HIRSCHSPRUNG'S DISEASE

NOW AND THE FURTHER ?

Poerwaqdi, Pediatic surgeon
Pediatric Devision, Departement of Surgery, Dr.
Soetomo, Teaching Hospital
SURABAYA

Abstract:

Hirschsprung disease ( HD ) or congenital megacolon is a development

disorder of the enteric nervous system and is characterized by an absence

of ganglion cells in the distal colon resulting in functional obstruction. Since

Ruysch ( 1691 ), Harold Hirschsprung ( 1886 ), until now the pthofisiology and

treatment of HD had not clear. Many theories and advance treatment were

performed, recently, such as minimally invasive procedures, Early diagnosis

have resulted in decreased morbidity and mortality for patients with HD.

Further research and its wider clinical application will many practical and

theoretical queries related to the use of gene or stem cell therapy for HD ?.

Introduction

HD is a developmental disorder of the enteric nervous system and is

characterized by an absence of ganglion cells in the distal colon resulting
in a functional obstruction. Varying lengths of the distal colon are unable
to relax, causing functional colonic obstruction. HD most commonly
involves the rectosigmoid region of the colon but can affect the entire
colon and, rarely the small intestine. The disease usually presents in
infancy, although some patients present with persistent, severe
constipation later in life. Symptoms in infants include falure / delayed to
pass meconium in the first hours of life, bilious vomiting , poor feeding,
poor weight gain, and progressive abdominal distention 9,11,13. Early
diagnosis is important to prevent complications (e.g., enterocolitis,
colonic rupture). Although this condition was described by Ruysch in
1691 and popularized by Harold Hirschsprung in 1886, the
pathophysiology was not clearly . Ovar Swenson in 1949 was described
the first consistent definitive procedure for HD. Since then, other
operations have been described, including the Duhamel and Soave
techniques. More recently, advances in surgical technique, including
minimally invasive procedures, and earlier diagnosis have resulted in
decreased morbidity and mortality for patients with HD. 1,2,6,3,9,17 .

Management HD in Surabaya has evolved significantly over the past 20

years. Surgical treatment of HD initially involved a three-stage sequence
with colostomy , then the pull-through procedure with creation of a
temporary “protecting” colostomy, followed by eventual colostomy
closure. We perform a two-stage procedure ( 1990 – 2000 ) with initial
colostomy and subsequent pull-through only, eliminating the need for a
final colostomy closure. Primary / one stage pull-through ( 2000 –
2004 ), in the newborn and those older infants and children with delay in
diagnosis has been advocated by some for several years. The minimally
invasive techniques ( Laparoscopy, transanal endorectal pull through )
were performed at 2004 until now. The experience, and instruments for
babies has allowed the application of this approach for the management
of HD in selected newborns and older children.

Stem cells have already been effectively used in the treatment of sickle
cell, leukemia, non-Hodgkin's lymphoma, other forms of cancer, life
threatening anemias, and autoimmune diseases.
Stem cells may hold the key to replacing cells lost in many devastating
diseases like Parkinson's disease, Spinal cord injury, multiple sclerosis,
Alzheimer's disease, diabetes, chronic heart disease, end-stage kidney
disease, liver failure and cancer. Lately stem cell use has been tried in
the treatment of burns, infertility, lupus and deafness, and how for HD ?
2,5,14,18.

Incidece & Epidemiology

HD is one of the most common causes of intestinal obstruction in the
neonates. It occurs in about 1 in 5,000 live births. The cause of HD is
multifactorial, and the disease can be familial or develop spontaneously.
It is more common in boys than girls with ratio 4 : 1. Approximately 3
to 5 % of male siblings and 1 % of female siblings of children with short-
segment disease also have the disease. However, the risk is substantially
higher (12.4 to 33 %) in siblings of children with total colonic
involvement. Eight genomes have been associated with HD however,
most cases are not considered familial. Current research is focusing on
the RET proto-oncogene on chromosome 10q11.2. HD associated with
this gene has been linked to multiple endocrine neoplasia, type IIA ( i.e.,
medullary carcinoma of the thyroid and adrenal tumors). Research on
the value of screening for this mutation to determine the risk of multiple
endocrine neoplasia, type IIA, is ongoing . 9,11,13,17,20.                                           
HD also can be associated with neurologic, cardiovascular, urologic, and
gastrointestinal abnormalities. Down syndrome (trisomy 21) is the most
common chromosomal abnormality associated with the disease,
accounting for approximately 10 percent of patients. Other conditions
that have been linked to HD include congenital deafness, hydrocephalus,
diverticulum of the bladder, Meckel's diverticulum, imperforate anus,
ventricular septal defect, renal agenesis, cryptorchidism, Waardenburg's
syndrome (pigment defects associated with deafness), neuroblastomas,
and Ondine's curse (primary alveolar hypoventilation). 3,5,9,11,

Pathophysiology :
Aganglionosis bowel in HD begins from the anus, which is always
involved, and continues proximally for a variable distance. Both the
myenteric (Auerbach) and submucosal (Meissner) plexus are absent,
resulting in reduced bowel peristalsis and function. The precise
mechanism underlying the development of HD is unknown.20,21

Enteric ganglion cells are derived from the neural crest. During normal
development, neuroblasts will be found in the small intestine by the 7th
week of gestation and will reach the colon by the 12th week of gestation .
One possible etiology for HD is a defect in the migration of these neuro-
blasts down their path to the distal intestine. Alternatively, normal
migration may occur with a failure of neuroblasts to survive, proliferate,
or differentiate in the distal aganglionic segment. Abnormal distribution
in affected intestine of components required for neuronal growth and
development, such as fibronectin, laminin, neural cell adhesion molecule
(NCAM), and neurotrophic factors, may be responsible for this theory.
Additionally, the observation that the smooth muscle cells of aganglionic
colon are electrically inactive when undergoing electrophysiologic studies
also points to a myogenic component in the development of Hd . Finally,
abnormalities in the interstitial cells of Cajal, pacemaker cells connecting
enteric nerves and intestinal smooth muscle have also been postulated
as an important contributing factor . 14,15,20,21

Three neuronal plexus innervate the intestine: the submucosal (ie,

Meissner) plexus, the intermuscular (ie, Auerbach) plexus, and the
smaller mucosal plexus. All of these plexus are finely integrated and
involved in all aspects of bowel function, including absorption, secretion,
motility, and blood flow. Normal motility is primarily under the control of
intrinsic neurons. Bowel function is adequate, despite a loss of extrinsic
innervation. These ganglia control both contraction and relaxation of
smooth muscle, with relaxation predominating. Extrinsic control is
mainly through the cholinergic and adrenergic fibers. The cholinergic
fibers cause contraction, and the adrenergic fibers mainly cause
inhibition. In patients with HD, ganglion cells are absent, leading to a
marked increase in extrinsic intestinal innervation.
The innervation of both the cholinergic and adrenergic systems is 2-3
times that of normal innervation. The adrenergic (excitatory) system is
thought to predominate over the cholinergic (inhibitory) system, leading
to an increase in smooth muscle tone. With the loss of the intrinsic
enteric inhibitory nerves, the increased tone is unopposed and leads to
an imbalance of smooth muscle contractility, uncoordinated peristalsis,
and a functional obstruction.11,13,17,16

Presentation :

Symptoms of HD range from neonatal intestinal obstruction to chronic

progressive constipation in older children .

History:

Approximately 10% of patients have a positive family history. This is

more common in patients with longer segment disease. HD should be
considered in any newborn with delayed passage of meconium or in any
child with a history of chronic constipation since birth. Other symptoms
include bowel obstruction with bilious vomiting, abdominal distention,
poor feeding, and failure to thrive.9,11,13,17

Prenatal ultrasound demonstrating bowel obstruction is rare except in

cases of total colonic involvement (Belin, 1995). About 10% of children
may present with diarrhea caused by enterocolitis, which is thought to
be related to stasis and bacterial overgrowth. This may progress to
colonic perforation, causing life-threatening sepsis (Teitelbaum,
1989).5,6,8,11,21,25
 TABLE 1
Symptoms of Hirschsprung's Disease
Infants
Failure to pass meconium in the first 24 hours of life
Bilious vomiting,
Progressive abdominal distention
Physical: Enterocolitis-associated diarrhea
Infrequent, explosive bowel movements; difficult bowel
movements
Physical examination in the
Poor feeding
newborn period is usually not Tight anal sphincter with an empty rectum
Older children
clearly for diagnostic, but it may Absence of soiling or overflow incontinence
Chronic progressive constipation, usually with onset in
reveal a distended abdomen
infancy
and/or spasm of the anus. Failure to thrive
Fecal impaction
A low imperforate anus with a Malnutrition
Progressive abdominal distention
perineal opening may have a
similar presentation to that of a patient with HD. Careful physical
examination will differentiates the two conditions.

In older children, however, a distended abdomen resulting from an

inability to release flatus is not uncommon.9,11,13,17

Differentials diagnosis :

HD can be differentiated from functional constipation if the child is

younger than 12 months is at onset in infancy ( failure to pass
meconium ); or presents with failure to thrive, absence of overflow
incontinence or soiling, fecal impaction and malnutrition. Symptoms
may recur after previously resolving with enemas, laxatives, or feeding
changes.13,17

HD in newborn can be differentiated with :

- Intestinal atresias or stenosis

- Small left colon syndrome
- Meconium blockage syndrome
- Anorectal malformations
- Prematurity
- Intestinal malrotation
- Neuronal intestinal dysplasia
 Intestinal Neuronal Dysplasia is characterised by decrease in intestinal
motility of distal colon. It is found in 0.3 - 40% of suction rectal biopsies
performed and the incidence with HD is 10-20%. It is a distinct
histopatologic entity and usually presents as long standing constipation
after pull-through operation in patients of HD. The diagnosis is usually
established by increased acetylcholine esterase staining and increase in
the ganglion cell number (larger ganglia with more than seven nerve
TABLE 2
Diagnoses Associated with a Newborn's Failure to Pass Meconium
Prevalence (incidence per
Diagnosis total births) Findings
Meconium plug syndrome One per 500 to 1,000 Meconium plugs
Cystic fibrosis-associated One per 2,800 Abdominal distention at birth, cystic
meconium ileus fibrosis
1,2
Hirschsprung's disease One per 5,000 See Table 1
Anorectal malformation One per 4,000 to 8,000 Anal fistula or an absent anus
Small left colon syndrome Rare Transition zone * at the splenic
flexure
Hypoganglionosis Rare Transition zone *
Neuronal intestinal dysplasia Rare Megacolon, abnormal ganglion cells
cells/ganglia). Diagnosis of Intestinal Neuroal Dysplasia is not made
until the patient develops defecation problem after a definitive pull-
through procedure. The medical treatment is usually the first line of
therapy i.e, enemas and cathartics. If there is no response to
conservative treatment for six months, internal sphincter myectomy is
the procedure of choice. 11,14,21,23,25

WORKUP

Lab Studies:

Chemistry panel: For most patients, electrolyte and renal panel

findings are within reference ranges. Children presenting with
diarrhea may have findings consistent with dehydration. Test results
may aid in directing fluid and electrolyte management. CBC count:
 This test is obtained to ensure that the preoperative hematocrit and
platelet count are suitable for surgery. In most cases, values are
within reference ranges. Coagulation studies: These studies are
obtained to ensure that clotting disorders are corrected before
surgery. Again, values are expected to be within reference ranges.

Imaging Studies:

Plain abdominal radiographs may show distended bowel loops with a

paucity of air in the rectum.

Barium enema

o Avoid washing out the distal colon with enemas before

obtaining the contrast enema because this may distort a low
transition zone.

o The catheter is placed just inside the anus, without inflation

of the balloon, to avoid distortion of a low transition zone
and the risk of perforation.

o Radiographs are taken immediately after hand injection of

contrast and again 24 hours later.

o A narrowed distal colon with proximal dilation is the classic

finding of Hirschsprung disease after a barium enema.
However, findings in neonates (ie, babies aged <1 mo) are
difficult to interpret and will fail to demonstrate this
transition zone approximately 25% of the time (Smith, 1991).

o Another radiographic finding suggestive of Hirschsprung

disease is the retention of contrast for longer than 24 hours
after the barium enema has been performed.
Other Tests:

Anorectal manometry

o Anorectal manometry detects the relaxation reflex of the

internal sphincter after distension of the rectal lumen. This
normal inhibitory reflex is thought to be absent in patients
with HD (Pensabene, 2003).

o Swenson initially used this test. In the 1960s, it was refined

but has recently fallen into disfavor because of its many
limitations. A normal physiological state is required, and
sedation is also usually necessary. Although some authors
find this test quite useful, false-positive results have been
reported in up to 62% of cases, and false-negative results
have been reported in up to 24% of cases.

o Because of these limitations and questionable reliability,

anorectal manometry is not commonly used in the United
States.

 Because cardiac malformation (2-5%) and trisomy 21 (5-15%) are

associated with congenital aganglionosis, cardiac evaluation and
genetic testing may be warranted. 9,11,13,17,19,24,25

Procedures:

Rectal biopsy

o The definitive diagnosis of Hirschsprung disease is confirmed

by rectal biopsy, ie, findings that indicate an absence of
ganglion cells.
 o The definitive method for obtaining tissue for pathologic
examination is by a full-thickness rectal biopsy.

o The specimen must be obtained at least 1.5 cm above the

dentate line because aganglionosis may normally be present
below this level.

o Disadvantages include the potential for bleeding and

scarring and the usual need for general anesthesia during
full-thickness biopsy procedures.

 Simple suction rectal biopsy

o More recently, simple suction rectal biopsy has been used to

obtain tissue for histologic examination.

o Rectal mucosa and submucosa are sucked into the suction

device, and a self-contained cylindrical knife cuts off the
tissue.

o The distinct advantage of the suction biopsy is that it can be

easily performed at the bedside.

o However, pathologically diagnosing HD from samples

obtained by suction biopsies is considerably more difficult
than pathologically diagnosing HD disease from samples
obtained by a full-thickness biopsy.

o Ease of diagnosis has been improved with the use of

acetylcholinesterase staining, which intensely stains the
hypertrophied nerve fibers throughout the lamina propria
and muscularis propria. 14,20,24,
Histologic Findings:

Both the myenteric (Auerbach) and submucosal (Meissner) plexus are

absent from the muscular layer of the bowel wall. Hypertrophied nerve
trunks enhanced with acetylcholinesterase stain are also observed. 14,20

Mortality/Morbidity:

 Approximately 20% of infants will have one or more associated

abnormality involving the neurological, cardiovascular, urological,
or gastrointestinal system (Ryan, 1992). HD has been found to be
associated with the following : Down syndrome, Neurocristopathy
syndromes, Waardenburg-Shah syndrome, Yemenite deaf-blind
syndrome, Piebaldism, Goldberg-Shprintzen syndrome, Multiple
endocrine neoplasia type II, Congenital central hypoventilation
syndrome.

 Untreated aganglionic megacolon in infancy may result in a

mortality rate of as much as 80%. Operative mortality rates for any
of the interventional procedures are very low. Even in cases of
treated HD, the mortality rate may be as high as 30% as a result of
enterocolitis.

Possible complications of surgery include anastomotic leak (5%),

anastomotic stricture (5-10%), intestinal obstruction (5%), pelvic abscess
(5%), and wound infection (10%). long-term complications include
ongoing obstructive symptoms, incontinence, and enterocolitis. although
many patients will encounter one or more of these problems
postoperatively, long-term follow-up studies have shown that most
children experience significant improvement and will do relatively well
(yanchar, 1999). patients with an associated syndrome and those with
long-segment disease have been found to have poorer outcomes (de la
torre, 2000; caniano, 1990; hackam, 2003).12,13,17,19

COMPLICATIONS :
Most patients treated for HD do not have complications. However, up to
10 percent may have constipation, and less than 1 percent may have
fecal incontinence. Enterocolitis and colonic rupture are the most serious
complications associated with the disease and are the most common
causes of HD related mortality. Enterocolitis occurs in 17 to 50 percent
of infants with HD and most commonly is caused by intestinal
obstruction and residual aganglionic bowel.5,6,11,21 Infants should continue
to be monitored closely for enterocolitis many years after corrective
surgery because the infection has been reported to occur up to 10 years
later. However, most postoperative enterocolitis cases occur within the
first two years of ileoanal pull-through anastomosis. 6,13,15,23

Early symptoms of enterocolitis ( Table 3 ) in patients with HD include

abdominal distention; foul-smelling, watery diarrhea; lethargy; and poor
feeding. Treatment with rectal irrigation several times per day and
antibiotics usually is effective.

Oral metronidazole (Flagyl) can be TABLE 3

used with rectal irrigation in Symptoms of Enterocolitis Associated with

Hirschsprung's Disease
patients with milder disease.6
More serious disease should be Early Late
Abdominal distention Emesis
treated intravenously with broad-
Foul-smelling, watery Fever
spectrum antibiotics and rectal stool
Lethargy Hematochezia
irrigation. Rectal irrigation is
Poor feeding Shock or death
performed by pushing normal
saline into the colon through a rubber catheter; this allows for discharge
of gas and stool. The saline (10 to 15 mL per kg) is pushed through the
tube, and it is allowed to empty at 10- to 15-mL increments as the
catheter is advanced gently. 12,13, 17
TREATMENT :

Medical Care: The general goals of medical care are 3-fold:

1. To treat the complications of unrecognized or untreated HD.
2. To institute temporary measures until definitive reconstructive surgery
can take place.
3. To manage bowel function after reconstructive surgery.

Management of complications of recognized aganglionosis is directed

toward reestablishing normal fluid and electrolyte balance, preventing
bowel overdistension (with possible perforation), and managing
complications such as sepsis. Thus, intravenous hydration,
nasogastric decompression, and, as indicated, administration of
intravenous antibiotics remain the cornerstones of initial medical
management.
Colonic lavage, consisting of mechanical irrigation with a large-bore
rectal tube and large volumes of irrigant, may be required.
Balanced salt solutions may help prevent electrolyte imbalances.
Nasogastric decompression, intravenous fluids, antibiotics, and
colonic lavage may also need to be used in postoperative patients who
develop enterocolitis as a complication. Sodium cromoglycate, a mast
cell stabilizer, has been reported to be of benefit in these patients as
well (Rintala, 2001).
Routine colonic irrigation and prophylactic antibiotic therapy have
been proposed as a means of decreasing the risk of enterocolitis
(Marty, 1995; Elhalaby, 1995).

Injecting the nonrelaxing internal sphincter mechanism with

botulinum toxin (BOTOX®) has recently been shown to induce more
 normal patterns of bowel movements in postoperative patients with
enterocolitis.

Surgical Care:

Surgical management of HD begins with the initial diagnosis, which often

requires a full-thickness rectal biopsy. Traditionally, treatment also
includes creating a diverting colostomy at the time of diagnosis, and,
once the child grows and weighs more than 10 kg, the definitive repair is
performed. This standard of treatment was developed in the 1950s after
reports of relatively high leak and stricture rates with the single stage
procedure were initially described by Swenson. However, with the advent
of safer anesthesia and more advanced hemodynamic monitoring, a
primary pull-through procedure without a diverting colostomy is
increasingly being performed. Contraindications to a one-stage procedure
include massively dilated proximal bowel, severe enterocolitis,
perforation, malnutrition, and inability to accurately determine the
transition zone by frozen section. 9,13,15,17,23,24,25,

For neonates who are first treated with a diverting colostomy, the
transition zone is identified and the colostomy is placed proximal to this
area. The presence of ganglion cells at the colostomy site must be
unequivocally confirmed by a frozen-section biopsy. Either a loop or end
stoma is appropriate, usually based on the surgeon's preference.

A number of definitive procedures have been used, all of which have

demonstrated excellent results in experienced hands. The 3 most
commonly performed repairs are the Swenson, Duhamel, and Soave
procedures. Regardless of the pull-through procedure chosen, cleaning
the colon prior to definitive repair is necessary.9,13,15

 Swenson procedure, 9
 o The Swenson procedure was the original pull-through
procedure used to treat Hirschsprung disease.
o The aganglionic segment is resected down to the sigmoid
colon and the remaining rectum, and an oblique
anastomosis is performed between the normal colon and the
low rectum.

 Duhamel procedure . 9,11,12,13

o The Duhamel procedure was first described in 1956 as a

modification to the Swenson procedure.
o Key points are that a retrorectal approach is used and a
significant portion of aganglionic rectum is retained.
o The aganglionic bowel is resected down to the rectum, and
the rectum is oversewn. The proximal bowel is then brought
through the retrorectal space (between the rectum and
sacrum), and an end-to-side anastomosis is performed on
the remaining rectum.

 Soave (endorectal) procedure, 9,11,13

o The Soave procedure was introduced in the 1960s and

consists of removing the mucosa and submucosa of the
rectum and pulling the ganglionic bowel through the
aganglionic muscular cuff of the rectum.
o The original operation did not include a formal anastomosis,
relying on scar tissue formation between the pull-through
segment and the surrounding aganglionic bowel. The
procedure has since been modified by Boley to include a
primary anastomosis at the anus.

 Anorectal myomectomy. 9,11,13

 o For children (and occasionally adults) with ultrashort-
segment Hirschsprung disease, removing a strip of posterior
midline rectal wall is an alternative surgical option.
o The procedure removes a 1-cm wide strip of extramucosal
rectal wall beginning immediately proximal to the dentate
line and extending to the normal ganglionic rectum
proximally.
o The mucosa and submucosa are preserved and closed.

 Procedures for long-segment Hirschsprung disease. 9,16,19

o Patients with total colonic involvement require modified

procedures to bypass the aganglionic colon yet preserve the
absorptive surface area and allow for proper growth and
nutritional support.
o Most procedures include a side-to-side anastomosis of the
ganglionic/propulsive small bowel to a short segment of the
aganglionic/absorptive colon.
o Whether a short right colonic patch or a small bowel-to-
rectal wall Duhamel anastomosis is created is perhaps less
important than maintaining a short patch length (<10 cm).
o Long-segment anastomoses, such as the Martin procedure,
are no longer advocated.

 A laparoscopic approach to the surgical treatment of Hirschsprung

disease was first described in 1999 by Georgeson. The transition
zone is first identified laparoscopically, followed by mobilization of
the rectum below the peritoneal reflection. A transanal mucosal
dissection is performed, followed by prolapsing of the rectum
through the anus and anastomosis. Functional outcomes appear
to be equivalent to open techniques based on short-term results
(Georgeson, 1999; de Lagausie, 1999; Curran, 1996).
  Transanal pull-through in which no intra-abdominal dissection is
performed has also been described (Langer, 1999; De La Torre-
Mondregan, 1998). The entire procedure is performed from below
in a manner similar to perineal rectosigmoidectomy. The transition
zone is identified and anastomosis is performed. Similar to the
laparoscopic approach, outcomes have been similar to open single
stage approaches with the benefits of minimal analgesia and
shortened hospital stays (Langer, 2000; De La Torre, 2000; Langer,
2003).

Consultations: -- -
Pediatric s
Pediatric gastroenterologists
Geneticists (if trisomy 21 is present)

Diet:
- The patient should have nothing by mouth before the operation.
-Institute tube feeding or formula/breast milk once bowel function .
- High-fiber diets and diets containing fresh fruits and vegetables may
optimize postoperative bowel function in certain patients.

DISCUSSIONS :

The exact cause of HD is unknown. The recent sophisticated molecular

and embryologic studies have established that the aganglionosis results
either from a failure of migration of neural crest cells to the correct site,
or failure to mature, or degeneration of neural cells, or failure of
differentiation in the altered micro-environment The recent studies have
also shown that the mutations in the endothelin B receptor gene
(EDNRB), endothelin 3 (EDN 3), RET protooncogene and glial cell linked
derived neurotrophic factor (GDNF) genes are responsible for occurrence
of congenital aganglionosis. 5,14,18,24

Treatment of HD ideally based on its cause i.e : genetic, stemsel or

medication not only surgery. Technics of operation make good strides,
until now many technics were introduced with its adavantage and
disadvantages.14,18

This question from HD parents : “ Our baby is suffering from long

segment Hirschsprung's disease. Currently, operated and waiting for
the second surgery. With advances in stem cell technology, is it
possible to treat this kind of a disease to generate new nerve cells ? “ (
This story has been adapted from a news release issued by University Of
Michigan Health System ). 18,27

Sarah Almond, David Edgar, Simon Kenny : “ Stem cell therapy in

Hirschsprung’s disease “ ; We have shown that the colonic ENS in mice
originates from a small number of neural crest-derived cells, the ENS
stem cells (ENSCs) that are characterized by asymmetric cell division to
produce another self-renewing stem cell and a daughter cell that has the
proliferative capacity to form a wide variety of neural cell phenotypes.
We have been able to isolate embryonic mouse ENSCs that can be grown
in tissue culture as spherical clusters of cells called neurospheres .
Significantly, when transplanted back into bowel, the cells derived from
neurospheres in vitro can generate new nerves that regulate gut motility.
Currently, we are attempting to isolate and culture ENSCs from human
newborn infants to see if they too have the ability to form neurons. This
is necessary for us to assess if such cells may be transplanted into HD
patients to provide them with a source of lacking nerve cells .

Gupta Devendra K :Department of Pediatric Surgery, All India Institute of

Medical Sciences, New Delhi, India : [email protected],
[email protected] : “ Stem cell therapy - Hope and scope in
pediatric surgery “ ; A stem cell is an undifferentiated cell in the body
with undetermined function capable of forming various tissues under
definite signals received from the body Current challenges with the use of
stem cells in clinical practice include the provisions to direct the
differentiation of embryonic stem cells into specialized cell populations,
and also devise ways to guard their development or proliferation once
placed in vivo. Only further research and its clinical application will solve
the many unanswered queries.

Pathologe. 2007 Mar;28(2):125-30. : Stem cells of the enteric nervous system:

causal therapy for Hirschsprung's disease? ;Stem cells are self-renewing cells with the
potential to generate different cell types. The human organism depends on stem cells for
organ development during embryogenesis. Upon completion of organogenesis, stem cells
are also necessary for organ maintenance ("homeostasis") and for tissue regeneration. In
view of the manifold functions of stem cells, it is not surprising that their malfunction
results in diseases like Hirschsprung's disease, a disorder of the enteric nervous system of
complex etiology. Potential stem cell application for the regeneration of diseased organs,
such as the enteric nervous system in Hirschsprung's disease, is currently a focus of
intense research.
Heanue TA, Pachnis V. ( Division of Molecular Neurobiology, MRC National
Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK ); Nat
Rev Neurosci. 2007 Jun;8(6):466-79. Erratum in: Nat Rev Neurosci. 2007
Jul;8(7):568. : “ Enteric nervous system development and Hirschsprung's disease:
advances in genetic and stem cell studies “.

The enteric nervous system (ENS) has been explored by developmental

neurobiologists and medical researchers for decades. Whereas
developmental biologists have been unravelling the molecular
mechanisms underlying the migration, proliferation and differentiation of
the neural crest derivatives that give rise to the ENS, human geneticists
have been uncovering the genetic basis for diseases of the ENS, notably
Hirschsprung's disease. Here we discuss the exciting recent advances,
including novel transgenic and genetic tools, a broadening range of
model organisms, and the pursuit of ENS stem cells as a therapeutic
tool, that are bringing these fields closer together.

SURGERY :
The surgery for HD is a staged procedure. In 1st stage, the obstruction is
relieved by establishing a loop enterostomy just above the transition zone
to allow dilatation and inflammation to resolve and no attempt at
resection is made. In 2nd stage, the definitive surgery is performed when
child is 10 months old and 10 lbs. in weight. The basic principle of
definitive surgery is the removal of poorly functioning aganglionic bowel
and an anastomosis of a normally innervated portion of the intestine to
the distal rectum. The various definitive procedures are Swenson’s -
proctocolectomy, the Duhamel procedure – posterior / retrorectal pull-
through with side-to side anastomosis to aganglionic rectum and
endorectal pull through or Soave procedure ( pull of ganglionated bowel
through the sleeve of rectum ). There are no important differences with
regard to outcome and long-term function in patients treated with these
surgical procedures. However, specific problems have been described for
each of these procedures.6,8,12,16,19
The Swenson operation is most physiological but is a difficult operation
and the extensive pelvic dissection leads to trauma to the pelvic
nerves.1,3,17

In 1960, Duhamel published a modification of the original operation. He

resected a portion of the distal defective segment as in the original
operation and made a side-to-side anastomosis between the proximal
normal colon and defective rectum.4,6
In 1963, Soave published another modification. It consisted of making a
circumferential cut through the muscular coat of the colon at the pelvic
peritoneal reflection. Working in an intramural plane, the mucosa is
separated from the muscular coat down to the anal canal. The freed
mucosa is excised and the proximal normal colon is pulled through this
retained viable spastic aganglionic muscular sleeve. A telescoping type of
anastomosis is made that adds an extra layer of colon wall at the
anastomosis. Marks reported cutting the sleeve posteriorly, a practice
now widely used.20,23

Boley further modified the method by making an extrapelvic

anastomosis between the anal canal mucosa and the mucosa of the
normal colon.12,16

During the past decade, there has been a trend to operate on infants in
the first weeks of life without a preliminary colostomy. Carccassonne was
a leader in introducing this change, and he reported results on 98 infants
treated in this manner in whom all the defective tissue was removed (M.
Carcassonne, personal communication). All the patients were under 3
months of age and there were no deaths. One anastomotic leak closed
promptly when a colostomy was instituted (M. Carcassonne, personal
communication). This strategy may prove to be an important change
because it merges the period of incontinence with the normal period of
training.

Contemporary laparoscopic surgery may also fit well with resecting

patients with Hirschsprung’s disease, especially recognizing that the
excised tissue can be removed through the anal canal.

Wulkan and Georgeson have reported an experience with this technique;

however, they leave the defective aganglionic muscular sleeve in place
and follow with a prolonged program of daily rectal dilatations.
Curran and Raffensperger, along with Arany et al, have demonstrated
that it is easy to remove all the defective aganglionic tissue with
laparoscopic technique with no need for daily rectal dilatations
postoperatively. Still another new technique achieves the entire resection,
leveling of ganglion cells, and definitive pull-through via the anal canal
without an abdominal incision. Small series have been reported with
reasonable complication rates.

About 4% to 5% of patients with congenital megacolon have no ganglion

cells in the entire colon. These smaller reported series have mortality
rates after surgical treatment ranging from 13% to 23.5%.
Martin suggested a technique that saves a portion of the defective colon,
uniting it with the terminal ileum with a side-to-side anastomosis, thus
providing additional surface for fluid absorption. Criticisms of this
modified Duhamel technique have been reported because of poor
emptying of the retained aganglionic colon. Better results in treating this
entity have been reported by Sherman et al. Nineteen patients were
treated with excision of the entire aganglionic colon with end-to-end
anastomosis of the terminal ileum to the anal canal with no deaths.
These patients were started on oral feedings shortly after operation;
however, they went through a difficult postoperative period with frequent
stools which at times produced perineal excoriation. With perseverance
they all gained stool control. The first patient treated in this manner
graduated from college, married, had several children and was doing well
until 40 years after his operation when he became anemic with blood in
his stool. At sigmoidoscopy the ileal mucosa was reddened. An ileostomy
was performed and 6 months later he was no longer anemic, and his
stool was negative for blood. A second patient went through the same
experience. Some surgeons have modified this procedure by constructing
a pouch to serve as a stool reservoir. A rare case of a colon transplant has
been reported with a short follow-up.
Morikawa Y et al from Japan found the extra anal mucosectomy in
conjunction with a laparoscopic assisted prolapsing technique, a safe
and reliable modality in the treatment of HD.
A transanal mucosectomy, colectomy and pull through (without
laparotomy and laparoscopy) is also recommended as an effective and
promising treatment modality in recent years[. The Albanese et al termed
the perineal one-stage operative pull-through as POOP procedure and
found it as a quick and easy technique to treat rectosigmoid HD. On
comparing the staged pull-through with primary pull-through it is found
that staged pull-through is not any safer than primary pull-through for
rectosigmoid HD and there is also no difference in complication rates.
Hence, the current trend is towards the primary pull-through at an early
age with or without laparoscopic assistance. Pull-through operations
have some problems and they may require redo operations.

The causes of redo-operations are severe anastomotic stricture,

rectourethral fistula, anastomotic disruption, enterocolitis and chronic
constipation. The Duhamel operation is the best option for a secondary
procedure [. The obstruction and/or enterocolitis after Hirschprung’s
surgery depends on the type of operation performed, the residual internal
sphincter function, the presence of stricture at anastomotic site, the
incomplete resection of aganglionic bowel and presence of neuronal
intestinal dysplasia in upstream bowel which is present in approximately
20% cases. In a recent publication, the HD associated intestinal
neuronal dysplasia was found in 40% of cases.

Cram RW : “Hirschprung's disease: long-term follow-up of 65 cases ( Can J

Surg 1982 Jul;25(4):435-7 ) : Overall mortality was 25% and related to
two factors: (a) delay in diagnosis and surgical treatment with a high
incidence of enterocolitis in the earlier years of the series; (b) a mortality
of 83% in patients with small bowel aganglionosis. Thirty-five resections
were done for colonic aganglionosis; there was one death that occurred
20 years ago, indicating that surgery is safe in this disease, delay in
treatment is not ocured. Of six patients with small bowel aganglionosis,
only three had resection and only one of these survived. The two patients
who died had very high small bowel aganglionosis, probably incompatible
with survival. The Rehbein type of procedure proved useful in high
colonic aganglionosis where, by necessity, anastomosis was done at up
to 7 cm above the white line of the pelvis, with excellent end results. All
have some degree of incontinence.6
Foster P, Cowan G, Wrenn EL Jr. ( Department of General Surgery, Rush-
Presbyterian-St Luke's Medical Center, Chicago, IL 60612 ) : “Twenty-five
years' experience with Hirschsprung's disease ) ; Sixty-three patients
with biopsy-proven HD were diagnosed at LeBonheur Children's Medical
Center, Memphis, TN between 1955 and 1980. Fifty-eight of these
patients had pull-through procedures performed by three similarly
trained pediatric surgeons. The follow-up was 100 percent, averaging 8
years from initial diagnosis. Demographics, surgical procedures
performed, and complications are reviewed. Significant findings are (1)
anastomotic strictures occurred most frequently when the level of
aganglionosis was at the sigmoid colon; (2) postoperative encopresis was
most likely when the endorectal pull-through procedures were performed
before the age of 10 months; and (3) with selective use of colostomies or
enterostomies performed prior to the pull-through procedure, the
incidence of enterocolitis was low, with 0% mortality. On the basis of
these findings, we recommend that, when the most proximal level of
aganglionosis is the sigmoid colon, it is important to critically inspect the
angulation of mesenteric blood vessels and viability of the splenic flexure
pull-through colon segment to prevent ischemia and therefore
anastomotic strictures. The endorectal pull-through procedure should be
delayed until after 10 months of age. Infants with Hirschsprung's disease
should have a colostomy or enterostomy prior to a pull-through
procedure. Patients diagnosed at 10 months of age or more, who have
not had earlier bouts of enterocolitis, are not low percentile weight, and
are without signs of severe obstruction, are candidates for pull-through
without a prior fecal diversion procedure.8
Rescorla FJ, Morrison AM, Engles D, West KW, Grosfeld J ( Department of
Surgery, Indiana University School of Medicine, Indianapolis) ;
“Hirschsprung's disease, Evaluation of mortality and long-term function
in 260 cases “ ; This report describes 260 patients treated for HD. There
were 213 boys (82%) and 47 girls (18%). Age at diagnosis was younger
than 30 days in 106 patients (41%), 1 month to 1 year in 90 patients
(35%), and older than 1 year in 64 patients (25%). Diagnosis was
achieved with barium enema and rectal biopsy. Aganglionosis involved
the rectum or rectosigmoid in 174 patients (67%), the left colon in 38
patients (15%), and the proximal colon in 23 patients (9%); 25 patients
(9%) had total colonic aganglionosis. Enterocolitis occurred in 47 cases
(18%). Following an initial colostomy or ileostomy, a definitive pull-
through procedure was performed in 247 patients (95%) (modified
Duhamel in 185, Soave in 25, Swenson procedure in 15, and
anomyectomy/sphincterotomy in 22); the overall survival rate was 93.8%
(244 of 260 patients). An increased mortality was associated with Down
syndrome, total colonic aganglionosis, and enterocolitis. Long-term
follow-up (mean, 6 years 10 months) was available in 103 patients who
underwent a Duhamel procedure. Sixty-seven (65%) had normal bowel
function, 28 (27%) occasionally used enemas or stool softeners, and eight
(8%) had severe constipation or soiling.19

Marty TL, Seo T, Matlak ME, Sullivan JJ, Black RE, Johnson
(DG.University of Utah) “ Gastrointestinal function after surgical
correction of Hirschsprung's disease: long-term follow-up in 135 patients
“ ; This study is a retrospective review of all children treated for
Hirschsprung's disease over the past 22 years at a single pediatric
institution. During this time 177 patients had definitive surgical
reconstruction. Five children died of causes unrelated to HD, and five
children died from enterocolitis after an uneventful postoperative course.
Clinical follow-up information was obtained from 135 (78%). Definitive
surgical procedures included endorectal pull-through / Soave ( 21% );
modified Duhamel ( 67% ); extended side-to-side ileocolic anastomosis
( 8% ); rectal myomectomy ( 4% ). Severe fecal soiling was reported in
7.1% patients after an endorectal pull-through, and in 12.1% patients
after the modified Duhamel. The difference in incidence of soiling after
these two procedures is not statistically significant. However, 40% (4/10)
of the patients after the long side-to-side anastomosis for total colonic
aganglionosis report severe problems with fecal soiling (P = .03).
Surgical reconstruction for Hirschsprung's disease provides near-normal
gastrointestinal function for the majority of children, but long-term follow-
up shows significant residual problems with soiling in 12.6% of the
patients. This is consistent with reported experience worldwide. 16

So HB, Becker JM, Schwartz DL, Kutin ND ( Long Island Jewish Medical
Center, Schneider Children's Hospital, New Hyde Park, NY, USA ) :
“ Eighteen years experience with neonatal Hirschsprung's disease treated
by endorectal pull-through without colostomy “ ; In the past 18 years,
the authors have treated 84 patients with HD, of these, 43 patients were
under 1 month of age and underwent endorectal pull-through without
colostomy. Some have undergone follow-up for as long as 18 years.
Thirty-four of these 43 (79%) newborn patients were available for follow-
up. Twenty-two were totally continent. The remaining 12 have normal
sphincter tone. Of the 41 patients above 1 month of age, 34 (83%) were
available for follow-up. Some have undergone follow-up for as long as 18
years. CONCLUSION: Twenty-two of this latter group (79%) have normal
bowel control.23
Bai Y, Chen H, Hao J, Huang Y, Wang W. ( Department of Pediatric
Surgery, The Second Clinical College, China Medical University,
Shenyang, China ): “Long-term outcome and quality of life after the
Swenson procedure for Hirschsprung's disease “ ; Forty-five patients who
underwent the Swenson procedure for HD underwent follow-up for 8 to
16 years. Long-term outcome and quality of life were assessed by
interviews and questionnaires including scoring systems. Forty-four
healthy children with similar age, sex, and education level distributions
used as controls RESULTS: In 45 patients, 23 (51.1%) had bowel
dysfunction. Seventeen patients (37.8%) suffered from fecal soiling.
CONCLUSIONS: Although most patients had good or fair quality of life
after surgical correction for HD, the long-term outcome and quality of life
are not as good as surgeons expected. The bowel function and quality of
life of the patients were poorer than those of healthy children. Fecal soiling
is very common and affects patients' quality of life. Long-term regular
follow-up is indispensable. Close attention should be paid to minimizing
bowel dysfunction for patients with HD postoperatively to improve their
quality of life.23. Poerwadi, (Devision of Pediatric surgery / Departement
of Surgery -Dr. Soetomo Teaching Hospital – Surabaya ) “ The
management of HD in Surabaya has evolved significantly over the past
20 years. Surgical treatment of HD initially involved a three-stage
sequence with colostomy , then the pull-through procedure with creation
of a temporary “protecting” colostomy, followed by eventual colostomy
closure.We perform a two-stage procedure ( 1990 – 2000 ) with initial
colostomy and subsequent pull-through only, eliminating the need for a
final colostomy closure. Primary pull-through ( 2000 – 2004 ), in the
newborn and those older infants and children with delay in diagnosis
has been advocated by some for several years. The minimally invasive
techniques ( Laparoscopy, transanal endorectal pull through ) were
performed at 2004 until now. The experience, and instruments for babies
has allowed the application of this approach for the management of HD
in selected newborns and older children.

CONCLUSIONS:

The pthofisiology and treatment of HD until now not clearly. The

management of HD has evolved significantly, many surgical procedures
was performed , with its advantages and disadvantages. Many theories
and treatment was performed, recently advanced in surgical technics ,
including minimally invasive procedures, and earlier diagnosis have
resulted in decreased morbidity and mortality for patients with HD.
Further research and its wider clinical application will many practical

and theoretical queries related to the use of gene or stem cell therapy.

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Stem cell therapy in Hirschsprung’s disease, 03 August 2007

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