What is the pathogenesis of cyclic vomiting syndrome (CVS)?

Updated: Oct 31, 2018
  • Author: Thangam Venkatesan, MD; Chief Editor: Carmen Cuffari, MD  more...
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The etiology and pathophysiology of CVS are not known. However, studies have suggested several potential brain-gut mechanisms.

Migraine-related mechanisms have been proposed. [1, 2] In one study, patients with CVS 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 CVS whose vomiting subsequently resolved developed migraine headaches. Approximately 80% of affected patients with family histories positive for migraine respond to antimigraine therapy. [1, 2]

Mitochondrial DNA (mtDNA) mutations may be involved in the pathogenesis of CVS. Boles et al demonstrated that 86% of children with CVS and neuromuscular disease had a history of migraines on the matrilineal side. In children with CVS, 2 mtDNA polymorphisms (16519T and 3010A) are expressed with a high degree of frequency and may serve as a surrogate marker for predisposition to the disease. [3]

The 16519T polymorphism is 6 times more common in pediatric CVS patients than in control populations. [4] The 3010A polymorphism increases the likelihood of CVS in subjects with 16519T by as much as 17 times. These mtDNA polymorphisms may account for the clustering of functional conditions and symptoms in the same individuals and families. One small (and possibly underpowered) study found that adult-onset CVS, unlike pediatric CVS, CVS is not associated with these polymorphisms, suggesting a degree of genetic distinction. [2]

Sympathetic hyperresponsiveness and autonomic dysfunction also appear to contribute to the pathogenesis of CVS. [5] Many associated symptoms, such as pallor, flushing, fever, lethargy, salivation, and diarrhea, are mediated by the autonomic nervous system. [6, 7, 8] Several studies support altered autonomic function in CVS.

Rashed et al [9] and To et al [10] demonstrated heightened sympathetic cardiovascular tone in patients with CVS. Kasawinah et al reported the successful use of dexmedetomidine, an alpha2-adrenergic agonist, to treat CVS. [11] In a small study involving 6 children with CVS, 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 CVS. [12]

To evaluate this association with autonomic dysfunction, a cross-sectional study was performed in which the Ohio dysautonomia (ODYSA) questionnaire was administered to 21 patients with CVS (3 children) and 46 patients with migraines. [13] The 2 patient groups had similar comorbid conditions, with fibromyalgia noted in 38% of subjects with CVS, orthostatic intolerance in 47% of subjects with CVS, functional dyspepsia in 9.5% of subjects with CVS, and complex regional pain syndrome in 24% of subjects with CVS.

The main limitation of this study was that the findings were not corroborated by means of either a physical examination or standard autonomic function testing. [13] However, the findings of orthostatic intolerance are of clinical significance because the use of pharmacologic therapy (eg, fludrocortisone and beta-blockers) may be considered in these patients.

In a prospective trial in adult CVS patients, Venkatesan et al found that most subjects with CVS (90%) had impairment of the sympathetic nervous system with postural tachycardia or sudomotor dysfunction while parasympathetic nerve function was intact. [14]

In this study, 17 (85%) of 20 adult CVS subjects and 2 (10%) of 20 control subjects had abnormalities on thermoregulatory sweat testing. [14] A total of 7 (35%) patients and 1 control subject had evidence of postural tachycardia with an increase of more than 30 beats/min in heart rate (HR) on standing. Of the subjects, 18 (90%) had abnormal sudomotor function, postural tachycardia, or both. The HR response to deep breathing was normal in 19 (95%) subjects with CVS and 18 (95%) controls.

The stress response, mediated by the hypothalamic-pituitary-adrenal (HPA) axis, can also potentially induce episodes of CVS. Infectious, psychological, and physical stressors are known triggers of episodes. [15, 16, 17, 18, 19, 68] Sato et al documented increased levels of adrenocorticotropic hormone (ACTH) and cortisol, associated with extreme lethargy and hypertension, before the onset of vomiting. [20, 21, 22, 23] Furthermore, Taché showed that central CRF induced gastric stasis, emesis, or both in animals. [24]

Therefore, CRF may be a brain-gut mediator of CVS that directly connects stress and vomiting. [25] If this theory holds true, CRF receptor antagonists currently in development could theoretically ablate vomiting by blocking the CRF receptor’s vagally mediated actions. [26]

Cannabis use in CVS has received considerable attention. Chronic marijuana use has been associated with hot showers or compulsive hot water bathing and CVS, though a cause-and-effect relation has not been confirmed. The endocannabinoid system (ECS) consists of the ligands 2-AG and anandamide and the cannabinoid receptors CB1 and CB2. This system is thought to play a role in nausea and vomiting and in coping with stress.

There is considerable evidence that activation of central and peripheral CB1 cannabinoid receptors inhibits nausea and vomiting; conversely, both nausea and vomiting are frequent adverse effects accompanying CB1 receptor antagonist use in humans. These and other data strongly suggest that that tone of the ECS regulates nausea and vomiting; further studies are needed to explore this possibility more fully. [27, 28]

That CVS has a central component has been suggested by functional magnetic resonance imaging (MRI) studies using whole-brain seed-based analysis. Patients with CVS exhibited a distinct alteration in resting state functional connectivity involving connections from the cingulate and inferior frontal gyrus (IFG), a known neural correlate of nausea. [29]

In conclusion, the pathogenesis of CVS is likely to be multifactorial, with multiple genetic, autonomic, central, and environmental factors playing a role. Further studies are needed to elucidate the exact mechanisms underlying this disorder.

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