eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology

Cyclic Vomiting Syndrome

Thangam Venkatesan, MBBS, Assistant Professor, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical College of Wisconsin
B UK Li, MD, Professor of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Director, Pediatric Fellowships and Gastroenterology Fellowship, Medical Director, Functional Gastrointestinal Disorders and Cyclic Vomiting Program, Medical College of Wisconsin; Attending Gastroenterologist, Children's Hospital of Wisconsin; Seth Marcus, MD, Fellow, Department of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Memorial Hospital, Northwestern University; Shikha Sundaram, MD, Fellow, Department of Gastroenterology, Hepatology and Nutrition, Children's Memorial Hospital of Chicago and Northwestern University; Abhilasha Pandey, MBBS, Froedtert Hospital, Medical College of Wisconsin

Updated: Oct 29, 2009

Introduction

Background

Cyclic vomiting syndrome (CVS) is a chronic functional disorder of unknown etiology that is characterized by paroxysmal, recurrent episodes of vomiting and was first described in children by Samuel Gee in 1882. Although this was initially thought to occur mostly in children, it is being recognized with increasing frequency in adults. Although the pathophysiology is unknown, various mechanisms such as corticotropin-releasing factor (CRF) and a heightened sympathetic response may play a role. Recent data also suggest a strong genetic component, with evidence of mitochondrial heteroplasmies that predispose to cyclic vomiting syndrome and other related disorders, such as migraine and chronic fatigue syndrome.

Cyclic versus chronic temporal patterns of recurrent vomiting. The number of emeses is plotted over a 2-month period. The chronic pattern, represented by a thin dashed line, has low grade on nearly a daily basis (eg, gastroesophageal reflux). The cyclic pattern, represented by a heavy solid line, involves high-intensity episodes intermittently once every several weeks (eg, cyclic vomiting syndrome).

Pathophysiology

The etiology and pathophysiology in cyclic vomiting syndrome are not unknown. Over the last decade, studies have proposed several potential brain-gut mechanisms. Migraine-related mechanisms have been proposed, and patients with cyclic vomiting syndrome have a significantly higher prevalence of family members with migraine headaches (82% vs 14% of control subjects with a chronic vomiting pattern). Furthermore, 28% of patients with cyclic vomiting syndrome whose vomiting subsequently resolved developed migraine headaches. Finally, 80% of affected patients with family histories positive for migraine respond to antimigraine therapy.^1,2

Mitochondrial DNA (mtDNA) mutations may be involved in the pathogenesis of cyclic vomiting syndrome. Boles et al have demonstrated that, among children with cyclic vomiting syndrome and neuromuscular disease, 86% have a history of migraines on the matrilineal side. Boles and colleagues also reported a large mitochondrial DNA deletion in a single child with cyclic vomiting syndrome and have identified additional mutations concentrated in the D-loop, a hypervariable locus of the control region, in other children with cyclic vomiting syndrome.³

In children with cyclic vomiting syndrome, 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. The mtDNA polymorphism, 16519T, was found to be 6 times more common in pediatric cyclic vomiting syndrome than in control populations.⁴ Another common mtDNA polymorphism, 3010A, was noted to increase the odds ratio for developing cyclic vomiting syndrome in subjects with 16519T as much as 17 times. These mtDNA polymorphisms may account for the clustering of functional conditions and symptoms in the same individuals and families. Unlike pediatric cyclic vomiting syndrome, adult-onset cyclic vomiting syndrome is not associated with these mtDNA polymorphisms, suggesting a degree of genetic distinction.

Children with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome are known to have both severe migraines and episodic vomiting, as in cyclic vomiting syndrome.⁵ Several children with cyclic vomiting syndrome, including 4 members of an Italian family, have recently been reported to have various mitochondrial mutations.^6,7

Sympathetic hyperresponsivity and autonomic dysfunction also appear to contribute to the pathogenesis of cyclic vomiting syndrome.⁸ Many associated symptoms, such as pallor, flushing, fever, lethargy, salivation, and diarrhea, are mediated by the autonomic nervous system.^9,10,11

Several studies support altered autonomic function in cyclic vomiting syndrome. Rashed et al¹² and To et al¹³ demonstrated a heightened sympathetic cardiovascular tone in patients with cyclic vomiting syndrome. Kasawinah et al reported the successful use of dexmedetomidine, an alpha-2 adrenergic agonist, to treat cyclic vomiting syndrome.¹⁴ In a small study involving 6 children with cyclic vomiting syndrome, 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 this disorder.¹⁵

The stress response, mediated by the hypothalamic-pituitary-adrenal (HPA) axis, can also potentially induce episodes of cyclic vomiting syndrome. Infectious, psychological, and physical stressors are known triggers of episodes.^{16,17,18,19,20} Sato et al documented increased levels of adrenocorticotropic hormone (ACTH) and cortisol, associated with extreme lethargy and hypertension, before the onset of vomiting.^21,22,23,24 Furthermore, Taché has definitively shown that central CRF induces gastric stasis, emesis, or both in animals.²⁵ Therefore, CRF may be a potential brain-gut mediator of cyclic vomiting syndrome that directly connects stress and vomiting.²⁶ If this theory holds true, CRF receptor antagonists currently in development could theoretically ablate the vomiting by blocking the CRF receptor's vagally mediated actions.²⁷

How these pathways fit together is still unclear. Li and Misiewicz have proposed that heightened neuronal excitability due to enhanced membrane ion permeability (ion channelopathy), mitochondrial energy deficits (due to dysfunction), or hormonal state (eg, menstrual periods) may be present.¹ Both physical (infection) and psychologic stressors (excitement) can initiate a known cascade that releases hypothalamic CRF, the suspected neuroendocrine trigger, resulting in vomiting. Altered brainstem regulation of these autonomic signals may be the necessary abnormality that allows the dysautonomia to feed forward and become self-sustained for days on end.

Frequency

United States

The true incidence and prevalence of cyclic vomiting syndrome are unknown. In central Ohio, amid a predominantly white population, the prevalence of cyclic vomiting syndrome in children (evaluated by the sole pediatric gastroenterology referral center) was 0.04%.²⁸

International

Limited epidemiologic data by Cullen and MacDonald estimate the prevalence of periodic vomiting in western Australia to be 2.3%.⁹ Similarly, Abu-Arafeh and Russell observed a prevalence of 1.9% in school-aged children in Aberdeen, Scotland.²⁹ Both of these figures estimate the prevalence in white populations and may not reflect all races or ethnic populations. In a study performed at KEM Hospital in Pune, India, cyclic vomiting syndrome accounted for 0.5% of admissions to pediatric wards during 1998-2000.

In a population based study in Ireland, the incidence of cyclic vomiting syndrome in Ireland was relatively common at 3.15 cases per 100,000 children in 2005 (95% confidence interval [CI], 2.19-4.11). This incidence is comparable to other major GI diseases of childhood (eg, Crohn disease) in Ireland.^30,31

Mortality/Morbidity

Although patients are well approximately 90% of the time, cyclic vomiting syndrome can be a medically and academically disabling disorder. More than 50% of patients require intravenous fluids, compared with less than 1% of patients with rotavirus gastroenteritis. The average annual cost of testing, treatment, and work absences totals $17,000. Children miss an average of 24 school days per year and often need home tutoring or, occasionally, home schooling. Additionally, because of its frequency during times of excitement, cyclic vomiting syndrome has ruined many birthdays, holidays, and vacations.²⁸

In adults, significant morbidity is associated with this disorder, perhaps due to a lack of awareness and resultant delay in diagnosis. In a study of 41 patients with cyclic vomiting syndrome, Fleisher found that 32% were completely disabled at the time of diagnosis.¹¹ A total of 293 procedures were performed in 41 patients, and none were indicative of organic etiology in these patients. In addition, 17 surgical procedures, including 10 cholecystectomies, appendectomies, exploratory laparotomies, a pyloroplasty, and a hysterectomy, were performed without any therapeutic benefit.

Adults and children with cyclic vomiting syndrome also have multiple emergency department visits, and the diagnosis is often unrecognized.³²

Table 1. Emergency Department Visits in Patients With Cyclic Vomiting Syndrome

Race

Cyclic vomiting syndrome occurs in all races but seems to disproportionately affect whites.

Sex

Females show a slight predominance over males; the female-to-male ratio is 57:43.

Age

The median age at onset is 4.8 years; however, cyclic vomiting syndrome has been observed in infants as young as age 6 days and in adults as old as age 73 years.¹ Typical delay in diagnosis from onset of symptoms is 2.7 years.¹

In adults, the average age of onset is 21 years and average age of evaluation for recurrent vomiting was 34 years.¹¹

Clinical

History

Cyclic vomiting syndrome (CVS) is characterized by recurrent, discrete, stereotypical episodes of rapid-fire vomiting between varying periods of completely normal health. This on-and-off stereotypic pattern of vomiting is nearly pathognomonic of cyclic vomiting syndrome. Although periods of complete normalcy typically occur between episodes, a pattern of coalescence has been described in many adult patients. Over time, these patients may lose the cyclic pattern of symptoms, and 63% of patients develop interepisodic symptoms (often nausea) between episodes, which is termed coalescence.¹¹

The Rome III diagnostic criteria for cyclic vomiting syndrome in children includes all of the following:

• Two or more periods of intense nausea and unremitting vomiting or retching, lasting hours to days
• Return to usual state of health that lasts weeks to months

The cut off of 2 episodes resulted in a significant proportion of misdiagnosis; thus, the guidelines were modified and the criteria as per the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) are as follows (all criteria must be met):³³

• At least 5 episodes, or a minimum of 3 over a 6-month period
• Episodic attacks of intense nausea and vomiting that lasts 1 hour to 10 days, occurring at least one week apart
• Stereotypical pattern and symptoms in the individual patient
• Vomiting during episodes occurs at least 4 times an hour for at least one hour
• A return to baseline health during episodes
• Not attributed to another disorder

• Stereotypical episodes of vomiting regarding onset (acute) and duration (>1 wk)
• Three or more discrete episodes in the prior year
• Absence of nausea and vomiting between episodes
• No metabolic, GI, or CNS structural or biochemical disorders

Supportive criteria include history of migraine headaches and family history of migraine headaches.

The vomiting in cyclic vomiting syndrome is typically much more severe and intermittent than is observed in gastroesophageal reflux. When children with cyclic vomiting syndrome were compared with children with chronic vomiting, children with cyclic vomiting syndrome had a much higher peak rate of emeses per hour (12.6 vs 1.9) but far fewer episodes per month (1.5 vs 36).¹ A cut-off criterion of at least 4 emeses per hour at peak and fewer than 2 episodes per week was 92% sensitive and 100% specific for the final diagnosis of cyclic vomiting syndrome.³⁴ With a larger cohort, the median peak rate of emeses is still 6 times per hour.¹⁷ Only Bacillus cereus food poisoning matches this high intensity of emesis.²⁸ This singularly severe vomiting (so-called cyclic vomiting pattern) typifies patients with cyclic vomiting syndrome and helps point toward a disorder that is localized outside the GI tract.

Persons with the cyclic pattern (high-intensity, low-frequency) tend to have extraintestinal disorders (eg, neurologic, renal, metabolic, endocrine), whereas persons with a chronic vomiting pattern (low-grade, daily) tend to have upper GI injury, such as gastroesophageal reflux and gastritis.²⁸ The emesis is often projectile (48%) and frequently contains bile (81%), mucous (72%), and blood (34%).¹ Hematemesis is more often due to retrograde herniation of the gastric cardia through the gastroesophageal junction (ie, prolapse gastropathy) than to a classic Mallory-Weiss tear.³⁵

The "on-off" stereotypical pattern often begins with a half-hour prodrome of nausea and pallor. Vomiting peaks in the first hour and then begins to decline over the ensuing 4-8 hours, lasting a mean of 24 hours (median, 43 h). Episodes commonly occur in the early morning (2-4 am) or upon awakening (6-8 am). The recovery period from the end of vomiting to the point of being able to eat and play lasts a mere 5 hours. Despite the label cyclic, only one half of patients have a stable periodicity; the rest have sporadic intervals.²⁸

Besides vomiting, patients may also experience other GI symptoms. Abdominal pain is present in 80% of patients and may initially be severe enough to mimic acute abdomen and result in a laparotomy.¹⁷ Patients may also have epigastric pain secondary to peptic injury of the esophagus.

Most patients experience retching (79%) and nausea (82%) and describe the nausea to be the most distressing symptom.¹ It is unrelenting, completely unrelieved by vomiting, and disappears only when the child is asleep or the episode is over.

Many of the behavioral symptoms commonly observed in patients with cyclic vomiting syndrome (eg, fetal positioning, social withdrawal, turning off lights and televisions) are attempts to lessen nausea.²⁸

Approximately one third of patients also experience fever, diarrhea, or both, complicating differentiation from gastroenteritis; this is likely due to associated autonomic symptoms. Autonomic symptoms are also common, particularly lethargy (93%) and pallor (91%).¹ Lethargy may be profound, and patients may be unable to walk or talk or may appear comatose. Excess salivation (27%) can also be dramatic.¹

Many patients with cyclic vomiting syndrome have neurologic symptoms, which supports the relationship between migraines and cyclic vomiting syndrome. Symptoms include headache (42%), photophobia (38%), phonophobia (30%), and vertigo (26%). Because fewer than one half of patients with cyclic vomiting syndrome have classic migraine symptoms, this precludes using the symptoms as diagnostic criteria for a migraine variant.¹

Approximately 68% of families are able to identify events that appear to precipitate a patient's episode.^9,36,17,20 The most common precipitating event is infection (41%), particularly chronic sinusitis.²⁸ Psychological stresses (34%) and food products, including chocolate, cheese, and monosodium glutamate (MSG), rank close behind chronic sinusitis.²⁸ Positive excitement, such as birthdays, holidays, vacations, and school outings, appear to trigger more episodes than do negative stresses. Others recognize physical exhaustion or lack of sleep (18%), atopic events (13%), motion sickness (9%), and menses (13%) as triggers.²⁸ Many patients experience remission in the summer, when the number of infections and school stressors decline.³⁷

The terms cyclic vomiting syndrome and abdominal migraine have often been used interchangeably because of overlap in clinical criteria. Indeed, the key criteria, except vomiting, in abdominal migraines are identical to those in cyclic vomiting syndrome and include recurrent, stereotypical, and severe episodes of abdominal pain; punctuating well periods; autonomic symptoms (eg, pallor, lethargy); and a family history of migraine headaches. Because 80% of children with cyclic vomiting syndrome have abdominal pain, and 50% of those with abdominal pain vomit, many children can be diagnosed with either cyclic vomiting syndrome or abdominal migraine. When both symptoms occur, the authors use the predominant or most consistent symptom as the primary label.

The following 3 additional criteria help strengthen the diagnosis of cyclic vomiting syndrome:²⁸

• Negative screening test results to exclude common GI, hepatobiliary, renal, metabolic, and endocrine disorders
• Subsequent development of migraine headaches
• A positive response to antimigraine medications

Table 2. Clinical Features in Adults and Children with Cyclic Vomiting Syndrome³⁸

Differential Diagnoses

Other Problems to Be Considered

• GI disorders
  • Gastroesophageal reflux disease (peptic esophagitis)
  • Peptic disorders (gastritis, duodenitis, Helicobacter pylori infection)
  • Inflammatory bowel disease (Crohn disease, ulcerative colitis)
  • Anatomic obstruction (malrotation with intermittent volvulus)
  • Hirschsprung disease
  • Intestinal pseudoobstruction
  • Cholelithiasis (gallbladder dyskinesia)
  • Choledochal cyst
  • Chronic appendicitis
  • Recurrent pancreatitis
• Neurologic disorders
  • Abdominal migraine with vomiting
  • Migraine headaches with vomiting
  • Chronic sinusitis
  • Subtentorial neoplasm (cerebellar medulloblastoma, brainstem glioma)
  • Chiari malformation
  • Familial dysautonomia (Riley-Day syndrome)
• Renal disorders
  • Acute hydronephrosis secondary to uteropelvic junction obstruction
  • Nephrolithiasis
• Metabolic disorders
  • Disorders of fatty acid oxidation
  • Urea cycle defects
  • Mitochondriopathy
  • Acute intermittent porphyria
• Endocrine disorders
  • Addison disease
  • Diabetes mellitus with ketoacidosis
  • Pheochromocytoma
  • Hyperemesis gravidum
• Psychological disorders
  • Munchausen syndrome by proxy
  • Anxiety
  • Depression
  • Bulimia
• Other - Pregnancy
• Cannabinoid hyperemesis
  • Allen et al reported 19 cyclic vomiting syndrome cases associated with chronic cannibas use. In this study, 10 patients were not included in follow-up; most of the remaining 9 who abstained from marijuana had symptom relief.³⁹ Other cases of cannabinoid hyperemesis have been reported, although no long-term follow-up is noted in most cases.⁴⁰
  • Evidence implicating marijuana use as the actual cause of vomiting is insufficient; no clear temporal relationship between the onset of vomiting and the actual initiation of marijuana use has been established. These patients may have cyclic vomiting syndrome and are using marijuana for its antiemetic properties.
  • Although the role of marijuana in cyclic vomiting syndrome has not been well established, a recent report by McCallum et al shows chronic marijuana use is a risk factor for lack of response to tricyclic antidepressants used in the treatment of this disorder. Thus, complete abstinence from marijuana may be recommended in patients with cyclic vomiting syndrome.⁴¹

Workup

Laboratory Studies

• A heterogeneous group of disorders can mimic cyclic vomiting syndrome (CVS), and these disorders must be excluded with systematic laboratory and radiographic testing. An analysis by Li and colleagues demonstrated 3 main categories to consider in the differential diagnoses: GI disorders, extraintestinal disorders, and idiopathic cyclic vomiting syndrome.⁴²
• When evaluating for GI diseases, screening blood work should include a CBC count with differential, erythrocyte sedimentation rate (ESR), and levels of hepatic transaminases, pancreatic amylase, and lipase.
• Nonanatomic renal disease can be detected using serum BUN and creatinine tests, urinalysis, and urine calcium-to-creatinine ratio.⁴³
• Screening for multiple metabolic and endocrine disorders can be accomplished by assessing electrolytes, pH, glucose, lactic acid, ammonia, amino acids, ACTH, and antidiuretic hormone (ADH).
• Urinary ketones, organic acids, ester-to-free carnitine ratio, porphobilinogen, and aminolevulinic acid may also guide diagnosis in the correct direction.⁴³ These metabolic and endocrine tests must be obtained during the episode to detect intermittent disorders (eg, disorder of fatty acid oxidation) or heterozygote disorders (eg, partial ornithine transcarbamylase deficiency).
• Blood and urine tests must be performed before starting intravenous fluids that contain glucose or other medical treatments.
• In a postmenarchal girl, the physician must consider a beta human chorionic gonadotropin (bhCG) test for pregnancy.⁴³

Imaging Studies

• When evaluating for GI diseases, an upper GI (UGI) with small-bowel followthrough (SBFT) radiography, esophagogastroduodenoscopy (EGD), abdominal ultrasonography, or CT and gastric-emptying scanning may provide definitive information.⁴³
• When evaluating for neurologic or otolaryngologic diseases, a sinus CT scan or brain MRI should be considered.⁴³ CT scans may not adequately visualize the subtentorial region.
• Obstructive renal disease can be revealed with renal ultrasonography or CT imaging.⁴³
• With a broad array of possible diagnoses and possible diagnostic approaches, an extensive evaluation may appear cumbersome. Olson and Li reported that UGI radiography followed by empiric antimigraine therapy for 2 months is the most cost-effective approach ($1600) for the initial treatment of recurrent episodic vomiting in children ($3020 for extensive diagnostic evaluation, and $1830 for empiric treatment alone).⁴⁴ Until prospective trials are conducted, the authors' current approach generally includes initial blood and urine screens, including metabolic screening and UGI at initial presentation.
• The presence of specific symptoms such as hematemesis, bilious vomiting, persistent headache, flank pain, acidosis, or uncharacteristically severe or atypical vomiting episodes should raise the clinician's index of suspicion of an underlying disorder and should warrant a prompt and more extensive or repeat evaluation.⁴⁴ The 4 tests with the highest yield include endoscopy, sinus radiography or CT imaging, small-bowel radiography, and head CT imaging or MRI.⁴³

Other Tests

• A psychological evaluation may reveal ongoing panic, anxiety, and eating disorders, and stress management may attenuate the stress triggers.⁴³
• In summary, because no biochemical markers have been identified, the recent NASPHAGN guidelines suggest that physicians must initially look for alarming symptoms and tailor their work up accordingly. Suspicious symptoms include the following:
  • Bilious vomiting, abdominal tenderness, and/or severe abdominal pain
  • Attacks precipitated by intercurrent illness, fasting, and/or high protein meal
  • Abnormal neurologic examination findings, including severe alteration of mental status, abnormal eye movements, papilledema, motor asymmetry, and/or gait abnormality (ataxia)
  • Progressively worsening episodes or conversion to a continuous or chronic pattern
• Depending on the presenting symptoms and signs other than vomiting, different diagnostic approaches are recommended. In addition, certain subgroups of patients are thought to be at high risk for metabolic disorders; if the following conditions are met, early referral to a metabolic specialist or neurologist should be considered:
  • Presentation younger than age 2 years (with cyclic vomiting or comorbidities below)
  • Vomiting episodes associated with intercurrent illnesses, prior fasting, and/or increased protein intake
  • Any neurological finding, including ataxia, dystonia, or another gait disturbance; mental retardation; or seizure disorder or acute encephalopathy (including true lethargy, severe irritability, confusion, psychosis, or rapidly changing/unstable mental status)
  • Laboratory metabolic findings, including hypoglycemia, substantial anion gap metabolic acidosis, respiratory alkalosis, or hyperammonemia

Treatment

Medical Care

In the absence of known pathophysiology, treatment of cyclic vomiting syndrome (CVS) remains empiric.^17,45 The following 5 management strategies are used for cyclic vomiting syndrome: avoidance of triggers, prophylactic pharmacotherapy, abortive therapy, supportive care during acute episodes, and family support.²⁸

Pharmacologic therapy is used to prevent episodes of vomiting or to decrease their frequency. Other medications may be used to abort or attenuate episodes once they begin. Preventive medications are normally used in patients with more than a single episode of cyclic vomiting syndrome per month. The mainstays of prophylactic therapy include cyproheptadine, amitriptyline, propranolol, phenobarbital, and erythromycin. If abortive therapy fails, supportive combinations such as ondansetron plus lorazepam or chlorpromazine plus diphenhydramine may attenuate an attack of cyclic vomiting in progress.

In some instances, avoiding identified dietary triggers, such as chocolate, cheese, and monosodium glutamate (MSG) can prevent episodes without the use of medication.²⁸ If psychological stressors trigger episodes, stress management techniques or benzodiazepine anxiolytics (lorazepam or diazepam) may help to abort attacks in the early stages. However, avoiding common triggers such as car rides and infection may be impractical or impossible. Interestingly, a 70% decrease in frequency of episodes (placebo effect) upon consultation and lifestyle changes without drug therapy has been noted.¹⁰

Daily prophylactic pharmacotherapy may be used to prevent episodes that occur more than once per month or if they are extremely severe and disabling (eg, lasting ³ 3 d).^46,47 Most of these drugs are non-GI medications, such as antimigraine agents, anticonvulsants, neuroleptics, and prokinetic drugs. A family history positive for migraines predicts a high response rate (80%) to antimigraine medications; therefore, these agents are a logical first choice.²⁸

In an open-label experience, with efficacy defined as greater than 50% reduction in episode frequency or severity, propranolol, cyproheptadine, and amitriptyline were effective 57%, 39%, and 67% of the time, respectively.^34,48 The NASPGHAN guidelines recommend cyproheptadine as first-line therapy in children younger than 5 years. However, cyproheptadine can cause substantial weight gain because of an increase in appetite. Amitriptyline is the first-line choice in children older than 5 years and adolescents.²⁸ Phenobarbital demonstrated a 79% success rate in one open-label trial in children who did not have EEG changes.⁴⁹ Erythromycin, a gastric prokinetic agent, demonstrated a 75% success rate in one open-label study.⁵⁰

Winner et al reported a significant reduction (>75%) in days with migraine headaches in patients receiving topiramate compared with placebo.⁵¹ Topiramate is currently used anecdotally in patients with cyclic vomiting syndrome. Another small therapeutic trial using L-carnitine reported reduced episode frequency and neurologic symptoms in patients with cyclic vomiting syndrome.⁵²

In adults few studies are available; in one study, the overall treatment response in 24 adult patients receiving amitriptyline (1 mg/kg/day) for at least 3 months indicated that 93% had decreased symptoms and 26% achieved full remission.⁵³

In another study, 20 adult patients with cyclic vomiting syndrome received zonisamide (median dose, 400 mg/d) or levetiracetam (median dose, 1000 mg/d) because tricyclic antidepressants alone were unsatisfactory as maintenance medications. At least moderate clinical response was reported in 15 subjects (75%), and 4 of these (20%) reported symptomatic remission during 9.5 ± 1.8 months of follow-up. Newer antiepileptic agents appeared beneficial as maintenance medications for nearly three fourths of adults with cyclic vomiting syndrome.⁵⁴

Abortive agents may be taken at the onset of an attack to stop progression when prophylactic medication fails or is not taken because of the sporadic and infrequent occurrence of cyclic vomiting episodes (<1/mo). These antinausea and antimigraine agents are best administered nasally, rectally, or parenterally because they are not usually tolerated by mouth during intractable emesis.⁴³ Sumatriptan, a 5-hydroxytryptamine receptor 1B/1D (5-HT_1B/1D) agonist used off-label, has a 46% efficacy rate when administered either intranasally or subcutaneously. The subcutaneous route has fallen out of favor because of a severe associated burning sensation in the chest and neck.⁵⁵

Ondansetron, a 5-hydroxytryptamine receptor 3 (5-HT₃) antagonist, is a potent and effective antiemetic that acts on the chemoreceptor zone in the brainstem. In cyclic vomiting syndrome, it is more effective at a higher dose of 0.3-0.4 mg/kg every 6 hours and is rendered more effective in severe episodes with use of a benzodiazepine or diphenhydramine as an adjunctive antinausea agent.¹ High-dose intravenous ondansetron has a 59% efficacy rate and ameliorates episodes more often than it aborts episodes. Aprepitant, a promising tachykinin (NK-1)-receptor antagonist, is used for chemotherapy-induced emesis and could have benefit in cyclic vomiting syndrome.⁴³

When both prophylactic and abortive therapy fail, supportive care becomes an essential aspect of treatment during acute episodes. Intravenous glucose-containing fluids may diminish the severity of episodes by as much as 42%.⁴³ Glucose may be the active ingredient by truncating the ketosis. However, the abdominal pain may be severe enough to require nonsteroid anti-inflammatory drugs (NSAIDs) or narcotics once a surgical abdomen has been excluded. Sedatives such as diphenhydramine, lorazepam, and chlorpromazine have been administered to permit sleep and to provide temporary respite from unrelenting nausea.⁴³ The combined use of lorazepam and ondansetron appears to be more effective than ondansetron alone.

Families are also encouraged to contact the Cyclic Vomiting Syndrome Association, which is an international voluntary organization that serves the needs of patients in the United States and Canada, for ongoing support and information.

Medication

Antiemetic agents

The CNS vomiting center (VC) may be stimulated directly by GI irritation, motion sickness, or vestibular neuritis. Increased activity of central neurotransmitters, such as dopamine in the chemoreceptor trigger zone (CTZ) or acetylcholine in the VC, appear to be major mediators of vomiting. An emetogenic episode may initiate the release of serotonin (5-HT) from enterochromaffin cells in the GI tract. 5-HT then binds to 5-HT₃ receptors that stimulate vagal neurons that transmit signals to the VC, resulting in nausea and vomiting. Pharmacologic agents are directed to the particular etiology or mechanism that stimulates the vomiting response.

Cyproheptadine (Periactin)

Nonselective antihistamine effective in CVS and for migraines.
Also an appetite stimulant. Therapeutic effects are observed within 1-2 wk. Excellent choice for children <5 y.

Dosing

Adult

Pediatric

0.3 mg/kg/d PO divided bid/tid

Interactions

Potentiates effects of CNS depressants; MAOIs may prolong and intensify anticholinergic and sedative effects of antihistamines

Contraindications

Documented hypersensitivity; narrow-angle glaucoma; stenosing peptic ulcer; symptomatic prostatic hypertrophy; bladder neck obstruction; pyloroduodenal obstruction; lower respiratory tract symptoms; overweight children

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution if predisposition to urinary retention, history of bronchial asthma, increased intraocular pressure, hyperthyroidism, cardiovascular disease, or hypertension; may thicken bronchial secretions caused by anticholinergic properties; may inhibit expectoration and sinus drainage; may cause common anticholinergic effects (eg, dizziness, dry mouth, constipation, blurred vision); sedation; substantial weight gain may limit utility

Amitriptyline (Elavil)

TCAs such as amitriptyline are excellent first-line choices in children >5 y. Has anticholinergic and sedating side effects; thus, best administered at bedtime. Cardiac arrhythmia, especially in overdose, has been described; monitoring the QTc interval both before starting and after reaching the target level is advised. Up to 1 mo may be needed to see clinical effects.

Dosing

Adult

Pediatric

0.3-0.5 mg/kg PO initially; titrate upward by 10 mg/wk to goal dose of 1 mg/kg/d qhs; typical doses are listed below:
<6 years: 10-30 mg/d PO
6-12 years: 30-50 mg/d PO
>12 years: 50-75 mg/d PO

Interactions

Phenobarbital may decrease effects; coadministration with CYP2D6 enzyme system inhibitors (eg, cimetidine, quinidine) may increase levels; inhibits hypotensive effects of guanethidine; may interact with thyroid medications, alcohol, CNS depressants, barbiturates, and disulfiram

Contraindications

Documented hypersensitivity; MAOIs in past 14 d; history of seizure, cardiac arrhythmia, glaucoma, or urinary retention

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in cardiac conduction disturbances, history of hyperthyroidism, and renal and hepatic impairment

Propranolol (Inderal)

Beta-adrenergic blocker and excellent first-line agent for prophylaxis when used at low doses. Has a 57% efficacy rate, with efficacy defined as 50% reduction in frequency and severity of episodes. Requires 1 wk for efficacy and requires gradual withdrawal over 1 wk. Dose may be monitored by fall in presleep resting pulse from baseline. Decline <15-20 bpm indicates dose may be further increased.

Dosing

Adult

Pediatric

0.5-1 mg/kg/d PO divided bid/tid; typical dose is 10-20 mg PO bid/tid

Interactions

Coadministration with aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, or rifampin may decrease propranolol effects; calcium channel blockers, cimetidine, loop diuretics, and MAOIs may increase propranolol toxicity; propranolol may increase toxicity of alpha1-blockers, hydralazine, haloperidol, benzodiazepines, and phenothiazines

Contraindications

Documented hypersensitivity; uncompensated congestive heart failure; bradycardia; cardiogenic shock; AV conduction abnormalities; asthma

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Beta-adrenergic blockade may decrease signs of acute hypoglycemia and hyperthyroidism; abrupt withdrawal may exacerbate symptoms of asthma or hyperthyroidism, including thyroid storm; slowly withdraw and closely monitor; common adverse effects include mild hypotension, bradycardia, and fatigue

Phenobarbital (Luminal)

May be used in patients with or without EEG changes. A 79% response rate has been observed in patients with CVS.

Dosing

Adult

Pediatric

2-3 mg/kg PO qhs; may require 2-3 wk to observe effect

Interactions

May decrease effects of chloramphenicol, digitoxin, corticosteroids, carbamazepine, theophylline, verapamil, metronidazole, and anticoagulants (patients stabilized on anticoagulants may require dosage adjustments if added to or withdrawn from their regimen); coadministration with alcohol may produce additive CNS effects and death; chloramphenicol, valproic acid, and MAOIs may increase phenobarbital toxicity; rifampin may decrease phenobarbital effects; induction of microsomal enzymes may result in decreased effects of oral contraceptives in women (must use additional contraceptive methods to prevent unwanted pregnancy; menstrual irregularities may also occur)

Contraindications

Documented hypersensitivity; severe respiratory disease; acute intermittent porphyria; marked impairment of liver function; nephritic patients

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

In prolonged therapy, evaluate hematopoietic, renal, hepatic, and other organ systems; caution in fever, hyperthyroidism, diabetes mellitus, and severe anemia because adverse reactions can occur; caution in myasthenia gravis and myxedema; long-term use can be associated with cognitive impairment

Erythromycin (E.E.S., Eryc, E-Mycin, Erythrocin)

Gastric prokinetic that stimulates coordinated gastric emptying. A 75% response rate has been demonstrated in patients with CVS.

Dosing

Adult

Pediatric

20 mg/kg/d PO divided bid/qid

Interactions

Coadministration may increase toxicity of theophylline, digoxin, carbamazepine, and cyclosporine; may potentiate anticoagulant effects of warfarin; coadministration with lovastatin and simvastatin increases risk of rhabdomyolysis; inhibits CYP3A4; caution with coadministration of isoenzyme substrates

Contraindications

Documented hypersensitivity; hepatic impairment

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in liver disease; estolate formulation may cause cholestatic jaundice; GI adverse effects are common; discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occurs; may cause cramping at higher doses

Ondansetron (Zofran)

This 5-HT₃ antagonist directly acts at the CTZ and vagal afferents from the GI tract. Attenuates or occasionally aborts an active episode of CVS. High dose more effective in patients with CVS.

Dosing

Adult

Pediatric

<3 years: Not established
>3 years: 0.3-0.4 mg/kg/dose IV q6h

Interactions

CYP450 inducers such as barbiturates, rifampin, carbamazepine, and phenytoin can potentially change half-life and clearance of ondansetron, but dosage adjustment usually not required

Contraindications

Documented hypersensitivity; hepatic impairment

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause constipation or headache

Sumatriptan (Imitrex)

This 5-HT_1B/1D agonist may effectively terminate an episode of CVS by constricting cerebral vasculature. High dose more effective in patients with CVS.

Dosing

Adult

Pediatric

<40 kg: Not established
>40 kg: Up to 20 mg intranasally prn

Interactions

Toxicity increases when administered concomitantly with ergot-containing drugs, SSRIs, and MAOIs

Contraindications

Documented hypersensitivity; ischemic heart disease; uncontrolled hypertension

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause burning sensation of chest or neck (<40% with injectable form, uncommon in nasal form); hypertensive crisis, coronary artery vasospasm, cardiac arrest, peripheral ischemia, and bloody diarrhea may rarely occur

Lorazepam (Ativan)

Because of both their sedative and antinausea properties, sedatives may be helpful. Induce sedation and anxiolysis through central GABA inhibition. Appears synergistic with the antinausea and antiemetic effects of 5-HT₃ antagonists. Concomitant sedation and induction of sleep provide sustained relief from intractable nausea.

Dosing

Adult

Pediatric

0.05-0.1 mg/kg/dose IV q6h prn; not to exceed 4 mg/dose

Interactions

Toxicity of benzodiazepines in CNS increases when used concurrently with alcohol, phenothiazines, barbiturates, and MAOIs

Contraindications

Documented hypersensitivity; preexisting CNS depression; hypotension; narrow-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal or hepatic impairment, myasthenia gravis, organic brain syndrome, or Parkinson disease

Diphenhydramine (Benadryl)

For treatment and prophylaxis of vestibular disorders that may cause nausea and vomiting. Provides mild sedation and synergistic antinausea and antiemetic action with 5-HT₃ antagonists.

Dosing

Adult

Pediatric

Infants: Contraindicated
Children: 1.25 mg/kg/dose PO q6h; not to exceed 300 mg/d

Interactions

Potentiates effects of CNS depressants; because of alcohol content, do not give syrup form to patients taking medications that can cause disulfiram-like reactions

Contraindications

Documented hypersensitivity; MAOIs; infants

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May exacerbate narrow-angle glaucoma, hyperthyroidism, peptic ulcer, and urinary tract obstruction; xerostomia may occur

Follow-up

Deterrence/Prevention

• In some cases of cyclic vomiting syndrome (CVS), avoiding identified dietary triggers such as chocolate, cheese, and monosodium glutamate (MSG) can prevent episodes without the use of medication.²⁸
• If psychological stresses trigger episodes, stress management techniques or benzodiazepine anxiolytics (lorazepam or diazepam) may help abort attacks. However, avoiding common triggers such as car rides and infection may be impractical or impossible.
• Interestingly, consultation with a sympathetic gastroenterologist without drug therapy may decrease the frequency of episodes as much as 70%.⁴³

Prognosis

• Most published series indicate that cyclic vomiting syndrome lasts an average of 2.5-5.5 years, resolving in late childhood or early adolescence. A few patients continue to be symptomatic through adulthood.
• As early as 1898, clinicians observed that some patients went on to develop migraine headaches. The fact that some children with cyclic vomiting syndrome progress to abdominal migraines and then to migraine headaches implies that a sequential progression of age-dependent manifestations of migraines may be noted.
• A survey by Abu-Arafeh and colleagues revealed the mean ages of children with cyclic vomiting syndrome, abdominal migraines, and migraine headaches to be 5.3 years, 10.3 years, and 11.5 years, respectively.²⁹ This supports the developmental progression from vomiting to abdominal pain to headache.
• In unpublished data, Li and Hayes found that nearly one third of patients develop migraines after resolution of cyclic vomiting syndrome and predict that nearly 75% develop migraines by age 18 years.

Patient Education

• Families are also encouraged to contact the Cyclic Vomiting Syndrome Association, which is an international voluntary organization that serves the needs of patients in the United States and Canada, for ongoing support and information.

Multimedia

Media file 1: Cyclic versus chronic temporal patterns of recurrent vomiting. The number of emeses is plotted over a 2-month period. The chronic pattern, represented by a thin dashed line, has low grade on nearly a daily basis (eg, gastroesophageal reflux). The cyclic pattern, represented by a heavy solid line, involves high-intensity episodes intermittently once every several weeks (eg, cyclic vomiting syndrome).

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Keywords

cyclic vomiting syndrome, CVS, vomit, emesis, migraine, syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis, strokelike episodes, MELAS syndrome, abdominal migraine, rotavirus gastroenteritis, gastroesophageal reflux

Contributor Information and Disclosures

Author

Thangam Venkatesan, MBBS, Assistant Professor, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical College of Wisconsin
Thangam Venkatesan, MBBS is a member of the following medical societies: American Gastroenterological Association and Indian Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

B UK Li, MD, Professor of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Director, Pediatric Fellowships and Gastroenterology Fellowship, Medical Director, Functional Gastrointestinal Disorders and Cyclic Vomiting Program, Medical College of Wisconsin; Attending Gastroenterologist, Children's Hospital of Wisconsin
B UK Li, MD is a member of the following medical societies: Alpha Omega Alpha, American Gastroenterological Association, and North American Society for Pediatric Gastroenterology and Nutrition
Disclosure: Nothing to disclose.

Seth Marcus, MD, Fellow, Department of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Memorial Hospital, Northwestern University
Seth Marcus, MD is a member of the following medical societies: American Academy of Pediatrics and North American Society for Pediatric Gastroenterology and Nutrition
Disclosure: Nothing to disclose.

Shikha Sundaram, MD, Fellow, Department of Gastroenterology, Hepatology and Nutrition, Children's Memorial Hospital of Chicago and Northwestern University
Shikha Sundaram, MD is a member of the following medical societies: American Academy of Pediatrics and American Medical Association
Disclosure: Nothing to disclose.

Abhilasha Pandey, MBBS, Froedtert Hospital, Medical College of Wisconsin
Disclosure: Nothing to disclose.

Medical Editor

Jayant Deodhar, MD, Associate Professor in Pediatrics, BJ Medical College, India; Honorary Consultant, Departments of Pediatrics and Neonatology, King Edward Memorial Hospital, India
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

David A Piccoli, MD, Chief of Pediatric Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia; Professor, University of Pennsylvania School of Medicine
David A Piccoli, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, and North American Society for Pediatric Gastroenterology and Nutrition
Disclosure: Nothing to disclose.

CME Editor

Steven M Schwarz, MD, FAAP, FACN, AGAF, Professor of Pediatrics, Children's Hospital at Downstate, SUNY-Downstate Medical Center
Steven M Schwarz, MD, FAAP, FACN, AGAF is a member of the following medical societies: American Academy of Pediatrics, American College of Nutrition, American College of Physician Executives, American Gastroenterological Association, American Pediatric Society, Gastroenterology Research Group, New York Academy of Medicine, North American Society for Pediatric Gastroenterology and Nutrition, and Society for Pediatric Research
Disclosure: TAP Pharmaceuticals Honoraria Speaking and teaching; Curemark, LLC Consulting fee Board membership; Centocor, Inc. Grant/research funds Independent contractor

Chief Editor

Carmen Cuffari, MD, Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine
Carmen Cuffari, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

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