Keywords

Introduction

The term “pseudo-obstruction” literally denotes the absence of a true mechanical occlusion. Intestinal pseudo-obstruction can be either acute or chronic in nature, reflecting the duration of obstructive symptoms [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 for their symptomatology [3]. In subsequent years, the existence of this pathological entity in both adults and children was substantiated by a number of other clinicians [4,5,6,7].

In 2018, an ESPGHAN-led group of experts introduced the term “pediatric intestinal pseudo-obstruction” (PIPO) in order to distinguish pediatric from adult-onset CIPO. The aforementioned group of experts defined PIPO as a clinical entity “characterized by the chronic inability of the gastrointestinal tract to propel its contents mimicking mechanical obstruction, in the absence of any lesion occluding the gut.” The group defined “chronic” as persistence of symptomatology for 2 months from birth or at least 6 months thereafter [8].

The pathophysiologic mechanism of PIPO is represented by abnormal antegrade propulsive activity of the gastrointestinal (GI) tract as a result of processes that affect its neurons, muscles, or interstitial cells of Cajal (ICC) [9]. This functional failure results in a number of clinical symptoms such as abdominal distention with or without abdominal pain, nausea, vomiting, and a reduced inability to tolerate enteral nutrition [10]. These symptoms are, however, nonspecific, 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 cause [10].

Although by definition the small intestine is always involved, any part of the GI tract can be affected in PIPO [1, 2, 8]. Esophageal involvement may lead to dysphagia from impaired peristalsis, in some cases akin to that seen in achalasia [11, 12]. Involvement of the stomach results in poor feed tolerance from gastroparesis suggested by the presence of delayed gastric emptying, while the large bowel by delayed colonic transit and constipation and the anorectum by sphincter dysfunction and defecation disorders [1].

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

Epidemiology

PIPO is a rare disease with scanty epidemiological data and poorly defined incidence and prevalence in both adult and pediatric populations. One of the few initiatives to elucidate its epidemiology suggested that approximately 100 infants are born in the USA every year with PIPO, suggesting an incidence of approximately 1 per 40,000 live births [13, 14].

Adult studies reveal that the disease is more frequent in females [15,16,17]. In a national survey conducted in Japan, 138 cases of chronic intestinal pseudo-obstruction 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 [18]. Moreover, a recently published nationwide survey for PIPO in Japan revealed that the prevalence of PIPO, among children younger than 15 years, was 3.7 per one million children. In the aforementioned population, 56.5% of children had developed PIPO during the neonatal period [19].

Undoubtedly, the development of national registries is of paramount importance to delineate more precise epidemiologic characteristics of this orphan clinical entity.

Classification

Classification of PIPO is challenging. Conditions can be classified by whether they primarily affect intestinal nerves (neuropathy), smooth muscle (myopathy), or ICC (mesenchymopathy) and can be further subdivided into primary or secondary, congenital or acquired, mode of inheritance 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, 8].

In primary PIPO, the disease is usually localized to GI tract, whereas in secondary cases, there is a systemic disorder that affects GI tract motility. It must be noted though that in some cases of primary PIPO extra-GI involvement may also be present, such as the urinary tract (hollow visceral myopathy and megacystis microcolon intestinal hypoperistalsis syndrome), the nervous system (central, peripheral, autonomous), and/or mitochondria (mitochondrial neurogastrointestinal encephalomyopathy, MNGIE) [2, 20,21,22]. Table 23.1 depicts the classification of PIPO. In children the disease may manifest with symptoms either during the nenonatal period (neonatal-onset form) or later (infantile or late-onset form); the majority of PIPO cases are congenital and primary, whereas in adults secondary forms of CIPO (mostly due to systemic disease) are more frequent [8, 23]. Based on histological findings, both primary and secondary PIPO can be further categorized into neuropathies, myopathies, and mesenchymopathies [24,25,26,27,28,29].

Table 23.1 Classification of Pediatric Intestinal Pseudo-obstruction [8]
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Etiology and Pathophysiology

The integrity of GI sensorimotor function relies on precise coordination between the autonomic nervous system, enteric nervous system (ENS), ICC, and smooth muscle cells. Any noxious stimulus, irrespective of its origin and etiology, that affects the neuromuscular elements and control of GI tract can lead to impaired peristalsis and the stasis of luminal contents [1]. A variety of disorders and pathophysiological mechanisms can potentially affect the structure or function of the neuromuscular elements of the GI tract and lead to PIPO (Table 23.1) [8]. Neurological (e.g., multiple endocrine neoplasia (MEN) type IIb, familial dysautonomia) and metabolic (e.g., diabetes mellitus) conditions may affect the extrinsic GI nerve supply [23]. Neurotropic viruses may evoke an inflammatory process targeting both the ENS and extrinsic neural pathways [97]. Paraneoplastic syndromes may also exert a destructive effect on the ENS by initiating an inflammatory process that targets the neurons of ganglia located in the submucosal and myenteric plexuses. This is mediated by both a cellular infiltrate and production of circulating antineuronal antibodies [23, 109]. Some pathologies (e.g., muscular dystrophy) may target enteric smooth muscle fibers, whereas others such as dermatomyositis, scleroderma, Ehlers–Danlos syndrome, and radiation enteritis may distort both ENS and gut smooth muscle leading to a mixed neuromyopathic disorder [14, 110, 111]. Finally, although entities such as celiac disease, hypothyroidism, hypoparathyroidism, and pheochromocytoma presumably cause PIPO by affecting the GI neuromuscular integrity, the exact mechanism is not fully understood.

Genetics

Although there has been considerable progress, the elucidation of the genetic basis of PIPO has been rather limited. The majority of PIPO cases are sporadic [8]. Some familial cases of PIPO have been recognized, but there appear to be several patterns of inheritance, perhaps 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, 15, 16, 110, 112]. More specifically, rare autosomal dominant mutations in the SOX10 gene, which encodes a transcription factor important in ENS development, result in a PIPO clinical phenotype along with features such as sensorineural deafness and pigmentary anomalies [113, 114]. Homozygosity on the region 8q23–q24 has been implicated in the pathogenesis of an autosomal recessive form of PIPO characterized by severe GI dysmotility, Barrett’s esophagus, and cardiac anomalies [115, 116].

X-linked inheritance (locus Xq28) with recessive transmission has been described in PIPO [17, 117, 118]. Mutations of filamin A (FLNA) and L1 cell adhesion molecule (L1CAM) genes, which are both located on chromosome Xq28, result in predominantly myopathic and neuropathic forms of PIPO, respectively. Additional involvement of the central nervous system, heart (patent ductus arteriosus), and blood (thrombocytopenia) in both conditions has also been described [118,119,120].

Mutations in mitochondria are increasingly implicated in PIPO. Mutations in the thymidine phosphorylase gene (TYMP, also termed as endothelial cell growth factor-1, ECGF1), or in the polymerase-γ gene (POLG) result in recessive myopathic forms of PIPO. The former is the cause of MNGIE, whereas the latter leads to a form without encephalopathy. Apart from the GI dysmotility, MNGIE is characterized by severe malnutrition, opthalmoplegia, and leucoencepalopathy on brain MRI [121,122,123]. Furthermore, mutations in the following genes, actin G2 [44], RAD21 [124], and SGOL1 [125], have been identified in recessive forms of PIPO with an associated syndromic phenotype.

Of note, with the advancement in genetic testing, novel mutations (MYLK, LMOD1, MYL9, MYH11, PDCL3, and ACTG2 variants) were identified and were subsequently related to the etiopathogenesis of megacystis microcolon intestinal hypoperistalsis syndrome [126,127,128,129,130,131,132].

Histopathology

In adults, GI histology is reported to be normal in approximately 10% of CIPO cases, while in the experience of the authors, this figure is likely to be higher in children. However, its role in PIPO remains crucial in order to inform prognosis and also guide further investigations for systemic diseases that require specific treatment; therefore, an adequate full-thickness biopsy is recommended whenever surgery is being considered [29]. Recent initiatives are addressing a more standardized and hopefully effective histological approach to diagnosis in GI motility disorders such as PIPO [29, 133, 134].

On the basis of histology, PIPO is classified into neuropathy, myopathy, or mesenchymopathy [29, 135]. However, mixed forms (e.g., neuromyopathy) are also recognized [29].

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) [136,137,138]. It has been proposed that five or more lymphocytes per ganglion are required for the diagnosis of myenteric ganglionitis [137, 139]. Of note, patients with lymphocytic infiltration of the myenteric plexuses may also develop increased titers of antinuclear antibodies (ANNA-1/anti-Hu, anti-voltage-gated potassium channel or VGKC) [49, 140,141,142]. These immunologic responses may result in neuronal degeneration and loss by activating apoptotic and autophagic mechanisms [143]. Infiltration of the myenteric ganglia with other cells such as eosinophils and mast cells has been described, but their exact clinicopathological significance is yet to be clarified given limited data [144,145,146]. All these data support the role of the immune system in the pathogenesis of inflammatory PIPO [135, 147].

Degenerative neuropathies are poorly understood given the limited amount of available data [133, 147,148,149]. Main histopathologic characteristics of this group include a decrease in the number of intramural neurons along with changes in nerve cell bodies and axons [46, 150]. It has been postulated that apoptotic mechanisms are involved in the degenerative process potentially caused by aberrant calcium signaling, mitochondrial disorders, production of free radicals, and abnormalities in the function of glial cells [151, 152].

Similarly to neuropathies, myopathies are also divided into inflammatory and degenerative. Inflammatory myopathies, also reported by the term “leiomyositis,” are characterized by infiltration of T lymphocytes into both the circular and longitudinal enteric muscle layers. This process if not treated appropriately with immunosuppressive agents may lead to a severe clinical picture of PIPO [121, 123].

The histopathologic findings in degenerative myopathies include smooth muscle fiber vacuolization and fibrosis [153]. Diverticula may also be present especially if the longitudinal muscle coat is more affected compared to the circular muscle layer [147, 154].

Novel immunohistochemical techniques, such as smooth muscle markers, namely, smoothelin, smooth muscle myosin heavy chain, and histone deacetylase 8, may reveal histiopathologic subtleties otherwise not detectable with conventional immunostaining and histochemistry methods [29].

Mesenchymopathies are defined by ICC abnormalities (decreased density of ICC network, intracellular abnormalities) and have been demonstrated in patients with chronic intestinal pseudo-obstruction [8, 9, 155]. Although sufficient data exist regarding their role in the pathogenesis of diabetic gastroparesis, further research is required regarding ICC involvement in the etiopathogenesis of other GI motility disorders [26].

Clinical Picture

In a few cases, the diagnosis of PIPO is suggested in utero by ultrasonographic findings of polyhydramnios, abdominal distention, and megacystis; however, the majority of cases present in the neonatal period or early infancy [9, 10, 156]. The symptomatology varies according to the age at diagnosis and the part of the GI tract, which is primarily affected. Approximately, one-third of children with congenital PIPO (myopathic and neuropathic) have intestinal malrotation [156]. Cardinal signs and symptoms of PIPO include those of obstruction, namely abdominal distention (88%), vomiting (72%, which can be bilious), and constipation (61%). Abdominal pain (44%), failure to thrive (31%), and diarrhea (28%) may also be part of the clinical picture [20, 122].

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. Intraluminal gut content stasis can also lead to small bowel bacterial overgrowth which can further exacerbate symptoms of diarrhea and abdominal distention [62].

PIPO may also manifest with extraintestinal signs and symptoms, such as recurrent urinary tract infections or neurologic abnormalities [155]. Furthermore, patients may complain of symptoms indicative of an underlying disorder that accounts for secondary PIPO (e.g., proximal muscle weakness in dermatomyositis) [10, 156].

The clinical course of PIPO is characterized by exacerbations and remissions, where the former can be precipitated by a number of factors such as surgery, general anesthesia, infections, and emotional stress [8]. In the most severe cases, the natural course of the disease leads to worsening intestinal function and ultimately to intestinal failure [8]. This is especially true in cases where the diagnosis and/or institution of appropriate treatment has been delayed.

Diagnosis

PIPO should be suspected in children with early onset, chronic, recurrent, or continuous signs of intestinal obstruction especially where a surgical cause cannot be established (e.g., repeated “normal” exploratory laparotomies). The diagnosis of PIPO should follow a structured algorithm as proposed by the ESPGHAN-led expert group [2, 156, 157]. Although a detailed history, clinical examination, and laboratory tests may suggest the presence of PIPO, or help elucidate its cause, the ESPGHAN-led expert group proposed that the definitive diagnosis requires at least two out of the four following criteria [158]:

  1. (i)

    Objective measure of small intestinal neuromuscular involvement (manometry, histopathology, transit studies)

  2. (ii)

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

  3. (iii)

    Genetic and/or metabolic abnormalities definitively associated with PIPO

  4. (iv)

    Inability to maintain adequate nutrition and/or growth on oral feeding (needing specialized enteral nutrition and/or parenteral nutrition support)

Careful clinical history and physical examination may help in defining the onset, the severity and progression of the disease, and the part of the GI tract primarily affected, and they also provide useful information regarding associations (e.g., family history), potential secondary causes (e.g., medications), and complications (e.g., dehydration). Laboratory tests [e.g., serum electrolytes, thyroid-stimulating hormone (TSH), lactic acid, specific autoantibodies] are useful in cases of secondary PIPO and in order to assess the clinical state of the patients admitted acutely or undergoing a diagnostic protocol.

Imaging

Plain abdominal radiographs may demonstrate a dilated GI tract, with air-fluid levels, whereas contrast GI series can reveal anatomical abnormalities (e.g., malrotation, microcolon) and exclude the presence of gut occlusive lesions (Fig. 23.1a) [159]. 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.

Fig. 23.1
figure 1

Investigation findings of a 3-year-old boy with a history of recurrent episodes of abdominal distension and vomiting since the neonatal period, and now showing a marked reduction in enteral feed tolerance. (a) Contrast follow-through study (administered via gastrostomy) showing filling of grossly dilated small intestinal loops, without any apparent hold up or change in caliber. (b) Plain abdominal radiograph taken following placement of antroduodenal manometry catheter into the same patient performed under fluoroscopic guidance. The tip of the catheter has been advanced beyond the duodenojejunal junction to facilitate optimal manometric recording of both the stomach and small intestine. (c) Antroduodenal manometry tracing from patient showing the presence of some gastric antral contractions and a migrating motor complex (phase III activity) passing down the small intestine. The amplitude of small intestinal contractile activity is very low (not exceeding 20 mmHg) suggesting a diagnosis of myopathic chronic intestinal pseudo-obstruction

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Novel imaging modalities such as cine MRI have been recently performed with promising results in adult series, but there are no data regarding their applicability and usefulness in pediatrics [160, 161].

Endoscopy

Endoscopy may identify fore- or hindgut mechanical occlusion previously missed on radiology, and it allows duodenal biopsies to exclude mucosal inflammation [9, 162, 163]. 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 [164].

Motility Investigations

These studies are performed to assess the GI motility and to define the underlying pathophysiologic process, and these studies form the hallmark of diagnosis in pediatrics. Investigations include GI manometries (esophageal, antroduodenal, colonic, anorectal), GI scintigraphy (e.g., gastric emptying, colonic transit), electrogastrography, and radiopaque markers. The usefulness of novel technologies, such as SmartPill, remains to be determined [165,166,167].

Although in children with PIPO the involvement of GI may be generalized, the small intestine is always affected; thus, antroduodenal manometry remains the most discerning test, and its optimal placement is pivotal (Fig. 23.1b) [168,169,170]. 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 (Fig. 23.1c) [171, 172]. 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 [156, 173, 174].

In the most challenging cases, exploratory surgery (laparotomy or laparoscopic-assisted procedures) may be required to definitively exclude mechanical obstruction from PIPO. One however should bear in mind that surgery may precipitate a pseudo-obstructive episode and may also lead to adhesions formation, which can further complicate future diagnostic or therapeutic procedures. Where possible, investigations and then diagnostic/therapeutic surgery should be performed in timeline sequence and in referral center.

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

Differential Diagnosis

PIPO has to be differentiated from mechanical obstruction; the latter is usually characterized by marked abdominal pain (in keeping with the abdominal distention), specific radiologic signs, and manometric patterns [111, 175]. 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 [9].

Treatment

The therapeutic approach in PIPO is threefold as it aims to (i) preserve growth and development by maintaining adequate caloric intake, (ii) promote GI motility with combined medical and surgical interventions, and (iii) treat disease-related complications or underlying pathologies that cause secondary PIPO. Despite the limited effects of the currently applied therapeutic modalities, refinements and evolution in nutritional, medical, and surgical strategies have considerably improved the overall management of PIPO [155]. Acute management of episodes of pseudo-obstruction is generally treated conservatively by nil by mouth, intravenous fluid, and drainage of stasis through nasogastric (NG) tube or preformed ostomies. Careful attention to fluid and electrolytes is imperative.

Nutrition

The role of nutrition in PIPO is of paramount significance as it is well known that gut motility improves with optimal nutritional support and declines in the face of under- or malnutrition [176,177,178,179,180]. In the long term, approximately one-third of PIPO patients require either partial or total parenteral nutrition, another third require a degree of intragastric or intra-enteral feeding, whereas the remaining children are able to tolerate sufficient oral nutrition. However, within all of groups, patients able to tolerate feeds may require some dietary modification in order to maintain enteral nutrition and avoid bezoar formation (e.g., bite and dissolvable feeds, restriction diets, hydrolyzed formula).

Although parenteral nutrition is lifesaving, it is associated with significant risk of complications, such as central line infections and liver disease, and therefore maintaining patients on maximally tolerated enteral nutrition is always strongly encouraged [169, 178]. In the more severe PIPO cases, continuous rather than bolus feeds administered via a gastrostomy or jejunostomy may be better tolerated particularly in children with impaired gastric motor function [8, 181,182,183,184].

Medications

The therapeutic role of drugs in PIPO patients is mainly limited to the control of intestinal inflammation, suppression of bacterial overgrowth, and promotion of GI motility [185].

Prokinetics (e.g., metoclopramide, domperidone, erythromycin, azithromycin, octreotide, neostigmine, pyridostigmine) usually combined with antiemetics (e.g., promethazine, ondansetron) have been used in an attempt to improve the GI motor function and reduce the severity of nausea and vomiting [186,187,188,189,190,191]. The use of some of these agents is limited by variable efficacy and unacceptable extraintestinal 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 [169, 192]. The need for new prokinetics with increased safety and efficacy has resulted in new products (e.g., prucalopride, aprepitant, ghrelin), but there are limited data of their use in pediatric PIPO, further impacted on by restricted availability and licensing [178, 193, 194].

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 [178, 193].

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) [195, 196].

Indeed, adequate bowel decompression 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 [197]. 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 [198,199,200,201]. Rate of significant surgical complications, such as stoma prolapse, infection, and leakage can be significant.

Novel surgical methods involve implantation of devices providing electrical pacing of the GI neuromusculature, but data in children are scanty and limited [8, 15,16,17, 144].

Small bowel transplantation remains the only definitive cure. Recent advances in both surgical techniques (e.g., multivisceral transplantation) and immunosuppression strategies have resulted in improved outcomes and survival as reported by centers with the relevant expertise showing a survival rate of 50% at 3 years [13, 25, 31, 202,203,204,205,206].

Natural History and Prognosis

Both pediatric and adult chronic intestinal pseudo-obstructions have a severe clinical course, characterized by repetitive relapses and remissions. Unfortunately, the low index of suspicion among physicians along with lack of well-defined diagnostic criteria and readily available facilities in performing specialized diagnostic tests (e.g., manometry) often accounts for delays in the diagnosis and repetitive unnecessary investigations and surgery [206].

The majority of the patients complain of symptoms, which progressively worsen and impact upon the tolerance of enteral nutrition and increasing reliance on total parenteral nutrition [179, 180]. 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) accounts for high morbidity, poor quality of life, and mortality rates up to 30% [13, 25, 31, 202,203,204,205,206].

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 [206].

Summary

PIPO is a debilitating 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 and evolve current diagnostic modalities and therapeutic options.