Excerpt from Cyclic Vomiting Syndrome

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Background

Cyclic vomiting syndrome (CVS) is a chronic functional disorder of unknown etiology that is characterized by paroxysmal, recurrent episodes of vomiting and was first described in children by Samuel Gee in 1882. Although this was initially thought to occur mostly in children, it is being recognized with increasing frequency in adults. Although the pathophysiology is unknown, various mechanisms such as corticotropin-releasing factor (CRF) and a heightened sympathetic response may play a role. Recent data also suggest a strong genetic component, with evidence of mitochondrial heteroplasmies that predispose to cyclic vomiting syndrome and other related disorders, such as migraine and chronic fatigue syndrome.

Pathophysiology

The etiology, pathophysiology, and target organ in cyclic vomiting syndrome remain unknown. Over the last decade, studies have proposed several potential brain-gut mechanisms. Migraine-related mechanisms have been proposed, and patients with cyclic vomiting syndrome have a significantly higher prevalence of family members with migraine headaches (82% vs 14% of control subjects with a chronic vomiting pattern). Furthermore, 28% of patients with cyclic vomiting syndrome whose vomiting subsequently resolved developed migraine headaches. Finally, 80% of affected patients with family histories positive for migraine respond to antimigraine therapy.¹

Mitochondrial DNA mutations may be involved in the pathogenesis of cyclic vomiting syndrome. Boles et al have demonstrated that, among children with cyclic vomiting syndrome and neuromuscular disease, 86% have a history of migraines on the matrilineal side. Boles and colleagues also reported a large mitochondrial DNA deletion in a single child with cyclic vomiting syndrome and have identified additional mutations concentrated in the D-loop, a hypervariable locus of the control region, in other children with cyclic vomiting syndrome.²

Children with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome are known to have both severe migraines and episodic vomiting, as in cyclic vomiting syndrome.³ Several children with cyclic vomiting syndrome, including 4 members of an Italian family, have recently been reported to have various mitochondrial mutations.^{4, 5}

Sympathetic hyperresponsivity and autonomic dysfunction also appear to contribute to the pathogenesis of cyclic vomiting syndrome.⁶ Many associated symptoms, such as pallor, flushing, fever, lethargy, salivation, and diarrhea, are mediated by the autonomic nervous system.^{7, 8, 9} 

Several studies support altered autonomic function in cyclic vomiting syndrome. Rashed et al (1999)¹⁰ and To et al (1999)¹¹ demonstrated a heightened sympathetic cardiovascular tone in patients with cyclic vomiting syndrome. Kasawinah et al (2003) reported the successful use of dexmedetomidine, an alpha-2 adrenergic agonist, to treat cyclic vomiting syndrome.¹² In a small study involving 6 children with cyclic vomiting syndrome, all patients had sympathetic autonomic dysfunction, affecting mainly the vasomotor and sudomotor systems. Symptoms developed during tilt testing in half of these patients, suggesting that these findings may play a role in the pathophysiology of this disorder.¹³

The stress response, mediated by the hypothalamic-pituitary-adrenal (HPA) axis, can also potentially induce episodes of cyclic vomiting syndrome. Infectious, psychological, and physical stressors are known triggers of episodes.^{14, 15, 16, 17, 18} Sato et al documented increased levels of adrenocorticotropic hormone (ACTH) and cortisol, associated with extreme lethargy and hypertension, before the onset of vomiting.^{19, 20, 21, 22} Furthermore, Taché (1999) has definitively shown that central CRF induces gastric stasis, emesis, or both in animals.²³ Therefore, CRF may be a potential brain-gut mediator of cyclic vomiting syndrome that directly connects stress and vomiting.²⁴ If this theory holds true, CRF receptor antagonists currently in development could theoretically ablate the vomiting by blocking the CRF receptor's vagally mediated actions.²⁵

How these pathways fit together is still unclear. Li and Misiewicz have proposed that heightened neuronal excitability due to enhanced membrane ion permeability (ion channelopathy), mitochondrial energy deficits (due to dysfunction), or hormonal state (eg, menstrual periods) may be present.¹ Both physical (infection) and psychologic stressors (excitement) can initiate a known cascade that releases hypothalamic CRF, the suspected neuroendocrine trigger, resulting in vomiting. Altered brainstem regulation of these autonomic signals may be the necessary abnormality that allows the dysautonomia to feed forward and become self-sustained for days on end.

Frequency

United States

The true incidence and prevalence of cyclic vomiting syndrome are unknown. In central Ohio, amid a predominantly white population, the prevalence of cyclic vomiting syndrome in children (evaluated by the sole pediatric gastroenterology referral center) was 0.04%.²⁶

International

Limited epidemiologic data by Cullen and MacDonald estimate the prevalence of periodic vomiting in western Australia to be 2.3%.⁷ Similarly, Abu-Arafeh and Russell observed a prevalence of 1.9% in school-aged children in Aberdeen, Scotland.²⁷ Both of these figures estimate the prevalence in white populations and may not reflect all races or ethnic populations. In a study performed at KEM Hospital in Pune, India, cyclic vomiting syndrome accounted for 0.5% of admissions to pediatric wards during 1998-2000.

In a population based study in Ireland, the incidence of cyclic vomiting syndrome in Ireland was relatively common at 3.15 cases per 100,000 children in 2005 (95% confidence interval [CI], 2.19-4.11). This incidence is comparable to other major GI diseases of childhood (eg, Crohn disease) in Ireland.^{28, 29}

Mortality/Morbidity

Although patients are well approximately 90% of the time, cyclic vomiting syndrome can be a medically and academically disabling disorder. More than 50% of patients require intravenous fluids, compared with less than 1% of patients with rotavirus gastroenteritis. The average annual cost of testing, treatment, and work absences totals $17,000. Children miss an average of 24 school days per year and often need home tutoring or, occasionally, home schooling. Additionally, because of its frequency during times of excitement, cyclic vomiting syndrome has ruined many birthdays, holidays, and vacations.²⁶

In adults, significant morbidity is associated with this disorder, perhaps due to a lack of awareness and resultant delay in diagnosis. In a study of 41 patients with cyclic vomiting syndrome, Fleisher found that 32% were completely disabled at the time of diagnosis.⁹ A total of 293 procedures were performed in 41 patients, and none were indicative of organic etiology in these patients. In addition, 17 surgical procedures, including 10 cholecystectomies, appendectomies, exploratory laparotomies, a pyloroplasty, and a hysterectomy, were performed without any therapeutic benefit.

Adults and children with cyclic vomiting syndrome also have multiple emergency department visits, and the diagnosis is often unrecognized.³⁰

Table 1. Emergency Department Visits in Patients With Cyclic Vomiting Syndrome

	Adults	Children
Number of emergency department visits (Median)	15 (Range, 1-200)	10 (Range, 1-175)
Number of emergency department visits prior to diagnosis of cyclic vomiting syndrome (Median)	7 (Range, 1- 150)	5 (Range, 0-65)
Diagnosis not made in the emergency department	94.5%	93%
Diagnosis not recognized in the emergency department in patients with an established diagnosis of cyclic vomiting syndrome	96.3%	82.5%
Number of different emergency departments visited (Mean ± standard deviation)	4.69 ± 4.72	2.6 ± 2.42

Race

Cyclic vomiting syndrome occurs in all races but seems to disproportionately affect whites.

Sex

Females show a slight predominance over males; the female-to-male ratio is 57:43.

Age

The median age at onset is 4.8 years; however, cyclic vomiting syndrome has been observed in infants as young as age 6 days and in adults as old as age 73 years.¹ Typical delay in diagnosis from onset of symptoms is 2.7 years.¹

In adults, the average age of onset is 21 years and average age of evaluation for recurrent vomiting was 34 years.⁹

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