Severe

Severe, intractable constipation: a new cause is
identified

                 John M Hutson
                 BS, MD(Monash) MD(Melb) FRACS
                 Professor of Pediatric Surgery and
                 Director, Department of General Surgery
                 Royal Children's Hospital and
                 University of Melbourne

Academic practice in pediatric surgery

            Address correspondence to:    Prof John Hutson
                                          General Surgery
                                          Royal Children's Hospital
                                          Parkville 3052
                                          Victoria

ABSTRACT

                  When faced with a child or infant with severe,
             intractable    constipation,   most   practitioners     would
             consider whether or not a rectal biopsy was indicated to
             exclude Hirschsprung's disease   . if such a biopsy was
             negative, no underlying cause was then identified leading
             to significant frustration for both doctor and family.
             Now new diagnostic methods, including laparoscopic biopsy
             and immunofluoresence for neuronal markers, have         been
             developed which enable some children with very severe
             chronic constipation to be diagnosed. They have been
             found to have intestinal neuronal dysplasia, where the
             nerves in the bowel are present but function abnormally
             because of    a   deficiency   in neurotransmitters.    The
             lifestyle of these children may be dramatically enhanced
             by an antegrade catheterizable enterostomy to enable
             direct washouts of the colon.

INTRODUCTION

                  Severe,' intractable constipation was once difficult
             to treat unless a child was identified as having
             Hirschsprung's disease. Now some of these children can be
             identified as having "intestinal neuronal dysplasia" by
             laparoscopic biopsy of the colon, enabling them to be
             treated more rationally. Using the appendix. an antegrade
             catheterizable enterostomy has been created surgically in
             some patients to enable bowel washouts to be carried out
               simply at home without the need for a District Nurse,
               admissions to hospital or significant distress to the
               child. These advances have dramatically improved the
               lifestyle of some children with severe constipation.

What is constipation?

                    Constipation is a common problem in infants and
               childhood where hard stools are passed infrequently. An
               anal fissure with blood in the nappy is a common
               consequence    of   constipation     in    toddlers.     Such
               constipation is usually treated easily by manipulation of
               the diet and the addition of laxatives. increased
               vegetable fibre in the diet is often sufficient to
               overcome the problem.

                   Unfortunately, some children have very severe or
               intractable constipation which fails to respond to
               dietary treatment   or laxatives.     Such   children    are
               probably rare (?), but are very difficult to treat
               because they   are   resistant   to   standard    treatment
               measures.

What causes constipation?

                   The commonest cause of constipation is a poor diet
               (Table 1). A small number of children have a frank
               mechanical obstruction such as anal stenosis, which is
             easily identified on physical examination of the anus. In
             general, constipation is caused by excessive water
             absorption in the colon or by decreased colonic motility.
             Abnormal gut motility is a relatively rare cause of
             constipation,    but   is   exemplified   by    Hirschsprung's
             disease in which the intrinsic nerves of the colon are
             absent.    Most children with Hirschsprung's disease have
             deficiency of the ganglion cells in the rectosigmoid
             colon. They are identified by delayed passage of meconium
             in the first 24 hours of life, followed by obstruction of
             the bowel in the neonatal period (Table 2). Some children
             are not diagnosed until they present later in childhood
             with profound chronic constipation and failure to thrive.
             The diagnosis is made on suction or open rectal biopsy of
             the submucosa which shows an absence of the ganglion
             cells in the submucosal plexus. Hirschsprung's disease is
             treated by excision of the aganglionic bowel and pull
             through of the normally innervated proximal bowel to the
             anus.

What is "Intestinal Neuronal Dysplasia"?

                  If   a   rectal   biopsy in     a child   with    severe
             constipation fails to identify Hirschsprung's disease
             then the child usually is assumed to be normal. However,
             some of these children, particularly the more severe
             one's, have turned out to have a functional abnormality
             of the nerves of the bowel known as intestinal neuronal
             dysplasia, or IND. IND has been diagnosed most frequently
             in Europe by sophisticated but indirect histological
             criteria using rectal biopsies. However, the validity and
             reliability    of    the    diagnostic    methods     remains
             controversial and many groups around the world have
             described not only different diagnostic criteria but also
             a variable clinical picture, calling into doubt the basic
             premise. The indirect nature of the rectal mucosal biopsy
             when    looking   for    a   functional    abnormality     in
             neuromuscular control led us to look more specifically at
             the nerves in the muscle. This has enabled us to
             recognize a new variant of IND where there is a
             deficiency in the neurotransmitters within the excitatory
             and/or inhibitory nerves of the circular and longitudinal
             muscle. Recent progress in basic understanding of the
             autonomic nerves of the bowel has shown that substance P
             is a neurotransmitter found excitatory nerves and that
             VIP is a neurotransmitter found in inhibitory nerves of
             the colon. By collecting laparoscopic biopsies of the
             colonic muscle a number of children with severe, chronic
             constipation have now been diagnosed as having a
             deficiency of substance P with or without concomitant
             deficiency of VIP (Figure 1).

How is IND recognised?

                  How can    "IND with substance P deficiency"          be
             recognized? These children often have delayed passage of
             meconium in the neonatal period and then go on to have
             severe, chronic constipation which becomes apparent
             either at birth, weaning or at toilet training (Table 3).
             The constipation has presented as very infrequent bowel
             actions, with some children    failing to pass a bowel
             motion for more than one to two weeks. However, other
             children have presented with severe soiling, which is
             likely to be spurious diarrhea from constipation with
             overflow. Failure to thrive    has also been present in
             some children with severe abnormalities. The ganglion
             cells appear normal on a rectal biopsy, but radiological
             transit studies show delay in colonic motility.

When to refer

                 When should patients with severe constipation be
             referred for further investigation of their bowel? Any
             child with severe constipation who fails to respond to
             good medical treatment probably warrants a suction or
             open rectal biopsy to exclude Hirschsprung's disease.
             This is a simple and widely available test that it is a
             good starting point for investigation of such children.
             For those children with very profound constipation,
             despite a negative biopsy for Hirschsprung's disease, a
             referral to find out whether they might have intestinal
             neuronal dysplasia would be warranted if there is no
             response to aggressive medical therapy (Table 4). A
             particularly high-risk group are those children requiring
             regular bowel washouts or enemas at home or in hospital
             (Figure 2).

Investigations before referral

                  What investigations are required prior to referral?
             As in all good clinical medicine the history and physical
             examination is priceless. Many children with simple
             dietary deficiency will be picked up and treated
             appropriately. A rectal examination is useful to exclude
             anal stenosis. Also, if a very hard fecal bolus is found
             in the rectum, IND is less likely, as most children so
             far identified have constipation despite relatively soft
             stool. Radiological confirmation of chronic constipation
             on a plain abdominal x-ray is also useful. If intestinal
             neuronal dysplasia needs to be considered a rectal biopsy
             to exclude Hirschsprung's disease should be done first.

What will the specialist do?

                 Prior to consideration of biopsy, the pediatric
             gastroenterologist or surgeon will arrange a bowel
             transit study and possibly anorectal manometry. If these
             studies show delayed colonic motility but with no loss of
             the anorectal reflex, then laparoscopic biopsy of the
             colonic muscle can be performed. Under a short general
             anaesthetic the serosa and muscle layers of the colon are
             biopsied in the ascending, transverse and sigmoid colon.
             Sophisticated   fixation    and    staining   allows     the
             neurotransmitters       to     be      identified       using
             immunofluorescence    labelling.    identification    of    a
             specific anatomical or functional abnormality, such as
             substance P deficiency, is a major advance in the
             management of these difficult children.

What is the best treatment?

                  Some children with IND require laxatives but no
             further intervention. However, those children requiring
             admissions to hospital or antegrade or retrograde washout
             of the colon may benefit from a new operation recently
             described in England. The appendix can now be used as an
             antegrade catheterizable microenterostomy through which
             bowel washouts can be given directly into the ascending
             colon. No    bag   or appliance    is required   and    the
             catheterization of the stoma is not painful. Older
             children can then do their own bowel washouts. Partial
             colectomy has been tried in a number of patients, but it
             does not appear to be sufficient to overcome the
             functional obstruction on its own. In a number of smaller
             children a permanent ileostomy or colostomy to by-pass
             the dysfunctional colon has been performed with success.

Conclusion

                 In conclusion, the practitioner need not despair
            when confronted with a child with severe intractable
            constipation: some may have a newly recognized condition
            which can be identified by       laparoscopic biopsy.   A
            definitive diagnosis is permitting rapid advances in
            understanding and the development of new treatments.

             Table 1        Causes of Constipation
             ---------------------------------------------------------
                  Inadequate diet
                  Mechanical obstruction
                       eq: anal stenosis
                  Excessive water absorption
                  Decreased gut motility
             --------------------------------------------------------

             Table 2        Hirschsprung's disease
             --------------------------------------------------------
                  delayed passage of meconium
                  +_ neonatal bowel obstruction
                  +_ severe chronic constipation
                  absent ganglion cells on
                  rectal biopsy
             -------------------------------------------------------
             Table 3        Intestinal Neuronal Dysplasia
             ---------------------------------------------------------
                  +_ delayed passage of meconium
                  severe chronic constipation
                  +_ soiling/failure to thrive
                  normal ganglion cells on
                      rectal biopsy
                  delayed transit in colon
                      on transit study
               ----------------------------------------------------

            Table 4         When to Refer for ? IND
            --------------------------------------------------------
                 No response to aggressive medical therapy
                 Requiring washouts/admissions to
                      hospital to overcome block
                 Negative rectal biopsy for
                      Hirschsprung's disease
            ---------------------------------------------------------

Figure 2.

                                severe constipation
                                  diet, laxatives
                           antegrade/retrograde washouts
                          exclude Hirschsprung's disease
                          consider IND if no improvement