Address for Correspondence G. Richard Locke, III, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel: 507-538-7637; fax: 507-538-5820; e-mail: email@example.com
Background Cyclic vomiting syndrome (CVS) is characterized by stereotypical episodes of vomiting separated by symptom-free intervals. However, the difficulty encountered in the management of patients with CVS may be a reflection of a deficiency in our understanding of the disorder. We aimed to evaluate whether clinical or gastric emptying (GE) data discriminate patients labeled as having CVS from functional vomiting (FV) or irritable bowel syndrome (IBS).
Methods The medical records of patients diagnosed with any vomiting (including CVS, FV) over a 13-year period (1993–2006) at our institution were carefully reviewed. Disease controls were age and gender matched subjects with IBS. Gastric emptying was performed by scintigraphy (99mTc-egg meal). The associations of clinical factors and GE data with patient status (CVS vs FV or IBS) were analyzed.
Key Results A total of 82 patients with CVS and 62 FV patients were identified. Younger age [per 10 years, OR = 0.7 (0.5, 0.9)], male gender [OR = 0.4 (0.2, 0.9)], and cannabinoid use [OR = 2.9 (1.2, 7.2)] were significantly associated with CVS compared with FV. However, there were no significant associations between patient status (CVS vs FV) and age, BMI, smoking, alcohol use, gastrointestinal symptoms, or GE. The proportion of cannabinoid users was significantly higher in patients with CVS compared with patients with IBS, whereas proportions for headaches and psychiatric disease were higher in subjects with IBS.
Conclusions & Inferences Cyclic vomiting syndrome (vs FV) was not associated with clinical factors, but was associated with younger age, male gender and cannabinoid use. A larger proportion of CVS (vs IBS) patients had used cannabinoids.
Functional gastrointestinal (GI) disorders are comprised of symptoms arising in the GI tract that are not otherwise attributable to a known structural or biochemical explanation.1,2 Vomiting that occurs in the absence of known structural or biochemical causes, i.e., non-organic, are classified as due to cyclic vomiting syndrome (CVS) or functional vomiting (FV).3 Usually patients with eating disorders, major psychiatric diseases, abnormalities in the GI tract or central nervous system or metabolic diseases are excluded.1,2
Cyclic vomiting syndrome is characterized by paroxysmal, recurrent, and stereotypical episodes of vomiting that are separated by healthy, symptom free intervals.1,3 Moreover, CVS remains a management challenge for clinicians as few satisfactory treatment options are available, and success rates have been relatively low.3 The majority of treatment options are aimed at alleviating symptoms associated with CVS, and complete resolution is rarely an outcome. The difficulty encountered in the management of patients with CVS may be a reflection of a deficiency in our understanding of the disorder. Most of the literature on CVS is based on studies of pediatric patients4–7 and only small series of adult patients have been reported.8,9 Overall the lack of awareness of CVS in adults has led to small numbers of diagnosed patients and paucity of published data on the causes, diagnosis and management of CVS in adults according to the recent consensus statement on cyclical vomiting in adults.3 Moreover, whether specific features aside from the cyclical pattern distinguish CVS from FV is uncertain,3,10 although the recent Rome III committee recommended the differentiation between CVS and FV in adults based on expert opinion.1 Further, several conditions have been reported to be associated with CVS, including migraine headache6,11 and psychological or psychiatric morbidities.12–14 Interestingly, some have suggested that marijuana-associated CVS (referred to as cannabinoid hyperemesis) is distinct from the condition in non-users but this is uncertain.15–18
Thus, the overall aim of our study was to document the clinical features including marijuana use and gastric emptying (GE) data in subjects with CVS and FV. We also aimed to investigate the role of conditions commonly speculated to be associated with CVS including migraine headaches, gastric motor abnormality, psychiatric disorders, and cannabinoid exposure, compared with subjects with FV or irritable bowel syndrome (IBS).
Study design and case ascertainment
A retrospective chart review was conducted on all patients identified by a computerized diagnostic index as having cyclic vomiting or functional vomiting from 1993 to 2006. The International Classification of Diseases (ICD)-9 307.54 (FV) and 536.2 CVS were used to identify the charts of the patients diagnosed as having ‘CVS’ and ‘FV’. Inclusion criteria used for chart abstraction and analysis was: patients seen at Mayo Clinic Rochester from 1993–2006; aged 18–80 years; both males and females. Furthermore, those with IBS who were age and gender frequency matched with patients with CVS were identified using (ICD)-9 564.1 (IBS) from Mayo Clinic Rochester. Patients who had concomitant active medical illness, history of esophageal or gastric surgery, or use of medications which may cause patient symptoms or altered GI function were excluded from the analysis. The diagnostic index of Mayo Clinic was designed to be sensitive and thus this broad search should have captured all clinically diagnosed cases. However, a detailed chart review was undertaken to improve specificity and ensure all cases actually had CVS or FV based on expert clinical review.
Cyclic vomiting syndrome Patients who met all of the following criteria were classified as having CVS1,3: (i) three or more recurrent discrete episodes of vomiting, (ii) varying intervals of completely normal health between episodes, (iii) stereotypical episodes that were repetitive with regard to symptom onset and duration, and (iv) absence of laboratory or radiographic findings of an alternative diagnosis.
Functional vomiting1 Must include all of the following and must not fulfill CVS criteria: (i) on average one or more episodes of vomiting per week, (ii) absence of criteria for an eating disorder, rumination, or major psychiatric disease according to DSM-IV, (iii) absence of self-induced vomiting and absence of abnormalities in the central nervous system or metabolic diseases that explain the recurrent vomiting.
Irritable bowel syndrome Patients with IBS were randomly selected from matched sets of potential ‘controls,’ matched on age, gender, and geographic referral region to patients with CVS. All controls were given a clinical diagnosis of IBS after an appropriate workup by board-certified physicians at Mayo Clinic in Rochester, Minnesota. We chose IBS as it is a very well-recognized disorder and we wanted a disease control group that would be subject to similar selection forces to the cases, to minimize selection bias.
The data was collected using a prepared data collection form. The data collection form allowed standardized retrieval of medical information for each patient and the entries were encoded in a computerized database. The following information was collected from the complete review of medical records:
1 Demographics; age at time of initial diagnosis and gender.
2 Body mass index (BMI) at the diagnosis of CVS, FV, or IBS.
3 Symptoms including nausea, vomiting, retching, abdominal pain, constipation, diarrhea, headache, and weight loss (more than 7 pounds over 6 months).
4 Socioeconomic factors: marital status (married or not) and educational level (college or professional training, high school, or less than high school).
5 Cigarettes and alcohol: We checked medical records for the use of cigarettes and alcohol abuse (yes for current use, no for never or not current use).
6 Cannabinoid use: Exposure to and use of cannabinoid was extracted from (i) a self reported health symptom inventory questionnaire (patient provided information) completed by all who consult at Mayo Clinic and (ii) electronic medical records of clinic visits.
7 Psychiatric/psychological disease, migraine, or abuse history: We abstracted diagnoses of depression, anxiety, any psychiatric disease, migraine, or abuse history from the medical records. In addition, we excluded subjects with eating disorders based on DSM-IV.
8 Diagnostic evaluations, including upper endoscopy, upper GI X-ray, small intestinal enteroclysis, abdominal CT, abdominal MRI, GE test, gastroduodenal manometry, or brain CT/MRI.
Description of gastric emptying study
Scintigraphic techniques were used to evaluate GE as described in prior studies conducted in our laboratory.19 Patients undergoing GE evaluation discontinued their medications 48 h before testing. After an overnight fast, a 99mTc-sulfur colloid labeled egg meal assessed GE. The eggs are served with one slice of buttered bread and an 8-oz glass of 1% milk (total calories: 296 kcal, 32% protein, 35% fat, 33% carbohydrate). Anterior and posterior gamma camera images were obtained 0, 1, 2, and 4 h after the test meal ingestion. Rapid GE was defined as isotope retention <50% at first hour and/or <30% at second hour.20 Delayed GE rate was defined as slower than 2 SD (standard deviation) of the normal mean at any time point at 2 or 4 h.19–21
The associations of clinical factors with patient status (CVS vs FV) adjusting for age and gender were assessed using logistic regression models, specifically conditional logistic regression models for the matched case control analysis, (CVS vs IBS) and unconditional logistic regression models for the unmatched analysis (CVS vs FV). The univariate associations of clinical features with (matched) case control status (CVS cases vs IBS controls) were assessed using McNemar’s test to account for the matching (a total of 82 matched pairs). Analyses were done with SAS version 9.1 (SAS Institute, Cary, NC, USA). A significance level of less than 0.05 was used, and all tests were two-sided.
Selection of subjects
A total of 263 subjects were identified to have ICD-9 307.54 (FV) and 536.2 (CVS). Of these, 82 subjects met the criteria for CVS and 62 subjects met the criteria of FV. These patients were abstracted and the data was included in the analysis. Based on 82 patients with CVS, 82 patients with IBS were randomly selected from potential controls matched to each CVS case based on age, gender, and geographic referral region.
Cyclic vomiting syndrome and functional vomiting
Table 1 summarizes the association of clinical features, including sociodemographic findings, GI symptoms, psychiatric disease status, and GE results, according to CVS or FV status. The mean age (±SD) of CVS was 30 years (±11), and 47% were female, while the mean age (±SD) of FV was 36 years (±13), and 54% were female. No statistically significant association was detected between group membership and marital status, education level, BMI, employment status, alcohol use, or smoking history. However, older age and female gender decreased the odds for CVS (compared with FV). Notably, cannabinoid use increased the odds for CVS [OR = 2.9, 95%CI (1.2, 7.2), P = 0.02, relative to non-cannabinoid users], but this depended on gender (see below). Interestingly, the presence of headache (relative to absence) did not significantly increase the odds for CVS (compared with FV) and specifically, migraine headache was not significantly associated with patient status (CVS vs FV).
Table 1. Patients with cyclic vomiting syndrome vs functional vomiting by specific demographic and clinical characteristics
CVS N = 82 (57%)
FV N = 62 (43%)
Odds ratio for CVS (95% CI)
FV, functional vomiting; CVS, cyclic vomiting syndrome; IBS, irritable bowel syndrome; CI, confidence interval; BMI, body mass index. *Model adjusted for age (per 10 years) and gender.
Age, mean (SD)
Female (n = 71)
Male (n = 73)
BMI, mean (SD) (available in n = 129)
Weight loss (n = 38)
No weight loss (n = 65)
Married (n = 64)
1.5 (0.6, 3.7)*
Not married (n = 77)
Education <high school (n = 14)
High school (n = 60)
College or professional training (n = 66)
Smoking (n = 43)
No smoking (n = 99)
Alcohol use (n = 38)
1.0 (0.5, 2.2)*
No alcohol use (n = 104)
Cannabinoid use (n = 38)
2.9 (1.2, 7.2)
No cannabinoid use (n = 104)
Nausea (n = 125)
No nausea (n = 19)
Retching (n = 80)
4.4 (2.0, 9.7)*
No retching (n = 64)
Abdominal pain (n = 107)
1.7 (0.8, 3.9)*
No abdominal pain (n = 37)
Diarrhea (n = 34)
2.2 (0.9, 5.2)*
No diarrhea (n = 110)
Headache (n = 37)
No headache (n = 107)
Migraine (n = 28)
No migraine (n = 113)
IBS (n = 7)
1.1 (0.2, 5.6)*
No IBS (n = 136)
Depression (n = 6)
No depression (n = 138)
Anxiety (n = 3)
No anxiety (n = 141)
Other psychiatric disease (n = 32)
No other psychiatric disease (n = 112)
Abuse history (n = 10)
No abuse history (n = 133)
The majority of GI symptoms were not associated with patient status; only retching (relative to no retching) was associated with a greater odds for CVS (compared FV). With respect to psychiatric disease, no associations were detected, except a history of other psychiatric disease (other than anxiety and depression, relative to no other psychiatric disease) was associated with a decreased odds for CVS (P = 0.006).
Cyclic vomiting syndrome and IBS
McNemar’s test was used to assess the association of clinical features with case control status (CVS vs IBS, Table 2). There were no significant associations with weight loss, marital status, smoking history, or abuse history. However, higher proportions of IBS patients (compared with CVS patients) were college graduates, reported alcohol use, experienced headaches and had psychiatric disease including depression, anxiety, and other psychiatric disease. Cannabinoid use was significantly higher in patients with CVS compared with patients with IBS (Table 2). The proportion of patients reporting headaches was higher in IBS patients compared with CVS patients (P = 0.02), whereas the proportion of migraine headache in IBS patients was similar to that of CVS patients.
Table 2. Characteristics of patients with CVS vs IBS
Table 3 shows the distribution of GE in subjects with CVS, FV, and IBS. Among subjects with CVS who underwent GE testing [n = 47 (57%)], 45% had fast GE, 51% normal GE, and 4% delayed GE. Among patients with FV who underwent GE test [n = 35 (56%)], 46% had fast GE, 37% normal GE, and 17% delayed GE. However, only 8% of patients with IBS had fast GE, though only 12 (15%) patients had undergone a GE test.
Table 3. Distribution of gastric emptying in subjects with CVS, FV, and IBS
CVS (n = 82) (%) [95% CI]
FV (n = 62) (%) [95% CI]
IBS (n = 82) (%) [95% CI]
FV, functional vomiting; CVS, cyclic vomiting syndrome; IBS, irritable bowel syndrome; CI, confidence interval; GE, gastric emptying. *Percentage of those actually tested or classified. **Percentage of total group.
21 (45%) [30,60]
16 (46%) [29,63]
1 (8%) [0.2,38]
24 (51%) [36,66]
13 (37%) [21,55]
10 (83%) [52,98]
2 (4%) [0.5,15]
6 (17%) [7,34]
1 (8%) [0.2,38]
No GE test/not classified, N(%**)
35 (43%) [32,54]
27 (44%) [31,57]
70 (85%) [76,92]
Figure 1 shows the proportions of cannabinoid users in CVS, FV, and IBS patients by gender. Cannabinoid use was most commonly reported in men with CVS relative to others. Specifically, although overall cannabinoid use was significantly associated with an increased odds for CVS compared with FV [OR = 2.9, 95% CI (1.2–7.2)], adjusted for age and gender, gender was confounded with cannabinoid use, and the odds for CVS (compared with FV) was significantly increased only in males using cannabinoids (OR = 3.9, P < 0.05, relative to male non-users), but not in females using cannabinoids (OR = 1.2, P = 0.77, relative to female non users). The proportion of cannabinoid users was also significantly higher in CVS patients compared with IBS (P < 0.001, Table 2).
In this study, we found that both CVS and FV, which are vomiting-related functional GI disorders, had very similar clinical features aside from cannabinoid use. Notably, subjects who were cannabinoid users were 2.4 times more likely to have CVS relative to patients with FV. Of particular interest, patients with FV and cyclic vomiting had similar patterns of GE, with about a quarter of patients having fast GE, compared with only 1% of patients with IBS who had fast GE.
The presence of certain GI complaints and migraine headaches has previously been described to be associated with CVS in a cohort of pediatric patients.22 We found that the prevalence of GI symptoms was similar in both CVS and FV patients, aside from retching which was more common in patients with CVS. Abdominal pain, nausea, and retching were the most commonly reported symptoms, and the prevalence of these symptoms in this adult population is similar to the published data in pediatric populations.23
We observed that the prevalence of headache and migraine headache was higher in patients with CVS, but was not statistically significant different from FV patients. It has been postulated that in children, CVS may be a form fruste of migraine.24 Similarities between CVS and migraine headaches include the temporal (on-off) patterns, similar associated signs (such as pallor), a positive family history of migraine in both entities, and progression from migraine to CVS or vice-versa within individuals. The postulated neural basis for migraine headaches,11 namely enhanced neural excitability and abnormal mitochondrial metabolism might apply to cyclic vomiting if a true association exists. However, at present, this association is speculative as the exact pathophysiologic mechanisms underlying migraine, and similarly CVS, remains to be determined. Moreover, we could not confirm this association; indeed, in our study, the prevalence of migraine headache was similar in matched patients with IBS compared with patients with CVS. In addition, Namin et al.12 showed that only 13% of patients reported migraine in adult CVS patients, which is consistent with our findings. We abstracted diagnoses of migraine from the medical records but notably this may have been subject to misclassification error as we do not know what criteria each clinician applied (or did not apply). Our study does not rule out migraine headache being associated with childhood CVS.
We also found lower frequencies of co-existing psychiatric disorders including depression and anxiety in CVS patients compared with IBS patients. In contrast, some other studies13,25–27 have shown high frequencies of psychiatric disease, such as depression or anxiety disorder compared with a healthy group. A limitation is that we could not systematically assess cases and controls for psychiatric disease and thus may have missed an association. On the other hand, our work supports the view that the rates of psychiatric disease are no higher in CVS than in the background population.13,14 An important finding in our study was the association between cannabinoid use and cyclical vomiting. Originally this association was described in a case series of nine adult CVS patients from Australia.16 In all cases, chronic cannabinoid abuse predated the onset of the cyclical vomiting illness, and cessation of cannabinoid abuse led to cessation of the cyclical vomiting illness in seven cases of nine CVS patients. The study concluded that chronic cannabinoid abuse was the cause of the cyclical vomiting illness in the majority of cases. The study provided a promising hypothesis of an etiologic factor for this rare condition. In contrast, Namin et al.12 reported another large series of 31 patients with CVS where only 13 patients admitted to daily to weekly cannabinoid use; among the 13 CVS patients with cannabinoid use, they observed that only two patients who ceased cannabinoid use had resolution of their vomiting cycles. However, we found that cannabinoid users were 2.4 times more likely to have CVS compared with FV patients; moreover, the proportion of cannabinoid users was significantly higher in CVS patients relative to matched IBS patients. Notably, our study showed that male cannabinoid users were most strongly associated with CVS but cannabinoid use did not account for all cases. Thus, our findings suggest that cannabinoid use can be associated with the development of vomiting symptoms, but we may have underestimated the effect because of under-reporting of cannabinoid use.
Another key finding of our study was the high prevalence of fast GE in subjects with CVS and FV, compared with patients with IBS. In a case series report of 92 adult CVS patients, Heijazi et al.13 showed that GE is generally either rapid (59%) or normal (27%) in adults CVS patients, while a small subset of CVS patients (14%) were delayed. Although the distribution of GE in the present study was somewhat different, our findings are consistent with the concept that CVS patients are more likely to have fast GE instead of delayed GE. A novel finding is that FV patients had a similar distribution of GE findings to CVS. Akin to dumping syndrome, rapid passage of food into the small bowel may induce hyperosmolarity and small bowel distention, promoting vomiting and vasomotor symptoms in predisposed individuals through the release of various GI peptide hormones including enteroglucagon, peptide YY, pancreatic polypeptide, vasoactive intestinal polypeptide, glucagon-like peptide 1 and neurotensin.28,29 Hejazi et al.27 showed that serum ghrelin levels in adult CVS patients were significantly elevated compared with normal subjects, which they suggested might induce rapid GE.30 Furthermore, Delgado-Aros et al.31 showed that the effects of erythromycin, which accelerate GE, were significantly associated with postprandial symptoms including nausea. Other studies32,33 also observed that accelerated GE by a drug or its presence in patients with functional dyspepsia was associated with nausea. One limitation of the present study is that we only had GE measurements on a subset (57%), and it is possible, albeit unlikely, that the study population assessed was not representative.
Treatment options for CVS and FV are limited by the lack of randomized controlled trials so management remains challenging and largely empiric.3 Open label use of low dose tricyclic antidepressants has been reported to provide a response in patients with CVS and reduce the number of subsequent CVS episodes in adults9,27,34, but the studies have been small and uncontrolled. In 20 patients who had failed tricyclic antidepressant therapy, the antiepileptic drugs zonisamide (median dose, 400 mg day−1) or levetiracetam (median dose, 1000 mg day−1) were tried with a benefit reported in three quarters,35 but side effects may not infrequently limit use. In addition, several other agents have been advocated for prophylaxis, including anti-migraine medications (e.g., low dose propanolol, sumatriptan, cyproheptadine),36–38 neuroleptics (e.g., phenobarbital, valproic acid, carbamazepine)39 and gastric prokinetic agents (e.g., erythromycin)23,40 but the data are very limited in adults. There is a recent case report of cognitive behavioral therapy and biofeedback training providing a benefit in CVS.41 The role of diet and supplements in adults is unknown, and coenzyme Q10 is of uncertain benefit. Therefore, the treatment of CVS remains challenging and further research is warranted.
In conclusion, this present study reports the largest and most comprehensively described clinical experience with adult CVS and FV in the literature. We reviewed 82 patients with CVS, 62 patients with FV, and 82 matched IBS subjects. Our data confirm that both cyclic vomiting syndrome and functional vomiting are rare disorders. CVS occurs most often in young males and rapid GE is common. Rapid GE is also more common in FV. Migraine headache and psychiatric disorders do not appear to more commonly co-exist with CVS, compared with IBS.
RSC, GRLIII, ARZ, and NJT participated in the design, analysis, and in writing manuscript; RSC and RML abstracted the medical record; ARZ and CDS provided the statistical analysis and assisted in writing the manuscript.
The authors wish to thank Lori R. Anderson for her assistance in the preparation of the manuscript. This study was made possible in part by the Rochester Epidemiology Project (Grant #R01-AR30582 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases).