Clinical manifestations

Presentation and course

The most commonly described form of cyclic vomiting syndrome is of childhood onset typically starting around age 4 to 5 years. The attacks are discrete and have a clear start and end and typically follow a pattern of prodromal phase, vomiting phase, and then recovery phase.

Similar to migraine, there can be a 1-to-2-hour prodrome of nausea, fatigue, anorexia, and pallor that can also rarely be associated with aura. This period is followed by the vomiting phase with very high frequency vomiting. During this time vomiting occurs at least four times an hour at peak but can be much higher, with rates of 70 times an hour reported. There are few conditions that can match this level of vomiting and it is this high frequency that can distinguish cyclic vomiting syndrome from other conditions. Emesis usually begins during the middle of the night or in the early morning. The vomiting phase typically lasts 24 hours. The recovery phase is typified by sleep and the child often awakens from sleep feeling well and back to normal. Frequency of attacks varies; the average frequency of attacks is 1 to 36 times/year (mean eight times) (22; 14).

There seem to be subgroups of those with cyclic vomiting that may point to different etiologies and treatment paradigms. This is best outlined in a paper by Li in 2018 (20). There is a migraine subgroup, which is the great majority of patients, who have a personal or family history of migraine and respond well to anti-migraine therapies. There is a “Sato variant” with associated hypertension and extreme sleepiness thought to be mediated by the hypothalamic-pituitary-adrenal axis. In this subgroup, attacks tend to be longer and more severe. Mitochondrial dysfunction can underly some with cyclic vomiting syndrome, mitochondrial DNA polymorphisms have been identified, and there are children who respond well to mitochondrial supplements like coenzyme q10 and carnitine.

There is also an adult-onset form of cyclic vomiting syndrome that is being increasingly recognized. The vomiting episodes start at age 18 years or later. The typical age of onset is 21 years, with the diagnosis often being made 8 to 10 years later. The Rome IV diagnostic criteria are used for adults and are similar to the pediatric criteria (33). There does not seem to be a significant difference in triggers, comorbid conditions, migraine history, or response to treatment in adult and pediatric cyclic vomiting syndrome. The only difference is that pediatric patients are more likely to be female (16).

Table 1. Diagnostic Criteria of Cyclic Vomiting Syndrome*

Prognosis and complications

The complications from cyclic vomiting syndrome are related to the profound vomiting. Esophagitis and esophageal tears can occur from the trauma of repetitive vomiting. In addition, severe dehydration can occur with associated metabolic derangements. The majority of patients will require a visit to the emergency room for intravenous therapy at least once, with an average of 10 visits in one study (35). At least 50% of children have had at least one overnight admission to the hospital for cyclic vomiting syndrome (09). A study found that two thirds of emergency room visits for cyclic vomiting syndrome result in hospitalization (01). Arriving in the emergency room more than 24 hours after symptom onset, male sex, younger age (younger than 10 years old), and delayed timing before the first dose of antiemetics in the emergency room were predictors for admission.

In children it is reported that the cyclic vomiting syndrome lasts an average of five years and will resolve in later childhood in 96% of patients (14). There is a strong link between cyclic vomiting syndrome and migraine, with 79% of patients developing migraine during or after cyclic vomiting syndrome onset, typically around age six years (24).

Clinical vignette

This clinical vignette is based on a real patient and some of the information has been changed for a more straightforward presentation.

The patient is now a 5-year-old boy who started having episodes of vomiting around one year of age. Each episode would start with him becoming pale and listless. Within two hours he would start to vomit, usually about five to six times per hour. The intense vomiting would continue for 3 to 4 hours and then would slow down to one to two times per hour. His attacks usually lasted for 3 to 4 days and often by the second day he was significantly dehydrated. He usually required admission to the hospital by the second day, where he was managed with intravenous fluids, lorazepam, and ondansetron. He had an evaluation including upper gastrointestinal series and endoscopy and in addition MRI of the brain, continuous 24-hour EEG, and metabolic evaluation including spinal tap and bloodwork. There were no abnormalities found. The patient has had two seizures thought to be secondary to hyponatremia at the time of the events (sodium in low 120s). After recovery from the events, he was well except for minor speech delay. These events occurred about five times a year. He was initially tried on cyproheptadine and then eventually propranolol. With the addition of carnitine and coenzyme Q10 to the propranolol his events reduced in frequency to twice a year and he was able to be managed at home. The cyclic vomiting has continued.

This case has several typical features of cyclic vomiting syndrome: the events are stereotyped and predictable; the patient becomes profoundly dehydrated requiring hospitalization with complications from the dehydration including hyponatremic seizures. Also, not uncommonly and subtyped as cyclic vomiting syndrome plus, between events he does have some developmental delay. This patient had thousands of dollars’ worth of testing done, which is not uncommon. The mean cost of evaluation for cyclic vomiting per child is approximately $6000 (23). The additional testing is not unwarranted in this child given his early age at presentation as well as his seizures. His response to typical migraine prevention is not unusual.

Biological basis

Etiology and pathogenesis

The pathophysiology of cyclic vomiting syndrome is unclear. Given the link between migraine and cyclic vomiting it is assumed that there are similarities in underlying cause. The initial link between migraine and cyclic vomiting syndrome was because of the high rates of personal (40% to 46%) and family history (28% to 82%) of migraine in those with cyclic vomiting syndrome (17). Migraine and cyclic vomiting often share common triggers including stress, change in sleep patterns, and certain foods. There also seems to be some overlap in the presumed mechanisms behind migraine and cyclic vomiting syndrome including mitochondrial dysfunction and autonomic dysfunction.

Mitochondrial dysfunction was initially implicated in the pathophysiology of cyclic vomiting syndrome because of the maternal inheritance pattern and abnormalities seen on laboratory studies performed during attacks, including lactic acidosis and urine organic acid patterns consistent with energy failure (07). Testing of mitochondrial DNA has revealed at least two polymorphisms that are highly correlated with pediatric cyclic vomiting syndrome. The 16519T polymorphism is six times more common in children with cyclic vomiting syndrome versus controls, and in those with the 3010A polymorphism who also have the 16519T polymorphism the likelihood of cyclic vomiting syndrome is increased by 17 times (41). Interestingly, these polymorphisms are not significant in adult-onset cyclic vomiting syndrome (39), although they have been found to be significantly associated in adult patients with migraine (41). In a study of whole exome sequencing in those with cyclic vomiting syndrome, the candidate genes identified were either involved with energy metabolism or positive ion transport (05).

The dysfunction of the autonomic nervous system in cyclic vomiting syndrome has been noted since the late 1990s when two groups of investigators noted increased sympathetic cardiovascular tone in patients with cyclic vomiting syndrome (29; 34). It is thought that hypersensitivity of the autonomic nervous system to emetic signals is what predisposes some to such abnormal vomiting reaction. In a natural history study following children with cyclic vomiting syndrome, 40% were found to have symptoms of dysautonomia (dizziness, nausea, fatigue, syncope) in adolescence (12). In autonomic testing of adult patients with cyclic vomiting syndrome 90% of the patients were impaired with postural orthostatic tachycardia syndrome (POTS) (35%) or sudomotor dysfunction (90%) (35).

Seventy-five patients with cyclic vomiting syndrome were compared to controls with next-generation genomic sequencing and there was a significantly associated mutation in the RYR2 gene. This gene codes a calcium channel that is used for excitation contraction coupling in the heart and is also found in the autonomic nervous system and seems to be part of a stress response (18). Anecdotally, propranolol can help treat cyclic vomiting syndrome patients with this mutation (21).

A review of a small number of adult and pediatric patients with cyclic vomiting syndrome noted that clinically the circadian nature of attacks, autonomic dysfunction, as well as objective findings on PET imaging implicate the hypothalamus as well as the insula (30). Insular involvement was echoed in a second study released that used functional MRI (10).

The connection between chronic marijuana use and a cyclic vomiting-like syndrome (cannabinoid hyperemesis syndrome) has also raised a question about the role of the endogenous cannabinoid system. This system is known to play a role in nausea and vomiting and it is possible that an imbalance in this system could also play a role in cyclic vomiting syndrome (27; 38). Polymorphisms in the genes for cannabinoid receptor type 1 and mu-opioid receptor, part of the endogenous cannabinoid system, have been shown to be associated with increased risk of cyclic vomiting syndrome whereas other polymorphisms appear protective against it (40).

Epidemiology

The onset of symptoms is usually age five years in children and 37 years in adults (15). The prevalence in children is about 2% (19). A large population-based study of adults in the U.S., United Kingdom, and Canada found the overall prevalence of cyclic vomiting syndrome to be similar to children at 1.2% (02). Cyclic vomiting syndrome occurs in all races but seems to affect whites disproportionately. The annual cost of a cyclic vomiting syndrome per child with the condition is around $17,035, and in the United States the cost of hospital stays for adults with cyclic vomiting syndrome totaled $400 million over two years (06).

Prevention

There are no known ways to prevent or mitigate the risk in those with cyclic vomiting syndrome. The inheritance pattern is partial and there are no clear predictive markers of the disorder. If a child presents for a first or second episode of severe vomiting and there is a strong family history of migraine it might raise cyclic vomiting syndrome higher on the differential list and allow for earlier identification.

Differential diagnosis

A single episode of recurrent vomiting is indistinguishable from many acute gastrointestinal illnesses. Until a temporal and intensity pattern is established leading to the clinical suspicion of cyclic vomiting syndrome, it is important to rule out many other disorders. In essence, cyclic vomiting syndrome is a diagnosis of exclusion. See below table for full differential list.

Panayiotopoulos syndrome is an epilepsy syndrome that occurs most frequently in the 3- to 6-year-old age range. It is typified by autonomic dysfunction as the ictal phenomenon. The majority of patients have vomiting as part of the seizure or at least nausea/retching. This syndrome is prone to be prolonged with up to half of patients having seizures that last for more than 30 minutes. Most events will progress to more typically recognized seizures with tonic or clonic activity. Often the events will start during sleep. In more than 90% of patients there will be interictal findings on EEG of either multifocal sharps or occipital spikes (26).

Abdominal migraine is often used interchangeably with cyclic vomiting syndrome. Although these conditions can overlap, there are separate diagnostic criteria. The hallmark of abdominal migraine is the periumbilical pain whereas the hallmark of cyclic vomiting syndrome is profound vomiting. There can certainly be vomiting with abdominal migraine; however, it does not meet the high frequency that is seen with cyclic vomiting syndrome. In cyclic vomiting syndrome there may be associated abdominal pain; however, the vomiting is a much more significant component.

Cannabinoid hyperemesis syndrome is recognized more in adults with cyclic vomiting but should also be questioned in teenage patients. It is typified by chronic marijuana use for years (typically daily or near daily for more than 1 year) and paroxysmal episodes of profound vomiting. This vomiting is usually improved with a hot shower, so there becomes a compulsive bathing that occurs during episodes. Symptoms should resolve with cessation of marijuana use. Although criteria for this syndrome was put forth in the Rome IV guidelines (32), it is not always a straightforward diagnosis. Many patients with cyclic vomiting syndrome use cannabis regularly, 41% in a study, and up to 21% are using regularly many times per week (36). Many patients find cannabis helpful in management of cyclic vomiting syndrome symptoms. In this study, even though 86% of cannabis users reported abstaining from cannabis use for at least one month, only one patient reported resolution of cyclic vomiting syndrome episodes after cannabis cessation.

A list of differential diagnostic possibilities is listed in Table 2.

Table 2. Differential Diagnosis of Cyclic Vomiting Syndrome

Diagnostic workup

First-line testing for cyclic vomiting syndrome includes an upper gastrointestinal series to evaluate for malrotation/volvulus. In addition, an abdominal ultrasound to look for hydronephrosis and biliary abnormalities should be performed at baseline and, if normal, repeated during an acute episode (25; 31). In addition, a set of electrolytes should be performed during an attack prior to administration of intravenous fluids.

If the patient has severe abdominal pain and bilious vomiting, which is more worrisome for gallbladder dysfunction, hepatitis, pancreatitis, or strictures/adhesions; these patients should also undergo testing of amylase, lipase, liver function testing, and possibly abdominal CT if ultrasound is unrevealing.

If there are intercurrent symptoms of gastrointestinal dysfunction or significant amount of hematemesis during attacks, endoscopy should be considered to evaluate for celiac disease, allergic esophagitis, or reflux.

In patients where there are signs of intercurrent or attack-related neurologic dysfunction (altered mental status, developmental delay or regression, hypotonia, personality changes, seizures) or attacks precipitated by fasting, protein, or illness, testing should be performed for fatty acid oxidation defects, amino/organic acidopathies, urea cycle defects, and mitochondrial dysfunction. A review by Gelfand and Gallagher outlines the appropriate approach to the workup for inborn errors of metabolism (11).

In children with alteration of mental status, headache, abnormal eye movements, ataxia, papilledema, seizures, or motor asymmetry present, MRI should be considered to look for hydrocephalus or intracranial mass. And in those children with seizures, transient alteration in mental status or other abnormal movements EEG should be performed in the awake and sleep states.

The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition has published a diagnostic flow-chart summarizing the recommended evaluation of a cyclic vomiting pattern in children older than two years of age (20).

Management

Standard medical approaches are lacking for cyclic vomiting syndrome, and there is a notable absence of controlled trials and rigorous scientific evidence. There are no medications that are FDA approved for cyclic vomiting. Treatment approaches include strategies for prevention of attacks and then management to abort or treat an attack. The majority of these recommendations are based on the management of migraines.

Prevention of attacks focuses on lifestyle measures that can help reduce triggers. All patients should have a diary that is used to help identify potential preceding events that made a vomiting attack more likely. The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Consensus Task Force concludes that lifestyle changes can significantly reduce episode frequency in children with cyclic vomiting syndrome, despite the lack of published evidence to this effect (20). Table 3 summarizes the recommended lifestyle changes that should be adopted.

Table 3. Lifestyle Changes in Cyclic Vomiting Syndrome (for 1 to 2 months or 1 to 2 cycles)

Table 4. Prophylactic Medications

Treatment of attacks focuses on early recognition and treatment. Migraine medicines, including triptans, have been looked at in aborting attacks and there are case reports of success using sumatriptan either nasal spray or subcutaneously. There is a slight tendency for those with a strong family history of migraine to respond better to triptan medications (13). Antiemetics can certainly help mitigate the symptoms and there are data in the pediatric literature to support the use of the NK-1 receptor antagonist aprepitant for abortive and preventive use (08). Dr. Li, an expert in cyclic vomiting syndrome, added aprepitant in his update to the treatment of cyclic vomiting syndrome in children (21). A retrospective review of the use of aprepitant in adults refractory to other medications showed it to be significantly helpful (28). However, cost of the medication can be prohibitive and limits use. Once the vomiting has begun the best methods of management are supportive, including hydration and sleep induction with analgesia as needed.

In addition, guidelines for treatment for cyclic vomiting syndrome in both adults and children recommend screening for, and addressing, common comorbid conditions in cyclic vomiting syndrome. These conditions include anxiety, depression, migraine, autonomic dysfunction (postural orthostatic tachycardia syndrome), sleep disorders, and substance use (particularly marijuana) (21; 37).

Outcomes

The preventive medicines have been available for many years and generally are considered safe. Cyproheptadine’s biggest issue is sedation and weight gain. Amitriptyline may also induce drowsiness so it should be given at night, and it can trigger cardiac arrhythmias in those that have prolonged QT and other cardiac abnormalities. The recommendation is to do a screening EKG on all patients prior to initiation of amitriptyline to look cardiac arrhythmias. Propranolol is generally well tolerated; however, it can produce bradycardia. Patients taking propranolol should be started on a low dose increased at minimum intervals of every two weeks. Blood pressure and heart rate should be followed closely.

A randomized controlled trial looking at the use of amitriptyline versus cyproheptadine in 64 children with cyclic vomiting syndrome between the ages of 3 and 15 years showed that both medications were effective. Fifty percent of those in the cyproheptadine group had full remission compared to 65.6% in the amitriptyline group (03).

Preventive medicines should reduce the severity and frequency of attacks. Hopefully, emergency room visits will decrease, and more attacks will be managed at home. Patients should be tried on medication for 2 to 3 months minimum before determining its efficacy.