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    Congenital Megacolon

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    Sep.22.2023

    Congenital Megacolon

    Synopsis

    Key Points

    • Congenital megacolon is defined by the absence of enteric neurons in the distal colon
    • Age of presentation and the type of symptoms that occur vary dramatically among patients
      • Failure to pass meconium within 48 hours of delivery is the classic presentation of congenital megacolon in neonates
      • After newborn period, infants typically present with abdominal distention, vomiting, and constipation
    • Barium enema showing transition zone and anal manometry showing absence of rectosphincteric reflex strongly suggest diagnosis
    • Rectal biopsy is necessary to confirm diagnosis r1
    • Surgical resection of aganglionic, denervated colon segment is definitive treatment (but not curative)
    • Main complication is enterocolitis (both preoperatively and postoperatively)
      • Following hospital admission, treat patients with Hirschsprung-associated enterocolitis with IV resuscitation, broad-spectrum IV antibiotics, and saline rectal washouts r1

    Urgent Action

    • Neonatal bowel obstruction
      • Stabilize hemodynamics with IV fluids and electrolyte replacement
      • Decompress gastrointestinal tract with nasogastric tube
      • Promptly consult pediatric general or gastrointestinal surgeon
    • Enterocolitis
      • Stabilize patient with IV fluids, electrolyte replacement, and gastrointestinal decompression, and begin empiric antibiotics
        • Single-agent IV antibiotic (metronidazole) for mild cases
        • Broad-spectrum IV antibiotics if there is concern for sepsis (hypotension, ill appearance)

    Pitfalls

    • Failure to recognize enterocolitis in a child with congenital megacolon can lead to sepsis and death
    • Rectal biopsy is not recommended during acute bowel obstruction or infection owing to high risk of perforationr2

    Terminology

    Clinical Clarification

    • Congenital megacolon is a disease of colonic dysmotility most commonly presenting with failure to pass meconium and symptoms and signs of large bowel obstruction r3
      • Defining developmental birth defect in which the enteric nervous system is missing from the distal bowel r4
    • Also referred to as Hirschsprung disease or congenital aganglionic megacolon

    Classification r5

    • Short-segment disease (most common; 85% of cases)
      • Confined to rectosigmoid region of colon
    • Long-segment disease (10%)
      • Extends past rectosigmoid region to splenic flexure
    • Total colonic aganglionosis (approximately 5%)
      • Affects entire colon

    Diagnosis

    Clinical Presentation

    History

    • Age of presentation and accompanying symptoms are highly variable r4
      • Neonates
        • Failure to pass meconium in first 48 hours of life is a hallmark symptom c1
      • Infants (most patients present at this age)
        • Constipation, poor feeding, and progressive abdominal distention c2c3c4
        • Other symptoms may include the following:
          • Bilious emesis c5
          • Diarrhea c6
          • Failure to thrive c7
        • Less commonly, enterocolitis in infants is the first presentation, marked by fever, vomiting, explosive bowel movements, and abdominal distention c8c9c10c11
      • Older children
        • Chronic constipation (infrequency and difficulty) c12

    Physical examination

    • Abdominal distention and tenderness c13c14
    • Tight anal sphincter c15
    • Empty rectum c16
    • Additional signs that occur with enterocolitis

    Causes and Risk Factors

    Causes

    • Congenital absence of ganglion cells in submucosal (Meissner) and myenteric (Auerbach) plexuses in distal bowel, extending proximally for variable distances c20
      • Caused by failure of ganglion cells to migrate cephalocaudally through neural crest during weeks 4 to 12 of gestation
      • Absence of parasympathetic plexuses in the affected bowel causes incomplete distention and spasmodic contractions, leading to functional obstruction with upstream bowel dilation r6
      • Length of aganglionic bowel is variable, but always extends proximally from the rectum in a contiguous manner r6

    Risk factors and/or associations

    Age
    • 80% of patients present in first few months of life r7c21
    • 15% of cases remain undiagnosed until age 5 years r8c22
    • Rarely, patients remain asymptomatic until adolescence c23c24
    Sex
    • More common in males than in females (2:1) r9c25c26
    Genetics
    • Inheritance pattern is nonmendelian, multigenic, and partially penetrant r4
    • Germline inactivating mutations in RET gene (ret proto-oncogene) are associated with approximately 50% of familial cases and 20% of sporadic cases r10c27c28
      • Very rarely (in approximately 2% of children), an activating mutation of RET will cause congenital megacolon and multiple endocrine neoplasia type 2 r4
    • Germline mutations in genes EDNRB (endothelin receptor type B) and EDN3 (endothelin 3) account for 10% of cases r10c29c30
    Other risk factors/associations
    • Approximately 30% of children have serious medical problems as a manifestation of other genetic defects and could include: r4
      • Down syndrome c31
      • Smith-Lemli-Opitz syndrome c32
      • Congenital deafness c33
      • Hydrocephalus c34
      • Meckel diverticulum c35
      • Imperforate anus c36
      • Ventricular septal defect c37
      • Congenital anomalies of kidney and urinary tract c38c39
      • Cryptorchidism c40
      • Waardenburg syndrome (pigment defects associated with deafness) c41
      • Neuroblastomas c42
      • Ondine curse (primary alveolar hypoventilation) c43
      • Congenital central hypoventilation syndrome c44
      • Mowat-Wilson syndrome c45
      • Bardet-Biedl syndrome c46

    Diagnostic Procedures

    Primary diagnostic tools

    • Suggestive history, genetic risk factors, and signs on physical examination may prompt further evaluation r4c47
      • In neonates, delayed meconium passage (no bowel movement for more than 48 hours after birth) or neonatal bowel perforation should raise suspicion of the disease
      • In older children, intractable constipation (ie, dependence on enemas or suppositories to pass stool) should raise suspicion
      • Combination of growth failure and abdominal distention should raise suspicion
      • Positive family history (parent, sibling) of congenital megacolon
      • Trisomy 21 plus any symptoms (threshold for evaluation lowered due to significantly elevated risk)
    • Imaging studies are the second step, followed by rectal biopsy, which is required to confirm the diagnosis
    • Begin diagnostic investigation with imaging when disease is suspected, as follows:
      • Plain radiography to determine if there is bowel obstruction; however, a negative finding does not rule out congenital megacolon
      • Barium enema or water-soluble contrast enema (perform in all suspected cases) to show dilated colon proximal to aganglionic region
      • Contrast enema can be interpreted as normal in approximately 20% of infants with the disease; false-positive contrast enema results also occur frequently, so imaging alone cannot be used to exclude or make a diagnosis r4
    • Anal manometry can be used as a diagnostic aid in stable patients, although it is not required
      • Most useful in neonates or patients with short-segment disease
      • Also useful to rule out the disease
    • Rectal biopsy is gold standard to secure diagnosis in all patients r1r11

    Imaging

    • Imaging starts with plain radiograph, followed by either barium or water-soluble contrast enema; imaging alone does not verify diagnosis, which requires rectal biopsy
    • Plain radiography of abdomen c48
      • Widely dilated colon with multiple air-fluid levels and narrow distal segment may signify bowel obstruction; if this finding is absent, further testing is still indicated
    • Barium enema c49
      • Standard imaging mode to evaluate for congenital megacolon
      • Identification of a transition zone (funnel-shaped region evident in the change from dilated colon proximally to narrowed aganglionic segment distally) is highly suggestive r12
      • Identification of transition zone also aids in preoperative planning r13
    • Low-osmolality water-soluble contrast enema c50
      • Best study to evaluate for transition zone between normal and aganglionic bowel
      • Preferred study (compared with barium enema) when there is suspected perforation or a high risk for perforation
      • Accuracy similar to that of barium enema, but inferior to those of rectal suction biopsy or anal manometry r14
        • Sensitivity approximately 70% r15r16
        • Specificity approximately 83% r15r16

    Functional testing

    • Anal manometry c51c52c53
      • Used as diagnostic aid in children when there is concern for congenital megacolon
        • Not necessary for diagnosis but can be useful to exclude the disease
      • Test records anal pressure changes during and after rectal distention with a balloon
      • Interpretation of results
        • Normal result: rectosphincteric reflex is elicited with distention
        • Positive result: absence of rectosphincteric reflex is indicative of congenital megacolon
      • Test is accurate but requires specialized expertise that may be available only in certain centers
        • Sensitivity is approximately 91% r16
        • Specificity is approximately 94% r16

    Procedures

    Rectal suction biopsy r15c54
    • General explanation
      • Tissue sample is acquired and submitted for histopathologic analysis with acetylcholinesterase staining
      • Gold standard for definitive diagnosis
      • High accuracy for diagnosis in infants aged 40 days or older r17
        • Sensitivity is approximately 93% r15r16
        • Specificity is approximately 98% r15r16
    • Indication
      • Infant or child with suggestive clinical and/or radiologic findings
      • Done to confirm diagnosis in all patients r1
    • Contraindications
      • Active infection (eg, enterocolitis)
      • Acute bowel obstruction
      • Bleeding diathesis
    • Interpretation of results
      • Absence of ganglion cells in Meissner and Auerbach plexuses confirms diagnosis

    Other diagnostic tools

    • Genetic testing for predicting associated medical problems r4c55
      • Approximately 30% of children with Hirschsprung disease have other medical problems due to associated genetic defects r4
      • Consider genetic evaluation as directed under the guidance of genetic counselors in children with apparent syndromic disease
      • Syndromic cases may be heralded by: r4
        • Sensorineural deafness and pigmentation defects
        • Central apnea
        • Short stature with alopecia and immunodeficiency
        • Kidney, heart, or immune system problems
        • Polydactyly, obesity, intellectual disability
        • Multiple organ malformations
        • Craniofacial defects

    Differential Diagnosis

    Most common

    • Other causes of failure to pass meconium
      • Benign transient nonorganic ileus of neonates r18c56
        • Similar to congenital megacolon in that it presents in an infant aged 2 to 4 weeks with abdominal distention, emesis, and constipation
        • Difficult to distinguish from congenital megacolon on the basis of symptoms, examination, and even barium enema
        • Usually requires anal manometry and/or rectal biopsy to differentiate
          • Anal manometry shows normal rectoanal inhibitory reflex in benign transient nonorganic ileus of neonates
          • Rectal biopsy identifies ganglion cells in the distal rectum in benign transient nonorganic ileus of neonates
      • Meconium plug r19c57
        • Transient distal colonic or rectal obstruction caused by inspissated, immobile meconium
        • Different from congenital megacolon by virtue of resolution of symptoms and normalization of bowel movements after the plug is passed
        • Contrast enema is diagnostic and therapeutic
        • Differentiate from congenital megacolon by barium enema or water-soluble contrast enema
      • Meconium ileus r19
        • Impaction of thick, tenacious meconium in distal small bowel
        • Different from congenital megacolon by virtue of abdominal distention at birth, increasing within hours
        • On plain radiograph, in right lower abdomen, meconium is seen mixed with air, producing a ground-glass appearance
        • Differentiate from congenital megacolon by plain radiographs, barium enema, or water-soluble contrast enema
      • Anorectal malformation (anal stenosis, imperforate anus) r19c58c59c60
        • Anatomic anomalies of the lower intestinal tract, due to failure of embryologic development
        • Similar to congenital megacolon in that it presents with abdominal distention and inability to pass meconium
        • Different from congenital megacolon by virtue of anal anatomy
        • Differentiate from congenital megacolon by physical examination, which identifies external malformations in anorectal area
    • Constipation r20c61
      • Similar to congenital megacolon in the difficulty or failure to pass stool
      • Different from congenital megacolon by virtue of onset after age 6 months, absence of lower intestinal obstruction, and no chronic abdominal distention or failure to thrive
      • Differentiate from congenital megacolon by presence of stool in rectum on examination and, if needed, by absence of signs of obstruction on plain abdominal radiograph

    Treatment

    Goals

    • Manage acute bowel obstruction
      • Correct volume deficits and restore electrolyte balance
      • Decompress gastrointestinal tract
    • Recognize and eradicate any coexisting infections (eg, enterocolitis)
    • Initial surgical goal is to eliminate functional obstruction caused by aganglionic bowel
    • Ultimate surgical goal is to reconstruct the intestine, connecting normally innervated bowel to the anal opening

    Disposition

    Admission criteria

    Admit infants and children with the following conditions, to stabilize before surgery:

    • Suspicion for or evidence of enterocolitisr1, when the following occur:
      • Signs and symptoms of dehydration
      • Evidence of electrolyte imbalance
      • Evidence of bowel obstruction
    • Failure to thrive and severe hypoproteinemia
    • Urinary retention
    Criteria for ICU admission
    • Hemodynamic instability
    • Sepsis due to enterocolitis

    Recommendations for specialist referral

    • Consult pediatric general or gastrointestinal surgeon for suspected congenital megacolon
    • Consider referral to genetic counselor for risk assessment of disease in siblings r4

    Treatment Options

    Surgery is required for definitive treatment

    Administer antibiotics for cases of suspected enterocolitis

    Supportive care includes IV fluids and, if obstruction makes them necessary, total parenteral nutrition and gastrointestinal decompression

    Drug therapy

    • For empiric treatment of suspected enterocolitis (from Staphylococcus aureus, anaerobes, or coliforms) r2
      • Mild episodes (hemodynamically stable)
        • Metronidazole c62
          • Metronidazole Solution for injection; Neonates 34 weeks postmenstrual age and younger†: 7.5 mg/kg/dose IV every 12 hours for 7 to 10 days.
          • Metronidazole Solution for injection; Neonates 35 to 40 weeks postmenstrual age†: 7.5 mg/kg/dose IV every 8 hours 7 to 10 days.
          • Metronidazole Solution for injection; Neonates older than 40 weeks postmenstrual age†: 7.5 mg/kg/dose IV every 8 hours for 7 to 10 days.
          • Metronidazole Solution for injection; Infants†, Children†, and Adolescents†: 22.5 to 40 mg/kg/day (Max: 1.5 g/day) IV divided 8 hours for 3 to 7 days.
      • Severe episodes (those with hemodynamic instability or sepsis) require broad-spectrum regimens using multiple drugs, such as the following 3-drug regimen:
        • Ampicillin c63c64c65
          • Ampicillin Sodium Solution for injection; Neonates 34 weeks gestation and younger and 0 to 7 days: 50 mg/kg/dose IV every 12 hours for 7 to 10 days.
          • Ampicillin Sodium Solution for injection; Neonates 34 weeks gestation and younger and older than 7 days: 75 mg/kg/dose IV every 12 hours for 7 to 10 days.
          • Ampicillin Sodium Solution for injection; Neonates older than 34 weeks gestation: 50 mg/kg/dose IV every 8 hours for 7 to 10 days.
          • Ampicillin Sodium Solution for injection; Infants, Children, and Adolescents: 100 to 200 mg/kg/day (Max: 8 g/day) IV divided every 6 hours for 3 to 7 days.
        • Gentamicin c66c67c68c69
          • Gentamicin Sulfate Solution for injection; Neonates 0 to 7 days weighing less than 1.2 kg: 2.5 mg/kg/dose IV/IM every 18 to 24 hours in combination with other appropriate antimicrobial agents.
          • Gentamicin Sulfate Solution for injection; Neonates 0 to 7 days weighing 1.2 to 2 kg: 2.5 mg/kg/dose IV/IM every 18 hours in combination with other appropriate antimicrobial agents.
          • Gentamicin Sulfate Solution for injection; Neonates 0 to 7 days weighing more than 2 kg: 2.5 mg/kg/dose IV/IM every 12 hours in combination with other appropriate antimicrobial agents; extend interval to 18 to 24 hours for neonates on ECMO with subsequent dosing based on serum concentrations.
          • Gentamicin Sulfate Solution for injection; Neonates 8 to 29 days weighing less than 1.2 kg: 2.5 mg/kg/dose IV/IM every 18 to 24 hours in combination with other appropriate antimicrobial agents.
          • Gentamicin Sulfate Solution for injection; Neonates 8 to 29 days weighing 1.2 to 2 kg: 2.5 mg/kg/dose IV/IM every 12 hours in combination with other appropriate antimicrobial agents.
          • Gentamicin Sulfate Solution for injection; Neonates 8 to 29 days weighing more than 2 kg: 2.5 mg/kg/dose IV/IM every 8 hours in combination with other appropriate antimicrobial agents; extend interval to 18 to 24 hours for neonates on ECMO with subsequent dosing based on serum concentrations.
          • Gentamicin Sulfate Solution for injection; Premature infants 30 days and older weighing less than 1.2 kg: 2.5 mg/kg/dose IV/IM every 18 hours in combination with other appropriate antimicrobial agents.
          • Gentamicin Sulfate Solution for injection; Infants: 2.5 mg/kg/dose IV/IM every 8 hours in combination with other appropriate antimicrobial agents for 4 to 7 days.
          • Gentamicin Sulfate Solution for injection; Children and Adolescents: 2 to 2.5 mg/kg/dose IV/IM every 8 hours in combination with other appropriate antimicrobial agents for 4 to 7 days.
        • Metronidazole c70c71c72c73
          • Metronidazole Solution for injection; Neonates 34 weeks postmenstrual age and younger†: 7.5 mg/kg/dose IV every 12 hours for 7 to 10 days.
          • Metronidazole Solution for injection; Neonates 35 to 40 weeks postmenstrual age†: 7.5 mg/kg/dose IV every 8 hours 7 to 10 days.
          • Metronidazole Solution for injection; Neonates older than 40 weeks postmenstrual age†: 7.5 mg/kg/dose IV every 8 hours for 7 to 10 days.
          • Metronidazole Solution for injection; Infants†, Children†, and Adolescents†: 22.5 to 40 mg/kg/day (Max: 1.5 g/day) IV divided 8 hours for 3 to 7 days.

    Nondrug and supportive care

    IV fluids c74

    Total parenteral nutrition for nutrient and calorie support if necessary c75

    Gastrointestinal decompression if intestinal obstruction is present c76

    Procedures
    Pull-through surgery r21c77
    General explanation
    • Resects aganglionic colon segment and connects the normally innervated bowel with anastomosis to an area just above the anus, at a level that prevents further functional obstruction but preserves fecal continence
    • Surgical approaches: 2 are common
      • Transanal (most widely used)
      • Laparoscopic abdominal: used in children with transition zones proximal to sigmoid colon
    • Outcomes: bowel function improves and obstruction is relieved for most patients with either approach r21r22
    Indication
    • Hemodynamically stable infant with congenital megacolon
    Contraindications
    • Sepsis
    • Severe malnutrition, as defined by the followingr23:
      • Very low weight for height (below −3 standard deviation score from median growth standards)
      • Visible severe wasting
      • Presence of nutritional edema
    • Intestinal perforation
    Complications
    • Persistent bowel symptoms, especially constipation (approximately 15% at age 3 years) r24

    Monitoring

    • Children with congenital megacolon should receive regular follow-up to adulthood within the context of an interdisciplinary care team led by a pediatric surgeon r1
      • Follow up more frequently during first year of life and maintain regular contact every 1 to 2 years thereafter r1

    Complications and Prognosis

    Complications

    • Enterocolitis r2c78
      • Occurs preoperatively or at diagnosis in up to 26% of cases and as a postoperative complication in approximately 15%
      • Diagnosis is largely clinical, on the basis of history, physical examination, and radiographic findings r25
      • Symptoms include fever, vomiting, and diarrhea with explosive, foul-smelling bowel movementsr1r25
      • Examination shows abdominal distention, with explosive discharge of gas and stool on rectal examination r25
      • Features on plain abdominal radiography include 1 or more of the following: r25
        • Multiple air-fluid levels
        • Dilated loops of bowel
        • Sawtooth appearance with irregular mucosal lining
        • Cutoff sign in rectosigmoid colon with absence of distal air
        • Pneumatosis
      • Suspect Hirschsprung-associated enterocolitis in patients with 4 or more points from the Pastor et al. Hirschsprung-associated enterocolitis score itemsr25r1
      • Toxic megacolon (acute dilation of colon) can complicate enterocolitis c79
      • Following hospital admission, treat patients with Hirschsprung-associated enterocolitis with IV resuscitation, broad-spectrum IV antibiotics, and saline rectal washouts r1
      • European Reference Network for rare inherited and congenital digestive anomalies recommends intersphincteric botulinum toxin injections for patients with recurrent or persistent symptoms of outlet obstruction and/or Hirschsprung-associated enterocolitis r1
    • Postoperative r26
      • Soiling or frank incontinence (approximately 25%; usually the former)
      • Enterocolitis (approximately 15%)
      • Constipation (approximately 10%)
      • Anastomotic stricture (approximately 7%)

    Prognosis

    • Untreated disease can cause death in childhood owing to bacteremia that occurs as a result of bowel inflammation (enterocolitis) or bowel perforation r4
    • Most patients attain satisfactory bowel function after surgery (85.7% in a large series) r22
    • Some achieve completely normal bowel function after surgery (21.4% in a large series) r22

    Screening and Prevention

    Screening c80

    Prevention c81

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