- Email: [email protected]
Chronic Idiopathic Nausea of Childhood
Chronic Idiopathic Nausea of Childhood Katja Kovacic, MD1, Adrian Miranda, MD1, Gisela Chelimsky, MD1, Sara Williams, PhD1, Pippa Simpson, PhD2, and B U. K. Li, MD1 Objectives To compare children with primary, chronic idiopathic nausea to those with secondary nausea associated with functional abdominal pain.
Study design Retrospective chart review of 45 children with a primary complaint of chronic nausea several times per week. Comparisons were made to prospectively collected data on 49 children with functional abdominal pain and comorbid nausea. Results The majority of those affected were adolescent Caucasian females. Subjects with chronic nausea had a more severe presentation with daily 88% (vs 26%) and constant 60% (vs 10%) nausea (P < .001), one-half with peak morning intensity. In the chronic nausea group, 62% had migraines, and 71% (vs 22%) had familial migraines (P < .001), 36% had postural tachycardia syndrome and 27% cyclic vomiting syndrome. Both groups suffered comorbid symptoms (anxiety, dizziness, fatigue, and sleep problems). The chronic nausea cohort underwent extensive, negative medical evaluations. Conclusions Chronic idiopathic nausea of childhood is a poorly described symptom. Patients with primary (vs secondary) chronic nausea were more likely Caucasian, older adolescent females with severe, daily nausea and comorbid conditions such as anxiety, dizziness, and fatigue as well as significantly more migraine features. Chronic nausea is a major, disabling symptom that requires increased recognition as a separate functional entity. Future studies may need to focus on comorbid conditions including migraine and dysautonomia. (J Pediatr 2014;164:1104-9).
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hronic nausea is a poorly characterized symptom in children. Nausea is defined as an extremely unpleasant sensation that often precedes vomiting but may occur as an isolated symptom.1 A variety of stimuli such as toxins, mucosal injury, visceral pain, inflammation, drugs, motion, memories, and emotions may trigger nausea. Although nausea is a highly subjective sensation, animal studies and human studies on motion sickness define certain physiological correlates.1,2 Some of these include autonomic arousal, endocrine changes, gastrointestinal (GI) dysmotility, and gastric dysrhythmias. Functional magnetic resonance imaging (fMRI) studies describe the neurobiology of motion-induced nausea and shed some light on the complex, neural pathways of nausea.3 Still, functional nausea is only described as a clinical symptom without a distinct, underlying physiologic mechanism. Adult chronic idiopathic nausea is defined as bothersome nausea, occurring several times per week, typically not associated with vomiting and without any identifiable organic cause.4 Adult 2006 Rome III criteria classify chronic idiopathic nausea under the category of functional nausea and vomiting disorders along with functional vomiting and cyclic vomiting syndrome (CVS).5 Prior to 2006, adult Rome II criteria categorized nausea as a symptom of dyspepsia. The pediatric Rome III criteria do not recognize chronic idiopathic nausea as a separate category even though children often experience refractory nausea that becomes their primary, debilitating complaint. We recently demonstrated that childhood nausea frequently occurs as a secondary complaint with other pain-associated, functional gastrointestinal disorders (FGIDs) such as functional dyspepsia, irritable bowel syndrome, abdominal migraine (AM), and functional abdominal pain (FAP).6 Of the pain-associated FGIDs, only AM includes nausea as supporting diagnostic criterion, but like CVS, the associated nausea is usually confined to the discrete episode of pain or vomiting rather than that occurring on a chronic, daily basis. Similarly, chronic nausea is a common complaint in children with postural tachycardia syndrome (POTS).7,8 Nausea as a secondary complaint associated with FGIDs is likely to go unrecognized and under investigated. There is a knowledge gap regarding proper work-up and treatment options for children with nausea.9 We hypothesized that children with primary chronic nausea suffer more frequent and severe symptoms that impact daily functioning, have more
5-HT3 AM AP CHW CT CVS FAP
5-hydroxytryptamine Abdominal migraine Abdominal pain Children’s Hospital of Wisconsin Computed tomography Cyclic vomiting syndrome Functional abdominal pain
FGIDs FHx GI MRI PMHx POTS
Functional gastrointestinal disorders Family history Gastrointestinal Magnetic resonance imaging Personal history Postural tachycardia syndrome
From the 1Center for Pediatric Neurogastroenterology, Division of Gastroenterology, Hepatology, and Nutrition, and 2Division of Quantitative Health Sciences, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI The views expressed in this article are not an official position by Medical College of Wisconsin. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.01.046
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Vol. 164, No. 5 May 2014 comorbid illnesses, and undergo more extensive diagnostic testing compared with those with secondary nausea. We aimed to describe the demographics, clinical presentation, comorbid disorders, diagnostic work-up, and treatment response in children with primary chronic nausea and compare them with children with FAP who have nausea as a secondary complaint.
Methods Participants included pediatric patients, ages 8-18 years, followed in the outpatient Pediatric Neurogastroenterology Clinic at Children’s Hospital of Wisconsin (CHW), between March 2006 and April 2012. The human research Institutional Review Board at CHW approved this study. Eligibility criteria for the chronic nausea group included a primary complaint of chronic nausea, occurring several times per week for a minimum of 2 months. Forty-five subjects met the inclusion criteria for the chronic nausea group, and we retrospectively reviewed the medical records of these after excluding 2 patients with a documented organic etiology. Inclusion criteria for the abdominal pain (AP) comparison group were as follows: a primary complaint of AP for a minimum of 2 months with nausea as part of their illness (secondary complaint). Forty-nine subjects met the inclusion criteria for the AP group after excluding 4 patients with an organic etiology. For comparison, we categorized patients as having daily nausea or constant nausea (continuous nausea throughout the day vs episodic) in both the chronic nausea and AP groups. Exclusion criteria for both groups were as follows: patients with developmental delay or a neurologic disorder, patients on a medication that could cause nausea, and those with a documented disorder that could explain the nausea and/or AP (ie, Helicobacter pylori gastritis, celiac disease, eosinophilic esophagitis/gastroenteritis, and inflammatory bowel disease). We retrospectively collected data on demographics, medical history, laboratory work, diagnostic imaging, endoscopic biopsies, and treatment response from systematic chart reviews of both groups. In both groups, prospective data from nonvalidated, parent-reported questionnaires were available on sleep and anxiety. The specific questions addressing sleep problems included: does your child have difficulties falling asleep at night and/or frequent night-time awakenings. If the parent answered yes to 1 or both of these questions, the child was considered to have sleep problems as perceived by the parent. We asked the following questions as a measure of anxiety: (1) Is your child anxious? and/or (2) Does your child worry about grades, schoolwork, or new situations? Prospectively collected (nonvalidated) clinical intake questionnaires were also reviewed on the 49 patients with FAP and nausea as a secondary complaint (AP group). These parent-reported questionnaires incorporated specific questions on nausea frequency, related GI symptoms, comorbid symptoms, family history (FHx), and school absence (reported as number of
school days missed because of symptoms over the 2 months prior to evaluation). An average of 2 or more days per month of missed school was considered to adversely affect school performance. For the chronic nausea group, retrospective data was collected from a standardized checklist that includes the symptoms reported in this study such as nausea frequency, co-morbid symptoms, and school absence (number of school days missed in the past month because of symptoms). Two or more missed days was considered to adversely affect school. Laboratory evaluation was defined as screening (ie, complete blood cell count, electrolytes, hepatic transaminases, lipase, celiac screen) or extensive (ie, metabolic or endocrine serum tests). Laboratory values were considered normal or abnormal based on norms established by CHW laboratory. Results of diagnostic imaging evaluation were collected for all subjects. Abdominal ultrasound and upper GI contrast study were performed in a high percentage of subjects in both groups. Therefore, any additional imaging study performed was defined as extensive. Treatment response to common first-line medications in patients with nausea and/or AP, such as proton pump inhibitors and 5-hydroxytryptamine (5-HT3) antagonists (ondansetron) were analyzed in the chronic nausea group. We also analyzed response to amitriptyline, another frequently used medication in patients with pain-associated FGIDs.10 Although it is standard to document nausea treatment response for the chronic nausea group in our clinic, it is not for the AP group, whose primary symptom was AP. In the chronic nausea cohort, response to each drug was assessed by the clinic physician at the initial (if tried prior to referral) and at each of subsequent visits after interviewing the patient and parent. Drug response was graded and defined as some (at least 25%-50% symptom reduction) or good (>50% improvement) and documented in the clinic note. To compare 2 groups, a Mann–Whitney U test was performed for continuous variables and c2 analysis or Fisher exact test was used for categorical variables. Median, IQR, and frequencies were reported for comparisons. Statistical analysis was performed with SPSS (SPSS Inc, Chicago, Illinois); SAS (SAS Institute, Cary, North Carolina); and StatXact (SAS Institute). An unadjusted P value of <.05 was considered significant.
Results The median age of symptom onset was not different between the 2 groups. However, in the chronic nausea cohort, the median age of presentation was higher than in the AP cohort: 15 (12.5-16.0) years versus 12 (10.0-15.0) years (Table I), representing a delay in time to GI consultation. Clinical Characteristics The number of subjects complaining of daily nausea and constant nausea were much higher in the chronic nausea 1105
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Table I. Demographic profile Female n (%) Caucasian n (%) Median age years (IQR) Median age nausea onset years (IQR)
Chronic nausea group
AP group
31 (69) 43* (96) 15† (12.5-16.0) 12 (10.0-14.5)
38 (78) 37 (76) 12 (10.0-15.0) 11 (9.0-13.0)
*P # .027. †P # .001.
compared with the AP group: 88% (37/42) versus 26% (12/ 46) suffered from daily nausea, and 60% (25/42) versus 10% (4/42) of subjects described it as constant (P < .001 for both variables). In the chronic nausea group, the average nausea intensity rating was 6.9 (on a 10-point scale). Nausea intensity rating was not available on the subjects with AP. Of 37 subjects with chronic nausea, 19 (51%) complained of peak nausea in the morning (data not available in the AP group). Nausea adversely affected school performance in 67% (30/45) of the subjects with chronic nausea and 54% (25/46) of those with AP (P = .285). For the subjects with available data, comorbid symptoms were more common in the chronic nausea than the AP group: anxiety 70% (23/33) versus 41% (20/49), headache 69% (31/45) versus 61% (30/49), dizziness 79% (27/34) versus 53% (26/49), fatigue 83% (25/30) versus 59% (29/ 49), and poor sleep 61% (20/33) versus 47% (23/49) (Figure 1). Of these, anxiety (P = .013), dizziness (P = .02), and fatigue (P = .028) were statistically more common in the chronic nausea group. FHx The FHx (first degree relative) was significantly more often positive in the chronic nausea group (n = 45) than in the AP cohort (n = 49) for a FHx of migraines in 71% (32/45) versus 22% (11/49) (P < .001) (Figure 2), and gastroesophageal reflux disease in 44% (20/45) versus 20% (10/ 49) (P < .016). In addition, the family histories were more
Figure 1. Percentage of subjects with comorbid symptoms in the chronic nausea and AP groups (*P < .05). CN, chronic nausea. 1106
Vol. 164, No. 5 often positive (not significantly) for anxiety or depression in 47% (21/45) versus 39% (19/49), irritable bowel syndrome in 36% (16/45) versus 33% (16/49), and CVS in 4% (2/45) versus none. Evaluation and Treatment In the chronic nausea group 80% had extensive laboratory testing and 84% had extensive imaging work-up (Table II). The imaging evaluation performed in the 45 subjects with chronic nausea included abdominal ultrasound (78%), upper GI contrast study (60%), brain computed tomography (CT) or MRI (58%), gastric emptying scan (38%), abdominal CT or MRI (31%), and hepatobiliary scan (24%). Furthermore, antroduodenal motility studies were performed in 13% of subjects with chronic nausea. Most subjects in the AP group did not undergo either extensive laboratory or radiologic testing (P < .001). High rates of diagnostic endoscopy (n = 44 in both chronic nausea and AP groups) with normal histologic results were similar between the 2 groups (Table II). Three classes of drugs commonly used in the treatment of functional pain and nausea disorders include proton pump inhibitors, 5-HT3 antagonists, and tricyclic antidepressants (amitriptyline); 44% (14/32) of patients with chronic nausea receiving amitriptyline had a good response (at least 50% symptom improvement) and 56% (18/32) had some response (ie, at least 25% symptom improvement). The mean maximum dose used was 50 mg (range, 20-100 mg). Of the 23 patients with chronic nausea receiving a proton pump inhibitor, only 22% (5) reported some response (at least 25% symptom improvement). Of the 30 patients with chronic nausea receiving a 5-HT3 antagonist (ondansetron), 50% (15) had some response; however, none had a good response (>50% improvement). Approximately one-third of subjects with chronic nausea did not respond to any medication. No comparative data was obtained on the treatment response in the AP group because the response was typically recorded for the primary symptom of AP. Migraines and Coexisting Functional Disorders Despite the lack of a defined diagnostic category in children, a significant portion of both groups was given a final diagnosis of functional nausea: 47% (21/45) of the chronic nausea and 18% (9/49) of the AP cohort. Nearly all subjects with chronic nausea (93%) had either a FHx of migraines and/or suffered from migraines themselves; 62% (28/45) of them had concomitant migraines. The vast majority of these migraine sufferers (71%) had isolated headache episodes separate from their chronic, daily nausea. In contrast, only 12% of the subjects with AP had migraines, most of these also had episodic migraines separate from their nausea. Fewer subjects with chronic nausea than AP met the Rome criteria for AM: 7% versus 14% (P = .321) (Figure 2). An additional 9 subjects with chronic nausea had episodic AP suggesting AM spells, however, they experienced chronic nausea between episodes and, thus, did not meet the AM criteria. Kovacic et al
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changes in vitals signs. POTS often coexisted with CVS; 5 (42%) of the 12 subjects with CVS were diagnosed with POTS.
Discussion
Figure 2. Percentage of subjects in the chronic nausea and AP groups with a positive FHx of migraines, PMHx of migraines, AMs, CVS, and POTS (*P < .05).
A subgroup analysis in the chronic nausea group revealed that 12 patients (27%) met diagnostic criteria for CVS but had concomitant interictal nausea apart from their vomiting episodes (Figure 2), when using the more stringent and specific 2008 North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition consensus statement (rather than the Rome III criteria) on CVS for diagnosis.11 An additional nine subjects developed chronic nausea after outgrowing CVS. Of those 9, 67% (6) had a personal history (PMHx) or a FHx of migraine headaches (some had both). When we performed a subgroup analysis to determine if the chronic nausea associated with CVS differed from those unassociated with CVS, the clinical characteristics were not statistically different in any of the variables. POTS was present in 63% (16/45) of patients with chronic nausea as determined by either orthostatic changes in vital signs (n = 11) or formal autonomic testing (n = 5). A positive orthostatic screen was defined as a heart rate increase of $30 beats/min during positional changes from 10 minutes in supine position to standing. An additional 8 subjects with chronic nausea had orthostatic symptoms strongly suggestive of POTS, such as lightheadedness, dizziness, headaches, syncope, and fatigue but did not meet the heart rate criteria or were not formally evaluated. This differed significantly from the AP group, where POTS was found in only 6% (P # .001) (Figure 2). Two of these subjects with AP were diagnosed by autonomic testing and 1 by orthostatic
Table II. Diagnostic workup
Extensive lab workup Extensive imaging workup Endoscopy Endoscopy normal
Chronic nausea group n (%)
AP group n (%)
36 (80*) 38 (84*) 41 (93) 40 (98)
1 (2) 3 (6) 37 (84) 37 (100)
*P < .001.
Chronic Idiopathic Nausea of Childhood
This study describes the demographic profile and clinical phenotype of a large series of children with chronic nausea either as a primary or a secondary complaint, commonly seen in our pediatric Neurogastroenterology Clinic. Children with primary chronic nausea, compared with secondary nausea, were adolescent Caucasian females who were more likely to: (1) suffer from a severe, daily nausea that often peaks in the morning; (2) experience comorbid symptoms (anxiety, fatigue, dizziness); (3) have a FHx or PMHx of migraines; and (4) have associated autonomic dysfunction. Patients with FAP who complained of nausea as a secondary symptom had a similar demographic profile but presented sooner and at a younger age with AP and had: (1) less severe symptoms; (2) fewer comorbid complaints; and (3) fewer migraine features. We speculate that the shorter duration before presentation in the AP group is due to the nature of the 2 complaints; AP is a more defined GI symptom than nausea, likely prompting earlier referral to a tertiary care GI clinic. Studies describing the phenotype of children with chronic unexplained nausea are lacking even though nausea is a common symptom.4,9,12 Weekly nausea is present in 23% (range, 13%-41%) of children based on a large, school-based study of AP and related GI complaints.13 In a population-based study in adults, 3% complained of nausea once per week.14 Despite the high prevalence of nausea in children, chronic idiopathic nausea is a disorder classified only by the adult Rome III criteria. In our study, nearly one-half of the chronic nausea cohort (47%) and one-fifth (18%) of the AP cohort received a final diagnosis of functional nausea, despite the lack of a pediatric classification for this condition. These findings are in line with other studies suggesting the need for further refinement of the pediatric Rome III criteria.15 We found a common association between chronic nausea and migraines or migraine equivalents such as CVS and AM. Nearly all patients (93%) in the primary (chronic nausea) cohort had migraine features characterized by concomitant migraine headaches and/or a FHx of migraine. The rate of FHx (71%) and PMHx (62%) of migraines in the chronic nausea group was significantly higher than that in the AP group (22% and 12%, respectively). Nausea is also commonly experienced during migraine headaches and constitutes 1 supportive diagnostic criterion.16 However, most (71%) of our chronic nausea cohort had chronic daily nausea separate from their episodic migraine headaches, indicating that the chronic nausea was not merely accompanying a migraine episode. Only 7% of subjects with chronic nausea met the criteria for AM. One-quarter (27%) of the chronic nausea cohort met the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition consensus statement criteria for CVS11 and another 20% did so in the past but had 1107
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outgrown their CVS. Because a large number appeared associated with CVS and could potentially bias our population, a subgroup analysis showed that patients with and without CVS-associated nausea had similar rates of migraine features (PMHx and FHx of migraine) and similar clinical characteristics including daily, constant nausea. These results underscore the need for clinicians to review migraine-related symptoms (headaches, photophobia) and FHx (migraines) in patients with nausea, as this may provide a clue to potential treatment approaches. Many (53%) of our patients with chronic nausea either met diagnostic criteria or had clinical features of POTS. GI symptoms including nausea are well described in patients with dysautonomia.8,17-20 Sullivan et al reported associations between orthostatic intolerance and chronic upper GI complaints as well as symptom resolution upon treatment of orthostasis.17 There are several other reports of functional GI complaints associated with sympathetic autonomic dysfunction.18,21 The association with POTS suggests the possibility that nausea could also be a manifestation of autonomic dysfunction. Identifying and treating orthostatic symptoms may help alleviate nausea in some adolescents. The majority of subjects with chronic nausea underwent numerous, unrevealing laboratory, radiographic, and endoscopic testing to elucidate an organic diagnosis. These included serologic tests for metabolic disorders, brain imaging, abdominal CT/MRI, gastric, and gallbladder emptying scans. Most patients in both groups also had upper endoscopy, and nearly all were normal (98% of those with chronic nausea and 100% of those with AP). Our results suggest that extensive diagnostic workup could be avoided in place of a detailed clinical history that also queries presence of migraine and orthostatic intolerance along with screening for POTS. In our practice approach, trials of acid blockers and/or 5-HT3 antagonists were attempted, followed by therapy targeted against migraines and autonomic dysfunction. Such an empiric, therapeutic approach could have significant cost-saving, positive clinical impact by limiting unnecessary evaluations. It is plausible that physical or emotional stress can manifest as, or exacerbate chronic nausea through activation of the brain-gut axis.9,22,23 A large percentage of our study population (both groups) was described as anxious by the parent. Anxiety is well described in children and adults with various functional GI disorders, migraine headaches, and CVS. 24-26 Still, the association is likely multifactorial with genetic, environmental, and psychosocial influences. A causal relationship between anxiety and nausea can, therefore, not be determined. Our results support the use of a biopsychosocial approach in the evaluation and management of these patients. There are limitations to our study design because of our retrospective chronic nausea data, gathered mainly by chart review compared with prospectively collected AP data. The total number of subjects with available data varied between the 2 groups on several measures, in 1108
Vol. 164, No. 5 particular on comorbid symptoms, with missing data on several measures for the chronic nausea group and nonresponses to questions in the AP group. This may cause a selection bias. The clinic physician evaluating the subjects with chronic nausea used a standardized checklist to document the presence or absence of symptoms, which strengthens the validity of our retrospective data. The medical decision-making in the 2 patient cohorts was mainly at the discretion of 2 respective physicians, adding potential bias to the diagnostic evaluation and treatment approach. The report of treatment response is limited by concurrent use of other medications (although the nausea-directed medications were trialed one at a time), inability to assess symptom progression and treatment response over time, and possible placebo effects. There was also a lack of comparable data on the medication response in the subjects with AP because nausea treatment was not a primary outcome variable. Other limitations include our use of questionnaires not specifically designed for the evaluation of nausea and using an orthostatic heart rate rise of 30 bpm as an office-based screening for POTS, while the 2012 proposed criteria for children uses 40 bpm during a formal tilt table test.27 Finally, nausea is a subjective sensation that is difficult to measure objectively based on chart review. The sensation of nausea may have a different meaning and/or perceived differently in younger children, such as those in our AP cohort who may confuse it with dyspeptic AP. However, we used fairly specific written phrases such as “does your child complain of feeling of throwing up” for the nausea assessment. In addition, the questions on AP (quality and pain location) specifically helped to differentiate it from nausea. We also limited the age range to greater than 8 years to eliminate a younger cohort that typically cannot localize AP and understand symptom descriptors. Prospective studies with validated questionnaires in patients with functional GI disorders are clearly needed for improved semiquantitative assessment of severity and impact of nausea on quality of life. We describe a large cohort of adolescents with chronic idiopathic nausea as a primary symptom, compared with a group suffering from nausea as a secondary symptom to FAP. The absence of positive findings on laboratory, radiographic, and endoscopic testing suggests that in the absence of alarm symptoms, a detailed history of migraine-related and orthostatic symptoms followed by a trial of antimigraine medications may be a reasonable initial, timelimited approach before performing extensive testing. Our study suggests that chronic unexplained nausea as a primary symptom, and to a lesser degree as a secondary symptom, is a common and debilitating functional GI complaint with an inordinate impact on health outcomes and school functioning. The current Rome III diagnostic schema does not classify chronic idiopathic nausea for pediatric functional GI disorders and lacks any standard diagnostic or treatment algorithms. We suggest that chronic idiopathic nausea deserves recognition as a separate clinical entity. Future Kovacic et al
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May 2014 studies need to focus on management strategies, especially comorbid symptoms including migraine and dysautonomia. n Submitted for publication Sep 19, 2013; last revision received Dec 10, 2013; accepted Jan 23, 2014. Reprint requests: Katja Kovacic, MD, Division of Gastroenterology, Hepatology, and Nutrition, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail: [email protected]
References 1. Stern RM, Koch KL, Andrews P. Nausea: mechanisms and management. USA: Oxford University Press; 2011. 2. Koch KL. Illusory self-motion and motion sickness: a model for braingut interactions and nausea. Dig Dis Sci 1999;44:53S-7S. 3. Napadow V, Sheehan JD, Kim J, Lacount LT, Park K, Kaptchuk TJ, et al. The brain circuitry underlying the temporal evolution of nausea in humans. Cereb Cortex 2013;23:806-13. 4. Talley NJ. Functional nausea and vomiting. Aust Fam Phys 2007;36:6947. 5. Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology 2006;130:1377-90. 6. Kovacic K, Williams S, Li BUK, Chelimsky G, Miranda A. High prevalence of nausea in children with pain-associated functional gastrointestinal disorders. J Pediatr Gastroenterol Nutr 2013;57:311-5. 7. Jarjour IT. Postural tachycardia syndrome in children and adolescents. Semin Pediatr Neurol 2013;20:18-26. 8. Ojha A, Chelimsky TC, Chelimsky G. Comorbidities in pediatric patients with postural orthostatic tachycardia syndrome. J Pediatr 2011; 158:20-3. 9. Olden KW, Chepyala P. Functional nausea and vomiting. Nat Clin Pract Gastroenterol Hepatol 2008;26:202-8. 10. Saps M, Youssef N, Miranda A, Nurko S, Hyman P, Cocjin J, et al. Multicenter, randomized, placebo-controlled trial of amitriptyline in children with functional gastrointestinal disorders. Gastroenterology 2009;137: 1261-9. 11. Li BUK, Lefevre F, Chelimsky GG, Boles RG, Nelson SP, Lewis DW, et al. North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition consensus statement on the diagnosis and management of cyclic vomiting syndrome. J Pediatr Gastroenterol Nutr 2008;47: 379-93. 12. Olden KW. Rumination. Curr Treat Options Gastroenterol 2001;4:351-8. 13. Saps M, Seshadri R, Sztainberg M, Schaffer G, Marshall BM, Di Lorenzo C. A prospective school-based study of abdominal pain and
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other common somatic complaints in children. J Pediatr 2009;154: 322-6. Talley NJ, Zinsmeister AR, Schleck CD, Melton LJ. Dyspepsia and dyspepsia subgroups: a population-based study. Gastroenterology 1992;102:1259-68. Chogle A, Dhroove G, Sztainberg M, Di Lorenzo C, Saps M. How reliable are the Rome III criteria for the assessment of functional gastrointestinal disorders in children? Am J Gastroenterol 2010;31: 2697-701. Maytal J, Young M, Shechter A, Lipton RB. Pediatric migraine and the International Headache Society (IHS) criteria. Neurology 1997; 48:602-7. Sullivan SD, Hanauer J, Rowe PC, Barron DF, Darbari A, OlivaHemker M. Gastrointestinal symptoms associated with orthostatic intolerance. J Pediatr Gastroenterol Nutr 2005;40:425-8. Chelimsky G, Boyle JT, Tusing L, Chelimsky TC. Autonomic abnormalities in children with functional abdominal pain: coincidence or etiology? J Pediatr Gastroenterol Nutr 2001;33:47. Chelimsky G, Madan S, Alshekhlee A, Heller E, McNeeley K, Chelimsky T. A comparison of dysautonomias comorbid with cyclic vomiting syndrome and with migraine. Gastroenterol Res Pract 2009; 8(Suppl):1-6. Chelimsky TC, Chelimsky GG. Autonomic abnormalities in cyclic vomiting syndrome. J Pediatr Gastroenterol Nutr 2007;44:326-30. Chelimsky G, Hupertz VF, Chelimsky TC. Abdominal pain as the presenting symptom of autonomic dysfunction in a child. Clin Pediatr (Phila) 1999;38:725-9. Tache Y, Martinez V, Million M, Wang L. Stress and the gastrointestinal tract III. Stress-related alterations of gut motor function: role of brain corticotropin-releasing factor receptors. Am J Physiol Gastrointest Liver Physiol 2001;280:G173-7. Kim SE, Chang L. Overlap between functional GI disorders and other functional syndromes: what are the underlying mechanisms? Neurogastroenterol Motil 2012;24:895-913. Yacob D, Di Lorenzo C, Bridge JA, Rosenstein PF, Onorato M, Bravender T, et al. Prevalence of pain-predominant functional gastrointestinal disorders and somatic symptoms in patients with anxiety or depressive disorders. J Pediatr 2013;163:767-70. Waters AM, Schilpzand E, Bell C, Walker LS, Baber K. Functional gastrointestinal symptoms in children with anxiety disorders. J Abnorm Child Psychol 2013;41:151-63. Tarbell S, Li BUK. Psychiatric symptoms in children and adolescents with cyclic vomiting syndrome and their parents. Headache 2008;48: 259-66. Singer W, Sletten DM, Opfer-Gehrking TL, Brands CK, Fischer PR, Low PA. Postural tachycardia in children and adolescents: what is abnormal? J Pediatr 2012;160:222-6.
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Study design Retrospective chart review of 45 children with a primary complaint of chronic nausea several times per week. Comparisons were made to prospectively collected data on 49 children with functional abdominal pain and comorbid nausea. Results The majority of those affected were adolescent Caucasian females. Subjects with chronic nausea had a more severe presentation with daily 88% (vs 26%) and constant 60% (vs 10%) nausea (P < .001), one-half with peak morning intensity. In the chronic nausea group, 62% had migraines, and 71% (vs 22%) had familial migraines (P < .001), 36% had postural tachycardia syndrome and 27% cyclic vomiting syndrome. Both groups suffered comorbid symptoms (anxiety, dizziness, fatigue, and sleep problems). The chronic nausea cohort underwent extensive, negative medical evaluations. Conclusions Chronic idiopathic nausea of childhood is a poorly described symptom. Patients with primary (vs secondary) chronic nausea were more likely Caucasian, older adolescent females with severe, daily nausea and comorbid conditions such as anxiety, dizziness, and fatigue as well as significantly more migraine features. Chronic nausea is a major, disabling symptom that requires increased recognition as a separate functional entity. Future studies may need to focus on comorbid conditions including migraine and dysautonomia. (J Pediatr 2014;164:1104-9).
C
hronic nausea is a poorly characterized symptom in children. Nausea is defined as an extremely unpleasant sensation that often precedes vomiting but may occur as an isolated symptom.1 A variety of stimuli such as toxins, mucosal injury, visceral pain, inflammation, drugs, motion, memories, and emotions may trigger nausea. Although nausea is a highly subjective sensation, animal studies and human studies on motion sickness define certain physiological correlates.1,2 Some of these include autonomic arousal, endocrine changes, gastrointestinal (GI) dysmotility, and gastric dysrhythmias. Functional magnetic resonance imaging (fMRI) studies describe the neurobiology of motion-induced nausea and shed some light on the complex, neural pathways of nausea.3 Still, functional nausea is only described as a clinical symptom without a distinct, underlying physiologic mechanism. Adult chronic idiopathic nausea is defined as bothersome nausea, occurring several times per week, typically not associated with vomiting and without any identifiable organic cause.4 Adult 2006 Rome III criteria classify chronic idiopathic nausea under the category of functional nausea and vomiting disorders along with functional vomiting and cyclic vomiting syndrome (CVS).5 Prior to 2006, adult Rome II criteria categorized nausea as a symptom of dyspepsia. The pediatric Rome III criteria do not recognize chronic idiopathic nausea as a separate category even though children often experience refractory nausea that becomes their primary, debilitating complaint. We recently demonstrated that childhood nausea frequently occurs as a secondary complaint with other pain-associated, functional gastrointestinal disorders (FGIDs) such as functional dyspepsia, irritable bowel syndrome, abdominal migraine (AM), and functional abdominal pain (FAP).6 Of the pain-associated FGIDs, only AM includes nausea as supporting diagnostic criterion, but like CVS, the associated nausea is usually confined to the discrete episode of pain or vomiting rather than that occurring on a chronic, daily basis. Similarly, chronic nausea is a common complaint in children with postural tachycardia syndrome (POTS).7,8 Nausea as a secondary complaint associated with FGIDs is likely to go unrecognized and under investigated. There is a knowledge gap regarding proper work-up and treatment options for children with nausea.9 We hypothesized that children with primary chronic nausea suffer more frequent and severe symptoms that impact daily functioning, have more
5-HT3 AM AP CHW CT CVS FAP
5-hydroxytryptamine Abdominal migraine Abdominal pain Children’s Hospital of Wisconsin Computed tomography Cyclic vomiting syndrome Functional abdominal pain
FGIDs FHx GI MRI PMHx POTS
Functional gastrointestinal disorders Family history Gastrointestinal Magnetic resonance imaging Personal history Postural tachycardia syndrome
From the 1Center for Pediatric Neurogastroenterology, Division of Gastroenterology, Hepatology, and Nutrition, and 2Division of Quantitative Health Sciences, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI The views expressed in this article are not an official position by Medical College of Wisconsin. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.01.046
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Vol. 164, No. 5 May 2014 comorbid illnesses, and undergo more extensive diagnostic testing compared with those with secondary nausea. We aimed to describe the demographics, clinical presentation, comorbid disorders, diagnostic work-up, and treatment response in children with primary chronic nausea and compare them with children with FAP who have nausea as a secondary complaint.
Methods Participants included pediatric patients, ages 8-18 years, followed in the outpatient Pediatric Neurogastroenterology Clinic at Children’s Hospital of Wisconsin (CHW), between March 2006 and April 2012. The human research Institutional Review Board at CHW approved this study. Eligibility criteria for the chronic nausea group included a primary complaint of chronic nausea, occurring several times per week for a minimum of 2 months. Forty-five subjects met the inclusion criteria for the chronic nausea group, and we retrospectively reviewed the medical records of these after excluding 2 patients with a documented organic etiology. Inclusion criteria for the abdominal pain (AP) comparison group were as follows: a primary complaint of AP for a minimum of 2 months with nausea as part of their illness (secondary complaint). Forty-nine subjects met the inclusion criteria for the AP group after excluding 4 patients with an organic etiology. For comparison, we categorized patients as having daily nausea or constant nausea (continuous nausea throughout the day vs episodic) in both the chronic nausea and AP groups. Exclusion criteria for both groups were as follows: patients with developmental delay or a neurologic disorder, patients on a medication that could cause nausea, and those with a documented disorder that could explain the nausea and/or AP (ie, Helicobacter pylori gastritis, celiac disease, eosinophilic esophagitis/gastroenteritis, and inflammatory bowel disease). We retrospectively collected data on demographics, medical history, laboratory work, diagnostic imaging, endoscopic biopsies, and treatment response from systematic chart reviews of both groups. In both groups, prospective data from nonvalidated, parent-reported questionnaires were available on sleep and anxiety. The specific questions addressing sleep problems included: does your child have difficulties falling asleep at night and/or frequent night-time awakenings. If the parent answered yes to 1 or both of these questions, the child was considered to have sleep problems as perceived by the parent. We asked the following questions as a measure of anxiety: (1) Is your child anxious? and/or (2) Does your child worry about grades, schoolwork, or new situations? Prospectively collected (nonvalidated) clinical intake questionnaires were also reviewed on the 49 patients with FAP and nausea as a secondary complaint (AP group). These parent-reported questionnaires incorporated specific questions on nausea frequency, related GI symptoms, comorbid symptoms, family history (FHx), and school absence (reported as number of
school days missed because of symptoms over the 2 months prior to evaluation). An average of 2 or more days per month of missed school was considered to adversely affect school performance. For the chronic nausea group, retrospective data was collected from a standardized checklist that includes the symptoms reported in this study such as nausea frequency, co-morbid symptoms, and school absence (number of school days missed in the past month because of symptoms). Two or more missed days was considered to adversely affect school. Laboratory evaluation was defined as screening (ie, complete blood cell count, electrolytes, hepatic transaminases, lipase, celiac screen) or extensive (ie, metabolic or endocrine serum tests). Laboratory values were considered normal or abnormal based on norms established by CHW laboratory. Results of diagnostic imaging evaluation were collected for all subjects. Abdominal ultrasound and upper GI contrast study were performed in a high percentage of subjects in both groups. Therefore, any additional imaging study performed was defined as extensive. Treatment response to common first-line medications in patients with nausea and/or AP, such as proton pump inhibitors and 5-hydroxytryptamine (5-HT3) antagonists (ondansetron) were analyzed in the chronic nausea group. We also analyzed response to amitriptyline, another frequently used medication in patients with pain-associated FGIDs.10 Although it is standard to document nausea treatment response for the chronic nausea group in our clinic, it is not for the AP group, whose primary symptom was AP. In the chronic nausea cohort, response to each drug was assessed by the clinic physician at the initial (if tried prior to referral) and at each of subsequent visits after interviewing the patient and parent. Drug response was graded and defined as some (at least 25%-50% symptom reduction) or good (>50% improvement) and documented in the clinic note. To compare 2 groups, a Mann–Whitney U test was performed for continuous variables and c2 analysis or Fisher exact test was used for categorical variables. Median, IQR, and frequencies were reported for comparisons. Statistical analysis was performed with SPSS (SPSS Inc, Chicago, Illinois); SAS (SAS Institute, Cary, North Carolina); and StatXact (SAS Institute). An unadjusted P value of <.05 was considered significant.
Results The median age of symptom onset was not different between the 2 groups. However, in the chronic nausea cohort, the median age of presentation was higher than in the AP cohort: 15 (12.5-16.0) years versus 12 (10.0-15.0) years (Table I), representing a delay in time to GI consultation. Clinical Characteristics The number of subjects complaining of daily nausea and constant nausea were much higher in the chronic nausea 1105
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Table I. Demographic profile Female n (%) Caucasian n (%) Median age years (IQR) Median age nausea onset years (IQR)
Chronic nausea group
AP group
31 (69) 43* (96) 15† (12.5-16.0) 12 (10.0-14.5)
38 (78) 37 (76) 12 (10.0-15.0) 11 (9.0-13.0)
*P # .027. †P # .001.
compared with the AP group: 88% (37/42) versus 26% (12/ 46) suffered from daily nausea, and 60% (25/42) versus 10% (4/42) of subjects described it as constant (P < .001 for both variables). In the chronic nausea group, the average nausea intensity rating was 6.9 (on a 10-point scale). Nausea intensity rating was not available on the subjects with AP. Of 37 subjects with chronic nausea, 19 (51%) complained of peak nausea in the morning (data not available in the AP group). Nausea adversely affected school performance in 67% (30/45) of the subjects with chronic nausea and 54% (25/46) of those with AP (P = .285). For the subjects with available data, comorbid symptoms were more common in the chronic nausea than the AP group: anxiety 70% (23/33) versus 41% (20/49), headache 69% (31/45) versus 61% (30/49), dizziness 79% (27/34) versus 53% (26/49), fatigue 83% (25/30) versus 59% (29/ 49), and poor sleep 61% (20/33) versus 47% (23/49) (Figure 1). Of these, anxiety (P = .013), dizziness (P = .02), and fatigue (P = .028) were statistically more common in the chronic nausea group. FHx The FHx (first degree relative) was significantly more often positive in the chronic nausea group (n = 45) than in the AP cohort (n = 49) for a FHx of migraines in 71% (32/45) versus 22% (11/49) (P < .001) (Figure 2), and gastroesophageal reflux disease in 44% (20/45) versus 20% (10/ 49) (P < .016). In addition, the family histories were more
Figure 1. Percentage of subjects with comorbid symptoms in the chronic nausea and AP groups (*P < .05). CN, chronic nausea. 1106
Vol. 164, No. 5 often positive (not significantly) for anxiety or depression in 47% (21/45) versus 39% (19/49), irritable bowel syndrome in 36% (16/45) versus 33% (16/49), and CVS in 4% (2/45) versus none. Evaluation and Treatment In the chronic nausea group 80% had extensive laboratory testing and 84% had extensive imaging work-up (Table II). The imaging evaluation performed in the 45 subjects with chronic nausea included abdominal ultrasound (78%), upper GI contrast study (60%), brain computed tomography (CT) or MRI (58%), gastric emptying scan (38%), abdominal CT or MRI (31%), and hepatobiliary scan (24%). Furthermore, antroduodenal motility studies were performed in 13% of subjects with chronic nausea. Most subjects in the AP group did not undergo either extensive laboratory or radiologic testing (P < .001). High rates of diagnostic endoscopy (n = 44 in both chronic nausea and AP groups) with normal histologic results were similar between the 2 groups (Table II). Three classes of drugs commonly used in the treatment of functional pain and nausea disorders include proton pump inhibitors, 5-HT3 antagonists, and tricyclic antidepressants (amitriptyline); 44% (14/32) of patients with chronic nausea receiving amitriptyline had a good response (at least 50% symptom improvement) and 56% (18/32) had some response (ie, at least 25% symptom improvement). The mean maximum dose used was 50 mg (range, 20-100 mg). Of the 23 patients with chronic nausea receiving a proton pump inhibitor, only 22% (5) reported some response (at least 25% symptom improvement). Of the 30 patients with chronic nausea receiving a 5-HT3 antagonist (ondansetron), 50% (15) had some response; however, none had a good response (>50% improvement). Approximately one-third of subjects with chronic nausea did not respond to any medication. No comparative data was obtained on the treatment response in the AP group because the response was typically recorded for the primary symptom of AP. Migraines and Coexisting Functional Disorders Despite the lack of a defined diagnostic category in children, a significant portion of both groups was given a final diagnosis of functional nausea: 47% (21/45) of the chronic nausea and 18% (9/49) of the AP cohort. Nearly all subjects with chronic nausea (93%) had either a FHx of migraines and/or suffered from migraines themselves; 62% (28/45) of them had concomitant migraines. The vast majority of these migraine sufferers (71%) had isolated headache episodes separate from their chronic, daily nausea. In contrast, only 12% of the subjects with AP had migraines, most of these also had episodic migraines separate from their nausea. Fewer subjects with chronic nausea than AP met the Rome criteria for AM: 7% versus 14% (P = .321) (Figure 2). An additional 9 subjects with chronic nausea had episodic AP suggesting AM spells, however, they experienced chronic nausea between episodes and, thus, did not meet the AM criteria. Kovacic et al
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changes in vitals signs. POTS often coexisted with CVS; 5 (42%) of the 12 subjects with CVS were diagnosed with POTS.
Discussion
Figure 2. Percentage of subjects in the chronic nausea and AP groups with a positive FHx of migraines, PMHx of migraines, AMs, CVS, and POTS (*P < .05).
A subgroup analysis in the chronic nausea group revealed that 12 patients (27%) met diagnostic criteria for CVS but had concomitant interictal nausea apart from their vomiting episodes (Figure 2), when using the more stringent and specific 2008 North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition consensus statement (rather than the Rome III criteria) on CVS for diagnosis.11 An additional nine subjects developed chronic nausea after outgrowing CVS. Of those 9, 67% (6) had a personal history (PMHx) or a FHx of migraine headaches (some had both). When we performed a subgroup analysis to determine if the chronic nausea associated with CVS differed from those unassociated with CVS, the clinical characteristics were not statistically different in any of the variables. POTS was present in 63% (16/45) of patients with chronic nausea as determined by either orthostatic changes in vital signs (n = 11) or formal autonomic testing (n = 5). A positive orthostatic screen was defined as a heart rate increase of $30 beats/min during positional changes from 10 minutes in supine position to standing. An additional 8 subjects with chronic nausea had orthostatic symptoms strongly suggestive of POTS, such as lightheadedness, dizziness, headaches, syncope, and fatigue but did not meet the heart rate criteria or were not formally evaluated. This differed significantly from the AP group, where POTS was found in only 6% (P # .001) (Figure 2). Two of these subjects with AP were diagnosed by autonomic testing and 1 by orthostatic
Table II. Diagnostic workup
Extensive lab workup Extensive imaging workup Endoscopy Endoscopy normal
Chronic nausea group n (%)
AP group n (%)
36 (80*) 38 (84*) 41 (93) 40 (98)
1 (2) 3 (6) 37 (84) 37 (100)
*P < .001.
Chronic Idiopathic Nausea of Childhood
This study describes the demographic profile and clinical phenotype of a large series of children with chronic nausea either as a primary or a secondary complaint, commonly seen in our pediatric Neurogastroenterology Clinic. Children with primary chronic nausea, compared with secondary nausea, were adolescent Caucasian females who were more likely to: (1) suffer from a severe, daily nausea that often peaks in the morning; (2) experience comorbid symptoms (anxiety, fatigue, dizziness); (3) have a FHx or PMHx of migraines; and (4) have associated autonomic dysfunction. Patients with FAP who complained of nausea as a secondary symptom had a similar demographic profile but presented sooner and at a younger age with AP and had: (1) less severe symptoms; (2) fewer comorbid complaints; and (3) fewer migraine features. We speculate that the shorter duration before presentation in the AP group is due to the nature of the 2 complaints; AP is a more defined GI symptom than nausea, likely prompting earlier referral to a tertiary care GI clinic. Studies describing the phenotype of children with chronic unexplained nausea are lacking even though nausea is a common symptom.4,9,12 Weekly nausea is present in 23% (range, 13%-41%) of children based on a large, school-based study of AP and related GI complaints.13 In a population-based study in adults, 3% complained of nausea once per week.14 Despite the high prevalence of nausea in children, chronic idiopathic nausea is a disorder classified only by the adult Rome III criteria. In our study, nearly one-half of the chronic nausea cohort (47%) and one-fifth (18%) of the AP cohort received a final diagnosis of functional nausea, despite the lack of a pediatric classification for this condition. These findings are in line with other studies suggesting the need for further refinement of the pediatric Rome III criteria.15 We found a common association between chronic nausea and migraines or migraine equivalents such as CVS and AM. Nearly all patients (93%) in the primary (chronic nausea) cohort had migraine features characterized by concomitant migraine headaches and/or a FHx of migraine. The rate of FHx (71%) and PMHx (62%) of migraines in the chronic nausea group was significantly higher than that in the AP group (22% and 12%, respectively). Nausea is also commonly experienced during migraine headaches and constitutes 1 supportive diagnostic criterion.16 However, most (71%) of our chronic nausea cohort had chronic daily nausea separate from their episodic migraine headaches, indicating that the chronic nausea was not merely accompanying a migraine episode. Only 7% of subjects with chronic nausea met the criteria for AM. One-quarter (27%) of the chronic nausea cohort met the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition consensus statement criteria for CVS11 and another 20% did so in the past but had 1107
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outgrown their CVS. Because a large number appeared associated with CVS and could potentially bias our population, a subgroup analysis showed that patients with and without CVS-associated nausea had similar rates of migraine features (PMHx and FHx of migraine) and similar clinical characteristics including daily, constant nausea. These results underscore the need for clinicians to review migraine-related symptoms (headaches, photophobia) and FHx (migraines) in patients with nausea, as this may provide a clue to potential treatment approaches. Many (53%) of our patients with chronic nausea either met diagnostic criteria or had clinical features of POTS. GI symptoms including nausea are well described in patients with dysautonomia.8,17-20 Sullivan et al reported associations between orthostatic intolerance and chronic upper GI complaints as well as symptom resolution upon treatment of orthostasis.17 There are several other reports of functional GI complaints associated with sympathetic autonomic dysfunction.18,21 The association with POTS suggests the possibility that nausea could also be a manifestation of autonomic dysfunction. Identifying and treating orthostatic symptoms may help alleviate nausea in some adolescents. The majority of subjects with chronic nausea underwent numerous, unrevealing laboratory, radiographic, and endoscopic testing to elucidate an organic diagnosis. These included serologic tests for metabolic disorders, brain imaging, abdominal CT/MRI, gastric, and gallbladder emptying scans. Most patients in both groups also had upper endoscopy, and nearly all were normal (98% of those with chronic nausea and 100% of those with AP). Our results suggest that extensive diagnostic workup could be avoided in place of a detailed clinical history that also queries presence of migraine and orthostatic intolerance along with screening for POTS. In our practice approach, trials of acid blockers and/or 5-HT3 antagonists were attempted, followed by therapy targeted against migraines and autonomic dysfunction. Such an empiric, therapeutic approach could have significant cost-saving, positive clinical impact by limiting unnecessary evaluations. It is plausible that physical or emotional stress can manifest as, or exacerbate chronic nausea through activation of the brain-gut axis.9,22,23 A large percentage of our study population (both groups) was described as anxious by the parent. Anxiety is well described in children and adults with various functional GI disorders, migraine headaches, and CVS. 24-26 Still, the association is likely multifactorial with genetic, environmental, and psychosocial influences. A causal relationship between anxiety and nausea can, therefore, not be determined. Our results support the use of a biopsychosocial approach in the evaluation and management of these patients. There are limitations to our study design because of our retrospective chronic nausea data, gathered mainly by chart review compared with prospectively collected AP data. The total number of subjects with available data varied between the 2 groups on several measures, in 1108
Vol. 164, No. 5 particular on comorbid symptoms, with missing data on several measures for the chronic nausea group and nonresponses to questions in the AP group. This may cause a selection bias. The clinic physician evaluating the subjects with chronic nausea used a standardized checklist to document the presence or absence of symptoms, which strengthens the validity of our retrospective data. The medical decision-making in the 2 patient cohorts was mainly at the discretion of 2 respective physicians, adding potential bias to the diagnostic evaluation and treatment approach. The report of treatment response is limited by concurrent use of other medications (although the nausea-directed medications were trialed one at a time), inability to assess symptom progression and treatment response over time, and possible placebo effects. There was also a lack of comparable data on the medication response in the subjects with AP because nausea treatment was not a primary outcome variable. Other limitations include our use of questionnaires not specifically designed for the evaluation of nausea and using an orthostatic heart rate rise of 30 bpm as an office-based screening for POTS, while the 2012 proposed criteria for children uses 40 bpm during a formal tilt table test.27 Finally, nausea is a subjective sensation that is difficult to measure objectively based on chart review. The sensation of nausea may have a different meaning and/or perceived differently in younger children, such as those in our AP cohort who may confuse it with dyspeptic AP. However, we used fairly specific written phrases such as “does your child complain of feeling of throwing up” for the nausea assessment. In addition, the questions on AP (quality and pain location) specifically helped to differentiate it from nausea. We also limited the age range to greater than 8 years to eliminate a younger cohort that typically cannot localize AP and understand symptom descriptors. Prospective studies with validated questionnaires in patients with functional GI disorders are clearly needed for improved semiquantitative assessment of severity and impact of nausea on quality of life. We describe a large cohort of adolescents with chronic idiopathic nausea as a primary symptom, compared with a group suffering from nausea as a secondary symptom to FAP. The absence of positive findings on laboratory, radiographic, and endoscopic testing suggests that in the absence of alarm symptoms, a detailed history of migraine-related and orthostatic symptoms followed by a trial of antimigraine medications may be a reasonable initial, timelimited approach before performing extensive testing. Our study suggests that chronic unexplained nausea as a primary symptom, and to a lesser degree as a secondary symptom, is a common and debilitating functional GI complaint with an inordinate impact on health outcomes and school functioning. The current Rome III diagnostic schema does not classify chronic idiopathic nausea for pediatric functional GI disorders and lacks any standard diagnostic or treatment algorithms. We suggest that chronic idiopathic nausea deserves recognition as a separate clinical entity. Future Kovacic et al
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May 2014 studies need to focus on management strategies, especially comorbid symptoms including migraine and dysautonomia. n Submitted for publication Sep 19, 2013; last revision received Dec 10, 2013; accepted Jan 23, 2014. Reprint requests: Katja Kovacic, MD, Division of Gastroenterology, Hepatology, and Nutrition, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail: [email protected]
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