History case

You - a pediatrician was called to a 3 months child who complains flaccidity, lack of appetite, frequent regurgitations, and lack of stool for 3 days. Anamnesis data there were no unassisted stools since birth; the defecation is possible only with enemas and is very difficult lately. The abdomen is distended.

The diagnosis of was suspected.

Rectal biopsy and barium enema were performed and

Rectal biopsy

H&E stain: normal structure presence of ganglion cells (circles) in the myenteric plexus (normal ileum)

H&E stain of the rectal biopsy of this pacient showing a lack of ganglion cells in the submucosa and large nerves (arrow).

Contrast enema

The aganglionic rectum (white arrows) in both studies is small and contracted. The proximal ganglionic colon (black arrows) is dilated. The transitional zone is pointed with red arrow.

Diagnosis???

Constipation, Hypothyroidism, Hirschsprung disease (colonic agangliosis), Ileus, Intestinal motility disorder, Irritable bowel syndrome.

N. Testemitanu State University of Medicine and Pharmacy Department of Pediatric Surgery, Orthopedics and Anesthesiology

Hirschsprung disease

Jalba Alexandru, MD, PhD, associate professor

Chisinau 2013

Definition o Hirschsprung disease 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.

Autonomic nervous system

Historical background

Although this condition was described by Ruysch in 1691 and popularized by Hirschsprung in 1886, the pathophysiology was not clearly determined until the middle of the 20th century, when Whitehouse and Kernohan described the aganglionosis of the distal intestine as the cause of obstruction in their series of patients. In 1949, Swenson described the first consistent definitive procedure for Hirschsprung disease, rectosigmoidectomy with coloanal anastomosis. 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 Hirschsprung disease. Most cases of Hirschsprung disease are now diagnosed in the newborn period. Hirschsprung disease should be considered in any newborn who fails to pass meconium within 24-48 hours after birth. Although contrast enema is useful in establishing the diagnosis, full-thickness rectal biopsy remains the criterion standard. Once the diagnosis is confirmed, the basic treatment is to remove the poorly functioning aganglionic bowel and to create an anastomosis to the distal rectum with the healthy innervated bowel (with or without an initial diversion).

Etiology

Cellular and molecular abnormalities in the development of the enteric nervous system, along with incomplete migration of the neural crest cells, are a major part of the cause of HD. Neural crest-derived neuroblasts appear in the developing esophagus at about 5 weeks gestation in the human fetus. These cells then migrate in both a cranial and caudal direction into the rest of the developing gut between 5 and 12 weeks gestation. The Hirschsprung phenotype is variable owing to a wide range of possible abnormalities during the development of the enteric nervous system and the different times at which arrest occurs in the migration of the neural crest-derived cells. The earlier the arrest in neural crest migration, the longer the segment of aganglionosis. Many other factors, such as an altered extracellular matrix, abnormalities in neurotrophic factors, and neural cell adhesion molecules have also been suggested as contributing to the development of HD

Genetic factors

HD often occurs as an isolated phenotype. However, there are strong associations that support a genetic etiology for the disease. Siblings of children with HD have an increased risk of being born with HD. There is an unbalanced gender ratio of approximately 4:1 favoring males over females. HD is also associated with known chromosomal anomalies. Genetic studies have documented at least 10 mutations in different genes associated with its development. The more common genetic mutations that have been identified include the RET gene (7%-35% of sporadic cases), the EDNRB gene (7%), and the END3 gene (<5%). More than 20 mutations have been described in the RET proto-oncogene. Some polymorphisms in this gene are associated with particular HD phenotypes.

Genetic factors

HD has been associated with other genetic abnormalities, such as:

trisomy 21, cardiac septal defects, congenital central hypoventilation syndrome, multiple endocrine neoplasia type 2, neurofibromatosis, Waardenburgs syndrome, and anorectal malformations.

Trisomy 21 is reported in approximately 7% of children with HD. HD has a complex inheritance with penetrance being highly variable. Studies have reported the risk of HD in the siblings of the proband to be 4%.

Epidemiology

The incidence of HD is approximately 1 in 5000 live births. Asian children seem to have the highest incidence at almost 3 per 5000 live births. However, HD is seen in almost all racial groups. It is possible that differences in the recognition of HD occur because of differences in diagnostic capabilities and reporting mechanisms. Although the male-to-female ratio of HD is approximately 4:1, it is 2:1 in longer-segment disease. In medically sophisticated cultures, the diagnosis of HD is often made in the first few weeks or months of life. Delayed passage of meconium in the newborn, constipation with intermittent diarrhea, a distended abdomen with bilious vomiting, and feeding intolerance with poor weight gain or even weight loss are frequent clinical signs of HD

Pathophysiology

The primary clinical feature of HD is obstruction caused by a lack of propagation of the peristaltic wave. This lack of propagation is associated with the absence of ganglion cells in the myenteric and submucosal plexus. The cause of the spasm in the aganglionic bowel is unclear. Cholinergic hyperenervation, inadequate distribution of nitric oxide synthetase, and abnormalities of the interstitial cells of Cajal have all been reported to be associated with HD. A comprehensive understanding of how these factors work to cause the disease has not been achieved.

Pathophysiology

The majority (75%) of patients with HD have ganglion cells down to the level of the rectosigmoid colon (Fig. 1A). Long-segment HD, which describes aganglionosis of the descending colon, splenic flexure, or transverse colon, occurs in approximately 15% of patients. Also, even longer segment cases have been described, including total colon aganglionosis, which occurs in 5% to 7% of patients (see Fig. 1B).

Fig.1. A, Classic case of rectosigmoid Hirschsprungs disease in a 2-year-old child. Note the contracted rectum (solid arrow) and the dilated proximal rectum and sigmoid colon. The transition zone is marked with the dotted arrow. B, A very small, contracted right colon, cecum, and terminal ileum (solid arrow) in a neonate with total colon aganglionosis. The normal, dilated ileum is noted proximal to the transition zone (dotted arrow).

Pathophysiology

Most neonates pass a meconium stool in the first 48 hours of life. However, the majority of children with HD fail to pass meconium in the first 48 hours of life. The onset of explosive, foul-smelling stools associated with fever and abdominal distention heralds the onset of HD enterocolitis. If unrecognized, HD-associated enterocolitis is a potentially fatal complication. In patients with a rectosigmoid colon transition zone, prompt saline irrigation of the sigmoid colon along with fluid resuscitation and antibiotic therapy are important measures to decrease the risk of death in these patients. Infants and children with longer segment disease and a more proximal transition zone are not as effectively treated by rectal irrigation. Some of these patients will require immediate exploration with a colostomy proximal to the aganglionic bowel. A delayed diagnosis of HD may lead to an increased risk of serious and occasionally fatal enterocolitis.

Diagnosis

Infants and children who failed to pass meconium in the first 24 to 48 hours of life, who suffer from severe constipation with bouts of intermittent diarrhea, who have abdominal distention, or who present with bilious vomiting are likely candidates for the diagnosis of HD. Diagnostic tests include: full-thickness rectal biopsy (gold standard), contrast enema (sensitivity [SN] 65%-80%, specificity [SP] 65%100%), anorectal manometry (SN 75%-100%, SP 85%-95%) and rectal suction biopsy (SN > 90%, SP > 95%). Typically, patients with HD show gaseous distention of the colon and small bowel. In patients with a classic rectosigmoid transition zone, the sigmoid colon is often noted to be redundant and dilated.

Diagnosis

A contrast enema often shows the presence of a transition zone and irregular colonic contractions in the distal, aganglionic segment (Fig. 2).

Fig. 2. A and B, These two barium enema examinations in different infants demonstrate Hirschsprungs disease. The aganglionic rectum (arrows) in both studies is small and contracted. The proximal ganglionic colon is dilated. A transition zone between the aganglionic and ganglionic colon is nicely seen in the both studies.

Diagnosis

Often, irregular mucosal ulcerations are seen on the contrast enema due to enterocolitis.

Fig. 2. A and B, These two barium enema examinations in different infants demonstrate Hirschsprungs disease. The aganglionic rectum (arrows) in both studies is small and contracted. The proximal ganglionic colon is dilated. A transition zone between the aganglionic and ganglionic colon is nicely seen in the both studies.

Diagnosis

Although anorectal manometry is rarely used in neonates to establish the diagnosis, it is a useful technique in older children. The classic finding is the absence of the rectoanal inhibitory reflex when the rectum is distended (Fig. 3). In normal children, distention of the rectum results in a transient increase in rectal pressure with a reduction in the anal internal sphincter pressure. Children with HD lack this inhibitory reflex and relaxation of the internal sphincter.
Rectal distension
mm Hg

Rectal distension

A
Time

Fig. 3. A, In the child undergoing anorectal manometry without Hirschsprungs disease, the rectoanal inhibitory reflex is normal. Note the drop in the internal sphincter pressure with rectal distention. B, A child with Hirschsprungs disease is seen to have ab- normally increased contraction of the anal canal and no relaxation of the internal sphincter with rectal distention. (The arrow points to the initiation of rectal distention in both A and B.)

Diagnosis

The standard diagnostic tool for documenting HD is an open or suction rectal biopsy. Normal colon has demonstrable myenteric and submucosal ganglion cells (Fig. 4A). The absence of ganglion cells in both the myenteric and submucosal plexus and the finding of hypertrophic nerve fibers are diagnostic of HD (see Fig. 4B). Additionally, the presence of increased acetylcholinesterase staining in the submucosa and mucosa is confirmatory of HD (see Fig. 4C).

Fig. 4. A, This biopsy specimen of normal ganglionated bowel has been stained with hematoxylin and eosin. A ganglion cell (arrow) is seen in the submucosa. B, This rectal biopsy specimen in a neonate with Hirschsprungs disease has been stained with hematoxylin and eosin. Ganglion cells cannot be found in the wall of the rectum. Also, the submucosal nerve trunks (arrow) are noted to be greater than 40 m in diameter, which strongly correlates with aganglionosis. C, This rectal biopsy specimen in a neonate with Hirschsprungs disease has been stained with acetylcholinesterase. The increased staining in the mucosa and submucosa (arrows) is diag- nostic of Hirschsprungs disease.

Diagnosis

In some pediatric centers, the presence of increased staining of acetylcholinesterase in the mucosa and submucosa is adequate to confirm the diagnosis in a patient with typical symptoms and a contrast enema that demonstrates a transition zone. A suction rectal biopsy, at least 2 or more above the dentate line, is the commonly used method for confirming HD in most centers. The presence of ganglion cells within 2 cm of the dentate line is variable. Both the absence of ganglion cells and an increase in acetylcholinesterase staining can be determined on these specimens. However, it is more difficult in older children to acquire adequate material on suction biopsy and these children usually require an open biopsy to obtain adequate tissue for diagnosis. Other enzyme-staining techniques have also been used to diagnose HD, such as lactate dehydrogenase, succinic dehydrogenase, and NADPHdiaphorase enzyme histochemistry.

Diagnosis

There also have been reports describing the use of rapid frozen section analysis for determining enzymatic activity of the ganglion cells in the transition zone because anatomically normal-appearing ganglion cells may lack normal enzymatic activity. With this approach, the transition zone is defined as the point where the ganglion cells have normal enzymatic activity. The proximal point of this enzymatically determined transition zone is then used as the neorectum for the coloanal anastomosis. Using the enzymatic activity of the ganglion cells to determine the proximal part of the transition zone has been reported to result in a lower incidence of complications and enterocolitis after pull-through for HD.

Treatment

Surgical approaches to HD should only be considered after the diagnosis has been firmly established by either suction or open rectal biopsy.
Historically, a two- or three-stage repair was performed with the first stage consisting of a diverting colostomy usually leveled at the point where the transition zone was identified by seromuscular biopsy. The second stage, performed 3 to 12 months later, consisted of resection of the aganglionic bowel with a coloanal anastomosis. The colostomy was closed either during the pull-through operation or subsequently as a thirdstage procedure.

Surgical techniques

Multiple operative approaches have been described for managing HD. All these operations conform to the original concepts for correcting HD espoused by Swenson. These principles for effective surgical treatment include resection of the aganglionic portion of bowel and identification of normally ganglionated proximal bowel with a leveled coloanal or enteroanal anastomosis. Additionally, the operation should preserve both fecal and urinary continence and normal sexual function. The most commonly used operations for HD have been developed by Swenson, Duhamel, Soave and Rehbein. The basic principle in all these procedures is to bring the ganglionic bowel down to the anus. The long-term results of any of these operations are very satisfactory if they are performed correctly.

Surgical techniques (biopsy)

The abdomen is opened via the Pfannenstiel incision.

The biopsy site is selected by observing the apparent transitional zone.

Fig. 5. Pfannenstiel incision

Fig. 6. Transitional zone (arrow).

Surgical techniques (biopsy)

In the usual case of rectosigmoid aganglionosis, three seromuscular biopsies are taken along the antimesenteric surface without entering the lumen.

Fig. 7. Biopsy sites.

Surgical techniques (biopsy)

One biopsy is taken from the narrowed segment of bowel, a second biopsy from the transition zone and a third biopsy from the dilated portion above the transition zone. Biopsies are assessed intraoperatively by frozen section, to determine the level of ganglionic bowel.

Fig. 7. Biopsy sites.

Surgical techniques (colostomy)

Many surgeons prefer to install as a first step the right transverse colostomy; others advocate performing colostomy just above the transition to ganglionic bowel.
Ileostomy is indicated in patients who have total colonic aganglionosis.

A right transverse colostomy is convenient in usual cases.

We prefer a loop colostomy over a skin bridge.

Surgical techniques (colostomy)

A V-shaped incision is made in the right upper quadrant (Fig. 8). The V-skin-flap upwards. is reflected

The external oblique is split and the internal oblique and transverse abdominis muscles are divided with diathermy. The peritoneum is opened.

Fig. 8. V-shaped colostomy

Surgical techniques (colostomy)

An opening is made in the mesocolon of the selected segment of transverse colon (Fig. 9). The skin flap is pulled through the opening in the mesocolon and sutured to the opposite skin margin (Fig. 10).

Fig. 9.

Fig. 10.

Surgical techniques (colostomy)

A few interrupted absorbable sutures of 4/0 or 5/0 are placed between the peritoneum, the muscle layers of abdominal wall and the seromuscular layer of colon. The colon is opened longitudinally along the antimesenteric border using diathermy (Fig. 10). The bowel is sutured to the skin using interrupted 4/0 absorbable sutures (Fig. 11).

Fig. 10.

Fig. 11.

Surgical techniques (one-stage transanal endorectal pull-through)

Many surgeons have reported good results with the primary neonatal pullthrough operation for HD. We prefer the one-stage transanal endorectal pull-through operation for classical recto-sigmoid HD and Swensons pull-through operation for long-segment HD because of their simplicity and lack of complications. We have not used diversionary colostomy for usual cases. Of patients with HD, 7580% have rectosigmoid aganglionosis.

Surgical techniques (one-stage transanal endorectal pull-through)

A one-stage pull-through operation can be successfully performed in these patients using a transanal endorectal approach without opening the abdomen.
This procedure is associated with excellent clinical results and permits early postoperative feeding, early hospital discharge and no visible scars. Once the diagnosis of HD is confirmed, rectal irrigations are carried out twice a day for 3 days before surgery. Intravenous gentamicin and metronidazole are started on the morning of operation.

Surgical techniques (one-stage transanal endorectal pull-through)

Fig. 12.

The patient is positioned on the operating table in the lithotomy position. The legs are strapped over sandbags. A Foley catheter is inserted into the bladder. A Denis-Browne retractor or anal retractor is placed to retract perianal skin. The rectal mucosa is circumferentially incised using the cautery, approximately 5 mm above the dentate line, and the submucosal plane is developed. The proximal cut edge of the mucosal cuff is held with multiple 4/0 silk sutures, which are used for traction.The endorectal dissection is then carried proximally, staying in the submucosal plane (Fig. 12).

Surgical techniques (one-stage transanal endorectal pull-through)

When the submucosal dissection has extended proximally to a point above the peritoneal reflection, the rectal muscle is divided circumferentially, and the full thickness of the rectum and sigmoid colon is mobilized out through the anus (Fig. 13). This requires division of rectal and sigmoid vessels, which can be done under direct vision using cautery or ligatures (Fig. 14).

Fig. 13.

Fig. 14.

Surgical techniques (one-stage transanal endorectal pull-through)

When the transition zone is encountered, full-thickness biopsy sections are taken and frozen section confirmation of ganglion cells is obtained. The rectal muscular cuff is split longitudinally either anteriorly or posteriorly. The colon is then divided several centimetres above the most proximal normal biopsy site (Fig. 15).

Fig. 15.

Surgical techniques (one-stage transanal endorectal pull-through)

A standard Soave-Boley anastomosis is performed (Fig. 16). No drains are placed. The patient is started on oral feeds after 24 h and discharged home on the third post-operative day. Digital rectal examination is performed 2 weeks after the operation. Routine rectal dilation is not performed unless there is evidence of a stricture.

Fig. 16.

Surgical techniques (Swenson procedure)

The Swenson technique utilizes a near-total proctectomy with the dissection plane close to the outside of the muscular wall of the rectum (Fig. 17). Swenson believed a diagonal resection of the distal rectum resulted in fewer strictures at the anastomotic line.

Proximal ganglionated bowel

Inverted rectosigmoid stump

Fig. 17. The principles of the Swenson pull-through procedure are seen in these drawings. A, The proximal ganglionated bowel is grasped through an incision in the prolapsed rectosigmoid stump. B, The ganglionated bowel is then sewn to the anus. Generally the procedure looks like in C.

Surgical techniques (Duhamel procedure)

The Duhamel technique employs dissection behind the rectum and leaves the aganglionic rectum in place.
The aganglionic proximal rectum and colon are then resected. The ganglionated bowel is brought down behind the rectum, creating two parallel cylinders (Fig. 18).
Rectorectal pullthrough of ganglionated segment

Fig. 18. With the Duhamel technique, the ganglionated bowel is delivered through an incision in the posterior aspect of the native aganglionated rectum and sewn to the anus. The septum between the ganglionated pull-through colon and the aganglionated native rectum is then divided using a stapler.

Surgical techniques (Duhamel procedure)

The lumen of the neorectum is sutured end to side to the lumen of the native rectum, approximately 2 cm above the dentate line.
The septum between the two cylinders of bowel is then ablated. Initially, this ablation was performed using large clamps placed in parallel with the handles of the clamps protruding out of the anus for up to 2 weeks.
Rectorectal pullthrough of ganglionated segment

Fig. 18. With the Duhamel technique, the ganglionated bowel is delivered through an incision in the posterior aspect of the native aganglionated rectum and sewn to the anus. The septum between the ganglionated pull-through colon and the aganglionated native rectum is then divided using a stapler.

Surgical techniques (Soave procedure)

The Soave technique utilizes a mucosectomy of the rectum, leaving a muscular cuff (Fig. 19). Soave originally described exteriorizing the neorectum out the anus and leaving it as a protuberant stump. The stump was trimmed 2 to 3 weeks later. Boley described a similar approach with a primary anastomosis. All of these procedures have a laparoscopic or transanal counterpart.

Fig. 19. A, For the Soave operation, there is extramucosal dissection of the rectum after circumferential incision of the rectal mucosa. B, The ganglionated colon is pulled through the aganglionic rectal cuff, and a coloanal anastomosis is performed.

Surgical techniques (Rehbeins procedure)

Rehbeins technique differs from the Swensons procedure, in that the

anastomosis

is

low,

anterior

colorectal anastomosis.

In this procedure, 3 to 5 cm of the

terminal aganglionic rectum is left

behind, which is anastomosed to the ganglionic bowel.
Fig. 20.

Conclusions

The vast majority of patients treated with any one of the standard pullthrough procedures achieve satisfactory continence and function with time.

The attainment of normal continence is dependent on the intensity of bowel training, social background and respective intelligence of patients.

Mental handicap, including Down syndrome, is invariably associated with

long-term incontinence.