B. U. K. Li

Cyclic vomiting syndrome in adults

Abstract  Cyclic vomiting syndrome (CVS) was initially described in children but can occur in all age groups. Cyclic vomiting syndrome is increasingly recognized in adults. However, the lack of awareness of CVS in adults has led to small numbers of diagnosed patients and a paucity of published data on the causes, diagnosis and management of CVS in adults. This article is a state‐of‐knowledge overview on CVS in adults and is intended to provide a framework for management and further investigations into CVS in adults.

Mitochondrial DNA control region sequence variation in migraine headache and cyclic vomiting syndrome

Migraine headache is a very common condition affecting about 10% of the population that results in substantial morbidity and economic loss. The two most common variants are migraine with (MA) and without (MO) aura. Often considered to be a migraine‐like variant, cyclic vomiting syndrome (CVS) is a predominately childhood condition characterized by severe, discrete episodes of nausea, vomiting, and lethargy. Disease‐associated mitochondrial DNA (mtDNA) sequence variants are suggested in common migraine and CVS based upon a strong bias towards the maternal inheritance of disease, and several other factors. Temporal temperature gradient gel electrophoresis (TTGE) followed by cyclosequencing and RFLP was used to screen almost 90% of the mtDNA, including the control region (CR), for heteroplasmy in 62 children with CVS and neuromuscular disease (CVS+) and in 95 control subjects. One or two rare mtDNA‐CR heteroplasmic sequence variants were found in six CVS+ and in zero control subjects (P = 0.003). These variants comprised 6 point and 2 length variants in hypervariable regions 1 and 2 (HV1 and HV2, both part of the mtDNA‐CR), one half of which were clustered in the nt 16040–16188 segment of HV1 that includes the termination associated sequence (TAS), a functional location important in the regulation of mtDNA replication. Based upon our findings, sequencing and statistical analysis looking for homoplasmic nucleotide changes was performed in HV1 among 30 CVS+, 30 randomly‐ascertained CVS (rCVS), 18 MA, 32 MO, and 35 control haplogroup H cases. Within the nt 16040–16188 segment, homoplasmic sequence variants were three‐fold more common relative to control subjects in both CVS groups (P = 0.01 combined data) and in MO (P = 0.02), but not in MA (P = 0.5 vs. control subjects and 0.02 vs. MO). No group differences were noted in the remainder of HV1. We conclude that sequence variation in this small “peri‐TAS” segment is associated with CVS and MO, but not MA. These variants likely constitute risk factors for disease development. Our findings are consistent with previous data demonstrating progression of CVS into MO in many cases, and the co‐segregation in a maternal inheritance pattern of CVS and MO within families. A mitochondrial component in the pathogenesis of migraine and CVS has therapeutic implications, especially concerning the avoidance of fasting.

Maternal inheritance in cyclic vomiting syndrome

Cyclic vomiting syndrome (CVS), characterized by severe discrete episodes of nausea, vomiting, and lethargy, is a fairly common, disabling, predominately‐childhood condition most often associated with migraine and dysautonomic features. Our group recently reported that children with CVS and additional neuromuscular disease manifestations demonstrate strong maternal inheritance of multiple disease manifestations and abnormal urine organic acids, suggesting the presence of predisposing mitochondrial DNA (mtDNA) sequence variants. In order to determine if maternal inheritance is present in CVS in general, a clinical interview was administered regarding 80 unrelated individuals with CVS ascertained randomly from the database of the Cyclic Vomiting Syndrome Association (CVSA). Disease manifestations consistent with potential mitochondrial dysfunction were far more common in matrilineal (sharing the same mtDNA sequence) versus in non‐matrilineal relatives, including mothers versus fathers (P = 3 × 10−9) and maternal versus paternal grandmothers (P = 2 × 10−6). Maternal inheritance is suggested in 52% of the 23 subjects with two or more neuromuscular abnormalities (“CVS+”) and in 54% of the 44 subjects without any neuromuscular abnormalities (“CVS−”). In both the CVS+ and CVS− sub‐groups, subjects, and affected matrilineal relatives of all ages suffer at a far higher incidence from several dysautonomic‐related conditions, including migraine and irritable bowel, as well as depression and hypothyroidism, while neuromuscular and cognitive disorders such as hypotonia and ADHD are common only in affected children. We conclude that mtDNA sequences predispose towards the development of protean disease manifestations in CVS patients ascertained through a disease‐specific association, as well as among their matrilineal relatives, whether or not neuromuscular disease is present in the proband. Since CVS was absent in all but one matrilineal relative of our probands, CVS is apparently a rare clinical presentation in individuals carrying the predisposing mtDNA sequences. The four conditions reported most frequently among the matrilineal relatives of our cases, migraine, depression, irritable bowel, and hypothyroidism, are known to segregate together in families, and our findings suggest that a common predisposing genetic factor is likely present on the mtDNA.

Maternal inheritance in cyclic vomiting syndrome with neuromuscular disease

Cyclic vomiting syndrome (CVS), characterized by severe discrete episodes of nausea, vomiting, and lethargy, is a predominately childhood condition associated with migraine and dysautonomic features. Disease‐associated mitochondrial DNA (mtDNA) sequence variants are suggested by a strong maternal bias in the inheritance of migraine, and the recent findings of mtDNA variants in a few children with CVS and additional neuromuscular disease manifestations (“CVS+”). A clinical interview using a questionnaire was administered (generally) to one parent of 62 children with CVS+. Non‐senile disease manifestations, including migraine, myopathy, seizures, and dysautonomia‐like symptoms, were far more common in matrilineal versus non‐matrilineal relatives, including being present in 75% of the mothers versus in only 11% of the fathers (P < 0.001). Overall, maternal inheritance is suggested in 86% of the families (in 65% strongly so). Disease manifestations in subjects and their affected matrilineal relatives are predominately intermittent and consistent with dysautonomia, including increased vital sign fluctuations. Body fluid metabolites and muscle biopsy findings are consistent with mitochondrial dysfunction in most cases tested. We conclude that mtDNA sequence variants are at least risk factors in the development of disease in most children at this “severe” end of the CVS spectrum, likely involving a maternally inherited propensity towards dysautonomia.

Autonomic nerve function in adults with cyclic vomiting syndrome: a prospective study.

Background  Cyclic vomiting syndrome (CVS) is a functional gastrointestinal disorder that is characterized by recurrent episodes of intense vomiting. There are several postulated mechanisms involved in its pathogenesis and one potential explanation for this disorder may be linked to autonomic dysfunction. The aim of our study was to evaluate autonomic nerve function in patients with CVS prospectively.

Psychiatric Symptoms in Children and Adolescents With Cyclic Vomiting Syndrome and their Parents

Objective.— To conduct a pilot study to evaluate the prevalence of psychiatric symptoms in children and adolescents with cyclic vomiting syndrome and to assess family history of psychiatric disorder.

High Prevalence of Nausea in Children With Pain-associated Functional Gastrointestinal Disorders: Are Rome Criteria Applicable?

Objectives: The aim of the study was to determine the prevalence of nausea in pediatric patients with pain-associated functional gastrointestinal disorders (FGIDs), examine the effect on social and school functioning, and examine the applicability of pediatric Rome III criteria. Methods: A total of 221 pediatric patients (6–18 years of age) with chronic abdominal pain prospectively completed a demographic, history, and gastrointestinal symptom questionnaire adapted from the Questionnaire on Pediatric Gastrointestinal Symptoms (QPGS). The 6-item, revised Pediatric Migraine Disability Assessment Score tool was used to assess the effect of symptoms on school, home, and social disability. Rome III criteria were applied to all subjects. Results: A total of 183 patients with pain and nausea for a minimum of 2 months were identified. Ninety-six patients were studied after excluding those with vomiting and/or organic disease. Among these, 53% had nausea at least 2 times per week and 28% experienced daily nausea. Frequency of nausea was significantly correlated with poor school and social functioning, and uniquely predicted social disability beyond pain. Although 87% met adult Rome criteria for functional dyspepsia, only 29% met corresponding pediatric Rome criteria. Additionally, 22% met the criteria for irritable bowel syndrome (IBS)-diarrhea, 13% for IBS-constipation, 13% for abdominal migraine, and 31% were classified as having functional abdominal pain. Pediatric IBS-diarrhea and IBS-constipation overlapped in 5% of patients. Conclusions: Nausea is a prevalent symptom in patients with pain-associated FGIDs and correlates with poor school and social functioning. There is substantial overlap among FGIDs in children with nausea.

A survey of emergency department use in patients with cyclic vomiting syndrome

BackgroundCyclic vomiting syndrome (CVS), a chronic disorder characterized by recurrent episodes of vomiting, is frequently unrecognized and is associated with high utilization of emergency department (ED) services.MethodsA web-based survey was posted on the Cyclic Vomiting Syndrome Association (CVSA) website to assess utilization of ED services in patients with CVS.ResultsOf 251 respondents, 104 (41.4%) were adult CVS patients and 147 (58.6%) were caregivers of pediatric and adult patients. In the adult group, the median number of ED visits for CVS symptoms was 15(range 1 - 200), with a median of 7 ED visits prior to a diagnosis of CVS (range 0 - 150). In the caregiver group, the median number of ED visits was 10 (range 1 - 175) and the median number of ED visits prior to a diagnosis of CVS was 5 (range 0 - 65). CVS was not diagnosed in the ED in 89/104 (93%) adults and 119/147 (93%) patients in the caregiver group. CVS was not recognized in the ED in 84/95 (88%) of adults and 97/122 (80%) of patients in the caregiver group, despite an established diagnosis of CVS.ConclusionThere is a sub-group of adult and pediatric CVS patients who are high utilizers of ED services and CVS is not recognized in the ED in the majority of patients. Improved efforts to educate ED physicians are indicated to optimize treatment of patients with CVS and to decrease potential overuse of ED services.

Health-Related Quality of Life in Children and Adolescents with Cyclic Vomiting Syndrome: A Comparison with Published Data on Youth with Irritable Bowel Syndrome and Organic Gastrointestinal Disorders

OBJECTIVE To evaluate health-related quality of life (HRQoL) in children with cyclic vomiting syndrome (CVS) and to compare child self-reports with those of their parents and with published reports of children with irritable bowel syndrome (IBS), children with organic gastrointestinal disorders, and a healthy control group. STUDY DESIGN Sixty-eight children aged 5-18 years with CVS confirmed in a gastroenterology clinic completed the Pediatric Quality of Life Inventory (PedsQL). Eighty-two parents completed the parent-proxy PedsQL for children aged 2-18 years. These results were compared with published data for children with IBS, organic gastrointestinal disorders, and a healthy control group using ANOVA. Intraclass correlation was used to evaluate concordance between child and parent reports of HRQoL. RESULTS HRQoL reported on the PedsQL by children with CVS was lower than that reported by children with IBS (P < .01) and healthy controls (P < .001), but did not differ from that reported by children with organic gastrointestinal disorders. Children with CVS also had lower HRQoL compared with healthy controls by parent-proxy report on the PedsQL (P < .001). Correlations between HRQoL reports by parents and children were moderate to good (intraclass correlation coefficients, 0.504-0.805; P < .01). Duration of CVS episodes, delay in CVS diagnosis, and number of school days missed due to CVS were associated with lower parent-rated HRQoL (P = .01). CONCLUSION Children with CVS reported lower HRQoL compared with those with IBS, and both parents and children reported lower HRQoL compared with healthy controls. Parent and child ratings of HRQoL converged. Improved recognition of CVS and school support might help mitigate the impact of CVS on HRQoL.

NextGen nuclear DNA sequencing in cyclic vomiting syndrome reveals a significant association with the stress-induced calcium channel (RYR2)

Cyclic vomiting syndrome (CVS) is a common, frequently disabling, ‘functional’ condition characterized by recurring, stereotypical attacks of intense nausea, vomiting, and lethargy, with the essential absence of these symptoms between episodes. Although the pathogenesis of CVS is yet unexplained, evidence has accumulated which suggest pathogenic roles for stress‐related, autonomic, neuroendocrine, and mitochondrial factors. The objective of this pilot study was to elucidate mechanism(s) by identifying genes involved in the presumed multifactorial pathogenesis of CVS.