Chronic Intestinal Pseudo-Obstruction (CIPO) is a rare syndrome characterized by chronic intestinal dilation  and dysmotility in the absence of mechanical obstruction. A definite diagnosis of CIPO can only be made after histological examination of intestinal tissues. The present case describes a CIPO in a 2.5-year-old Bernese Mountain dog with a history of recurrent gastro-intestinal complaints suggestive for pseudo-obstruction. Histological lesions of small intestinal samples consisted of severe loss of smooth muscle cells of the tunica muscularis and diffuse infiltration of mononuclear cells. In addition, a hypertrophy of the lamina muscularis  mucosa of the small intestinal tract was present. On the basis of these findings and the results of immunohistochemistry,  a myopathic form of CIPO was diagnosed

Chiers, Koen

Daminet, Sylvie

Ducatelle, Richard

Paepe, Dominique

Vandenberge, Valerie

Vercauteren, Griet

English

Ghent University Academic Bibliography

Vlaams Diergeneeskundig Tijdschrift, 2009, 78 Case report   117INTRODUCTIONChronic intestinal pseudo-obstruction is a rare andsevere syndrome characterized by impaired intestinalfunction mimicking mechanical obstruction in the ab-sence of any intestinal occluding lesion (Amleida andPenna, 2000). The diagnosis is mainly clinical, sup-ported by radiographic and ultrasonographic exami-nations revealing dilated intestines with air-fluid level(Antonucci et al., 2008). Full thickness biopsies of af-fected and non-affected alimentary tracts should be ob-tained for histopathological examination to make adefinite diagnosis. CIPO is a heterogeneous group of syndromes thatmainly affect intestinal motility due to severe diseaseof the neuromuscular system. It is classified into threemain categories: 1) neuropathies: disorders of myen-teric plexi, which are further subdivided into inflam-matory and degenerative neuropathies; 2) mesen-chymopathies: abnormalities of the interstitial cells ofCajal; and 3) myopathies: primary involvement ofsmooth muscle cells. Immunohistochemistry is oftenhelpful in establishing a correct diagnosis (Antonucciet al.).In dogs, only a few cases of CIPO have been des-cribed (Arrick and Kleine, 1978; Moore and Carpen-ter, 1984; Swayne et al., 1986; Lamb and France,1994; Dvir et al., 2001; Petrus et al., 2001; Eastwoodet al., 2005; Couraud et al., 2006; Johnson et al.,2007).  Histological samples of the small and large in-testines of most cases demonstrated atrophy and infil-tration with a mononuclear cell infiltration, as well asfibrosis of the tunica muscularis.  Occasionally, dege-neration of smooth muscle fibers and diffuse inflam-matory cell infiltration in the tunica muscularis of thestomach and/or bladder were present.  Although ex-tensive immunohistochemistry was not performed inthe cases described by Moore and Carpenter (1984),Swayne et al.(1986), Eastwood et al. (2005) and Cou-raud et al. (2006), they probably reflect a myopathicform of CIPO, in view of the high degree of involve-ment of smooth muscle cells.  In three other cases, theneurological form of CIPO can be suspected, since le-sions were observed in submucosal plexi and/or my-enteric plexi (Lamb and France, 1994; Dvir et al.,2001; Petrus et al., 2001). Here, we report the histological and immunohisto-chemical characterization of myopathic CIPO withhypertrophy of the lamina muscularis mucosa in a Ber-nese Mountain Dog.Chronic intestinal pseudo-obstruction in a Bernese Mountain DogChronische intestinale pseudo-obstructie bij een Berner Sennenhond1V. Vandenberge, 2D. Paepe, 1G. Vercauteren, 2S. Daminet, 1R. Ducatelle, 1K. Chiers1Department of Pathology, Bacteriology and Poultry Diseases, 2Department of Small Animal Medicineand Clinical Biology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133,B-9820 Merelbeke, BelgiumABSTRACTChronic Intestinal Pseudo-Obstruction (CIPO) is a rare syndrome characterized by chronic intestinal di-lation and dysmotility in the absence of mechanical obstruction. A definite diagnosis of CIPO can only bemade after histological examination of intestinal tissues. The present case describes a CIPO in a 2.5-year-oldBernese Mountain dog with a history of recurrent gastro-intestinal complaints suggestive for pseudo-ob-struction.  Histological lesions of small intestinal samples consisted of severe loss of smooth muscle cells of thetunica muscularis and diffuse infiltration of mononuclear cells. In addition, a hypertrophy of the lamina mus-cularis mucosa of the small intestinal tract was present. On the basis of these findings and the results of im-munohistochemistry, a myopathic form of CIPO was diagnosed.SAMENVATTINGChronische intestinale pseudo-obstructie (CIPO) is een zeldzame aandoening en wordt gekenmerkt door hypo-motiliteit van het darmstelsel. Dit veroorzaakt symptomen van obstructie. Een histologisch onderzoek is noodzake-lijk om een definitieve diagnose van CIPO te kunnen stellen. In dit artikel wordt een geval beschreven van CIPO bijeen 2,5 jaar oude Berner Sennenhond met recidiverende gastro-intestinale klachten kenmerkend voor obstructie. Bijhet histologisch onderzoek van de dunne darmen werd een sterke atrofie van de tunica muscularis waargenomen.Deze was diffuus geïnfiltreerd met monomorfe leukocyten. Daarnaast werd eveneens een hypertrofie van de laminamuscularis mucosa in de dunne darmen waargenomen. Deze bevindingen alsook de resultaten van het immunohis-tochemisch onderzoek wijzen in de richting van een myopathische vorm van CIPO.118 Vlaams Diergeneeskundig Tijdschrift, 2009, 78CASE REPORTCase historyA 2.5-year-old male Bernese Mountain Dog wasreferred to the Small Animal Clinic of the Faculty ofVeterinary Medicine with a history of anorexia, diar-rhea and vomiting for a period of 2 weeks and weightloss occurring over 2 months. Neither the antibiotics(ceftiofur, lincomycin and marbofloxacin) nor the anti-emetics (primperan) given by the referring veterina-rian had had any effect. On physical examination, poorbody condition and a distended, painful abdomen werefound. Abdominal auscultation did not reveal borbo-rygmi. Complete blood count, urinalysis, and serumbiochemistry profile including serum electrolyte con-centrations showed no abnormalities. Abdominalradio-graphy demonstrated severely distended smallintestinal loops filled with watery content and gas. Thedescending colon was dilated and filled with feces.The other parts of the colon were distended and filledwith gas. Abdominal ultrasonography revealed sever-ely dilated, fluid filled and flacid small intestines. Bac-teriological and parasitological fecal examination werenegative. Based on the clinical and radiographic fin-dings, a diagnosis of intestinal obstruction was made.A midline exploratory celiotomy was performed. Thesmall intestines were markedly distended and filledwith fluid and gas.  There was no evidence of peris-talsis, but a mechanical obstruction could not be found.Large amounts of impacted contents were present inthe large bowel. The intestinal content was removedby gentle massage. In addition, a moderate amount ofserosanguineous fluid was present in the abdominalcavity. A jejunal biopsy revealed atrophy of the villiand multifocal necrosis of the mucosa. There was asignificant mucosal infiltration with macrophages,lymphocytes and plasma cells that extended into thetunica muscularis. Several muscle cells of the tunicamuscularis were hypereosinophilic and fragmentated.Postoperatively, the dog received fluid therapy, anti-biotics (amoxicillin/clavulanic acid and metronida-zole), ranitidine, primperan and cisapride, withoutimprovement of the general condition. Because of thepoor prognosis and the absence of response to treat-ment, the dog was euthanized 8 days after surgery.Autopsy and histological findingsAt necropsy, the duodenum was severely dilatedand filled with yellow-brown fluid. The jejunum andileum were moderately dilated and contained the samefluid, as well as impacted content. A moderate amountof impacted feces was present in the colon. Histologi-cal samples were taken from the esophagus, stomach,duodenum, jejunum, ileum, colon, trigeminal ganglionand urinary bladder. These tissues were fixed in 10%neutral buffered formalin and embedded in paraffinwax. Histological sections were stained with hemo-toxylin-eosin (HE) and Van Gieson’s staining. The tis-sues were immunolabeled with MAC 387 (reactivemacrophages), CD 3 (T cells), CD 20 (B cells), smoothmuscle actin (smooth muscle cells), S100 (enteroglialcells), GFAP (enteroglial cells), NSE (neurons), c-kit(interstitial cells of Cajal) and synaptophysin (degene-rating neurons). The lamina propria of the mucosa of the duodenum,jejunum and ileum was diffusely infiltrated with neu-trophils, eosinophils, lymphocytes and plasma cells.Hypertrophy of the lamina muscularis mucosae wasobserved. The tunica submucosa was mildly edema-tous and infiltrated with moderate numbers of leuko-cytes. There was almost a complete loss of smoothmuscle cells in both the longitudinal and the circularlayers of the tunica muscularis (Figure 1). Both layerswere also severely infiltrated with lymphocytes,plasma cells and histiocytes. As demonstrated with im-munohistochemistry, T-cells, B-cells and macrophageswere present, but there appeared to be a larger num-ber of T-lymphocytes (mean of 51 T-cells/hpf to 14 B-Figure 2. Small intestine, CIPO.  Smooth muscle cells(colored brown) are prominent in the lamina muscularismucosae (→) and almost absent in tunica muscularis(►).  M = tunica mucosa; s = tunica submucosa; M = tu-nica muscularis; S = tunica serosa  Smooth muscle actinimmunolabeling, Bar 100 µm.Figure 1. Small intestine, CIPO.  The lamina muscularismucosae is hypertrophic (→). The tunica muscularis isathrophic and infiltrated with inflammatory cells (►).M = tunica mucosa; s = tunica submucosa; M = tunicamuscularis; S = tunica serosa.  HE, Bar 100 µm.Vlaams Diergeneeskundig Tijdschrift, 2009, 78 119cells/hpf). Only small numbers of smooth muscle cellswere present in the tunica muscularis, as demonstra-ted by actin immunolabeling (Figure 2). Fibrosis wasnot detected by Van Gieson’s staining. Histologicaland immunohistochemical examination of the neuro-nal plexi and cells of Cajal did not reveal any abnor-malities.  A transition to the normal tunica musculariswas noted in the colon. In samples of esophagus, tri-geminal ganglion and stomach, lesions were not ob-served. On the basis of these findings, a diagnosis ofmyopathic CIPO was made.DISCUSSIONIn human medicine, CIPO is a rare but well-knowndisease and is defined as an intestinal obstruction with-out mechanical basis. CIPO is idiopathic (primary) inthe majority of cases (Antonucci et al., 2008). How-ever, every disease that affects one of the control me-chanisms of intestinal functioning can be responsiblefor secondary CIPO, such as central and peripheral ex-trinsic autonomic nervous system disorders in neuro-pathies or myothonic dystrophy (congenital disordercharacterized clinically by progressive muscle weak-ness and wasting) and systemic sclerosis (abnormalaccumulation of fibrous tissue in skin and multiple or-gans) in myopathies. However, CIPO can also be ob-served in patients with hypothyroidism or hypo-parathyroidism. In the present case, no indications ofa concurrent disease affecting intestinal motility wereobtained. Therefore, the CIPO in this Bernese Moun-tain Dog was most probably idiopathic.In veterinary medicine, 11 cases of CIPO in dogshave been described, without predisposition for breed,age or sex (Arrick and Kleine, 1978; Moore and Car-penter, 1984; Swayne et al., 1986; Lamb and France,1994; Dvir et al., 2001; Petrus et al., 2001; Eastwoodet al., 2005; Couraud et al., 2006; Johnson et al.,2007). The present case is the second case reported ina Bernese Mountain Dog. All dogs had symptoms ofrecurrent gastrointestinal problems, mostly vomitingand inappetance (Moore and Carpenter, 1984; Swayneet al., 1986; Lamb and France, 1994; Dvir et al., 2001;Eastwood et al., 2005; Couraud et al., 2006). Basedon the clinical and radiographic findings, most cases,as in human medicine, were suspected of intestinal ob-struction. At laparascopy or laparatomy, the intestinalloops were severely dilated, but no physical obstruc-tion was found (Moore and Carpenter, 1984; Lamb andFrance, 1994; Dvir et al., 2001; Couraud et al., 2006).In one case, cecal impaction was present (Eastwood etal., 2005). In our case, as well as in the cases reportedin the literature, treatment did not have any effect andmost dogs died or were euthanized. If a necropsy wasperformed, severely dilated intestinal loops with a flac-cid wall and watery contents were found (Lamb andFrance, 1994; Dvir et al., 2001). In one case, necropsyrevealed thickened small intestine (Swayne et al.,1986). Both in the present case and in most of the re-ported cases in the literature, histological samples ofthe intestines demonstrated atrophy and infiltrationwith a mononuclear cell infiltration of the tunica mus-cularis (Moore and Carpenter, 1984; Lamb and France,1994; Dvir et al., 2001; Eastwood et al., 2005; Cou-raud et al., 2006). In contrast to our case, fibrosis of thetunica muscularis is a common finding in dogs withCIPO (Moore and Carpenter, 1984; Swayne et al.,1986; Lamb and France, 1994; Dvir et al., 2001). Anabrupt transition between affected and normal tunicamuscularis was present at the transition between ileumand colon.  It is tempting to speculate that this could bedue to a specific reaction to the small intestinal tract.However, information in the literature concerning tis-sue specificity of CIPO is lacking. Interestingly, in thepresent case, hypertrophy of the lamina muscularismucosa was observed. This has only been described in2 dogs (Arick and Kleine, 1978; Swayne et al., 1986).The reason for this finding is not clear, although itcould reflect a compensatory phenomenon.In the present case, a definite diagnosis of CIPOwas made after necropsy and histological examination.Although a full thickness biopsy of the jejunum washistologically examined, CIPO was not definitely di-agnosed.  Since only 1 biopsy of the small intestinaltract was examined, the observed lesions could repre-sent a focal process. Also, it was not evident that tunicamuscularis was primarily affected, since inflammationwas also observed in the tunica submucosa and necro-tic enterocytes were present. For this reason, and alsobecause CIPO is an extremely rare disease in dogs,other conditions affecting the small intestinal tractwere suspected, rather than a primary myopathy. As aconsequence, several full thickness biopsies from di-lated and non-dilated tracts of the alimentary canalshould be obtained for histopathological examination(Antonucci et al., 2008).In human medicine, several different immunohis-tochemical markers are applied on histological slidesof full thickness biopsies to characterize neuropathic,mesenchymopathic and myopathic forms of CIPO.Neuronal markers, such as GFAP, S100, NSE and sy-naptophysin, can be used to demonstrate loss of neu-rons or neuronal degeneration in myenteric plexi.  Ifthe inflammation or degeneration is invariably confi-ned to the myenteric plexus, a neuropathic form ofCIPO can be suspected.  The enteric mesenchymopa-thic form is associated with lesions in the interstitialcells of Cajal.  The decreased density of these cells canbe assessed using immunohistochemical markers suchas KIT (Antonucci et al., 2008).  The myopathic formis characterized by a selective decrease or even ab-sence of smooth muscle actin in tunica muscularis.Hence, immunolabelling for smooth muscle actin isconsidered a biological marker for this type of CIPO.In the present case, several immunohistochemical mar-kers were used and a myopathic form of CIPO wassuggested, based on the decrease in smooth musclecells in tunica muscularis and the absence of lesionsin myenteric plexi and in cells of Cajal. Immunolabeling for leukocytes revealed the pre-dominant presence of T-cells. This is in agreementwith a case of fibrosing myositis (Johnson et al.,120 Vlaams Diergeneeskundig Tijdschrift, 2009, 782007). Also in humans, a large population of T-cells(mainly CD8+) is observed in patients with CIPO andan autoimmune enteric leiomyositis is suggested aspossible underlying cause (Haas et al., 2005; Ruuskaet al., 2002). In conclusion, clinical suspicion of CIPO should beconfirmed by histological examination of full thick-ness biopsies of different sites of the intestinal tract.Furthermore, immunolabeling can be performed tobetter characterize the lesion. ACKNOWLEDGEMENTS We wish to thank Delphine Ameye, Christian Put-tevils and Sarah Loomans for their help with the dif-ferent stainings. We also want to express ourappreciation to all the clinicians of the Small AnimalClinic of the Faculty of Veterinary Medicine, GhentUniversity.REFERENCESAntonucci A., Fronzoni L., Cogliandro L., Cogliandro R.F.,Caputo C., De Giorgio R., Pallotti F., Barbara G., Cori-naldesi R., Stanghellini V., (2008). Chronic intestinalpseudo-obstruction. World Journal of Gastroenterology14, 2953-2961.Amleida P.S., Penna F.J. (2000). Chronic intestinal pseudo-obstruction in childhood. International Pediatrics 15, 83-90.Arrick R.H., Kleine L.J. (1978). Intestinal pseudo-obstruc-tion in a dog. Journal of the American Veterinary MedicalAssociation 172, 1201-1205.Couraud L, Jermyn K., Yam P.S., Ramsey I.K., PhilbeyA.W. (2006). Intestinal pseudo-obstruction, lymphocyticmyosistis and atrophy of the muscularis externa in a dog.The Veterinary Record 159, 86-87.  Dvir E, Leisewitz A.L., Van Der Lugt J.J. (2001). Chronicidiopathic intestinal pseudo-obstruction in an Englishbulldog. Journal of Small Animal Practice 42, 243-247.Eastwood J.M., McInnes E.F., White R.N., Elwood C.M.,Stock G. (2005). Caecal impaction and chronic intestinalpseudo-obstruction in a dog. Journal of Veterinary Medi-cine A 52, 43-44.  Haas S., Bindl L., Fischer H.P. (2005). Autoimmune entericleiomyositis: a rare cause of chronic intestinal pseudo-ob-struction with specific morphological features. HumanPathology 36, 576-580.Johnson C.S., Fales-Williams A.J., Reimer S.B., Lotsikas,P.J., Haynes J.S. (2007). Fibrosing gastrointestinal lei-omyositis as a cause of chronic intestinal pseudo-ob-struction in an 8-month-old dog. Veterinary Pathology 44,106-109.Lamb W.A., France M.P. (1994). Chronic intestinal pseudo-obstruction in a dog. Australian Veterinary Journal 71,84-86. Moore R, Carpenter J. (1984). Intestinal sclerosis withpseudo-obstruction in three dogs. Journal of the Ameri-can Veterinary Association 184, 830-833. Petrus D.J., Nicholls P.K., Gregory S.P. (2001). Megacolon;secondary to autonomic ganglioneuritis in a dog. The Ve-terinary Record 148, 276-277.Ruuska T.H., Karikoski R., Smith V.V., Milla P.J. (2002).Acquired myopathic intestinal pseudo-obstruction may bedue to autoimmune enteric leiomyositis. Gastroenterology122, 1133-1139.Swayne D.E., Tyler D.E., Farrell R.L., Cornelius L.M.(1986). Sclerosing enteropathy in a dog. Veterinary Patho-logy 23, 641-643.

Chronic intestinal pseudo-obstruction in a Bernese Mountain Dog

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Chronic intestinal pseudo-obstruction in a Bernese Mountain Dog

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