Even though the etiology and pathophysiology of CVS are not known, studies have suggested several potential brain-gut mechanisms.
CVS is considered to be a manifestation of migraine diathesis. The majority of children and adults have migraine diathesis as evidenced by the occurrence of migraine headaches in themselves and/or in their first or second-degree relatives. Li’s analysis of a cohort of 214 children with CVS sub‐divided patients into two categories: 82% had migraine‐ associated CVS and 18% had non‐migraine‐associated CVS.
Furthermore, 28% of patients with CVS, whose vomiting subsequently resolved, developed migraine headaches.
Patients with migraine‐associated CVS were more likely to benefit from migraine prophylaxis. Approximately 80% of affected patients with migraines in their family history respond to anti-migraine therapy. Children with no migraine features responded poorly to anti‐migraine drugs.
Anxiety may also be important to the pathogenesis and course of CVS. Pediatric patients are prone to anxiety, and anxiety disorders affect 84% of adults. Anxiety disorders may be complicated by panic attacks in adult patients. Panic attacks trigger cyclic vomiting episodes in the majority of adult patients.
The stress response, mediated by the hypothalamic-pituitary-adrenal (HPA) axis, may also potentially induce episodes of CVS. Infectious, psychological, and physical stressors are known triggers of episodes.
Sato and associates documented increased levels of adrenocorticotropic hormone (ACTH) and cortisol, associated with extreme lethargy and hypertension, before the onset of vomiting. Taché showed that central CRF induced gastric stasis, emesis, or both in animals. Thus, CRF may be a brain-gut mediator of CVS that directly connects stress and vomiting. If this theory holds true, CRF receptor antagonists currently in development could theoretically ablate vomiting by blocking the CRF receptors vagally mediated actions.
Gastrointestinal motility dysfunction is postulated as a possible etiology in CVS. Abell et al. have shown that gastrointestinal dysmotility (hypermotility, hypomotility, or dysrhythmia) involving either the stomach or the small bowel is present even during asymptomatic periods in CVS patients. However, a prospective comparative study done at the Mayo Clinic in Rochester, NY showed that asymptomatic CVS patients have rapid early-phase (1 and 2h) gastric emptying and are more likely to have accelerated phase two emptying in comparison to normal controls.
It cannot be determined, from the current gastric emptying data, whether underlying gastrointestinal motility disorders are the cause of some episodes of CVS, or if CVS results from central nervous system dysfunction that affects the gastrointestinal tract.
Sympathetic hyperresponsiveness and autonomic dysfunction also appear to contribute to the pathogenesis of CVS.
Many associated symptoms, such as pallor, flushing, fever, lethargy, salivation, and diarrhea, are mediated by the autonomic nervous system. Several studies support altered autonomic function in CVS.
Khasawinah et al. reported the successful use of dexmedetomidine, an alpha2-adrenergic agonist, to treat CVS. In a small study involving six 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.
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. The two 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 is that the findings were not corroborated by means of either a physical examination or standard autonomic function testing. However, the findings of orthostatic intolerance are of clinical significance because the use of pharmacologic therapy (e.g. 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.
In this study, 17 of 20 adult CVS subjects (85%) and 2 of 20 control subjects (10%) had abnormalities on thermoregulatory sweat testing. A total of 7 patients (35%) and 1 control subject had evidence of postural tachycardia with an increase of more than 30 beats per minute 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 subjects (95%) with CVS and 18 controls (95%).
Most cases of CVS have been described as sporadic, but family history may be an important factor. Several families have multiple members involved, and in these familial cases of CVS, the mode of inheritance is predominantly matrilineal.
Cyclic vomiting has been reported in individuals with the A3243G ‘MELAS’ mutation in the mitochondrial DNA (mtDNA). In addition to this, Dr. Richard Boles and colleagues demonstrated that 86% of children with CVS and neuromuscular disease had a history of migraines on the matrilineal side. In children with CVS, two 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.
Boles’ hypothesis is that defects in mitochondrial energy production due to mutations may predispose the onset of episodes of vomiting during periods of heightened demands for energy; for example, stress or excitement.
These mtDNA polymorphisms may account for the clustering of functional conditions and symptoms in the same individuals and families, although universal genetic associations of CVS are yet to be identiﬁed.
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Food allergies have been suggested as a possible etiology of CVS. Lucarelli et al. evaluated eight children with CVS. None of these children had a history of allergic reactions to food. However, most of these children had a positive skin prick test and the speciﬁc IgE present for various foods, including cow’s milk proteins, soy, and egg whites. Eliminating the offending foods from their diets led to signiﬁcant clinical improvement of their CVS symptoms.
Cyclic Vomiting Syndrome and Mitochondrial Dysfunction and treatment