A large proportion of children with IBS are still categorized under a broad umbrella of recurrent abdominal pain, and the prevalence of IBS in children is underrecognized. Subcategorizing children presenting with chronic abdominal pain into IBS, dyspepsia, and functional abdominal pain is important because it helps to narrow down the differential diagnosis, reduces the number of unnecessary investigations, and helps to better target the therapy. In a study of 478 children referred to a large gastroenterology clinic with functional abdominal pain, 26% of the subjects had symptoms of diarrhea-predominant IBS [2]. Another pediatric study of 171 subjects with chronic abdominal pain reported that 68% of subjects fulfilled the clinical criteria for the diagnosis of IBS [3]. Community-based studies from North America and China suggest that 8–17% of school children have IBS-like symptoms [4, 5].

In a majority of patients, a good clinical history is sufficient to diagnose IBS and differentiate it from organic diseases that can mimic IBS symptoms (Table 52.1). To standardize the diagnosis of IBS, symptom-based criteria have been developed and amended by the Pediatric Rome Committee (Table 52.2) [6]. Specific alarm symptoms, which alert the clinicians to the increased likelihood of an underlying organic disease, can help in the management and planning of investigative workup. In a large study of 606 children, the following alarm symptoms were more likely in children with Crohn disease compared to those with pain-associated functional gastrointestinal disorders (FGIDs) including IBS, hematochezia, weight loss, and difficulty in gaining weight. Although included in the Rome criteria, nocturnal abdominal pain and sleep disruption were not helpful in differentiating children with IBS from those with Crohn disease in this study [7].

Abdominal pain is a prerequisite for the diagnosis of IBS. The pain can vary in intensity and location but is usually restricted to the lower abdomen; it can be episodic or superimposed on a background of constant ache. It is usually relieved by the passage of stool or flatus and exacerbated by meals. Almost 50% of adults with IBS also have symptoms of dyspepsia, and overlap between other pain-associated FGIDs and IBS has been reported [8]. Urinary bladder irritability and pelvic pain have also been associated with IBS-like symptoms.

Most patients with diarrhea-predominant IBS pass liquid or semiformed stool at frequent intervals. It can be accompanied with the passage of mucus but passage of blood is rare. A majority of patients will report difficulty falling asleep, rather than sleep disruption. In patients with constipation-predominant IBS, the constipation initially can be episodic but usually becomes continuous. With time symptoms become refractory to treatment with laxatives. Stool consistency can be hard and the stool may be narrow in caliber. It can be associated with the feeling of incomplete evacuation; the child can spend a long time sitting on the toilet straining unsuccessfully to have a bowel movement. This can lead to rectal mucosal prolapse and development of solitary rectal ulcer syndrome, associated with passage of blood in the stool and tenesmus [9]. Adults with dyssynergia, a disorder where the subject is unable to coordinate bearing down with pelvic floor relaxation during defecation, can have symptoms that mimic IBS [10]. Constipation associated with dyssynergia can improve with biofeedback training, and this should be considered in the differential diagnosis in adolescents with constipation and lower abdominal pain. Some patients have periods of constipation alternating with diarrhea. Abdominal bloating, belching, and flatulence are also common symptoms.

The pathophysiology of IBS is likely to be multifactorial, and alterations in GI sensory perception, central neuronal dysfunction, abnormal motility, stress, psychological abnormalities, and luminal factors have all been implicated. The submucosal nerve plexuses receive sensory input from the bowel lumen through the sensory receptors. The enteric nervous system communicates with the brain through neural pathways as well as by immune and endocrine systems. The pain signals are transmitted from the primary sensory afferent neurons with cell bodies in the dorsal root ganglia to the dorsal horn of the spinal cord. Spinal pathways run to the thalamus and relay messages to the limbic system and the sensory cortex. The combined functioning of the GI motor, sensory, and central nervous system activity is termed the brain-gut axis. Abnormalities along the brain-gut axis such as altered peripheral sensory perception, hypersensitivity of sensory neurons in the dorsal horn, and increased activation of brain regions associated with visceral pain sensation have been reported in IBS [11].

Visceral hyperalgesia (an exaggerated pain response to a sensory stimulus) has been reported in children with IBS [12, 13]. Visceral hyperalgesia could result from sensitization of primary sensory afferent fibers innervating the gut or the neurons receiving input from visceral afferents along the brain-gut axis (Fig. 52.1) [11]. Peripheral sensitization of nerves within the GI tract can result from noxious injury and the release of inflammatory mediators and nerve growth factor by the fibroblasts and mast cells in the bowel wall. The resulting increase in transcription of the neuropeptides, substance P, and calcitonin gene-related peptide initiates nerve activation and the release of yet more substance P and recruitment of previously silent nociceptors [11].

Recent advances in functional brain imaging have provided a novel insight into the pathophysiology of chronic pain states and how supraspinal mechanisms of brain reorganization facilitate pain learning behavior and long-term maintenance of central sensitization. Tillisch and coworkers conducted a meta-analysis of 18 adult studies in which functional MRI or PET scans of the brain had been performed together with balloon distension of the rectum in patients with IBS and healthy controls [14]. Patients with IBS demonstrated a greater spatial extent of brain activity than controls, specifically in regions associated with pain modulation and emotional arousal. The authors concluded that published data supports a role for central nervous system dysregulation in the pathogenesis of IBS [14]. A novel functional connectivity analysis approach to functional brain imaging studies allows one to measure temporal correlation of neurophysiological events and estimate how spatially distinct brain regions coactivate or work together in a specific brain states, therefore offering a practical tool for evaluating cortical modulatory effects on brain functioning during rectal distension stimulation in health and IBS. The human brain, intrinsically, is organized into distinct functional networks supporting various sensory, motor, emotional, and cognitive functions. Of particular relevance to the understanding of visceral hypersensitivity and altered brain-gut interaction in IBS is an intrinsic brain network, the salience network [15]. The salience network plays an important role in disparate attentional, cognitive, affective, and regulatory functions. In a recent study of adolescent patients with IBS, rectal balloon distension showed greater activation of neural structures associated with homeostatic afferent and emotional networks, especially the anterior cingulate and insular cortices. Compared to healthy controls, IBS subjects also showed excessive coupling of the salience network with the default mode network and executive control network [16]. Adult IBS patients show greater engagement of cognitive and emotional brain networks including the salience network during contextual threat, suggesting that they may overestimate the likelihood and severity of future abdominal pain [17].

There is also a suggestion that patients with IBS handle small bowel gas differently, and there is slow transit of gas directly infused into the small bowel in adults with IBS³³. Abdominal bloating and flatulence can also result from higher colonic fermentation in IBS [33, 35, 36]. Some patients without evidence of small bowel bacterial overgrowth can benefit from treatment with unabsorbable antibiotics [37], which raises the question of a qualitative change in bowel bacterial flora in IBS.

Plasma 5-HT concentration is elevated in IBS patients [39], and the proportion of 5-HT secreting enteroendocrine cells is elevated in the GI tract in postinfectious patients with IBS¹⁸. Increased rectal mucosal 5-HT concentration has also been reported in children with IBS. The presence of low-grade inflammation was associated with higher 5-HT concentration in rectal mucosa in this study [25]. Symptom relief by serotonergic agents including 5-HT₃ antagonists and 5-HT₄ agonists provides additional support for a possible role of 5-HT in IBS pathophysiology [40].

Bowel injury and inflammation can induce functional and structural changes in the enteric neurons and muscles. Increased numbers of ganglion cells, axonal degeneration, and a reduced number of interstitial cells of Cajal have been reported in IBD [21]. In Crohn disease there is increase in substance P and its receptors in the GI tract [21]. The bowel innervation shifts from a predominantly cholinergic to a substance P predominant innervation in ulcerative colitis (UC) [21]. Increased expression of nerve fibers expressing transient receptor potential vanilloid type 1 (TRPV1) receptor in IBD and IBS has been reported [52] as well as in quiescent IBD patients with IBS-like symptoms [53]. The expression of TRPV1 is a feature of afferent pain fiber and upregulated by inflammation [53]. These changes can cause alteration in bowel sensory perception. Patients with active UC show a decreased threshold for painful and non-painful rectal distension stimulus [54]. The hypersensitivity can be widespread, and a lower pain threshold to esophageal distension has been reported in adults with UC [55]. In contrast, patients with isolated ileal Crohn disease have an increased pain threshold following rectal distension [56]. It appears that the development of visceral hypersensitivity in IBD may depend on the disease activity, type of inflammation, and region of the GI tract involved.

There is a considerable overlap between IBS and IBD symptoms. Adults who develop IBD may have a prodrome of IBS-like symptoms that can be as long as 7 years [57]. Some of these patients could have a delayed diagnosis of IBD, but some may have GI inflammation not severe enough to make a diagnosis of IBD but sufficient to cause IBS-like symptoms. Up to 57% of adults with Crohn disease and 33% with UC have symptoms like pain and bloating when in clinical, laboratory, and endoscopic disease remission [58]. Since a few inflammatory cells located strategically near the enteric nerves or myenteric ganglion cells can alter bowel function in IBS, similar changes could be responsible for the functional symptoms in patients with Crohn disease, which cause transmural inflammation [59–61].

Evaluation of placebo response in Crohn disease provides indirect evidence to the existence of functional GI disorders in these patients. Placebo therapy can alter the natural course of Crohn disease. In a meta-analysis of 23 adult studies using Crohn’s Disease Activity Index (CDAI) to measure Crohn disease activity, the pooled median remission rate with placebo was 19% (range 0–50%) [62]. Significant predictors of a placebo response were duration of participation in the study and number of clinic visits. The placebo effect increased with the increasing study duration (Fig. 52.2), suggesting that frequent contact with medical professionals relieved symptoms in some patients. A high CDAI and CRP at recruitment showed a negative correlation with the placebo response, suggesting that patients with a low or normal CRP and a comparatively mild clinical disease activity were more likely to respond to a placebo. Therefore, the obvious question is whether some of these patients with Crohn disease had functional GI symptoms to begin with and were therefore more likely to respond to a placebo.

The diagnosis of IBS is based on clinical symptoms and signs (Fig. 52.3). Investigative workup and endoscopic evaluation may be necessary in a small percentage of children especially in the presence of alarm features. In one large pediatric study, anemia, hematochezia, and weight loss were most predictive of Crohn disease in children presenting with chronic abdominal pain, with a cumulative sensitivity of 94% and specificity of 62% [7]. Adult studies suggest that 5–17% of celiac disease patients have IBS-like symptoms, and in one study of 1032 adults with celiac disease, 37% were diagnosed with IBS prior to the diagnosis of celiac disease [63]. Abdominal pain is a common symptom in children with celiac disease but the prevalence of IBS is unknown. More than 90% of these adults have improvement in IBS-like symptoms after starting gluten-free diet. Lactose intolerance has been reported in 15–25% of adults with IBS. However, it is yet to be determined if lactose exclusion results in resolution of IBS symptoms.