describe the usefulness of concomitant parenteral and enteral nutrition. However, a lack of any
marked contribution of enteral nutrition to the improvement in bowel obstruction symptoms has also
been reported.8) Although some trends support the efficacy of semi-digested nutrients or digestive
nutrients, they may not be able to be administered in cases with aggravated symptoms. Further
investigation into what kinds of enteral nutrients are most useful is needed.

References
1 ） Antonucci A, Fronzoni L, Cogliandro L, et al. Chronic intestinal pseudo-obstruction. World J
Gastroenterol, 2008; 14: 2953-61.
2）Munoz-Yague MT, Marin JC, Colina F, et al. Chronic primary intestinal pseudo-obstruction fromvisceral myopathy. Rev Esp Enferm Dig. 2006; 98:292-302.
3 ） Iida H, Inamori M, Sekino Y, et al. A review of the reported cases of chronic intestinal
pseudo-obstruction in Japan and an investigation of proposed new diagnostic criteria. Clinical Journal of72

Gastroenterology. 2011; 4: 141-6.
4）Reif S, Tano M, Oliverio R, et al. Total parenteral nutrition-induced steatosis: reversal by parenterallipid infusion. JPEN J Parenter Enteral Nutr. 1991; 15:102-4.
5）Gillis DA, Grantmyre EB: Megacystis-microcolon-intestinal hypoperistalsis syndrome: survival of amale infant. J Pediatr Surg. 1985; 20: 279-81.
6）Kubota A, Okuyama H, Takahashi T, et al. 【Pathology and Treatment of Intestinal Torsion in Children】
A Case Report of CIIPS caused by intestinal malrotation - Consideration on the Difference Between
CIIPS and MMIHS. Japanese Journal of Pediatric Surgery. 2005; 37: 824-31．(Article in Japanese)7）Yahano S, Furuya S, Kadowaki H. A case of 8-year-old girl with CIIP – Clinical course and problems on
long-term TPN. Japanese Journal of Pediatric Surgery. 1983; 15: 1129-33. (Article in Japanese)
8）Ozawa M, Yamada R, Oohama M. Two cases of Chronic Idiopathic Intestinal Pseudo-ob-struction
Syndrome (CIIPS). Japanese Journal of Pediatric Surgery. 1983; 15: 1139-46. (Article in Japanese)9）Horiuchi I, Ito H, Yamashita T, et al. A case of Chronic idiopathic intestinal pseudo-obstruction
developed in neonates. J. Jpn. Soc. Pediatr. Surg. 1992; 28: 1359-63. (Article in Japanese)10 ） Tachibana M, Nakazawa Y, Sakamoto Y, et al. A case of Chronic idiopathic intestinal
pseudo-obstruction – Complications and problems on long-term management. Gastroenterology. 1987; 6:
421-8. (Article in Japanese)11）Kume M, Iwasa M, Yamamoto A, et al. An example of Chronic idiopathic intestinal pseudo-obstruction
reintegrated by long-term home parenteral nutrition (HPN). The Journal of Japanese Society for
Parenteral and Enteral Nutrition. 1996; 11: 46-9. (Article in Japanese)
12）Ament ME, Vargas J: Diagnosis and management of chronic intestinal pseudo-obstruction syndromes
in infancy and childhood. Arq Gastroenterol. 1988; 25: 157-65.
13）Tsuda K, Yokoyama Y, Kouzaki T, et al. A case of Selenium deficiency with Chronic idiopathic
intestinal pseudo-obstruction on long-term Home parenteral nutrition. Clinics in Gastroenterology.
1997; 2: 73-7. (Article in Japanese)
14）Michiura H, Katsumi M, Kawano N, et al. A case of Chronic idiopathic intestinal pseudo-obstruction
with mitral valve divergence syndrome. The Japanese Journal of Gastroenterological Surgery. 1988; 21:1134-7．(Article in Japanese)
15）Suita R, Sai H, Izumi H. An autopsy case of Chronic idiopathic intestinal pseudo-obstruction
syndrome (CIIPS). Japanese Journal of Pediatrics. 1983; 36: 135-42. (Article in Japanese)
16）Adachi Y, Yabana T, Koorito S. A Case of Chronic Idiopathic Intestinal Obstruction in Sjogren’s
Syndrome. Journal of Japanese Society of Gastroenterology. 1990; 87: 1223-7. (Article in Japanese)17 ） Asabe H, Nagasaki A, Yamada K, et al. An experience of Chronic idiopathic intestinal
pseudo-obstriction and investigation of cases in Japan. Japanese Journal of Pediatric Medicine. 1990; 22:443-8. (Article in Japanese)
18）Hirayama T, Kamishima M, Eji S, et al. A case of Chronic idiopathic intestinal pseudo-obstruction
supported effectively with semi-digestive nutrient alone. Japanese Journal of Nutritional Assessment.
1999; 16: 77-82. (Article in Japanese)
7319）Matsuura A, Kikuchi Y, Ooshima T, et al. A case of Chronic idiopathic intersitnal pseudo-obstruction
combined transverse colon axial torsion. J Abdom Emerg Med. 1996; 16: 1321-4. (Article in Japanese)745. CQ5: Is radical surgical treatment recommended for the treatment of isolated hypoganglionosis,
MMIHS, and CIIP?
CQ5-1: Is radical surgical treatment (other than stoma construction) recommended for the treatment ofisolated hypoganglionosis?
Recommendation: Avoiding radical surgical treatment is proposed.
Strengthofrecommendation

1 (Strong): Recommend to “perform” or “not to perform”
2 (Weak): Proposed to “perform” or “not to perform”○

Evidence

A (Strong)

B (Moderate)

C (Weak)○

D (Very weak)Commentary
Isolated hypoganglionosis is an allied disorder of Hirschsprung's disease that causes intestinal motility
disorder despite the presence of ganglion cells in the bowel wall. The ganglion cells are congenitally smallin size, and an extreme reduction in the number of ganglia plexi and ganglion cells is observed. Although
there is a difference in the degree, a reduction in the number of ganglion cells is observed all across theintestinal tract. Nutrition support using central venous nutrition and enteral nutrition, and enterostomy
at an appropriate site for decompression in order to prevent congestive enteritis are required in thetreatment.1) The effectiveness of intestinal resection at the anal side of enterostomy has also been showedin some case reports. A systematic review showed that intestinal resection and tapering improved bowel
obstruction symptoms.2) However, as peristaltic disorder is observed all over the intestinal tract2, 3),radical surgery is not yet established.

References
1）Tuzovic L, Anyane-Yeboa K, Mills A, et al. Megacystis-microcolon-intestinal hypoperistalsis syndrome:case report and review of prenatal ultrasonographic findings. Fetal Diagn Ther. 2014; 36(1): 74-80.
2）Dingemann J, Puri P. Isolated hypoganglionosis: systematic review of a rare intestinal innervation
defect. Pediatr Surg Int. 2010; 26: 1111-5.
3）Puri P, Fujimoto T. Diagnosis of allied functional bowel disorders using monoclonal antibodies andelectronmicroscopy. J Pediatr Surg. 1988; 23: 546-54.

75

CQ5-2: Is radical surgical treatment (other than stoma construction) recommended for the treatment of
megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS)?
Recommendation: Resection of dilated intestines does not improve ileus symptoms in MMIHS, so
avoiding radical surgical treatment is proposed.
Strengthof
1 (Strong): Recommend to “perform” or “not to perform”
recommendation
2 (Weak): Propose to “perform” or “not to perform”○
Evidence
A (Strong)
B (Moderate)
C (Weak)
D (Very weak)○Commentary
Four case reports had useful findings for this CQ. No symptom improvement has been reported. Both
Martin type jejunum side-to-side anastomosis, and additional small intestinal resection and righthemicolectomy were reported not to improve the symptoms.1) Resection of the dilated segment did not
improve the symptoms of abdominal distension or ileus, nor was the effectiveness of radical surgery
confirmed in the literature.2)

References
1）Hirakawa H, Ueno S, Matuda H, et al. Effect of the herbal medicine dai-kenchu-to on gastrointestinal
motility in patients with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) andchronic idiopathic intestinal pseudo-obstruction (CIIP): report of two cases. Tokai J Exp Clin Med. 2009;34: 28-33.
2）Patel R, Carty H. Megacystis-microcolon-intestinal hypoperistalsis syndrome: a rare cause of intestinal
obstruction in the newborn. Br J Radiol. 1980; 53: 249-52.

76

CQ5-3: Is radical surgical treatment (other than stoma construction) recommended for the treatment ofchronic idiopathic intestinal pseudo-obstruction (CIIP)?
Recommendation: Concomitant use of antegrade continence enema and antidromic enema is suggested
for the treatment of CIIP to improve defecation.
In cases with duodenal dilatation, duodenojejunostomy is suggested to improve the intestinal transit. It
may relieve the pseudo-obstructive symptoms to some extent.
Intestinal resection dose not improve the pseudo-obstructive symptoms, so avoiding radical surgicaltreatment is suggested.
Strength ofrecommendation
Evidence

1 (Strong): Recommend to “perform” or “not to perform”
2 (Weak): Propose to “perform” or “not to perform”○
A (Strong)

B (Moderate)

C (Weak)

D (Very weak)○Commentary
Six case reports had useful findings for this CQ.

Beneficial outcomes:
Antegrade continence enema improved defecation remarkably, but improved abdominal distension
mildly.1) Duodenojejunostomy, in the case of duodenal dilatation, improved the transit of the dilated
intestine remarkably, and improved the symptoms to some extent.2) Ileocecal resection reduced thetransit time of contrast medium to reach the colon in imaging examinations.3)

Harmful outcomes:
Ileocecal resection4) and colectomy5) did not improve bowel obstruction symptoms. Based on the report ofsurgery-related death6), attempting radical surgery for chronic intestinal pseudo-obstruction could be
harmful.

References
1）Kubota A, Kawahara H, Hasegawa T, et al. Surgical treatment for Chronic constipation. Japanese
Journal of Pediatric Surgery. 2008; 40: 226-34. (Article in Japanese)2 ） Amano Y, Nakahata R, Akahane T. Cases of siblings with Chronic idiopathic intestinal
pseudoobstruction (CIIP). The Journal of Pediatric Practice. 1985; 48: 937-41. (Article in Japanese)3 ） Nishina M, Kido N, Fujii C, et al. Surgical experience of Chronic idiopathic intestinal
pseudo-obstruction. Hukubuiryo no shinpo. 1987; 7: 635-9. (Article in Japanese)
4）Nozawa H, Hori T, Kubo K. An older child with chronic idiopatic intestinal pseudo-obstruction
presenting chronic constipation – problems on diagnosis. Japanese Journal of Pediatric Surgery. 1983; 15:1135-8. (Article in Japanese)5）Ozawa M, Yamada R, Oohama M. Two cases of Chronic Idiopathic Intestinal Pseudo-ob-struction
Syndrome(CIIPS). Japanese Journal of Pediatric Surgery. 1983; 15: 1139-46. (Article in Japanese)
6）Dalgic B, Sari S, Dogan I, et al. Chronic intestinal pseudoobstruction: report of four pediatric patients.
Turk J Gastroenterol. 2005; 16: 93-7.

77

6. CQ6: Is small bowel transplantation recommended for the treatment of isolated hypoganglionosis,
MMIHS, and CIIP?
CQ6-1: Is small bowel transplantation useful for the treatment of isolated hypoganglionosis?
Recommendation: Small bowel transplantation is proposed for the treatment of isolated
hypoganglionosis, as it may be useful for the following cases: patients in whom discontinuing parenteralnutrition (PN) is difficult even after the maximum use of the native intestinal tract under intestinal
rehabilitation; patients in whom the number of central venous access routes is lacking; patients withrepeated episodes of sepsis; and patients with progressive hepatopathy.
Strengthof
1 (Strong): Recommend to “perform” or “not to perform”
recommendation
2 (Weak): Propose to “perform” or “not to perform”○
Evidence

A (Strong)

B (Moderate)

C (Weak)

D (Very weak)○Commentary
According to the Intestinal Transplant Registry, small bowel transplantation was performed in 2,600
cases or more by 2011 all over the world. Among them, patients with motility disorder as primary diseaseaccounted for 15% of adults and 19% of children. In Japan, the first small bowel transplantation was
performed in 1996, and 26 transplantations in 23 cases were performed by 2014. The postoperative
patient survival and graft survival rates at 1, 5, and 10 years are 87%, 68%, 58%; and 80%, 59%, 44%,
respectively. The short-term results are relatively good, but the long-term prognosis is still poor.1)
Articles from overseas regarding small bowel transplantation for isolated hypoganglionosis cannot befound, probably because there are no common worldwide diagnostic criteria. Only one case from Tohoku
University has been addressed in papers.2, 3) A 14-year-old boy who had a history of 10 laparotomies was
experiencing progressive difficulty with oral intake due to multiple stenoses of the small bowel secondary
to repeated enteritis and abdominal pain, and a progressive lack of central venous access routes. The
patient reportedly achieved successful oral intake after the transplantation, which led to discontinuingparenteral nutrition and being discharged.4, 5)
The following five institutions have performed small bowel transplantation: Kyoto University, Osaka
University, Tohoku University, Keio University, and Kyushu University. An overview of small boweltransplantation cases for hypoganglionosis in Japan as of January 2016 based on a report from theJapanese Intestinal Transplantation Registry and confirmation with the transplantation institutions isshown in Table 6. Nine small bowel transplantations (living donors: 6, brain-dead donors: 3) in 8 cases
have been performed so far; the patient survival was 7/8 (88%), and the graft survival was 5/9 (56%).
Among the 5 cases of graft survival, complete discontinuation without requiring any transfusion at all
was achieved in 3/5 (60%) cases, and 2/5 (40%) cases temporarily or always required transfusion. Stoma
closure was performed in 1/5 (20%) cases; partial closure, such as Bishop-Koop and Santulli, wasperformed in 2/5 (40%) cases; and 2/5 (40%) cases remained open.
Small bowel transplantation for isolated hypoganglionosis has been performed in cases where disease
management is difficult due to a lack of central venous access or repeated episodes of sepsis. While there
are patients who benefitted from transplantation, such as achieving successful oral intake and a reduced
dependency on parenteral nutrition, acute rejection and chronic rejection may result in graft removal in78many cases. Given that the graft survival rate has remained at 56%, we should carefully determine theindications of small bowel transplantation as a surgical treatment for isolated hypoganglionosis, andestablishing control with the patient’s own intestine should be given the highest priority.

References
1) Ueno T, Matsuura T, Fukuzawa M, et al. Report on the cases of small intestinal transplantation in
Japan. Japanese Journal of Transplantation. 2015; 50: 191-5. (Article in Japanese)2) Ishii T, Wada M, Nishi K, et al. Living-related intestinal transplantation for a patient withhypoganglionosis. Pediatr Transplant. 2006; 10: 244-7.
3）Ishii T, Wada M, Nishi K, et al. Two cases of living-related intestinal transplantation. Transplant Proc.
2006; 38: 1687-8.
4）Wada M, Ishii T, Kato T, et al. Living-related small bowel transplantation: two cases experiences.
Transplant Proc. 2005; 37(2): 1381-2.
5) Wada M, Ishii T, Kato T, et al. Experiences of two cases with Living small intestinal transplantation.
Transplantation Now. 2005; 18: 145-51. (Article in Japanese)

Table 6. Cases of small bowel transplantation for isolated hypoganglionosis in Japan

Table. Cases of small bow el transplantation for hypoganglionosis in Japan
CaseYear of transplant

Institution

Age

Sex

1

2003

Tohoku University

14

Male

Repeated sepsis

Indication for transplantation

Living/Brain-dead Patient survival
LivingSurvival

Survival Complete discontinuation

Partial opening

2

2006

Keio University

14

Male

PN dependence, Lack of central venous access

LivingSurvival

Survival Complete discontinuation

Partial opening

3

2007

Keio University

11

Male

PN dependence, Lack of central venous access

LivingSurvival

Survival

Partial opening

4

2007

Tohoku University

28

Female Repeated sepsis, Lack of central venous access

LivingSurvival

Resection (ACR)

Dependence

Partial opening

4'

2007

Tohoku University

27

Female Graft failure due to ACR

Brain-deadSurvival

Resection (CR)

Dependence

After graft removal (Partial opening before removal)

5

2011

Keio University

13

Male

LivingSurvival

Resection (CR)

Dependence

After graft removal (Opening before removal)

6

2011

Kyoto University

10

Female Hepatopathy, Nutritional deficiency, CRBSI

Brain-dead

DeathPatient death

Dependence

Opening7

2013

Tohoku University

20

Male

Brain-deadSurvival

Survival Complete discontinuation

Opening8

2014

Keio University

10

Male

LivingSurvival

Survival

Opening

PN dependence, Lack of central venous access

Repeated sepsis, Lack of central venous access

Graft survival

PN

Stoma

Partial discontinuation

Partial discontinuation

Case 4' is the re-transplantation case of case 4.

79

CQ6-2: Is small bowel transplantation useful for megacystis-microcolon-intestinal hypoperistalsis
syndrome (MMIHS)?
Recommendation: Small bowel transplantation is proposed for cases not complicated with liver or renal
failure. Multiple organ transplantation is proposed for cases complicated with liver or renal failure.
Strengthofrecommendation

1 (Strong): Recommend to “perform” or “not to perform”
2 (Weak): Propose to “perform” or “not to perform”○

Evidence

A (Strong)

B (Moderate)

C (Weak)

D (Very weak)○Commentary
MMIHS is the most serious type of diseases presenting with functional ileus. In many cases, thesymptoms develop from an early stage after birth with a poor prognosis.1) The associated causes of death
include sepsis, malnutrition, hepatic failure, renal failure, and multiple organ failure, and no specificmethod of treatment has been established.2, 3)
Small bowel transplantation for MMIHS has never been performed in Japan (as of January 2016).
Papers on organ transplantation have been reported only from overseas, and most of the cases reported
are multiple organ transplantations including the stomach, small bowel, colon, liver, pancreas, andkidney, as hepatic failure and renal failure are accompanied at the time of transplantation in the majorityof reported cases.1, 2, 4-6) There is one case report of an eight-year-old girl without hepatic or renal failure
at the time of transplantation, and isolated small bowel transplant helped her to achieve oral intake. 7)
Another case describes a one-year-old girl who successfully received combined living donor liver/small
bowel transplantation from her mother.8) In multiple organ transplantation, there are many cases inwhich the stomach is simultaneously transplanted to prevent postoperative gastric motility disorder.
However, in cases of isolated small bowel transplantation and combined living donor liver/small boweltransplantation, the postoperative gastric emptying function was improved in both cases, and it has beensuggested that the stomach does not necessarily need to be transplanted simultaneously.
The patient and graft survival rates after small bowel transplantation are poor in the long term.
However, considering the otherwise extremely poor prognosis of MMIHS, multiple organ transplantation
historically only being performed overseas, and the difficulities of combined liver/small boweltransplantation in Japan, isolated small bowel transplantation might be useful when the disease is notcomplicated with hepatic failure. This is the current situation of small bowel transplantation for MMIHS
in Japan.

References
1) Loinaz C, Rodríguez MM, Kato T, et al. Intestinal and multivisceral transplantation in children withsevere gastrointestinal dysmotility. J Pediatr Surg. 2005; 40: 1598-604.
2) Gosemann JH, Puri P. Megacystis microcolon intestinal hypoperistalsis syndrome: systematic review ofoutcome. Pediatr Surg Int. 2011; 27: 1041-6.

803) Puri P, Shinkai M. Megacystis microcolon intestinal hypoperistalsis syndrome. Semin Pediatr Surg.
2005; 14: 58-63.
4) Masetti M, Rodriguez MM, Thompson JF, et al. Multivisceral transplantation for megacystis
microcolon intestinal hypoperistalsis syndrome. Transplantation. 1999; 68: 228-32.
5) Nathan JD, Rudolph JA, Kocoshis SA, et al. Isolated liver and multivisceral transplantation for total
parenteral nutrition-related end-stage liver disease. J Pediatr Surg. 2007; 42: 143-7.
6) Pohl J, Chandra R, Corpuz G, et al. Hypertriglyceridemia and megacystis-microcolon-intestinal
hypoperistalsis syndrome. J Pediatr Gastroenterol Nutr. 2008; 47: 507-13.
7) Huang CM, Tseng SH, Weng CC, et al. Isolated intestinal transplantation for megacystis microcolon
intestinal hypoperistalsis syndrome: case report. Pediatr Transplant. 2013; 17: E4-8.
8) Raofi V, Beatty E, Testa G, et al. Combined living-related segmental liver and bowel transplantation formegacystis-microcolon-intestinal hypoperistalsis syndrome. J Pediatr Surg. 2008; 43: e9-e11.

81

CQ6-3: Is small bowel transplantation useful for chronic idiopathic intestinal pseudo-obstruction(CIIP)?
Recommendation: Small bowel transplantation for the treatment of CIIP is proposed, as it may be
useful for the following cases: patients whose symptoms remain intolerable even with adequate
parenteral nutrition, enteral nutrition, and gastrointestinal decompression therapy; patients in whom
the number of central venous access routes is lacking; and patients with repeated episodes of sepsis.
The possible impairment of the native gastric outlet function needs to be considered when small boweltransplantation is planned and performed.
Strengthof
1 (Strong): Recommend to “perform” or “not to perform”
recommendation
2 (Weak): Propose to “perform” or “not to perform”○
Evidence

A (Strong)

B (Moderate)

C (Weak)

D (Very weak)○Commentary
CIIP is a functional bowel obstruction with an unknown etiology. Treatment may start with conservative
treatments, such as drug therapy and intravenous and enteral nutrition, and then shift to invasive
treatments, such as decompression by tubing or enterostomy, as the condition progresses. In the cases inwhich intolerable pain is present despite these treatments, and in which the disease is complicated by alack of central venous access or repeated episodes of sepsis, small bowel transplantation may be
performed as a final measure.
Since this disease is often characterized by disorder of gastric emptying, multiple organtransplantation including the stomach has been generally performed overseas.1, 2) A group from the
University of Bologna in Italy performed transplantation in 11 cases with CIPO accompanied byfunctional disorder of gastric emptying. Multiple organ transplantation was performed only for two cases,
and for the remaining nine cases, isolated small bowel transplantation and partial gastrectomy withgraft-gastric and graft-duodenal anastomoses were performed.3) In 6 (86%) out of the 7 surviving cases,
oral intake was enabled, and in 5 cases (71%), gastric emptying was normalized.
In Japan, small bowel transplantation for CIIP has been performed in three cases. In two of thesecases, two anastomoses were performed at the oral side to add graft-duodenal or graft-jejunal
anastomosis to graft-gastric anastomosis. In both cases, however, oral intake was not easily established.
Only one out of the three cases has survived.
CIIP is an intractable disease with an unknown etiology for which an effective treatment method has
not yet been established. Small bowel transplantation may be the only therapy for severe cases, but theoral intake is not easily established after transplantation. As for the current situation regarding small
bowel transplantation for CIIP in Japan, multiple organ transplantation is not feasible. Isolated small
bowel transplantation should be provided carefully with close consideration of the appropriate
anastomosis approach for ensuring the gastric emptying function in each case.

References
1 ） Loinaz C, Mittal N, Kato T, et al. Multivisceral transplantation for pediatric intestinal
pseudo-obstruction: single center's experience of 16 cases. Transplant Proc. 2004; 36: 312-3.
822）Sigurdsson L, Reyes J, Kocoshis SA, et al. Intestinal transplantation in children with chronic intestinal
pseudo-obstruction. Gut. 1999; 45: 570-4.
3 ） Lauro A, Zanfi C, Pellegrini S, et al. Isolated intestinal transplant for chronic intestinal
pseudo-obstruction in adults: long-term outcome. Transplant Proc. 2013; 45: 3351-5.

83

7. CQ7: What is the prognosis of isolated hypoganglionosis, MMIHS, and CIIP?
CQ7-1: What is the prognosis of isolated hypoganglionosis?
Recommendation: Long-term survival can be expected with appropriate treatment. In many cases,
adequate nutritional support and intestinal stoma care are required for a long period of time.
Evidence

A (Strong)

B (Moderate)

C (Weak)○

D (Very weak)Commentary
In article of a systematic review1), multidisciplinary treatment improved the survival rate from 12.6% in
1977 to 55.6% in 2011. When patients receive appropriate therapy, a longer survival can be expected. Of
these cases, there are some in which disease control was obtained with oral intake alone, in which normal
growth or only mild growth disorder was observed, and in which school attendance was achieved.
However, many cases may require long-term management of nutrition and enterostomy.

References
1）Friedmacher F, Puri P. Classification and diagnostic criteria of variants of Hirschsprung's disease.
Pediatr Surg Int. 2013; 29: 855-72.

84

CQ7-2: What is the prognosis of megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS)?
Recommendation: Patients with MMIHS have a poor prognosis in comparison to healthy children;
however, long-term survival can be expected with appropriate treatment. In many cases, adequate
nutritional support and intestinal stoma care are required, and the functional prognosis is poorer thanthat of healthy children.
Evidence
A (Strong)
B (Moderate)
C (Weak)
D (Very weak)○Commentary
A cross-sectional study in Japan showed that 10 out of 19 cases were surviving and 9 cases were dead,with a 5-year survival rate of 62.8% and 10-year rate of 56.5%. The main causes of death were hepatic
failure and sepsis. In 2 systematic reviews, the number of surviving cases was 43 out of 218 cases1) and23 out of 182 cases2), indicating that this disease is a serious condition with a poor prognosis. Its poor
prognosis has often been reported in case reports and case-series. The age of death ranges fromimmediately after birth to 15 years old, and about 80% die in infancy (<1 year after birth).
Among case reports, we found a report on an infant who successfully self-defecated andself-urinated at the age of 1 year and 10 months3) and another report on an infant who successfully
achieved a normal intake at the age of 2 years and 6 months.4) The physical and mental development ofchildren with MMIHS has been reported to be delayed in one report5) and normal in another.3) Two
reports have described patients starting school under home parenteral nutrition.5, 6)

References
1）Gosemann JH, Puri P. Megacystis microcolon intestinal hypoperistalsis syndrome: systematic review
of outcome. Pediatr Surg Int. 2011; 27: 1041-6.
2）Puri P, Shinkai M. Megacystis microcolon intestinal hypoperistalsis syndrome. Semin Pediatr Surg.
2005; 14: 58-63.
3）Shimizu H, Ise K, Yamashita K, et al. A case of Megacystis- microcolon-intestinal hypoperistalsis
syndrome successfully treated with surgery. J. Jpn. Soc. Pediatr. Surg. 2013; 49: 1117-21．(Article inJapanese)4）Kubo M, Sanbonmatsu T. A case of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome(Incompetent type) underwent fetal bladder puncture．Japanese Journal of Pediatric Surgery. 1997; 29:
1351-6. (Article in Japanese)5)

Hirato J, Nakazato Y, Koyama H, et al. Encephalopathy in megacystis-microcolon-intestinal

hypoperistalsis syndrome patients on long-term total parenteral nutrition possibly due to selenium
deficiency. Acta Neuropathol. 2003; 106:234-42.
6) Oohama M, Take H, Yamamot H, et al. Allied disorders of Hirschsprung’s disease – clinical course ofChronic Idiopathic Intestinal Pseudo-obstruction Syndrome (CIIPS); Surgical complications and superlong-term central venous nutrition. Japanese Journal of Pediatric Surgery. 1996; 28:1073-8. (Article inJapanese)85

CQ7-3: What is the prognosis of chronic idiopathic intestinal pseudo-obstruction (CIIP)?
Recommendation: The actual prognosis of CIIP developed in childhood is not poor; however, adequate
nutritional support and intestinal stoma care are required for a long period in many cases. The
functional prognosis of CIIP is poor.
Evidence

A (Strong)

B (Moderate)

C (Weak)○

D (Very weak)Commentary
In Japan, out of 62 cases of children with CIPO, only 4.8% (3 out of 62 cases) died of enteritis or sepsis,and the prognosis of children CIPO seems to be relatively good. However, long-term central venous
nutrition management is required for life support, and their quality of life is accordingly limited.
In a questionnaire survey of 45 cases at 1 to 21 years of age, 38% of the cases depended on parenteralnutrition, 17% on enteral nutrition via tube, and 4% on parenteral nutrition with enteral nutrition via
tube. In other case series and case reports, many patients depended on parenteral nutrition, and theirfunctional prognosis was poorer than that of healthy people.
The physical development was reported to be normal at 21) and 8 years of age.2)
Regarding school and work, situations of CIPO patients to be equivalent to those of healthy people inthree out of four cases3), and another showed that schooling was equivalent in two out of three cases; inone case, however, the patient was in a class for handicapped children.4)

References
1) Tazuki Y, Wasa M, Fukuzawa M. 【Learn allied disorders of Hirschsprung’s disease】A case of MMIHS
under management of TPN supplemented with enteral nutrition via enterostomy. Japanese Journal of
Pediatric Surgery. 2006; 38:715-9. (Article in Japanese)
2) Yahano S, Furuya S, Kadowaki H. A 8-year-old girl with CIIP – clinical course and problems on
long-term TPN. Japanese Journal of Pediatric Surgery. 1983; 15:1129-33. (Article in Japanese)
3）Terui K, Yoshida H. 【Today’s progress in Home parenteral nutrition】（Part-7）Nutritional managementat Home for shortbowel syndrome – Cases with intestinal failure requiring long-term central vein
nutrition. Rinsho Eiyo（JCN selection 8 Home parenteral and enteral nutrition- Today’s progress）. 2013;suppl: 204-8．(Article in Japanese)4）Ootu K, Furuta Y, Onitake M. 【Learn allied disorders of Hirschsprung’s disease】 Experiences of 3
cacses with intractable allied disorders of Hirschsprung’s disease. Japanese Journal of Pediatric Surgery.
2006; 38: 729-36．(Article in Japanese)

86

VII.

Planning after public release

1.Organization after public release
Name of organization

Actions after public release

Guideline steering committee

Guideline development group

SR team

The representative of this guideline steering committee shall belong to
the Department of Pediatric Surgery, Faculty of Medical Sciences,
Kyushu University. This guideline is planned to be revised five years
after public release, and the organization for the revision group will be
re-organized mainly by the Department of Pediatric Surgery, Faculty of
Medical Sciences, Kyushu University.
When the committee recognizes the need to modify the recommendation
statements substantially, it will reconvene the guideline developmentgroup, announce a temporary stop of the usage or revision on the website
after discussion, and conduct a complete revision. The expiration of theguideline will be discussed with the guideline development management
office and the guideline development group.
The group will publicly release this guideline on the homepages of theresearch partner institutions. When revision is required, it will bereported to the steering committee for discussion. Furthermore, when arevision is conducted in five years, the members will answer the steeringcommittee’s call to cooperate for the organization of the revisioncommittee.
This team will be broken up at the completion of this guideline.
However, when this guideline is revised in the future, the team members
will cooperate with the revision group to provide as much advice aspossible based on their experience in the guideline development.

2. Introduction
The detailed version will be published in research reports and distributed tomajor institutions. The practical version will be published as a book so that it
may be utilized in daily clinical practice.
The practical version will be released for free (on the Japanese Society ofPediatric Surgeons homepage, the Japanese Society for Pediatric
Proactive use of wide
Gastroenterology, Hepatology and Nutrition homepage, Minds homepage, thisrangeofinformation
guideline’s management office homepage, Research partner institutions'media
homepage). Furthermore, media outlets, such as newspapers, magazines, andthe Internet, will be used to increase the public recognition.
Promoting and inhibiting (Promoting factors) Increase in public recognition, establishment of a family
factors for the effective use association, establishment of a social security system, and consolidation ofof the clinical practice cases(Inhibiting factors) Conventional medical practices
guideline
Creationversionofsummary

3. Evaluation of effectivenessEvaluation method

Specific policies

Retrospective study

A nationwide survey on the short and long-term outcomes of the cases after the
public release of this guideline is to be conducted, and the outcomes will bereexamined using historical controls.

87

Standardization of treatments based on this guideline and a prospective,
multi-center study to evaluate the effectiveness are to be conducted.

Prospective study

4. Revision
Items
Periodimplementation

Methodimplementation

Organization
implementation

Policyofofof

Revision is expected five years later (2021).

The guideline steering committee will organize a guideline revision group. However,
if no financial support from related medical societies or the Research Project on
Measures for Intractable Diseases of Ministry of Health, Labour and Welfare is
obtained, reexamination is required.
The guideline steering committee of this guideline and the guideline developmentgroup will cooperate to reorganize a guideline revision group.

88