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The Cyclic Vomiting Syndrome Threshold: A Framework for Understanding Pathogenesis and Predicting Successful Treatments - PubMed

  • ️Fri Jan 01 2016

The Cyclic Vomiting Syndrome Threshold: A Framework for Understanding Pathogenesis and Predicting Successful Treatments

David J Levinthal. Clin Transl Gastroenterol. 2016.

Abstract

Cyclic vomiting syndrome (CVS) is an uncommon, idiopathic disorder defined by recurrent, sudden-onset attacks of repetitive retching and vomiting that are separated by symptom-free intervals. CVS was long regarded as a disorder primarily experienced by children but is now known to present de novo in adulthood. Adult CVS has garnered more research attention over the past 20 years, and these efforts have identified some acute and prophylactic treatments for this disorder. However, CVS still lacks a unifying disease model, and this has hindered the development of new therapies. Here adult CVS is reframed as a neurogenic disorder, driven by various endophenotypic factors that shape patterns of activity within the neural circuits required for disease expression. The concept of the "CVS threshold" is put forth in parallel with exploring the remarkable similarity of adult CVS with features of chronic migraine, epilepsy, and panic disorder. Because of such shared neural mechanisms and overlapping endophenotypes, many therapies that have been developed for these other disorders could also be useful in managing CVS. This review seeks to achieve three primary aims: (1) to develop a comprehensive, explanatory framework for adult CVS pathogenesis, (2) to use this framework for identifying potentially novel therapies for CVS, and (3) to describe future research directions that are needed to move the field forward.

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Figures

Figure 1
Figure 1

Overlap in temporal patterns of illness between (a) cyclic vomiting syndrome (CVS), (b) chronic migraine, (c) epilepsy, and (d) panic disorder. Each illness has a quiescent, inter-episodic phase, punctuated by the sudden onset of a prodrome, followed immediately by the acute attack, and then a recovery phase with lingering symptoms before returning to baseline.

Figure 2
Figure 2

Conceptual model of endophenotypes that mediate the development of CVS in adults. CVS is envisioned as a complex disorder derived from the summative contribution of individual endophenotypes that lead to the final common phenotype. The left side of the figure lists a few potential endophenotypes, which are genetically determined and present in childhood. With life experiences, chronic stress, and/or exposure to drug abuse, and based upon genetic susceptibility to those exposures, some endophenotypic factors may undergo changes over time (represented by black dashed outlines and changes in the size of the ovals). Thus, these changed endophenotypes and symptoms become risk factors that predict the development of adult CVS (right side of the figure). In this particular example, the adult CVS patient has developed disordered cognition and a tendency to catastrophize, as well as comorbid panic disorder. They experience wildly dysregulated autonomic patterns during intense emotional stress, occasionally to the point of causing neurocardiogenic syncope. The patient also has developed subclinical endophenotypes with a disordered sleep architecture and a generally decreased threshold to experience nausea. Other innate endophenotypes on the left side of the figure that are not circled are relatively insensitive to change in this patient. They are present in adulthood (not shown), but do not contribute significantly to CVS in this individual.

Figure 3
Figure 3

Graphical representation of the CVS threshold concept. In panel (a), two successive CVS triggers (a and b) summate to increase neuronal excitability to a point that crosses the CVS threshold. This then precipitates a CVS attack (represented at the top of the panel to mirror Figure 1a). In panel (b), the same two successive CVS triggers (a and b) now do not reach the CVS threshold, which has been raised by prophylactic medications that decrease neuronal excitability within key neural circuits. The lack of a CVS attack is represented by a solid black line at the top of the panel. In panel (c), the CVS threshold remains the same, but the impact of CVS triggers is minimized by interventions such that the summative impact of exposure to the triggers is now not sufficient to precipitate a CVS attack. Again, the lack of a CVS attack is represented by a solid black line at the top of the panel.

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