Cyclic Vomiting Syndrome: Recognition and Guidelines for Treatment

Nausea and vomiting have many etiologies, and cyclic vomiting syndrome (CVS) is not the first diagnosis that comes to mind for an adult presenting to the emergency department. Even when physicians recognize the episodic nature of the patient’s distress, CVS has historically been considered a pediatric disease, when, in fact, it occurs in 1%-2% of adults. Adults with CVS almost always receive fragmented care, and a diagnostic delay of five to six years from the onset of symptoms is typical. David Levinthal, MD, PhD, co-director of the UPMC Program for Gut-Brain Health, is one of only a handful of international CVS experts. Dr. Levinthal stresses that recognition of CVS is key to treatment. Moreover, effective treatments exist for most patients.

CVS is characterized by four phases. 

Figure 1. The four phases of CVS. Originally published by Fleisher et al. Reused under the terms of the Creative Commons Attribution License.

Each attack begins with a prodromic phase, followed by an emetic phase, and then a recovery phase. Between episodes, there is a “well” phase, during which the patient is typically, but not always, asymptomatic. Sweating and nausea are common during the prodrome phase, which is similar to the prodrome experienced by migraine sufferers. Episodes often begin suddenly in the early morning. Patients describe this sudden onset as “feeling like a switch flipped,” which suggests a nervous system state change. Sympathetic nervous system activation likely contributes to CVS pathogenesis, and CVS episodes are typically accompanied by tachycardia, dizziness, salivation, and paleness of the skin. During the emetic phase, the patient experiences severe nausea and vomits or retches repeatedly. Stomach pain may accompany vomiting. The emetic phase can last for hours or days. The recovery phase begins when vomiting and retching stop and lasts until normal energy and appetite return. Intravenous fluids may be required to rehydrate the patient and allow recovery. 

Patients with CVS experience multiple episodes of vomiting each year. The diagnostic criteria known as the Rome IV criteria define the cyclic nature of CVS as two acute-onset episodes within six months that are at least a week apart and each lasts for less than seven days with an absence of vomiting between episodes. Laboratory tests, upper GI endoscopy, and imaging tests are used to rule out other causes of nausea and vomiting. 

CVS has many features in common with migraine, epilepsy, and panic disorder. All four disorders are triggered by similar internal and external conditions. Patients suffering from each disorder experience some form of prodrome and symptom onset with a circadian pattern, notably an early morning onset in many. Prior adverse or traumatic life events are linked with an increased likelihood of each condition. These similarities suggest a common neurogenic etiology and, moreover, suggest that patients with CVS could benefit from trials of therapies that are currently available for the treatment of migraines, seizures, or panic disorder. 

In 2019, the American Neurogastroenterology and Motility Society (ANMS) and the Cyclic Vomiting Syndrome Association (CVSA) published guidelines for the management of CVS in adults. Dr. Levinthal developed these guidelines with his colleagues, fellow experts in neurogastroenterology. The guidelines are a fundamentally important tool for the recognition of CVS by primary care and emergency medicine physicians and for getting patients the diagnosis and treatment required to mitigate CVS. 

Similar to migraines, CVS is treated with prophylactic therapies, such as preventive medication and identifying and avoiding triggers, and abortive therapies for relief when an attack occurs. Most patients respond to readily available medications. For prophylaxis, tricyclic antidepressants, such as amitriptyline, are strongly recommended as a first-line medication in patients with moderate-to-severe CVS.

Topiramate or aprepitant are recommended as alternative prophylactic medications. Prophylactic lifestyle changes include identifying and avoiding triggers, regular exercise, good sleep hygiene, stress management, avoiding fasting and dehydration, and avoiding cannabis and opiates. Additionally, evidence-based psychotherapy may be indicated to address psychiatric comorbidities that can contribute to CVS. 

When patients present to the emergency department during a CVS episode, a combination of anti-emetics, analgesics, and sedation is likely to yield relief. Serotonin antagonists and triptans are conditionally recommended by the ANMS and the CVSA to abort acute attacks after symptoms develop. At UPMC, we are participating in the CVS Hope trial (NCT04645953), a clinical trial of a serotonin type III receptor inhibitor that is administered with a novel delivery system. The delivery system works like a vaping device and has kinetics similar to IV administration. This may provide patients with an easy-to-administer and effective abortive medication for rapid relief at home when an episode of CVS begins. 

Due to the rarity of the disorder, clinical studies of CVS could be substantially accelerated by the development of a nationwide CVS disease registry with recruitment of CVS patients from multiple tertiary-care centers. At UPMC, Dr. Levinthal is developing a registry of patients with gut-brain disease and has accrued approximately 50 CVS patients from the UPMC GI registry. Additionally, Dr. Levinthal actively collaborates with Thangam Venkatesan, MBBS, at the Medical College of Wisconsin, who maintains a registry with approximately 1,000 patients with CVS. Analyses using this large registry or a nationwide disease registry hold great promise to reduce the incidence of CVS and improve the quality of life of adults with CVS. 

In one such study, Drs. Levinthal and Venkatesan examined intolerance to uncertainty in adults with CVS by recruiting patients from Dr. Venkatesan’s database to complete validated questionnaires measuring their intolerance to uncertainty, their anxiety, and their quality of life. CVS patients with a higher intolerance to uncertainty had a poorer quality of life, quantitated using both physical-health and mental health scales, and higher rates of anxiety disorders. The patient’s intolerance to uncertainty did not affect the frequency of their CVS episodes or their utilization of health care for CVS episodes. Intolerance of uncertainty is a modifiable cognitive trait, and cognitive behavior therapy can be considered as a targeted therapy to improve the quality of life of patients with CVS based on their disease etiology. Identification of similar modifiable cognitive traits that contribute to the morbidity of CVS will likely improve the quality of life of CVS sufferers. 

When caring for patients with gut-brain disorders at the UPMC Neurogastroenterology and Motility Center, Dr. Levinthal is frequently the first health care provider to diagnose CVS and set a patient who has been suffering for years on a path toward management of their disease. He stresses that this does not need to be the case, however. Primary care physicians, emergency department providers, and gastroenterologists can be on the lookout for patients with symptoms indicative of CVS and expand their examination to include a patient’s history of vomiting, family history of migraine, and whether a prodrome phase occurs during each episode. Recognition of CVS is key to improving the lives of these patients. CVS is treatable in most patients with drugs that are widely available and known to be well-tolerated. Guidelines are available to help non specialists catch and care for patients with CVS who respond readily to standard treatments. The UPMC Neurogastroenterology and Motility Center is a resource for both patients and physicians seeking expertise in CVS, as well as other GI conditions that require holistic, cross-disciplinary treatment approaches due to their complexity.

References and Further Reading 

Stanghellini V, Chan FK, Hasler WL, et al. Gastroduodenal Disorders. Gastroenterology. 2016;150(6): 1380-92. 2. 

Levinthal DJ. The Cyclic Vomiting Syndrome Threshold: A framework for understanding pathogenesis and predicting successful treatments. Clin Transl Gastroenterol. 2016;7(10):e198.  
Venkatesan T, Levinthal DJ, Tarbell SE, et al. Guidelines on management of cyclic vomiting syndrome in adults by the American Neurogastroenterology and Motility Society and the Cyclic Vomiting Syndrome Association. Neurogastroenterol Motil. 2019;31 Suppl 2:e13604. 

Levinthal DJ, Romutis S, Rajalaban A, et al. Greater intolerance to uncertainty predicts poorer quality of life in adults with cyclic vomiting syndrome. Neurogastroenterol Motil. 2021:e14159. 
Fleisher DR, Gornowicz B, Adams K, et al. Cyclic Vomiting Syndrome in 41 adults: the illness, the patients, and problems of management. BMC Medicine. 2005;3(1):2