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Achalasia or acalasia is a failure of a ring of muscle (as a sphincter) to relax (completely). It refers most commonly to esophageal achalasia, which is a neuromuscular disorder of the esophagus characterized by the reduced ability to move food down the esophagus (peristalsis). In addition, the inability of the cardia ( also called lower esophageal sphincter)- to relax in response to swallowing (there is increased LES pressure- spasms). more...

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Synonyms are achalasia cardiae, cardiospasm, dyssynergia esophagus, esophageal aperistalsis.

Signs and symptoms

  • Dysphagia
  • Regurgitation of undigested food
  • Heartburn
  • Chest pains : increases after eating and may radiate to the back, neck, and arms.
  • Weight loss
  • Coughing, especially at night or when lying down


Due to the similarity of symptoms, achalasia can be misdiagnosed as other disorders, such as gastroesophageal reflux disease (GERD) and Chagas disease

  • X-ray with a barium swallow or esophagography . Shows narrowing at the level of the gastroesophageal junction ("bird beak"), and various degrees of megaesophagus (esophageal dilation).
  • Endoscopy, which provides a view from within the esophagus.
  • Manometry, the key test for establishing the diagnosis. Measures the pressure induced in different parts of the esophagus and stomach during the act of swallowing.
  • CT scan, which provides further visual evidence.


  1. Gastroesophageal reflux disease-GERD or heartburn.
  2. Barrett's esophagus or Barrett's mucosa: in 10% of patients.
  3. There are two kinds of esophageal cancer: squamous cell carcinoma and adenocarcinoma. There are predisposing conditions that, if present for a long time, may lead to esophageal adenocarcinoma, like achalasia (in up to 5% of cases, Barrett's esophagus leads to esophageal adenocarcinoma).

Treatment and new expectations

  • Balloon (pneumatic) dilation. The muscle fibers will be stretched. Gastroesophageal reflux (GERD) occurs after dilatation in 25% to 35% of patients. Is a risk to later Heller myotomy.
  • Medication:
    • Intra-sphincteric injection of botulinum toxin (or botox), to paralyze cardia and prevent spasms. It is transitory and symptoms will return in the majority of patients within a year.
    • Drugs that reduce LES pressure such as nifedipine and nitroglycerin may be useful.
  • Heller myotomy laparoscopic surgery.
  • Transplant and artificial cardia.


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Distribution of interstitial cells of Cajal in the internal anal sphincter of patients with internal anal sphincter achalasia and hirschsprung disease
From Archives of Pathology & Laboratory Medicine, 9/1/03 by Piotrowska, Anna Piaseczna

* Context.-Interstitial cells of Cajal (ICCs) are pacemaker cells in the smooth muscles of the gut. The internal anal sphincter (IAS) is the most caudal part of gastrointestinal tract. It has the important function of maintaining fecal continence. It has been proposed that ICCs in the IAS mediate the inhibitory innervation of the recto-anal reflexes.

Objective.-To investigate the distribution of ICCs in the normal IAS and in the IAS of children diagnosed with internal anal sphincter achalasia (IASA) and Hirschsprung disease (HD).

Methods.-At the time of IAS myectomy, specimens of the IAS were taken from 8 patients with IASA, 4 patients with HD, and 4 normal controls. All specimens were examined using anti-c-Kit and antiperipherin antibodies; immunolocalization was detected with light microscopy. of the ICCs was graded by computerized image analysis.

Results.-There was strong peripherin immunoreactivity in the ganglia cells and nerve fibers in the normal IAS. The number of peripherin-positive nerve fibers was markedly reduced in the IAS in patients with IASA. In HD patients, there was lack of peripherin immunoreactivity in the IAS, but hypertrophic nerve trunks stained strongly. Many c-Kit-positive ICCs were present among the muscle fibers and between the muscle bundles in the normal IAS. In HD and IASA patients, ICCs were absent or markedly reduced.

Conclusion.-Altered distribution of ICCs in the internal sphincter in IASA and HD may contribute to motility dysfunction in these patients.

Internal anal sphincter achalasia (IASA) is a clinical condition with presentation similar to that of Hirschsprung disease (HD) but with the presence of ganglion cells on rectal biopsy.1-7 The diagnosis of IASA is made on anorectal manometry, which shows the absence of rectosphincteric reflex on balloon inflation. Hirschsprung disease is characterized by absence of ganglion cells in the distal bowel and extending proximally for varying distances.1,2,5

Interstitial cells of Cajal (ICCs) are pacemaker cells in the smooth muscle layer of the gastrointestinal tract; these cells generate slow waves and facilitate active propagation of electrical events, and they mediate neurotransmission.8-11 Interstitial cells of Cajal are present along the gastrointestinal tract from the esophagus to the anorectum as networks of cells associated with neuronal plexuses within the gut musculature, where they are connected to each other by long processes via gap junctions. They are also found dispersed within the circular muscle layer, including the internal anal sphincter (IAS).8-11 The transmembrane tyrosine-kinase receptor c-Kit is a specific marker for ICCs and mast cells in the gastrointestinal tract.12,13 c-Kit and its ligand, the cytokine stem cell factor, form a trophic system that is required for the development of ICCs.12,13 Immunohistochemistry using a c-Kit antibody provides a selective technique for labeling ICCs in the gastrointestinal tract.8-13 Defect of the c-kit/stem cell factor system in animals (rats, mice) results in a lack of ICC development, causing motility dysfunction and failure to thrive.13

The aim of this study was to investigate the distribution of ICCs in the normal IAS, and in the IAS of children diagnosed with IASA and HD.


Specimens of IAS were taken from 8 patients with IASA, aged 7 months to 12 years, at the time of posterior IAS myectomy. The diagnosis of IASA was established by anorectal manometry, which showed the absence of rectosphincter reflex on rectal balloon inflation. Hirschsprung disease was excluded in these patients by the presence of ganglia cells and normal acetylcholinesterase activity in the suction rectal biopsies. After the diagnosis of IASA was confirmed, all patients were given a trial of laxatives, with or without enemas, for a minimum period of 6 months. Laxatives failed to improve constipation; therefore, all 8 patients underwent internal sphincter myectomy. The myectomy was performed posteriorly, starting at the level of pectinate line, and a 1-cm-wide strip of muscle was resected, extending proximally for varying lengths, ranging from 15 to 30 mm. Four patients continued to have severe persistent constipation after Swenson pull-through operation and underwent IAS myectomy after failed conservative management.

For normal controls, samples of IAS muscle were taken at the time of autopsy from 4 patients, aged 4 months to 14 years, with no evidence of gastrointestinal disease. All specimens were fixed in neutral buffered formaldehyde and embedded in paraffin wax.

Serial 4-[mu]m sections were mounted on silane-coated slides (Dako, Ely, United Kingdom) and used for immunohistochemical staining.


Sections were deparaffinized in xylene and rehydrated in graduated ethanol solutions. To unmask antigenic sites, slides were heated in a pressure cooker in 10 mmol/L citrate buffer (pH 6.0) for 5 minutes. Endogenous peroxidase activity was quenched with 0.3% hydrogen peroxide in absolute methanol (v/v) for 30 minutes at room temperature. To prevent nonspecific absorption of immunoglobulin, sections were incubated for 30 minutes in 10% goat serum (Dako), in Tris-HCl buffer with 0.05% Tween 20 and 1% bovine serum albumin (pH 7.6), following an incubation with the primary antibody, rabbit polyclonal anti-c-Kit (Oncogene, Boston, Mass; concentration 0.1 [mu]g/mL) or mouse monoclonal antiperipherin (Novocastra, Newcastle upon Tyne, United Kingdom; dilution 1:100) in antibody diluent with background-reducing components (Dako) overnight at 4[degrees]C. Subsequently, sections were incubated at room temperature for 1 hour with a biotin-conjugated goat anti-rabbit immunoglobulin for c-Kit anti-body or goat anti-mouse immunoglobulin for peripherin, in Tris-HCl buffer (dilution 1:300), followed by a 30-minute incubation period in avidin-biotin complex (Dako). Each incubation period was followed by gently washing in Tris-buffered saline. Staining was visualized using 3,3'-diaminobenzidine (Sigma-Aldrich, Dublin, Ireland) containing 10 mmol/L hydrogen peroxide. Counterstaining was performed with hematoxylin, and sections were coverslipped with Glycergel mounting medium (Dako).

Analysis of Density of ICCs

Microscopic images were scanned with a Zeiss Axioskop microscope with color video camera and were analyzed with an image analyzer, Interactive Image Processing System (IPS version 4.01, Alcatel TITN Answare, Cedex, France). Interstitial cells of Cajal were counted in 20 x 40 objective fields (within 2 x 40 objective fields of the muscle layer) of the IAS, IASA, and HD samples. Numbers of ICCs/mm^sup 2^ were then calculated; each field had an area of 0.4 mm^sup 2^.

Statistical Analysis

The unpaired t test was used to compare the statistical difference between the ICCs in the normal IAS controls, IASA patients, and HD patients. A P value less than .05 was considered statistically significant.


Peripherin-immunoreactive nerve fibers were abundant in the normal IAS and were uniformly distributed both between and within muscle bundles. A few small ganglion cells were demonstrated between muscle bundles (Figure 1, A. Peripherin-immunoreactive nerve fibers were markedly reduced in IASA specimens, but single small ganglion cells were demonstrated between the smooth muscle bundles (Figure 1, B).

In the HD specimens, we noted a lack of ganglion cells and peripherin-positive nerve fibers in the muscle. Hypertrophic nerve trunks stained strongly (Figure 1, C).

In the normal IAS specimens, large numbers of ICCs were observed among smooth muscle cells and between muscle bundles (Figure 2, A). The density of ICCs was markedly reduced in IASA specimens compared to normal IAS (Figure 2, B). The ICCs were absent or sparse in IAS of HD patients (Figure 2, C).

In the muscle layer of normal IAS, the number of ICCs (6.9 + or - 2.1) was significantly higher than in IASA (3.2 + or - 1.8) and IAS of HD (1.1 + or - 0.3) samples (P


To our knowledge, this is the first study that has examined ICC distribution in IASA and IAS of HD patients. Our study has clearly demonstrated the presence of a large number of ICCs in nonpathologic human IAS and absence or marked reduction of these cells in IASA and IAS of HD patients. The presence of ICCs in the human IAS was previously described by Hagger et al,8 who demonstrated significant lower density of ICCs in normal IAS compared to smooth muscle layer in the rectum. They examined the density of ICCs in the normal adult IAS and found it to be very sparse (0-1 cell bodies per high-power field). In our study, the number of ICCs in the IAS varied from 3 to 9 cell bodies per high-power field. These findings suggest that distribution of ICCs in the IAS in children is greater than in the adult IAS and probably is age dependent. Further studies are required to confirm this finding. In animal studies, it has been reported that c-Kit expression by ICCs may wane with increasing age.14

Immunohistochemistry using anti-tyrosine-kinase receptor c-Kit antibody identifies ICCs in both human and animal gastrointestinal tracts.8-15 Interstitial cells of Cajal are present in the IAS, and their pattern of distribution in association with the different proposed functions of ICCs could be responsible for normal physiological motility of the anorecrum.8,9 A decrease in the number of ICCs has been reported in several human gastrointestinal motility disorders, including HD,16,17 infantile hypertrophic pyloric stenosis,18 anorectal malformations,19 hypoganglionosis,20 ulcerative colitis,21 and chronic idiopathic intestinal pseudo-obstruction,22,23 suggesting that ICCs are involved in these motility disorders. In all of these diseases, it was suggested that the colonic hypomotility is caused by the absence or marked reduction of ICCs in the smooth muscle layer.

The functions of ICCs include the generation of electrical pacemaker activity, generation of slow waves, and neurotransmission between the enteric nervous system and smooth muscle cells.9-11 It has been proposed that ICCs in certain regions of the gut may not act as pacemakers, but as stretch receptors.24 A stretch receptor role has been proposed for certain ICC networks, especially in the anorectum.8,9 The rectum can relax to accommodate an increase in volume of luminal contents, meaning that the rectal wall is capable of detecting distending force and then initiating relaxation of the smooth muscle cells. It is suggested that ICCs express neuronal nitric oxide synthase and heme oxygenase-2, 2 enzymes responsible for the production of nitric oxide and carbon monoxide, respectively, which play a role as messenger molecules between ICCs and smooth muscle cells.25-30 Colocalization of both enzymes in the enteric plexus of anorectum and in ICCs suggests a modulatory role for the heme oxygenase pathway in the neuronal nitric oxide synthase-mediated, non-adrenergic, noncholinergic inhibitory neurotransmission of the IAS.26-28 The rectoanal inhibitory reflexes include relaxation of the IAS in response to inhibitory neuronal inputs, involving a nonadrenergic, noncholinergic pathway. After stimulation by nitric oxide, ICCs amplify the production of nitric oxide or carbon monoxide in the positive feedback response.8,27,28 These findings suggest that ICCs may mediate the inhibitory innervation of the efferent loop of the rectoanal reflexes.

The exact pathogenesis and pathophysiology of IASA is not fully understood. Several authors have reported innervation abnormalities in the IASA. 1-7 Nitrergic nerve depletion, abnormal peptidergic innervation, and defective innervation of the neuromuscular junctions have been reported in IASA. The present study examined the status of IAS innervation using immunohistochemistry for antiperipherin antibody (type III intermediate filament, a specific marker for peripheral neurons, including enteric ganglion cells).31 Peripherin-immunoreactive nerve fibers were markedly reduced in IASA. Our findings demonstrate that in the IAS, achalasia patients not only have a defective intramuscular innervation, but also altered distribution of ICCs, which are the coordinators of gastrointestinal motility. The lack or deficient expression of ICCs in the IASA may lead to defective generation of pacemaker activity, thus causing motility dysfunction.


1. Kobayashi H, Hirakavva H, Puri P. Abnormal internal anal sphincter in patients with Hirschsprung's disease and allied disorders. J Pediatr Surg. 1996;31: 794-799.

2. Hirakawa H, Kobayashi H, O'Brian DS, Puri P. Absence of NADPH-diaphorase in internal anal sphincter (IAS) achalasia. J Pediatr Gastroenterol Nutr. 1995; 20:54-58.

3. Oue T, Puri P. Altered intramuscular innervation and synapse formation on the internal sphincter achalasia. Pediatr Surg Int. 1999:15:192-194.

4. VanderWall KJ, Bealer JN, Adzick NS, Harrison MR. Cyclic GMP relaxes the internal anal sphincter in Hirschsprung's disease. J Pediatr Surg. 1995;30: 1013-1016.

5. Holschneider AM. Anal sphincter achalasia and ultrashort Hirschsprung's disease. In: Holschneider AM, Puri P, eds. Hirschsprung's Disease and Allied Disorders. Amsterdam, The Netherlands: Harwood Academic Publishers; 2000.

6. Fadda B, Welskop J, Muntefering H, Meier-Ruge W, Engert J. Achalasia of the anal sphincter: enzyme-histotopochemical studies of internal sphincter muscle biopsies. Pediatr Surg Int. 1987;2:81-85.

7. De Caluwe D, Yoneda A, Aki U, Puri P. Internal anal sphincter achalasia: outcome after internal sphincter myectomy. J Pediatr Surg. 2001;36:736-738.

8. Hagger R, Charaie S, Finlayson C, Kumar D. Distribution of the interstitial cells of Cajal in the human anorectum. J Auton Nerv Syst. 1998:73:75-79.

9. Hagger R, Finlayson C, Jeffrey I, Kumar D. Role of the interstitial cells of Cajal in the control of gut motility. Br J Surg. 1997:84:445-450.

10. Liu LWC, Farraway L, Berezin I, Huizinga JD. Interstitial cells of Cajal: mediators of communication between circular and longitudinal muscle layers of canine colon. Cell Tissue Res. 1998:294:69-79.

11. Sanders KM, Ordog T, Sang Don Koh, Word SM. A novel pacemaker mechanism drives gastrointestinal rhythmicity. News Physiol Sci. 2000:15:291-298.

12. Wu JJ, Rothman TP, Gershon MD. Development of the interstitial cells of Cajal: origin, kit dependence and neuronal and nonneuronal sources of kit ligand. J Neurosci Res. 2000:59:384-401.

13. Ward SM, Sanders KM. Physiology and pathophysiology of the interstitial cells of Cajal: from bench to bedside, I: functional development and plasticity of interstitial cells of Cajal networks. Am J Physiol Gastrointest Liver Physiol. 2001; 281:G602-C611.

14. Torihashi S, Ward SM, Nishikawa S. C-kit-dependent development of interstitial cells and electrical activity in the murine gastrointestinal tract. Cell Tissue Res. 1995:280:97-111.

15. Hagger R, Gharaie S, Finlayson C, Kumar D. Regional and transmural density of interstitial cells of Cajal in human colon and rectum. Am J Physiol. 1998: 275:C1309-G1316.

16. Vanderviden JM, Rumessen JJ, Liu H, Descamps D, De Laet MH, Vander-haeghen JJ. Interstitial cells of Cajal in human colon and in Hirschsprung's disease. Gastroenterology. 1996:111:901-910.

17. Rolle U, Piaseczna Piotrowska A, Nemeth L, Puri P. Altered distribution of interstitial cells of Cajal in Hirschsprung disease. Arch Pathol Lab Med. 2002; 126:928-933.

18. Yamataka A, Fujiwara T, Kato Y, Okazaki T, Sunagawa M, Miyano T. Lack of intestinal pacemaker (c-kit-positive) cells in infantile hypertrophic pyloric stenosis. J Pediatr Surg. 1996:31:96-99.

19. Kenny SE, Cornell MG, Rintala RJ, Vaillant C, Edgar DH, Lloyd DA. Abnormal colonic interstitial cells of Cajal in children with anorectal malformations. J Pediatr Surg. 1998:33:130-132.

20. Rolle U, Yoneda A, Solari V, Nemeth L, Puri P. Abnormalities of c-kit positive cellular network in isolated hypoganglionosis. J Pediatr Surg. 2002:37:709-714.

21. Rumessen JJ. Ultrastructure of interstitial cells of Cajal at the colonic submuscular border in patients with ulcerative colitis. Gastroenterology. 1996;111: 1447-1455.

22. Huizinga JD. Neuronal injury, repair and adaptation in the GI tract, IV: pathophysiology of GI motility related to interstitial cells of Cajal. Am J Physiol. 1998;275:G381-G386.

23. Yamataka A, Ohshiro K, Kobayashi H, et al. Abnormal distribution of intestinal pacemaker (c-kit-positive) cells in an infant with chronic idiopathic intestinal pseudoobstruction. J Pediatr Surg. 1998:33:859-862.

24. Faussone Peilegrini MS. Histogenesis, structure and relationships of interstitial cells of Cajal (ICC): from morphology to functional interpretation. Eur J Morphol. 1992:30:137-148.

25. Farrugia G, Szurszewski J. Heme oxygenase, carbon monoxide and interstitial cells of Cajal. Microsc Res Tech. 1999:47:321-324.

26. Rattan S, Chakder S. Influence of heme oxygenase inhibitors on the basal tissue enzymatic activity and smooth muscle relaxation of internal anal sphincter. J Pharmacol Exp Ther. 2000:294:1009-1016.

27. Battish R, Cao G-Y, Lynn RB, Chakder S, Rattan S. Heme oxygenase-2 distribution in anorectum: colocalization with neuronal nitric oxide synthase. Am J Physiol. 2000;278:G148-G155.

28. Chakder S, Cao G-Y, Lynn RB, Rattan S. Heme oxygenase activity in the internal anal sphincter: effects of nonadrenergic, noncholinergic nerve stimulation. Gastroenterology. 2000:118:477-486.

29. Rattan S, Chakder S. Inhibitory effect of CO internal anal sphincter: heme oxygenase inhibitor inhibits NANC relaxation. Am J Physiol. 1993;265:G799G804.

30. Piaseczna Piotrowska A, Solari V, Puri P. Immunolocalisation of heme oxygenase 2 and interstitial cells of Cajal in normal and aganglionic colon. J Pediatr Surg. 2003:38:73-77.

31. Szabolcs MJ, Visser J, Shelanski ML, O'Toole K, Schullinger JN. Peripherin: a novel marker for the immunohistochemical study of malformations of the enteric nervous system. Pediatr Pathol Lab Med. 1996;16:51-70.

Anna Piaseczna Piotrowska, MD; Valeria Solari, MD; Prem Puri, MS, FRCS

Accepted for publication April 15, 2003.

From the Children's Research Centre, Our Lady's Hospital for Sick Children, University College Dublin, Dublin, Ireland.

Reprints: Prem Puri, MS, FRCS, FRCS(Ed), Children's Research Centre, Our Lady's Hospital for Sick Children, Crumlin, Dublin 12, Ireland (e-mail:

Copyright College of American Pathologists Sep 2003
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