Meconium Ileus Without Cystic Fibrosis Due to Immature Intestinal Nerve Cells (Ganglion/Interstitial Cells of Cajal)

(aka Immature Intestinal Ganglion Cells or Immature Ganglion Cells)

Summary: If your newborn baby has meconium ileus (MI) -- a blockage of the small intestine due to meconium buildup -- the predominant diagnosis seems to be cystic fibrosis (CF). However, there is also a chance that it is not CF, with estimates ranging from 20 - 50% of cases of MI. Recent research seems to indicate that one potential cause of this non-CF related MI is immaturity of the ganglion cells (specifically the interstitial cells of Cajal) in the intestine. This seems to be especially true in Asian populations (e.g., Japanese, Chinese, Korean), where CF is very rare, and yet MI occurs with some frequency. Thus, this cause seems to be perhaps underappreciated in the US.

As nicely diagrammed by Toyosaka et al. (1994 -- see below), the immature intestinal nerve cells result in reduced levels of peristalsis, which causes the meconium to take longer to move through the intestine. The slower passage allows more liquid to be absorbed from the meconium, making it more solid and difficult to pass. The reduced peristalsis and more solid meconium cause the blockage.

It is not clear what causes this delayed maturity. In all cases reported in the literature, the nerve cells just mature on their own, and the condition appears to fully resolve itself -- surgery is required just to allow feeding to occur while the gut matures. Thus, the prognosis is excellent!

Key Papers

• Toyosaka Et Al, 1994 PDF Immaturity of the myenteric plexus is the aetiology of meconium ileus without mucoviscidosis: a histopathologic study. This is an excellent paper that is a must-read. Reports on 9 cases of MI without CF (aka mucoviscidosis), all have symptomology described below. Shows that size of ganglion cells is immature.
• Yoo Et Al, 2002 PDF Delayed maturation of interstitial cells of Cajal in meconium obstruction. Most recent paper we could find, uses analysis of Kenny et al (1998) on ICC in 6 cases. Ileostomies were closed between 39 and 104 days of age.
• Kenny Et Al, 1998 PDF Delayed maturation of the interstitial cells of Cajal: a new diagnosis for transient neonatal pseudoobstruction. Report of two cases. More detailed analysis of the immaturity, showing that the delayed maturity of the interstitial cells of Cajal (ICC) may be the key player. Suggests what to look for in a biopsy to diagnose this condition.
• Kenny Et Al, 1999 PDF Ontogeny of interstitial cells of Cajal in the human intestine. More detailed normative data for performing diagnosis of abnormalities in ICC cells.
• Fakhoury Et Al, 1992 Meconium ileus in the absence of cystic fibrosis. (rate of MI without CF was 8 of 37 or 21.6%)
• Shimizu Et Al, 1997 The estimated incidence of cystic fibrosis in Japan. (they estimate about 1/350,000; numbers for caucasian population is more like 1/3,000).
• Chang Et Al, 1992 Meconium ileus-like condition in Chinese neonates.
• Ng, Wong and Lee, 1993, comment on Chang Et Al, 1992, entitled: Whilst cystic fibrosis is virtually nonexistent among Orientals, meconium-like condition is by no means rare in our population. (unable to retrieve online).

Symptoms and Typical Treatment History

• Blockage of the intestine: neonate does not pass meconium stool in first days of life, has green bile emesis (spitup, vomiting). There may be normal bowel sounds.
• The next step is usually a "barium enema" (contrast enema) x-ray study, which should show a microcolon (colon shrunken from disuse), with higher (proximal) regions of the small intestine enlarged (from backup behind the blockage). Contrast agent should not penetrate much up into the small intestine, as it is blocked.
• The next step is often a Gastrografin enema (meglumine diatriazoate), to attempt to wash out the meconium. If this does not do the trick, then a surgical operation is required to remove the meconium.
• During the surgery, the meconium is not pellet-like (unlike in CF, where pellet-like meconium is caused by decreased pancreatic enzyme output) but is instead a viscous sticky/muddy consistency (as more fluid has been drawn out of it). This is probably the first key distinguishing feature from CF MI.
• Biopsy of intestinal ganglion cells (typically taken to test for Hirshsprung's disease) should reveal a normal number of cells, but they should be smaller, immature-looking cells. This may result in a test coming back as inconclusive from the pathologist. There are better, more precise tests, as documented in the work of Kenny et al. and Yoo et al. (papers above). Getting a more careful pathological report on this biopsy is probably the best basis for early diagnosis.
• Contrast agent for "barium enema" remains in the system for a long time (many days); normally this would be passed in 24hr or so. This indicates that motility is reduced (even though normal bowel sounds might be present, and passage is clear).
• After relieving the blockage, normal stooling does not occur, and feedings are not tolerated (green bile emesis continues).
• The next step is to perform an ileostomy at the point just above the blockage, so that the top (proximal) part of the intestine can empty out into a bag (enabling normal feeding to occur), and the blocked bottom (distal) part can be flushed. This requires a double-barreled ileostomy (Mikulicz resection), where the intestine is cut and the two cut ends are brought out to the abdomen skin surface.
• The stool from the top portion of the intestine coming out the ileostomy should be solid (in contrast w/the watery stool that would be expected from a normal intestine). This is because the transit time of stuff down the intestine is slowed from reduced peristalsis, causing more water absorption, resulting in more solid stool. When the stool becomes watery, that is an indication that things are moving faster, and the ganglion cells have matured. This may take a month or more. The clinical test for closing the stoma back up is that contrast agent is cleared within 24hr.
• In all the cases in the literature, everything resolves and there are no further complications!

Synonyms/Glossary

• Meconium plug syndrome (Clatworthy HW Jr, Howard WHR, Lloyd J. The meconium plug syndrome. Surgery 1956; 39: 131-142. Ellis DG, Clatworthy HW Jr. The meconium plug syndrome revisited. J Pediatr Surg 1966; 1: 54-61.) Seems to be more associated with colon (large intestine) blockage, rather than ileum (small intestine).
• Meconium disease (Rickham PP, Boeckman CR. Neonatal meconium obstruction in the absence of mucoviscidosis. Am J Surg 1965; 109: 173-177). Like plug syndrome but associated with ileum.
• mucoviscidosis = cystic fibrosis
• Transient Neonatal Pseudoobstruction (Kenny Et Al)
• Meconium obstruction (Yoo Et Al)

Links

• eMedicine article on Meconium Ileus Contains this quote:
  "In addition, meconium ileus can occur in the absence of any apparent abnormality of the pancreas in rare cases. These last infants have a favorable outcome after decompression because they do not have cystic fibrosis. Instead, their problem is likely related to gut immaturity, resulting in decreased intestinal motility and impaired passage of meconium."
• eMedicine article on Surgical Aspects of Cystic Fibrosis and Meconium Ileus. Describes the different ileostomies.
• Univ. of Michigan Pediatric Surgery article on Meconium Ileus.