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Functional Nausea in Children

Kovacic, Katja; Di Lorenzo, Carlo

Journal of Pediatric Gastroenterology and Nutrition: March 2016 - Volume 62 - Issue 3 - p 365–371
doi: 10.1097/MPG.0000000000001076
Invited Review
Free

ABSTRACT Chronic nausea is a highly prevalent, bothersome, and difficult-to-treat symptom among adolescents. When chronic nausea presents as the predominant symptom and is not associated with any underlying disease, it may be considered a functional gastrointestinal disorder and named “functional nausea.” The clinical features of functional nausea and its association with comorbid conditions provide clues to the underlying pathophysiological mechanisms. These may include gastrointestinal motor and sensory disturbances, autonomic imbalance, altered central nervous system pathways, or a combination of these. This review summarizes the current knowledge on mechanisms and treatment strategies for chronic, functional nausea in children.

*Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Center for Pediatric Neurogastroenterology, Motility, and Autonomic Disorders, Medical College of Wisconsin, Milwaukee

Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nationwide Children's Hospital, Columbus, OH.

Address correspondence and reprint requests to Katja Kovacic, MD, Division of Gastroenterology, Hepatology, and Nutrition, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226 (e-mail: kkovacic@mcw.edu).

Received 18 September, 2015

Accepted 8 December, 2015

The authors report no conflicts of interest.

What Is Known

  • Functional nausea is common in children with functional bowel disorders.
  • Gastric motor disturbances including gastric emptying and accommodation abnormalities commonly present with nausea.
  • Plausible mechanisms involve complex vagal neural circuits and higher brain regions such as the limbic system.
  • Altered sensations and visceral hypersensitivity likely play a role but mechanisms remain unclear.

What Is New

  • Nauseous patients experience many comorbidities, greater symptom severity, and psychosocial disability.
  • Migraines, cyclic vomiting syndrome, and autonomic dysfunction appear closely linked to functional nausea.
  • Treatment is mainly empiric or aimed at comorbid features.

Chronic nausea is a frequent complaint encountered by pediatric gastroenterologists. It is usually described as an unpleasant and painless sensation of imminent vomiting. It tends to cluster with several functional gastrointestinal disorders (FGIDs) but may also present as a primary symptom, not associated with any demonstrable underlying disease (1). As such, it is often termed “functional nausea” because of the lack of diagnostic biomarkers. The adult Rome III criteria define chronic idiopathic nausea as occurring several times per week, typically not associated with vomiting and without an organic cause (2). The current pediatric Rome III criteria do not yet recognize a category for chronic nausea despite its high prevalence in adolescents, but the Rome IV pediatric committee is considering adding “functional nausea” to the next iteration of the criteria.

A recent study reported a 53% prevalence of chronic nausea in children with pain-associated FGIDs (3). Notably, more frequent nausea was associated with impaired social and school functioning. Functional nausea can be highly distressing but given its subjective nature, the absence of evidence-based guidelines for a diagnostic workup, and the lack of proven effective treatments, it is often neglected by medical providers. Other, more episodic FGIDs, such as abdominal migraines and cyclic vomiting syndrome (CVS), are also highly associated with nausea and may evolve into debilitating, daily chronic nausea. Nausea is also a common manifestation of many acute and chronic medical conditions, drug or toxin effects, gastrointestinal (GI) motility disorders, motion, autonomic or central nervous system (CNS) pathology, and emotional arousal and anxiety. Despite this broad prevalence, surprisingly little is known about the pathophysiology underlying chronic nausea. This review summarizes the current concepts and knowledge regarding the clinical features, possible mechanisms, and available treatments for functional nausea in children.

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CLINICAL FEATURES

Genetic vulnerability and psychosocial susceptibility are cardinal features of several FGIDs. The biopsychosocial model for FGIDs represents a broadly accepted term that encompasses interactions among genetic, environmental, physiologic, and psychosocial factors. Patients with chronic nausea share many features and comorbidities with other FGIDs including chronic pain, fatigue, headaches, sleep disturbances, anxiety, and family history of FGIDs. There is, however, increasing evidence that nauseated patients experience more severe symptoms. A study comparing patients with primary (likely “functional”) chronic nausea to those with nausea associated with functional abdominal pain found that these comorbidities are prevalent in both groups but are present at an even higher rate in those with primary nausea (1). This same study found that chronic nausea is more common in white adolescent girls and that 70% experienced anxiety. A large, prospective study of children with functional abdominal pain found a 45% prevalence of nausea and noted the presence of more severe GI and somatic symptoms, depression, low self-esteem, disability, and family stress in subjects with nausea (4). Long-term nausea was also linked to greater disability, anxiety, and depression. Persistent nausea in adult patients with migraines is also more common in white girls and linked to greater pain, disability, and depression. Many of these features appear to be closely linked to an altered brain-gut axis and heightened visceral sensitivity, akin to the broadly accepted concept of FGIDs that is based on abnormal processing of afferent signals, altered microbiota, and heightened reactivity to both noxious and physiologic visceral signals.

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PSYCHOLOGICAL COMORBIDITY

Psychological factors are known to influence digestive symptom perception and coping strategies in FGIDs. Chronic GI distress may also influence pathways that process sensations of discomfort and nausea, leading to amplified perception. In irritable bowel syndrome (IBS) there is evidence that both physical and mental stress may increase proinflammatory cytokines through the autonomic nervous system and hypothalamic-pituitary-adrenal axis (5). A large community-based survey in adults found that anxiety significantly increased the risks of nausea (6). Anxiety appears more prevalent in adolescents with chronic nausea and nausea is associated with long-term psychological distress and disability (1,4). A study in adolescents with chronic nausea linked nausea to social disability and worse school functioning (3). A morning surge in cortisol production has been associated with anxiety disorders and may explain the common clinical presentation of morning nausea in adolescents, who then slowly tend improve later in the day (3,7). It is unclear from these studies whether psychological distress is a primary or secondary manifestation of chronic nausea in children. The disabling nature of the symptoms coupled with frequent diagnostic uncertainty and lack of effective therapies may account for a higher mental distress in this population.

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NAUSEA AND EMETIC PATHWAYS

Nausea is historically viewed as a prodrome of emesis or as a low-grade activation of the emetic pathway (8). The main pathways of emesis include activation of the area postrema by circulating emetogenic substances and hormones, vestibular pathways, CNS activation, and signals through abdominal vagal afferent chemo- and mechanoreceptors (1,9). The latter responds to changes in tension and contractility of the gastric wall and may underlie the sensations of functional dyspepsia, including nausea and postprandial fullness (10). Signals from chemoreceptors responding to substances (eg, serotonin, cholecystokinin, substance P) released from enteroendocrine cells are carried by vagal afferent nerve fibers to higher brain centers (Fig. 1) (11). The blockage of these signals by serotonin (5-HT3) antagonists accounts for some of the effectiveness of these drugs in vomiting induced by chemotherapy, toxins, and viruses. Yet, there is limited evidence to support the classic emetic pathways as the model for functional nausea (8,12). Chronic functional nausea and chemotherapy-induced nausea do not respond particularly well to standard antiemetic therapies such as 5-HT3 antagonists (5). These clinical observations coupled with recent neuroimaging studies point to a broader network of higher cortical centers involved in the generation of functional nausea (13).

FIGURE 1

FIGURE 1

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CENTRAL MECHANISMS

There is growing evidence that apparently distinct emetic pathways converge to the brainstem nucleus tractus solitarius (NTS) and from there to higher cortical regions where they evoke the sensation of nausea. The limbic system also has inputs to the NTS and is a plausible path to how nausea and vomiting signals influence the autonomic nervous system. The NTS is not just a simple brainstem relay center. It receives descending modulation signals from higher cortical regions (hypothalamus, vestibular, and limbic systems) and is modulated by gut hormones and various afferent inputs (8). Afferent signals carried by the vagus nerve relay a vast amount of sensory information from the GI tract to the brainstem dorsal vagal complex (NTS, area postrema, and dorsal motor nucleus of the vagus) (14). There is ample support for a major role of the vagal neurocircuitry in the generation of nausea and vomiting. Activation of mechano- and chemoreceptors in the GI tract initiate vagovagal reflexes (sensory and motor vagal fibers) that carry signals to and from the CNS. Furthermore, the integrity of the abdominal vagus nerve appears essential for initiation of emesis (14).

A study using functional magnetic resonance imaging evaluated the involvement of the limbic brain structures in experimentally induced nausea (motion induced) (13). In that study, transition to strong nausea caused phasic activation mainly in brainstem and limbic brain regions known to process stress, emotion, and fear conditioning (amygdala, ventral putamen, and dorsal pons/locus coeruleus). Once strong nausea was experienced, there was, however, a “sustained” activation in a broader network of interoceptive, limbic, somatosensory, and cognitive regions. There are also data indicating the presence of altered white matter microstructure in individuals susceptible to motion-induced nausea (15). These studies suggest that nausea is a multidimensional state involving several higher brain structures. It is, however, unclear whether the data based on motion-induced nausea translate to other mechanisms of nausea.

GI pain and emetic signals transmitted to the CNS may be amplified or attenuated depending on environment, emotions, and internal perceptions specific to each individual. The limbic system appears to play a key role in regulating these signals. Thus, a complex interconnected neurocircuitry appears involved in the input signals for nausea.

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AUTONOMIC DYSFUNCTION AND MIGRAINES

The sensation of nausea is associated with physiologic correlates of autonomic outflow such as diaphoresis, salivation, palpitations, pallor, and stomach awareness. Multiple studies have shown evidence for autonomic dysregulation in several FGIDs, IBS being the most commonly studied condition (16,17). Heart rate variability studies in motion-induced nausea also suggest altered sympathovagal balance. Although some studies are conflicting and methodologies differ, there is evidence for gradual sympathetic activation with increased nausea and decreased parasympathetic tone during nausea (18,19). Autonomic dysfunction is also well described in clinical studies of FGIDs with chronic nausea as a frequent complaint (20,21). In a small study, Sullivan et al described significant associations between orthostatic intolerance and chronic GI complaints, including nausea, and GI symptom improvement with treatment of orthostasis (22). Retrospective data on adolescents with chronic idiopathic nausea also noted a high cooccurrence of dizziness, fatigue, migraines, and postural tachycardia syndrome (1).

CVS is another disorder with features of autonomic dysregulation and reported autonomic abnormalities (23). It is thought to represent a migraine variant and often evolves into either true migraines or a chronic, debilitating nausea. These overlapping features suggest the possibility of a primary disorder of autonomic function in some children presenting with chronic nausea with or without other functional bowel complaints and autonomic symptoms. The latter may include dizziness, lightheadedness, syncope, chronic fatigue, mental clouding, anxiety, headaches upon sitting/standing, and more worrisome symptoms such as palpitations and shortness of breath. Autonomic imbalance should thus always be considered in the differential diagnosis of patients with chronic nausea.

Autonomic abnormalities are commonly found in patients with migraine headaches, and there is a migraine subcategory termed syncopal migraine (24). Nausea is also a cardinal feature and part of the diagnostic criteria for migraine headaches (25). The complex pathophysiology of migraines involves inappropriate activation of the trigeminocervical pain system, possibly mediated by the brainstem (26). Nausea is highly associated with pain during migraine attacks, but it is also a feature of the migraine prodrome, suggesting that nausea also occur independent of pain (27). A recent neuroimaging study with positron emission tomography scans in migraine patients with nausea showed activation of central medullary brain structures including the NTS, dorsal motor nucleus of the vagus, and the nucleus ambiguous in addition to the periaqueductal grey (28). These same nuclei were not activated in patients with migraine without nausea. Another large survey of patients with migraine reported that frequent, persistent (>2 years) nausea is common in migraineurs and carries twice the risk of progression to chronic migraine compared with migraineurs without nausea (11). Nausea in tension-type headaches is also a predictor of chronic migraines in a population-based study (29). These observations support the concept of centrally driven nausea in patients with comorbid migraines.

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GASTRIC EMPTYING ABNORMALITIES

Nausea is one of the cardinal symptoms associated with delayed gastric emptying. Unfortunately, nausea and other symptoms of gastroparesis (vomiting, early satiety, postprandial fullness, bloating, and abdominal discomfort) are nonspecific and overlap with other FGIDs such as functional dyspepsia. A large study in adults with gastroparesis reported nausea as the most common (84%) and often the most bothersome symptom, but nausea was equally prevalent in subjects with normal gastric emptying (30). In a smaller study of children with delayed compared with normal 4-hour gastric emptying of a solid meal, nausea was the only symptom linked to delayed gastric emptying (31). A larger, retrospective study in children with gastroparesis based on 2-hour gastric emptying scans found nausea to be the third most common symptom (after vomiting and abdominal pain) (32). In younger children, there is some evidence that vomiting is the most common clinical feature, whereas older children with gastroparesis have more predominant nausea and abdominal pain (33).

Nausea as a result of functional dyspepsia may be difficult to differentiate from that associated with gastroparesis as the clinical presentation is similar. Furthermore, an estimated 25% to 50% of patients with functional dyspepsia have delayed gastric emptying, and there is controversy whether these conditions are part of the same spectrum of disorders (34,35). Nausea can also be a presentation of rapid gastric emptying, which presents with symptoms overlapping with gastroparesis. Two studies in adults with “symptoms of delayed gastric emptying” reported rapid gastric emptying in 11% and 28% of patients (36,37). Rapid gastric emptying is also described in adult patients with CVS (38) and in autonomic dysfunction, with the majority (80%) of individuals experiencing nausea (39).

Constipation may represent another plausible link between nausea and gastric emptying abnormalities. Clinically, it is commonly recognized that constipated children have concurrent nausea and dyspeptic symptoms. A Brazilian study demonstrated an association between childhood functional fecal retention and delayed gastric emptying based on liquid gastric emptying scans (40). Another study of children with dyspepsia showed an association between constipation and delayed gastric emptying based on ultrasound measurements of gastric emptying time (41). In this study, laxative therapy improved both gastric emptying time and dyspeptic symptoms. A “cologastric brake,” whereby colorectal impaction stimulates reflex inhibition of gastric motor activity, is a postulated mechanism.

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OTHER GASTRIC AND DUODENAL ABNORMALITIES

Postprandial nausea is one of the classic features of functional dyspepsia. Concurrent symptoms of postprandial fullness, early satiety, and meal-induced epigastric discomfort suggest that the nausea may originate from gastric accommodation abnormalities. The gastric accommodation reflex consists of relaxation of the proximal stomach to accept food without an increase in gastric pressure. Impaired proximal stomach function in response to food ingestion is well documented through electronic barostat studies in adults with functional dyspepsia (42). Abnormal distribution of the gastric contents in the distal stomach is also described (43). Apart from gastric emptying abnormalities, there is evidence that both structural and functional duodenal abnormalities exist in patients with dyspepsia (35). Postprandial nausea appears to occur both during gastric and duodenal transit of food, suggesting that the mechanism may not solely involve poor stomach compliance (44). Other plausible mechanisms include gastric and duodenal hypersensitivity to mechanical distention but also sensitivity to duodenal acid and lipids as well as mucosal inflammation (35). Duodenal hypersensitivity to acid has been correlated with sensation of nausea in patients with dyspepsia (45). Lee et al (46) have demonstrated increased duodenal acid exposure during daytime and postprandially in patients with prominent nausea. The role of hypersensitivity to gastric distention is also well established in functional dyspepsia and may be a factor in the sensation of nausea (47). There is increasing evidence of low-grade inflammation with increased mast cell counts and eosinophilia in functional bowel disorders such as IBS and functional dyspepsia (48). Duodenal eosinophilia has been linked to dyspeptic symptoms in children, with nausea being the most common symptom (49). The mechanisms may involve immunological alterations with release of mediators that increase excitability of enteric nerves and resulting hypersensitivity to distention (50,51).

Finally, gastric myoelectrical disturbances are abnormalities in the normal 3 cycles per minute slow wave activity of the stomach. Gastric dysrhythmias have been recorded by electrogastrography in subjects with autonomic dysfunction, gastroparesis, and unexplained nausea and vomiting (52–54). Diagnostic usefulness is, however, limited because of inconsistent correlation among electrogastrography disturbances, symptoms, and gastric emptying rates (55).

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DIAGNOSIS

Based on clinical experience and retrospective data, there is little role for extensive diagnostic evaluations in patients with features of functional, chronic nausea (1). A thorough clinical history and assessment of nausea characteristics such as timing, frequency, relation to meals, and concurrent GI symptoms (pain, bloating, postprandial fullness, early satiety, heartburn, concurrent vomiting, stooling pattern) are essential. It is equally important to assess comorbid symptoms such as autonomic disturbances, migraine headaches, sleep problems, chronic fatigue, and psychological distress. A family history of functional disorders or migraines may be supportive of functional nausea rather than organic conditions. Alarm features such as weight loss, neurological symptoms, severe morning vomiting/headaches, and bilious or bloody emesis should prompt further workup. Pregnancy always needs consideration in postpubertal girls. Allergic and inflammatory conditions, celiac disease, and peptic or Helicobacter pylori mucosal diseases deserve consideration in patients with chronic nausea if supported by other clinical symptoms or personal/family history. It is important to note that in the absence of clinical red flags, endoscopy has low yield in the evaluation of patients with chronic nausea. Nearly all (98%) of endoscopies were normal in a larger cohort of children with chronic nausea (1). A 4-hour nuclear medicine gastric emptying study may be justified, especially when symptoms persists hours after meal ingestion. Comorbid symptoms and clinical features should closely guide diagnostic workup.

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TREATMENT

There are no published treatment trials on chronic nausea to guide therapy. Treatment of functional nausea is challenging and generally based on empiric strategies. Retrospective data suggest little benefit of classical antiemetics such as 5-HT3 antagonists (ondansetron) (1). Alternative therapies such as ginger, STW5, and peppermint oil may have some efficacy for meal-related nausea. In a systematic review, ginger 1 g daily was found more effective than placebo for a wide variety of causes of nausea and vomiting, including pregnancy, postoperative, and motion-induced nausea (56). STW5 is an herbal supplement with proven efficacy in clinical trials for functional upper GI symptoms including nausea (57). This supplement is not yet approved for use in the United States. Peppermint oil has shown efficacy in children with IBS (58) and although never studied in nausea, children with nausea and dyspeptic features may benefit from it.

Like in many other functional disorders, an interdisciplinary approach addressing psychosocial burden is likely to represent the most effective intervention. Educating family on the role of stress in functional disorders, using simple analogies to explain brain-gut connections and establishing a trustworthy relation will facilitate treatment. After careful medical history and assessment, providing reassurance and nonpharmacological alternatives that are unlikely to be associated with adverse effects is often well received by families. Early involvement of a psychologist and emphasis on coping strategies and maintaining functioning with continued school attendance is a primary goal. Cognitive behavioral therapy, biofeedback, and relaxation strategies may be of great benefit. Dietary guidance with a focus on low fat, liquid calories and more frequent meals may help those experiencing postprandial nausea even in the absence of gastroparesis. There is evidence that stimulation of the wrist acupuncture point P6 is as effective as medications in preventing postoperative nausea and vomiting (59). Based on the same principle, there are now several commercially available devices that are marketed for nausea of pregnancy or motion sickness, which may also provide benefit to adolescents with chronic functional nausea.

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Medications

Psychotropic medications such as tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors may be reserved for more refractory symptoms but are frequently used in FGIDs (Table 1). Amitriptyline is perhaps the most commonly used TCA for a variety of FGIDs including IBS, functional abdominal pain, abdominal migraine, and CVS. It is also a primary prophylactic migraine drug (60) with both antimigraine and visceral analgesic functions. Given the plausible relations of chronic nausea with these disorders, empiric therapy with TCAs is often trialed. Retrospective data in children with chronic nausea indicate that nearly half have good response (>50% improvement) to amitriptyline at a mean dose of 50 mg nightly (1). Other migraine therapies such as beta-blockers and anti-epileptics, including topiramate and levetiracetam, have shown efficacy in related disorders such as CVS (61,62) and may prove beneficial in nausea as well.

TABLE 1

TABLE 1

If clinical history reveals symptoms of autonomic imbalance, nausea may be approached with several lifestyle measures. These include aggressively increasing hydration and salt intake, regular sleep and exercise, and carefully addressing comorbid symptom burden. The addition of a low-dose mineralocorticoid (fludrocortisone) may improve nausea as documented by Fortunato et al in 2 studies (63,64).

Cyproheptadine is another drug commonly used for FGIDs and migraine prophylaxis (65,66). Cyproheptadine has antiserotonergic and antihistamine effects and is postulated to improve gastric accommodation in patients with functional dyspepsia (67). It also stimulates appetite and therefore may help many patients with chronic, meal-related nausea with dyspeptic features and weight loss. Given the possible role of immune alterations and mast cell activation, other antihistamine therapies may be effective. Limited pediatric data suggest efficacy of montelukast (a leukotriene receptor antagonist) in children with dyspepsia (68). Buspirone is an anxiolytic shown to reduce symptoms in adults with dyspepsia by improving gastric accommodation as measured by barostat studies (69). Although proton-pump inhibitors are often trialed in patients with dyspeptic features and postprandial symptoms, there is no available data to support their use in functional nausea.

Prokinetics may improve symptoms of nausea if there is evidence of delayed gastric emptying. Dopamine-2 receptor antagonists such as metoclopramide and domperidone were mainstay treatments for gastroparesis in the past. Their use has, however, been limited more recently because of the potential for serious adverse effects. Domperidone is currently available only in the United States through Food and Drug Administration exemption. Erythromycin is a motilin receptor agonist with potent prokinetic activity. Long-term use may be limited because of the common development of tachyphylaxis. Furthermore, erythromycin may induce pain as it increases gastric tone (70). Case reports of refractory nausea because of gastroparesis suggest that agents such as mirtazapine (antiserotonergic, antihistamine properties) and the neurokinin-1 receptor antagonist aprepitant have potential efficacy for nausea (71,72). When nausea is associated with gastroparesis, endoscopic injection of botulinum toxin in the pylorus may be beneficial (73).

Cannabinoids have been studied extensively for nausea and vomiting associated with chemotherapy (74), but their use is still controversial because of the potential for abuse. Many states in the United States now, however, permit medical use of cannabis (75). Synthetic cannabinoids such as dronabinol and nabilone may have efficacy for refractory nausea but are mainly recommended for chemotherapy-induced nausea and vomiting and appetite stimulation (76).

Finally, there is increasing evidence that gastric neuromodulation with intraabdominal implantation of gastric pacemaker improves drug-refractory gastroparesis and refractory nausea and vomiting of unclear etiology. Although gastric emptying is not always improved, symptom response rates between 50% and 70% are reported (77–79). Various mechanisms including central, autonomic, and/or enteric have been proposed. More long-term data are needed to determine the effectiveness and target population for GI neuromodulation in children.

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CONCLUSIONS

Nausea is a highly prevalent, yet poorly characterized symptom. The pathophysiology of functional nausea may be multifactorial but likely involves autonomic, central, and GI pathways coupled with psychological comorbidity. Because of the lack of objective biomarkers and effective therapies, the burden of disease remains high. Future studies should attempt to characterize patients with chronic functional nausea through both clinical and pathophysiologic phenotyping. As underlying mechanisms are complex and poorly understood, further studies are needed to find more targeted and effective therapies.

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Acknowledgment

The authors thank Scott Stoll for the illustration.

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Keywords:

chronic nausea; cyclic vomiting syndrome; functional gastrointestinal disorders; migraines

© 2016 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,