Learning points

1. Cyclic vomiting syndrome is a disorder of gut-brain interaction, and the biopsychosocial model can be used to conceptualise the genesis, evolution, and treatment of the disease.
2. Cyclic vomiting syndrome has a stereotypical pattern of symptoms characterised by a prodromal phase, emetic phase, recovery phase, and asymptomatic phase.
3. Cyclic vomiting syndrome is distinct from cannabinoid hyperemesis syndrome.

List of abbreviations

CVS: cyclic vomiting syndrome

CHS: cannabinoid hyperemesis syndrome

DGBI: disorder of gut-brain interaction

Case study

A 17-year-old female patient presented to her general practitioner with repeated bouts of nausea and vomiting over the past 12 months, which clustered around her school exams. She has a past medical history of endometriosis and postural tachycardia syndrome. She has a family history of migraines. Her only regular medication is paracetamol. She denies any illicit drug use. Clinical examination was unremarkable and a pregnancy test was negative. The patient was diagnosed with cyclic vomiting syndrome (CVS) and started on amitriptyline 5mg for 20 days, which was up-titrated to 10 mg daily. This prophylactic agent stopped the occurrence of nausea and vomiting.

Background

CVS was first described in the English language in 1882 by Dr Samuel Gee, a British Paediatrician, who documented patterns of ‘fitful vomiting in children’ (1). Since 1882, CVS has been shown to affect both children and adults and its clinical description has remained largely unchanged, still characterised by “fits of vomiting that recur after intervals of uncertain length. The intervals themselves are free from signs of disease. The vomiting continues for a few hours or days. When it has been severe the patients are left much exhausted” (1). CVS is an under-recognised condition and its prevalence in the UK outpatient gastroenterology setting has been reported at 10.8% (2), whilst population-based surveys suggest a lower prevalence of 2% of CVS in adults (3). Whether CVS is associated with the female or male sex is debated in the literature (4).

The evolution of CVS can be divided into four distinct phases (5):

1. Prodromal phase – patients have a premonition of an impending attack and experience symptoms such as nausea, sweating, loss of appetite, belching, and fatigue.
2. Emetic phase – patients have severe nausea, vomiting and retching. The frequency of vomiting can vary considerably and may occur anywhere from one episode every three hours to 30 times an hour or more.
3. Recovery phase – nausea and vomiting begin to subside and patients may begin to tolerate oral intake.
4. Asymptomatic phase – patients are typically, but not always, symptom free.

Aetiology

As with other disorders of gut-brain interaction (DGBI), formerly known as functional gastrointestinal disorders, there is no single pathogenic mechanism contributing to symptoms. Rather, the biopsychosocial model can be used to conceptualise the genesis and evolution of the disease. Genetic factors, dysautonomia, dysfunction of the endocannabinoid system, and a dysregulated hypothalamic-pituitary-adrenal axis are some pathophysiological factors that have been proposed in the genesis of CVS (6).

CVS shares several common features with migraine, in which episodes are triggered by various psychological or physiological stimuli, followed by asymptomatic periods. Indeed, a personal or family history of migraine disorder features in up to 24%-70% of adult sufferers of CVS (6), and it features as a supportive remark in the ROME Foundation’s CVS diagnostic criteria (5).

Anxiety, panic, and depression are commonly reported in patients with CVS (7) but, as is the case with other DGBI, it is unclear to what extent these conditions lead to CVS or, alternatively, are caused by misdiagnosis and mismanagement of the condition itself.

CVS diagnostic criteria

According to the ROME IV criteria (5), patients can only be diagnosed with CVS if they meet the following conditions for the last six months with symptom onset at least three months before diagnosis:

• Stereotypical episodes of vomiting regarding onset (acute) and duration (< 1 week).
• ≥3 discrete episodes in the prior year and 2 episodes in the past 6 months, occurring ≥1 week apart.
• Absence of vomiting between episodes, but other milder symptoms can be present between cycles.

Supportive remarks: Personal or family history of migraine headaches

Cyclic vomiting syndrome vs. cannabinoid hyperemesis syndrome

Patients with CVS should not be assumed to be taking illicit drugs, such as cannabis. Both CVS and cannabinoid hyperemesis syndrome (CHS) have common clinical presentations and are not easy to differentiate between clinically, except for the fact that patients with CHS have a clear history of chronic, regular cannabis use preceding the onset of CVS-like episodes (5). While cannabis use may temporarily improve symptoms of nausea and vomiting in CHS, complete relief is only achievable following sustained cannabis cessation. Classically, the symptoms of nausea and vomiting in CHS are temporarily relieved by hot water bathing, but this may also feature in some patients with CVS. For readers who wish to learn more about approaches to differentiating between CVS and CHS, we recommend an article published by Venkatesan et al. (8)

Diagnostic work-up and differential diagnoses

CVS has a stereotypical pattern of symptoms which distinguishes it from other gastrointestinal and non-gastrointestinal causes of nausea and vomiting, so a thorough clinical history should eliminate non-CVS conditions. Full blood count, urea and electrolytes, liver function testing, amylase, urinalysis (including a pregnancy test in patients of child-bearing age), and plain film radiography can be undertaken to exclude any obvious organic cause of nausea and vomiting, and can help to eliminate potential complications of CVS (e.g., electrolyte disturbances / renal dysfunction) during the acute phase (9). Some conditions that may mimic CVS are outlined in table 1.

Table 1. Conditions that may mimic CVS

General management

Recommendations for the management of CVS revolve around the biopsychosocial model, and the overall aim is to prevent future attacks and abort symptoms acutely (6).

Prophylaxis

Triggers for CVS, which can be identified and avoided with the aid of a symptom diary, can vary between individuals and can include stressful events (both positive and negative), travel/motion sickness, sleep deprivation, and food. Unfortunately, some triggers, such as menstruation (catamenial CVS) and changes in weather conditions, are unavoidable. Techniques such as meditation, relaxation, and sleep hygiene are important non-pharmacological treatments in prophylaxis.

Tricyclic antidepressants (e.g., amitriptyline) are generally recommended as first-line prophylactic pharmacological agents to good effect (10), but supporting randomised controlled data are lacking. Alternative prophylactic agents include antiepileptics (topiramate) and aprepitant, a neurokinin-1 receptor antagonist (7). Some studies have proposed mitochondrial supplements (coenzyme Q10, L-carnitine, and riboflavin) as alternative prophylactic therapies (10), but the dosing regimens of these agents have not been appropriately evaluated.

Acute treatment

Ondansetron, a 5-hydroxytryptamine type 3 (5-HT₃) receptor antagonist, delivered sublingually or rectally (reformulated), is generally recommended as the first-line therapy at the onset of the prodrome phase of CVS (11). Response to ondansetron can be variable and some patients may benefit from combination therapy with both ondansetron and an anxiolytic (benzodiazepine) during the acute phase. Other patients may require an alternative anti-emetic, such as aprepitant. Sumatriptan (a 5-HT₁ receptor antagonist) is helpful in aborting CVS attacks, especially if taken intranasally, and is particularly efficacious in patients who have migraineous features to their CVS symptoms (9). In cases of severe emesis and/or where oral intake is not possible, patients should be hospitalised to undertake blood tests (i.e., to assess renal function and any electrolyte abnormalities), as well as receive intravenous hydration and medications.

Once a formal CVS diagnosis is made, patients may benefit from an emergency department plan to ensure swifter recognition and treatment. An at-home admission avoidance plan can also be developed by the multidisciplinary team.

Prognosis

In the largest systematic study (n=455) to determine the natural history and outcomes of adult CVS to-date (mean duration of follow-up: 47.4 ± 37.2 months), only 19% of patients had complete resolution of episodes at follow-up (12). Non-white race, comorbidity count, cannabis use, and aprepitant use were associated with a reduced odds of complete resolution of CVS episodes (12), the reasons for which warrant further investigation.

Summary

CVS is a debilitating DGBI which is characterised by four discreet phases (prodromal, emetic, recovery, and asymptomatic phases). The genesis, evolution, and treatment of CVS can be conceptualised using the biopsychosocial model. Management is approached by using prophylactic (e.g., avoiding triggers and the use of tricyclic antidepressants) and abortive (e.g., an anti-emetic with or without an anxiolytic) treatments. CVS is a poorly understood condition which poses significant constraints on people’s quality of life, so clinicians should be reminded of the importance of holistic and compassionate care.

Patient and public involvement: approved by Robin Dover, from the Cyclical Vomiting Syndrome Association UK Charity

Author Biographies

Dr Mohsin Butt (pronouns: he/him)

Mohsin is an NIHR Academic Clinical Fellow in Gastroenterology at the Nottingham Digestive Diseases Centre and a Clinical Research Fellow at the Wingate Institute of Neurogastroenterology, London. He is an elected member of the Neurogastroenterology and Motility Section of the British Section of Gastroenterology, and Trainee Editor of Neurogastroenterology and Motility.

Dr Maura Corsetti (pronouns: she/her)

Maura is Associate Professor in Gastroenterology and Consultant Gastroenterologist at the Nottingham Digestive Diseases Centre where she leads the gastrointestinal motility unit. She is Chair of the Neurogastroenterology and Motility Section of the British Society of Gastroenterology, Editor-in-Chief of Neurogastroenterology and Motility (the official journal of the American and European Societies of Neurogastroenterology and Motility), and Co-Chair of the ROME V Committee for Bowel Disorders.