Keywords

Introduction

The term pseudo-obstruction literally denotes obstruction in the absence of true mechanical occlusion. Intestinal pseudo-obstruction can be either acute or chronic in nature depending on the duration of obstructive symptoms (chronicity defined as symptoms’ duration longer than 6 months) [1, 2]. Chronic intestinal pseudo-obstruction (CIPO) was first described in 1958 by Dudley and colleagues to report a series of 13 patients with symptoms suggestive of intestinal occlusion. These patients underwent exploratory laparotomies, which failed to identify a mechanical cause [3]. The existence of this pathological entity, in both the adult and pediatric population, was later substantiated by a number of other clinicians [4,5,6,7]. Research and clinical experience have shown considerable differences between the adult and pediatric population with intestinal pseudo-obstruction and the term pediatric intestinal pseudo-obstruction (PIPO) is now proposed to specifically characterize the condition in children.

Abnormal antegrade propulsive activity of the gastrointestinal (GI) tract, resulting from processes affecting its neurons, muscles, or interstitial cells of Cajal (ICC), is the pathophysiologic mechanism of PIPO [8]. This functional disability of the gut is responsible for a number of clinical symptoms such as abdominal distention, with or without abdominal pain, nausea, vomiting, and a reduced ability to tolerate oral and/or enteral nutrition [9]. Such symptomatology is, however, non-specific and the condition can remain undiagnosed for a long period of time during which patients may undergo multiple diagnostic investigations and often repeated surgical explorations in an effort to identify the underlying cause [9].

Although, by definition, the small intestine is always involved, any part of the GI tract can be affected in CIPO [1, 2] (Fig. 25.1). Esophageal involvement may lead to dysphagia due to impaired peristalsis, in some cases similar to that seen in achalasia [10, 11]. Involvement of the stomach results in poor feed tolerance due to gastroparesis suggested by the presence of delayed gastric emptying, while involvement of the large bowel and anorectum manifest with constipation (delayed colonic transit) and defecation disorders (sphincteric dysfunction), respectively [1].

Fig. 25.1
An X-ray of the abdomen illustrates the enlarged and hugely dilated small bowel loops.

Plain abdominal X-ray in a 7-year-old girl with PIPO. Note the enlarged and hugely dilated small bowel loops

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This chapter will focus on various aspects of PIPO and will attempt to address areas of controversy by exploring the most recent advances in the overall approach and management of this clinical entity.

Definition

According to an expert European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN)/International expert consensus paper on the disorder [12], CIPO in children has clear distinctions from CIPO in adults with the proposal that it be designated pediatric intestinal pseudo-obstruction (PIPO) rather than CIPO and be defined as follows: “Paediatric intestinal pseudo-obstruction is a disorder characterised by the *chronic inability of the gastrointestinal tract to propel its contents mimicking mechanical obstruction, in the absence of any lesion occluding the gut (*chronic is defined as persistence for 2 months from birth or at least 6 months thereafter).” The working group has suggested that the diagnosis of PIPO requires at least two out of four of the following criteria:

  1. 1.

    Objective measure of small intestinal neuromuscular involvement (abnormal validated transit; manometric and/or histopathology studies).

  2. 2.

    Recurrent and/or persistently dilated loops of small intestine with air–fluid levels.

  3. 3.

    Genetic, metabolic, or other abnormalities definitively associated with intestinal pseudo-obstruction.

  4. 4.

    Inability to maintain adequate nutrition and/or growth on normal oral feeding (therefore needing specialized oral and/or enteral nutrition and/or parenteral nutrition support) [12].

Epidemiology

PIPO is a rare disease; scanty epidemiological data exist regarding its incidence and prevalence in both adult and pediatric populations. A survey-based study estimated that approximately 100 infants are born in the United States every year with PIPO, suggesting an incidence of approximately 1 per 40,000 live births [13, 14]. A more recent nationwide survey for pediatric PIPO performed in Japan revealed that among children younger than 15 years of age, the prevalence of PIPO was 3.7 in one million children, of whom 56.5% developed PIPO in the neonatal period [15]. In another nationwide Japanese survey, 138 cases of PIPO were identified, with an estimated prevalence of 1.0 and 0.8 cases, and incidence of 0.21 and 0.24 cases, per 100,000 males and females, respectively [16]. Although adult studies reveal that the disease is more frequent in females [17,18,19], a recent epidemiological study in US hospitals focusing on PIPO revealed that the incidence of inpatient admission was 29/100,000 patients, with children of male gender and of Caucasian origin being more likely to be admitted [20]. Without doubt the development of national registries is pivotal in order to precisely define the epidemiological characteristics of this orphan disease.

Classification

The classification of PIPO is still challenging. Conditions resulting in PIPO can be classified by whether they primarily affect intestinal nerves (neuropathy), smooth muscle (myopathy), or interstitial cells of Cajal (ICC) (mesenchymopathy). The above-mentioned conditions can be further subdivided into primary or secondary, congenital or acquired, and diffuse or segmental, depending on the mode of inheritance, presentation, likely etiopathogenesis, or what part of the GI tract is involved. Where classification is not possible, they are defined as idiopathic. In truth, there is a considerable overlap [1, 2].

In primary PIPO the disease is usually localized to gastrointestinal tract, whereas in secondary cases there is a systemic disorder that directly or indirectly affects GI tract motility. Notably, in some cases of primary PIPO extra-gastrointestinal involvement may also be part of the clinical picture; examples include disorders of the urinary tract (e.g., hollow visceral myopathy and megacystis-microcolon-intestinal hypoperistalsis syndrome), the nervous system (e.g., central, peripheral, or autonomic neuropathies), and/or mitochondria (e.g., mitochondrial neurogastrointestinal encephalomyopathy [MNGIE]) [2, 21, 22]. Approximately 50% of PIPO cases qualify as secondary PIPO, as presented in Table 25.1 (this is particularly true for adult CIPO patients, whereas in pediatrics the disease is predominantly idiopathic or due to primary causes) [23]. Based on histological findings, both primary and secondary PIPOs can be further categorized into neuropathies, myopathies, and mesenchymopathies [24,25,26,27,28,29]. Although the onset of the disease is used to label whether PIPO is congenital or acquired, in children this area needs further elucidation [2, 8, 30].

Table 25.1 Classification of chronic intestinal pseudo-obstruction
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Etiology and Pathophysiology

The integrity of gastrointestinal sensorimotor function relies on a precise coordination between the autonomic nervous system, enteric nervous system (ENS), ICC, and smooth muscle cells. Any noxious stimulus, as depicted in Table 25.1, which affects the GI neuromusculature may lead to impaired peristalsis and the stasis of luminal contents [1]. Neurologic and metabolic disorders may affect the extrinsic GI neurons, whereas neurotropic viruses could evoke an inflammatory process insulting both the ENS and extrinsic nerve pathways [23, 98]; furthermore, evidence of enteric angiopathy and neuromuscular hypoxia has been identified in patients with mitochondrial neurogastrointestinal encephalomyopathy [150]. Paraneoplastic syndromes could also target the ENS by initiating an inflammatory process that affects the ganglia of the submucosal and myenteric plexuses, via a cellular infiltrate and production of circulating antineuronal antibodies [23, 151]. Some pathologies (e.g., muscular dystrophy) target the enteric smooth muscle fibers whereas entities such as dermatomyositis, scleroderma, Ehlers–Danlos syndrome, and radiation enteritis lead to a mixed neuromyopathic disorder [14, 152, 153]. Celiac disease, hypothyroidism, hypoparathyroidism, and pheochromocytoma could also lead to PIPO by affecting the GI neuromusculature; however, the exact mechanism is not fully defined.

Genetics

Elucidation of the genetic basis of PIPO has been somewhat disappointing but has recently improved because of the availability of genome sequencing.

Familial cases of PIPO have been historically recognized with several patterns of inheritance, reflective of the great heterogeneity of PIPO conditions. Both autosomal dominant and recessive modes of inheritance have been described for neuropathic and myopathic types of PIPO [5, 17, 18, 152, 154]. Mutations in filamin A [155], actin γ-2 [45], thymidine phosphorylase (TYMP) [156], polymerase γ (POLG1) [157], and, finally, RAD21 [158] and SGOL1 genes [159] have also been identified in recessive forms of PIPO with an associated syndromic phenotype. More recently, with the advancement in genetic testing, novel mutations (MYLK, LMOD1, MYL9, SGOL1, MYH11, PDCL3, and ACTG2 variants) have been identified and subsequently related to the etiopathogenesis of chronic intestinal pseudo-obstruction [160,161,162,163,164,165,166,167,168,169,170]. Of these, the smooth muscle actin γ-2 gene (ACTG2) is one of the most commonly implicated genes in Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) and prenatal and neonatal myopathic PIPO.

Three patients with a syndromic phenotype of PIPO combined with Waardenburg–Shah features (pigmentary abnormalities and sensorineural deafness) and an underlying “apparently normal” enteric innervation have been demonstrated to carry de novo heterozygous mutations of SOX10 [171, 172].

Specific genetic mutations are associated to complications. Medullary thyroid carcinoma associated with MEN2b and neurogangliomatosis should be searched for by measuring serum calcitonin levels, and early prophylactic thyroidectomy may be considered [173]. In cases with cardiac involvement (SGOL1), a pacemaker is indicated since severe bradycardia may occur [159]. Of note, a recently described cohesinopathy with SGOL1 mutation in four children represents a late-onset but severe PIPO etiology associated with severe bradycardia for which three of the four patients required a pacemaker because of sinus dysfunction at the time of PIPO diagnosis [174]. Filamin A gene on chromosome X as well as thymidine phosphorylase mutations are both associated to seizures and impaired neurological development [155].

Histopathology (See Chap. 19)

The role of histopathology in the confirmation of PIPO is still controversial. Studies in adults reveal that GI histology can be normal in up to 10% of cases, although in the experience of the authors this figure is likely to be higher in children. Adequate full-thickness bowel biopsy (preferably a circumferential sleeve of at least 1–2 cm) is recommended whenever surgery is being considered [8, 30, 175]. Recent initiatives support a more standardized histological approach for the diagnosis in GI dysmotilities such as PIPO [29, 176, 177].

On the basis of histology, PIPO is classified into neuropathy, myopathy, or mesenchymopathy; mixed forms (e.g., neuromyopathy) are also recognized [29, 178,179,180].

Neuropathies and myopathies can be further subdivided into inflammatory and degenerative. Inflammatory neuropathies are characterized by an infiltration of T-lymphocytes and plasma cells in the myenteric plexuses (myenteric ganglionitis) and neuronal axons (axonopathy); five or more lymphocytes per ganglion are required for the diagnosis of myenteric ganglionitis [29, 181]. Interestingly, patients with lymphocytic infiltration of the myenteric plexus may also develop increased titers of antinuclear antibodies (ANNA-1/anti-Hu, anti-VGKC); the latter could result in neuronal degeneration and loss via apoptotic and autophagic mechanisms [182,183,184,185]. Infiltration of the myenteric ganglia with other cells such as eosinophils and mast cells has also been identified but their clinicopathological significance is yet to be determined [186,187,188,189].

Degenerative neuropathies are defined by a decrease in the number of intramural neurons along with changes in nerve cell bodies and axons [176, 181, 190,191,192]. It has been postulated that aberrant calcium signaling, mitochondrial disorders, production of free radicals, and abnormalities in the function of glial cells initiate apoptotic mechanisms that are involved in the degenerative process [176, 178, 193, 194].

Myopathies are also categorized as inflammatory and degenerative. Inflammatory myopathy, also termed leiomyositis, is characterized by infiltration of T-lymphocytes into both the circular and longitudinal enteric muscle layers and if not treated appropriately with immunosuppressive agents may lead to a severe clinical picture of PIPO [47, 195]. A distinctive presumably acquired degenerative myopathy of unknown etiology, called African degenerative leiomyopathy (ADL), has been described in African populations in southern Africa [196]. The Ret gene implicated in Hirschsprung disease appears to confer susceptibility to ADL although the exact mechanism is not known [197].

Histopathology in degenerative myopathies reveals vacuolization and fibrosis of the smooth muscle fibers [198, 199]. In the cases where the longitudinal muscle is more affected compared to the circular muscle layer, diverticula may be identified [200, 201].

Novel techniques in immunohistochemistry, for example, smooth muscle markers such as smoothelin, smooth muscle myosin heavy chain, and histone deacetylase 8, may reveal subtle histopathologic abnormalities otherwise not detectable with conventional methods [202].

Mesenchymopathies are defined by ICC abnormalities (decreased density of ICC network, intracellular abnormalities) and have been identified in PIPO patients [176, 203]. Despite the fact that adequate data exist regarding the role of ICC in the pathogenesis of diabetic gastroparesis, further research is required to elucidate their involvement in the pathogenesis of other GI dysmotilities [29].

Clinical Picture

Signs and Symptoms

The symptomatology varies according to the age at diagnosis and the part of the GI tract, which is primarily affected. Intestinal malrotation is present in approximately one-third of children with congenital PIPO (myopathic and neuropathic) [26]. Cardinal signs and symptoms of PIPO include those of obstruction namely abdominal distention (88%), vomiting (69%, which can be bilious), and constipation (54%). Abdominal pain, failure to thrive, and diarrhea may also be part of the clinical picture (Table 25.2) [8, 9, 175].

Table 25.2 Clinical symptoms in children with chronic intestinal pseudo-obstruction
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The diagnosis of PIPO is difficult due to the variable clinical presentation and the lack of a specific diagnostic test. The diagnosis should be suspected in children presenting with signs and symptoms of intestinal obstruction without an occluding lesion. The diagnosis of PIPO should be also considered when there is persistent vomiting after a Ladd’s procedure for malrotation [58], when intestinal obstruction is associated with bladder dysmotility, or when, in a full-term neonate, there is persistent or recurrent obstruction after exclusion of Hirschsprung disease and hypothyroidism. The differential diagnosis should be carefully considered because establishing a diagnosis of PIPO may be invasive, and the psychological consequences in children and their families are significant.

Dehydration (which can be severe) and malnutrition are often underdiagnosed especially given that weight can be an unreliable measure due to pooling of significant volumes of fluid (third spacing) within distended gut loops. Delayed transit of gut content can also lead to small bowel bacterial overgrowth, which can further exacerbate symptoms of diarrhea and abdominal distention [175].

Extra-intestinal signs and symptoms may as well be part of the PIPO clinical presentation, for example, recurrent urinary tract infections or neurologic abnormalities [21, 156]. Furthermore, patients may complain of symptoms indicative of an underlying disorder that accounts for secondary PIPO (e.g., proximal muscle weakness in dermatomyositis) [62].

The clinical course of PIPO is characterized by exacerbations and remissions; the former can be precipitated by various factors such as surgery, general anesthesia, infections, and emotional stress [30]. In the most severe cases, the natural course of the disease leads to significant deterioration of the intestinal function and ultimately to intestinal failure [9, 175].

Prenatal Symptoms

Although the majority of PIPO cases present in the neonatal period or early infancy, in a few cases the diagnosis is supported in utero by ultrasonographic findings of polyhydramnios, abdominal distention, and megacystis [8, 30]. Prenatal signs can be detected in about 20% of cases [25, 204]. Megacystis is the most frequently reported sign, whereas dilated bowel at this age is quite rare. This has been noted in megacystis-microcolon-intestinal hypoperistalsis syndrome in which an antenatally enlarged bladder is seen by ultrasound in 88% of cases, hydronephrosis in 53%, increased volume of amniotic fluid in 34%, and gastric distension in only 10% [205]. Although some reports have described the detection of these signs by ultrasound as early as 16 weeks, more often the abnormalities are noted much later in gestation [206]. Antenatally diagnosed non-obstructive megacystis, with neonatal urological symptoms, may precede GI symptoms of pseudo-obstruction by several months.

Clinical Presentation After Birth

Fifty percent to two-thirds of patients present within the first month of life and 80% by 1 year of age. The remainder are detected sporadically throughout the first two decades of life [13, 24, 25, 204]. The clinical presentation is dependent on the age at onset.

Neonatal-Onset Form

In the neonatal form, PIPO presents as severe abdominal distension with bilious vomiting. Although not a universal finding, the abdominal X-ray may show dilated bowel loops with air–fluid levels suggestive of an organic intestinal obstruction. In megacystis-intestinal-hypoperistalsis syndrome, an obstructed urinary system leading to an abdominal distension may be the presenting feature (Fig. 25.2), with symptoms of intestinal obstruction appearing within days to 12 months later. In order to avoid unnecessary surgery, an exploratory laparotomy should be deferred in a neonate with antenatal diagnosis of megacystis. In these neonatal cases, the air–fluid levels on X-ray may be missing. Some affected infants may present with abdominal distension and diarrhea secondary to bacterial overgrowth.

Fig. 25.2
Three X-rays of the abdomen. Left, A colonic opacification of a small nonfunctional microcolon. Middle, A cystography of an enlarged bladder with footprints of digestive loops. Right, depicts malrotation and nonfunctional small bowel.

Girl neonate with megacystis-microcolon-hypoperistalsis syndrome. Left: Colonic opacification showing small non-functional microcolon. Middle: Cystography demonstrating enlarged bladder with “footprints” of digestive loops. Right: Small bowel follow-through showing malrotation and non-functional small bowel. In neonates, despite the small bowel involvement precluding any enteral feeding, the small bowel loops may not be enlarged converse to older children in whom dilated small bowel is always present

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PIPO may be mimicked by immaturity of intestinal motility in preterm infants, and thus this diagnosis should be made with caution in this group as the migrating motor complex does not appear in its mature form until a gestational age of 34–35 weeks [207, 208].

Infantile or Late-Onset Form

Major Forms

The symptoms depend on the regions of the gastrointestinal tract primarily involved. Patients present with subacute and/or recurrent episodes of gastric, intestinal, and/or colonic obstruction, necessitating frequent drainage and fluid replacement. This picture may be acute or insidious and chronic and persistent or more often intermittent. Exacerbations may be precipitated by a variety of causes including intercurrent infections, fever, vaccines, general anesthesia, and emotional stress. Diarrhea due to bacterial overgrowth is frequent and may alternate with constipation or episodes of partial obstruction. Stasis of intestinal contents is common in PIPO, and chronic dilatation leads to decompensation and elongation of the bowel, further impairing motility. When fluid and air accumulate in these decompensated loops, torsion caused by mechanical forces is possible. Dehydration (which can be severe) and malnutrition are often underdiagnosed, especially given that weight can be an unreliable measure due to pooling of significant volumes of fluid (third spacing) within distended gut loops [147]. Mechanical obstruction is normally absent in PIPO patients, but it can, however, be a complication of PIPO, especially after multiple interventions. Volvulus of the splenic flexure and colonic volvulus have been reported in numerous PIPO cases due to torsion of fluid-filled bowel loops [209,210,211].

Abdominal pain is often severe enough to lead to feeding difficulties resulting in malnutrition. Although esophageal involvement is frequently detected by manonetry, dysphagia is rarely reported [212]. Recurrent episodes of functional partial bowel obstruction may be very difficult to differentiate from true mechanical obstruction in the child who has undergone a prior laparotomy and who may have adhesions. A change in symptoms such as the new occurrence of abdominal pain may suggest the latter.

Urinary tract involvement occurs in 33–92% of cases, independent of the type of PIPO [204, 213,214,215]. Megacystis with a hypocontractile detrusor, and increased bladder capacity and compliance, is the most frequent pattern of urological abnormality (bladder adynamia). Ureterohydronephrosis is seen in 56–68% of cases but vesico-ureteral reflux occurs in less than 10% [215]. Urinary tract infections are frequent but may be asymptomatic. The renal prognosis is generally good, provided that careful, active evaluation and management of the poorly dynamic bladder are performed, to ensure adequate bladder emptying and to prevent urinary tract infection [215]. Where they are taken bladder biopsies show non-specific fibrotic changes in both neuropathic and myopathic forms of PIPO and are thus not useful for subtype classification.

Comorbidities

Malrotation is frequent, especially in neonates (up to 40% of cases) [24, 25, 204], and has been reported in an X-linked familial syndrome associating PIPO, malrotation, and pyloric non-hypertrophic stenosis (Fig. 25.3) [155, 216,217,218].

Fig. 25.3
An X-ray of the abdomen. A small bowel follow-through illustrates the malrotation, narrowed pylorus, and enlarged bowel.

Small bowel follow-through in a 6-month-old boy with an X-linked filamin-A mutation-related PIPO. Note the malrotation, narrowed pylorus, and enlarged bowel loops

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The physical examination should encompass a thorough neuromuscular assessment, including testing for pupillary reactions to light and accommodation and external ocular movements to help identify conditions associated with autonomic neuropathy or mitochondrial diseases. Testing for orthostatic stability should be performed in children, especially where postural dizziness, visual disturbances, and sweating abnormalities may suggest the presence of an underlying autonomic neuropathy [44].

External ophthalmoplegia associated with deafness may suggest a mitochondrial defect namely mitochondrial neurogastrointestinal encephalopathy (MNGIE). The onset of symptoms (gastrointestinal or ocular or both) generally occurs during adolescence, although very early-onset disease has been reported (5 months of age) [219]. Peripheral neuropathy and diffuse muscle weakness are the predominant manifestations, although almost all patients have indices of leukoencephalopathy on magnetic resonance imaging (MRI) of the brain [50]. Thymidine phosphorylase activity and plasma thymidine should be measured when suspecting such a diagnosis [220]. Audiological assessment is important to rule out deafness, seen in patients with a SOX10 gene mutation [171, 172]. The dermatological examination should note signs of connective tissue disease (i.e., scleroderma, dermatomyositis, lupus), including: Raynaud’s phenomenon, skin eruption, palmar erythema, telangiectasia, nodules, and scleroderma of the hands, feet, face, and forearms. Digestive symptoms may precede the skin involvement in these disorders [221].

Neural crest-derived tumors (neuroblastoma) and pheochromocytoma should be suspected and ruled out in children and infants with Chronic Intestinal Pseudo-obstruction (CIP): appropriate computed tomography (CT) imaging and ultrasound studies should be considered to exclude the presence of thoracic or abdominal tumors [222, 223].

Cardiac rhythm and function must be evaluated by electrocardiography (ECG) and echocardiography, since dysfunction of cardiac sinus node may be associated to PIPO [224] and abnormal cardiac contraction should lead one to suspect muscular diseases such as desmin myopathies [225].

Patients with suspected autoimmune GI dysmotility can present with acute or subacute (<8 weeks) onset of GI symptoms, family history of autoimmune diseases, an infectious episode preceding the onset, and extra-intestinal neurological symptoms like dysautonomia [103, 104].

Diagnosis

Chronic intestinal pseudo-obstruction should be suspected in children with early onset, chronic, recurrent, or continuous signs of intestinal obstruction especially where imaging or indeed surgery fails to reveal a mechanical obstruction of the gut (e.g., repeated “normal” exploratory laparotomies). Since the symptoms of PIPO are not specific, a careful differential diagnosis is of paramount importance.

The diagnosis of PIPO should be guided by a structured algorithm, and the ESPGHAN criteria previously described should be applied [12]. A detailed history combined with a meticulous clinical examination and laboratory tests (e.g., serum electrolytes, thyroid stimulating hormone [TSH], lactic acid, specific autoantibodies) may suggest the presence of PIPO and potentially elucidate its cause; however, the establishment of a definitive diagnosis should rely on the use of targeted investigations to: (1) exclude mechanical occlusion of the gut lumen; (2) confirm GI dysmotility, and (3) rule out treatable causes.

The diagnostic tests, which exclude luminal obstruction and confirm the presence of impaired GI motility in children, thus ruling in the diagnosis of PIPO, are discussed below.

Imaging

Since small bowel is always involved, plain abdominal radiographs demonstrate a dilated GI tract with air–fluid levels while contrast GI series can demonstrate anatomical abnormalities (e.g., malrotation, microcolon) and also exclude the presence of gut occlusive lesions [2, 175, 229]. It needs to be kept in mind that a water-soluble substance should be used instead of barium in order to prevent flocculation and inspissation of the contrast material (Figs. 25.1, 25.2, and 25.3).

Novel imaging modalities such as multidetector row helical CT and cine-MRI have been recently performed with promising results in adult series but there are currently limited data regarding their applicability and usefulness in pediatrics [230,231,232,233,234,235].

Endoscopy

Endoscopy may identify upper or lower bowel mechanical occlusion previously missed on radiology, and allows for duodenal biopsies to exclude mucosal inflammation [224]. Novel techniques (e.g., natural orifice transluminal endoscopic surgery—NOTES) may revolutionize the role of endoscopy in the diagnosis of gut motility disorders by providing the ability of full-thickness biopsy sampling in a safe and minimally invasive way [236, 237].

Motility Investigations

These studies are performed in order to assess the GI motility and to define the underlying pathophysiologic process; in pediatrics, they form the hallmark of diagnosis. The aforementioned studies include gastrointestinal manometries (esophageal, antroduodenal, colonic, anorectal; see Chaps. 10–13), scintigraphy (e.g., gastric emptying, colonic transit; see Chap. 16), electrogastrography, and radio-opaque marker studies (see Chap. 17). The usefulness of novel technologies, such as SmartPill, remains to be determined [8, 238,239,240].

Although in children with PIPO the involvement of GI tract may be generalized, the small intestine is always affected; thus antroduodenal manometry remains the most discerning test. It needs to be stressed though, that the optimal placement of the manometric catheter is of pivotal significance for a lege artis execution and precise interpretation of the this test [241]. Neuropathic cases manifest with uncoordinated contractions, which are of normal amplitude, whereas in myopathic PIPO motor patterns have normal coordination; however, the amplitude of intestinal contractions is low [212, 242, 243]. Of note, a newly proposed enhanced Antroduodenal Manometry (ADM) analysis and associated score Great Ormond Street London Antroduodenal Manometry Scoring System (GLASS score) has proven useful in order to discriminate between PIPO and non-PIPO patients and also between distinct histopathological pathologies [244]. Additionally, manometry may facilitate the dynamic assessment of potential pharmacotherapeutic options and feeding strategies (e.g., feasibility of oral or enteral feeds) as well as indicate disease prognosis [245,246,247]. Antroduodenal manometry features suggestive of PIPO are depicted in Table 25.3 and also described in Chap. 11.

Table 25.3 Features in antroduodenal manometry associated with PIPO
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In the most challenging cases, exploratory surgery (laparotomy or laparoscopic-assisted procedures) may be required to definitively exclude mechanical obstruction; however, it should be borne in mind that surgery may precipitate a pseudo-obstructive episode and may also lead to intra-abdominal adhesion formation, which in turn can further complicate future diagnostic or therapeutic procedures as well as lead to secondary mechanical obstruction. Where possible, investigations and then diagnostic/therapeutic surgery should be performed in timeline sequence and in referral centers with relevant expertise in the management of PIPO patients.

Histopathology along with both genetics and antroduodenal manometry can also be very useful in establishing or confirming the diagnosis of PIPO, highlighting the underlying pathophysiologic process and thus aiding the overall management.

Figure 25.4 summarizes the basic steps in the diagnostic evaluation of pediatric patients with suspected PIPO.

Fig. 25.4
An algorithm. A child with obstruction symptoms undergoes examination, blood tests, and G I tract assessment. If P I P O is confirmed, then do symptomatic treatment for primary and secondary P I P O.

Suggested diagnostic algorithm for pediatric intestinal pseudo-obstruction. (Modified from Rudolph CD, Hyman PE, Altschuler SM, Christensen J, Colletti RB, Cucchiara S, et al. Diagnosis and treatment of chronic intestinal pseudo-obstruction in children: report of consensus workshop. J Pediatr Gastroenterol Nutr. 1997;24(1):102–12; Thapar N, Saliakellis E, Benninga MA, Borrelli O, Curry J, Faure C, et al. Paediatric Intestinal Pseudo-obstruction: Evidence and Consensus-based Recommendations From an ESPGHAN-Led Expert Group. J Pediatr Gastroenterol Nutr. 2018 Jun;66(6):991–1019, with permission [2, 12])

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Differential Diagnosis

PIPO has to be differentiated from mechanical obstruction of the GI tract; the latter is usually characterized by marked abdominal pain (in keeping with the abdominal distention), specific radiologic signs, and manometric patterns [248,249,250]. Acute functional obstruction (e.g., postoperative ileus), functional GI disorders (e.g., rumination syndrome), and pediatric condition falsification should be considered and appropriately investigated and managed [175, 251, 252]. Table 25.4 provides differential diagnoses of PIPO.

Table 25.4 Differential diagnosis of PIPO in children
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Treatment

The therapeutic approach in PIPO is threefold as it aims to: (1) preserve growth and development by maintaining adequate nutritional intake; (2) preserve and even promote GI motility with combined medical and surgical interventions; and (3) treat disease-related complications or underlying pathologies in the cases of secondary PIPO.

In spite of the limited effect of the currently applied therapeutic options, refinements and evolution in nutritional, medical, and surgical strategies have considerably improved the overall PIPO management [153, 253]. Acute episodes of pseudo-obstruction are generally treated conservatively by intravenous fluid administration (patients remain nil by mouth) and decompression of the affected bowel with drainage of luminal contents via Nasogastric (NG) tube or preformed ostomies. Careful attention to fluid and electrolytes’ balance is imperative.

Nutrition

The role of nutrition in PIPO is of paramount significance as it is well established that gut motility improves with optimal nutritional support and declines in the face of under- or malnutrition [8]. In the long term, approximately one-third of pediatric PIPO patients require either partial or total parenteral nutrition, another third requires a degree of intragastric or enteral feeding, whereas the remaining children are able to tolerate sufficient oral nutrition [8]. Within all of the above-mentioned groups, patients able to tolerate feeds may require some dietary modification in order to maintain enteral nutrition and avoid bezoar formation (e.g., low-residue feeds, bite and dissolvable food, restriction diets, hydrolyzed formula).

Although parenteral nutrition is life-saving, it is associated with significant risk of complications, such as central line infections and liver disease; thus, maintaining patients on maximally tolerated enteral nutrition is always strongly encouraged [30]. In the more severe PIPO cases, continuous rather than bolus feeds administered via a gastrostomy or jejunostomy may be better tolerated; the latter is particularly true in those children with impaired gastric motor function [254,255,256].

Medications

Pharmacotherapy in PIPO patients is mainly confined to the control of intestinal inflammation, suppression of bacterial overgrowth, and promotion of GI motility [246, 256]. In cases of suspected autoimmune GI dysmotility or proven inflammatory process confirmed on full-thickness intestinal biopsies, urgent immunosuppressive therapy with high doses of intravenous steroids, intravenous immunoglobulins, or apheresis should be considered, especially if antineuronal antibodies are detected [103, 104].

Prokinetics (e.g., metoclopramide, domperidone, erythromycin, azithromycin, octreotide, neostigmine, pyridostigmine, prucalopride) and antiemetics (e.g., promethazine, ondansetron) have been used to reduce the severity of nausea and vomiting and improve GI motor function along with enteral feed tolerance [257,258,259,260,261,262,263]. The use of some of these agents is limited because of their variable efficacy and unacceptable extra-intestinal side-effects (e.g., metoclopramide, neostigmine). The best studied and tested prokinetics, that is, cisapride and tegaserod, have been withdrawn from the market due to safety concerns [264]. Recent data suggest that antibiotics such as co-amoxiclav may have prokinetic effects and induce an increased number of migrating motor complexes during the fasting phase of antroduodenal manometry. The need for novel prokinetics with increased safety profile and efficacy has resulted in the development of new products (e.g., prucalopride, aprepitant, ghrelin), but there are limited data regarding their use in pediatric PIPO, further impacted on by restricted availability and licensing [265,266,267]. Undoubtedly, current medical regimens for PIPO are based on limited literature and/or expert opinion (e.g., combined use of octreotide and erythromycin) and are yet to be tested in future in the context of controlled trials [246, 268].

A small pilot study has recently demonstrated the safety of using fecal microbiota transplantation (FMT) in adults with CIPO, with improvement in symptoms, tolerance of oral feeding, and with no severe adverse events [269]. The utility of FMT in PIPO has not been determined.

Surgery

Surgery remains a valuable intervention on patients with PIPO as it has a multidimensional role in both the diagnostic (e.g., full-thickness biopsies) and therapeutic processes (e.g., insertion of feeding tubes, formation of decompressing ostomies such as gastrostomy, ileostomy) [256, 270, 271].

Indeed, adequate bowel decompression (e.g., gastrostomy, gastrojejunostomy, ileostomy) is crucial not only in providing symptomatic relief by reducing the frequency and the severity of pseudo-obstructive episodes but also in limiting further deterioration of the intestinal motor activity secondary to chronic distention, and in enhancing the tolerance of enteral feeding [24, 25, 256, 270, 272,273,274,275]. Long decompression enteral tubes and extensive bowel resections are approaches mainly reported in adult CIPO cohorts but remain untested in terms of practicality, efficacy, and safety in pediatrics [276,277,278]. Moreover, small bowel resections may lead to short gut syndrome and intestinal failure-associated liver disease [270, 279]. One additional concern is that resections of small intestine may decrease the abdominal domain required for the successful outcome of a potentially necessary future intestinal transplantation [270, 279].

Enterostomy-associated complications (e.g., ostomy prolapse) [280, 281], recurrent pancreatitis [282], diversion colitis [283], excessive fluid losses with high ileostomy output [284], and hemodynamic collapse due to cardiac dysfunction and abdominal compartment syndrome [285] have been reported in patients with chronic intestinal pseudo-obstruction. In patients with gastric and upper digestive tract involvement, gastric perforation and gastric bezoars may occur [204].

Closure of the decompressive ileostomy and restoration of the gut continuity may be attempted in carefully selected patients who have demonstrated significant and clear improvement post ileostomy formation, and have managed to wean parenteral nutrition and remain on full enteral and/or oral feeds without experiencing any troublesome symptoms for a period of at least 2 years. In the opinion of the authors, this is most likely to occur in neuropathic cases of PIPO and least in myopathies. In patients who show recovery with an ileostomy in situ, an ileo-rectal Duhamel pull-through has proven to be the most effective approach [25, 204, 278, 286].

Incidences of the enterostomy-associated complications are not insignificant in PIPO patients as these patients do have an increased rate of stomal prolapse along with a high risk of intestinal necrosis [280, 281]. A meticulously constructed ileostomy combined with careful management of the ostomy, reduces the probability of stomal prolapse thus minimizing the risk of additional intestinal resection [25, 280].

Novel surgical methods involve implantation of devices providing electrical pacing of the GI neuromusculature, but data on children are scanty and limited [287]. Significant progress has been made in regenerative medicine (see Chap. 49), especially with neural cell replacement within the bowel [288, 289]. This has not yet reached clinical trials and is hampered by poor disease characterization [290].

Small bowel transplantation still remains today the only definitive cure for PIPO. The outcomes and survival rates in experienced centers have significantly improved (up to 50% survival rate at 3 years) during the last decade owing to advances in both the surgical approach (e.g., multivisceral transplantation) and the immunosuppressive treatment [291,292,293,294,295,296,297,298,299] (see Chap. 51).

Natural History, Outcome, and Prognosis

Both pediatric and adult PIPO patients have a severe clinical course, characterized by repetitive relapses and remissions. Regrettably, the low index of suspicion among physicians along with the lack of well-defined diagnostic criteria and readily available facilities in performing specialized diagnostic tests (e.g., manometry), often account for repetitive unnecessary investigations and surgery as well as delayed diagnosis and thus initiation of appropriate management.

The majority of the patients complain of symptoms, which progressively worsen and impact upon the tolerance of enteral nutrition consequently increasing reliance on total parenteral nutrition [227, 228]. The latter in conjunction with disease-related adverse events (e.g., central line infections, impairment of the liver function, immunosuppression after small bowel transplantation, surgical procedures) account for high morbidity, poor quality of life, and mortality rates up to 30% [13, 25, 32, 204, 205, 226, 300,301,302].

Despite recent diagnostic and therapeutic advances PIPO in children remains a serious, life-threatening disease with significant impact on the well-being not only of patients themselves but also of their families [301].

Outcomes

In secondary and acquired forms of PIPO, outcome is dependent on the underlying disease responsible for the dysmotility. In cases of destruction of enteric innervation or musculature (autoimmune GI dysmotility), deterioration may occur rapidly without specific treatment [103, 104, 303].

Most often viral infection resolve spontaneously [304] but some chronic cases have been reported [305, 306].

In primary forms of PIPO, the prognosis is poor. In one series of 105 patients, two-thirds required parenteral nutrition and 41% could not be enterally fed. More than half of the patients were Total Parenteral Nutrition (TPN)-dependent for periods ranging from 2 months up to 16 years. Eleven patients (10%) received TPN for more than 10 years. Twenty-four of the 58 patients who underwent bypass surgery were able to eat normally and 20 of those eventually had their stoma closed [204]. Heneyke and colleagues reported that if TPN is required for more than 6 months, the child will probably be TPN-dependent for at least 4 years [25].

Mortality

Progress in the management of parenteral nutrition and the use of bowel decompression have modified the high mortality rate reported in historical series in neonates, for whom up to 90% of patients died before 1 year of age [59, 205]. In series published more recently, mortality varied from 4.8% (3/62 patients) [15] to 10% (10/105) [204], 25% (22/85) [24], and, in one study, just over 30% (14/44) [25]. Of these, underlying PIPO is rarely the primary cause of death except in cases with MEN2b and medullary carcinoma. In pediatric series reported to date, the high mortality rate is almost always due to iatrogenic complications. Long-term TPN-related complications, including central venous catheter-associated sepsis, liver failure, and thrombo-embolic events, as well as post-transplantation complications are the major contributing factors to mortality and morbidity in PIPO patients [24, 25, 204]. Sudden cardiac arrest has been reported in two patients with chronic intestinal pseudo-obstruction [307].

Prognostic Factors

In the large pediatric series published to date, comparison between patients requiring and those no longer requiring artificial feeding shows significant clinical differences in terms of likelihood of neonatal onset, urinary tract involvement, requirement for surgery during the course of the disease, and myopathic disorders, all features that are more frequent in cases with a poor prognosis [24, 25, 204, 227, 228]. The presence of phase III of the Migrating Motor Complex (MMC) on antroduodenal manometry has been reported by several groups to be a good prognostic indicator for tolerance of enteral feeding [212, 254], response to cisapride [245], and mortality [247]. Malrotation is also a factor associated with worse prognosis [25].

Summary

Pediatric PIPO is an enigmatic disease with poorly defined etiopathogenesis, which is reflected on the limitations encountered in both the diagnostic process and therapeutic management. Clearly, multinational initiatives are required to raise awareness, establish stringent diagnostic criteria, and evolve current therapeutic modalities.