BASICS
DESCRIPTION
- An idiopathic chronic functional GI disorder characterized by discrete, recurrent, stereotypical episodes of high-intensity nausea and vomiting lasting hours to days, separated by symptom-free intervals
- Subsets
- Cyclic vomiting syndrome (CVS) plus two or more neuromuscular disorders in association
- Catamenial CVS: associated with menstrual cycle (1)[B]
- CVS has four distinct phases:
- Interepisodic: symptom-free period
- Prodromal: often marked by nausea with or without abdominal pain; able to take oral medications; minutes to hours (2)[B]
- Vomiting: nausea, vomiting, and retching
- Recovery: Nausea remits, and patient recovers appetite, strength, and energy (3)[B].
EPIDEMIOLOGY
Incidence
Unknown
Prevalence
- 0.04-1.9% in general population
- Whites affected more than other races
- Predominant sex: female > male (55:45)
- More common in children; mean age of diagnosis is 5 years in children and 35 years in adults; average is 3 years between onset of symptoms and diagnosis.
ETIOLOGY AND PATHOPHYSIOLOGY
- Unknown
- Strong link between CVS and migraine, with similar symptoms, frequent family history of migraines, and effectiveness of antimigraine therapy
- Proposed mechanism
- Heightened neuronal excitability owing to enhanced ion permeability, mitochondrial deficits, or hormonal state → increased susceptibility to physical or psychological trigger → release of corticotropin-releasing factor (CRF) → vomiting
- Vomiting perpetuated by altered brainstem regulation → sustained vomiting
- Possible maternal inheritance, based on family history of migraines and link to mitochondrial DNA (mtDNA) mutations (4)[B].
- Multiple theories:
- GI motility dysfunction
- Autonomic dysfunction: sympathetic (3)[B]
- Food allergy or intolerance
Genetics
- Likely matrilineal inheritance, especially with childhood onset (1)[B]
- A3243G or other mitochondrial DNA mutations including mitochondrial dysfunction (4)[B]
- Ion channel mutations
RISK FACTORS
- Family history of migraine headaches
- Depression and/or anxiety
- Chronic cannabis use
- Possibly food allergies or hypothalamic-pituitary-adrenal axis dysfunction
COMMONLY ASSOCIATED CONDITIONS
- Irritable bowel syndrome (67%)
- Headaches (52%)
- Motion sickness (46%)
- Migraines (11-40%)
- Seizure disorder (5.6%)
DIAGNOSIS
HISTORY
- Children often present with bilious emesis (83%), severe abdominal pain (80%), and/or hematemesis.
- The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition consensus criteria for diagnosing CVS:
- At least five attacks in any interval or a minimum of three attacks during a 6-month period
- Episodic attacks of intense nausea and vomiting lasting 1 hour to 10 days and occurring at least 1 week apart
- Stereotypical pattern and symptoms
- Vomiting at least 4 times per hour for at least 1 hour during attack
- Return to baseline between episodes
- Not attributable to another disorder
- Rome III criteria for adults
- Stereotypical onset (acute) and duration (<1 week) of vomiting episodes
- ≥3 discrete episodes in the prior year
- Absence of nausea and vomiting between episodes
- Supporting criterion: history or family history of migraine headaches
- Adult hallmarks
- Prominence of epigastric or diffuse abdominal pain
- Increased prevalence of anxiety and depression
- Normal or rapid gastric emptying
- Successful suppression of attacks by chronic amitriptyline therapy (3)[B]
PHYSICAL EXAM
Evaluate for dehydration (seen in 30%)
- Orthostatic hypotension
- Tachycardia
- Skin turgor, decreased
- Mucous membranes, dry
- General physical exam often otherwise normal
DIFFERENTIAL DIAGNOSIS
- GI disorders: GERD; Helicobacter pylori, cholelithiasis, pancreatitis, obstruction, gastroparesis
- Neurologic disorders: migraine headaches; Chiari malformation, intracranial mass
- Renal disorders: nephrolithiasis; obstruction; metabolic and endocrine disorders: porphyria; Addison disease, diabetic ketoacidosis; hyperemesis gravidarum; pheochromocytoma
- Behavioral disorders: M ¼nchausen by proxy; anxiety; bulimia nervosa; depression
- Pregnancy
- Cannabinoid abuse
- Any child with suspected CVS should be evaluated for a possible metabolic or neurologic etiology if:
- Child is <2 years of age.
- Vomiting episodes are associated with concurrent illnesses, prior fasting, or increased protein intake.
- Any focal findings on neurologic exam
- Hypoglycemia, anion gap metabolic acidosis, hyperammonia, or other findings suggest metabolic disorders.
DIAGNOSTIC TESTS & INTERPRETATION
CVS is a diagnosis of exclusion (4)[B]. Tests help rule out other diagnoses and assess for complications from excessive vomiting.
Initial Tests (lab, imaging)
- Electrolytes: hypokalemia (Addison disease exhibits hyponatremia and hypoglycemia.)
- CBC: hemoconcentration and leukocytosis
- Amylase and lipase (pancreatitis)
- ESR
- Hepatic transaminases: (hepatitis or gallbladder disease)
- Urinalysis: granular casts, ketosis
- Pregnancy test
- Lactate, ammonia, amino acids, urine organic acids, adrenocorticotropic hormone-particularly during an acute episode in young children to exclude metabolic disease
- Upper GI series to exclude malrotation
- Abdominal US to exclude transient hydronephrosis, gallstones, and ureteropelvic junction obstruction
- Esophagogastroduodenoscopy (EGD) if active hematemesis is present
Follow-Up Tests & Special Considerations
- Counseling-behavioral health for management of anxiety, depression, eating disorders, or cannabis abuse (if applicable)
- CT or MRI of head-assess for structural lesions of the brain or causes of increased ICP.
- CT of the abdomen and pelvis-evaluate biliary and urinary tracts and to exclude structural causes.
Diagnostic Procedures/Other
- EGD: to evaluate for clinical suspicion of peptic ulcer disease or sign of hematemesis
- Electroencephalogram: seizure disorder evaluation
- Gastric emptying studies: to exclude gastroparesis (3)[B]
- Autonomic testing
- Neuropsychiatric testing
TREATMENT
GENERAL MEASURES
- Patient reassurance
- Avoid triggers (stress, sleep deprivation, chocolate, cheese, monosodium glutamate, red wine) (5).
- Nonstimulating environment
- Relaxation techniques and psychological testing
- Avoid recreational drugs (marijuana).
MEDICATION
First Line
- Lifestyle changes:
- Avoid sleep deprivation, triggering foods, and motion sickness to reduce episode frequency.
- Prophylactic pharmacotherapy can be considered if an affected child is having repeated episodes requiring frequent hospitalization or school absences.
- Prophylactic medications (decrease frequency or severity by >50%)
- Amitriptyline (67-82%): children >5 years: 0.2 to 2 mg/kg/day not recommended for children <5 years; slow titration over 2 to 3 weeks to avoid side effects
- Cyproheptadine (39-66%): children 2 to 5 years: 0.25 to 0.5 mg/kg/day divided BID-TID; appetite stimulant; usually first-line treatment for children <5 years; especially if associated with migraines (5)
- Propranolol (57%): children: 0.5 mg/kg/day divided BID-TID; adults: 10 to 20 mg/day BID to TID especially if associated with migraines (5)
- Adjuncts
- Topiriramate: adults with CVS and chronic headaches; 20 to 100 mg daily (5)[A]
- Ondansetron: children: 0.3 to 0.4 mg/kg/dose q6h; adults: 4 mg IV/PO q6-8h
- Lorazepam: children: 0.05 to 0.1 mg/kg/dose IV (not to exceed 4 mg/dose); adults: 1 mg PO QID to reduce anxiety (5)[A]. Sumatriptan: >40 kg/20 mg intranasal PRN
Second Line
- Prophylactic
- Phenobarbital (79%): 2 to 3 mg/kg/day
- Erythromycin (75%): 20 mg/kg/day divided BID-TID
- Valproic acid (not calculated): 10 to 40 mg/kg/day
- Levetiracetam: 500 to 3,000 mg daily (5)[A]
- Zonisamide: 100 to 700 mg daily (5)[A]
- Abortive
- Hydromorphone: children: 0.015 mg/kg/dose IV for 1 dose; adults: 2 to 4 mg PO PRN or 0.5 to 2 mg IM/SC for 1 dose
- Diphenhydramine: children: 1.25 mg/kg/dose q6h, not to exceed 300 mg/day; adults: 25 to 50 mg q4-6h PRN
ISSUES FOR REFERRAL
Behavioral health-regular appointments; Consultation with a supportive gastroenterologist can decrease episodes of CVS and reduce pharmacotherapy (2).
ADDITIONAL THERAPIES
Relaxation techniques:
- Deep breathing
- Biofeedback
- Guided imagery
COMPLEMENTARY & ALTERNATIVE MEDICINE
Coenzyme Q10 up to 300 mg daily and carnitine up to 3 g daily has been shown to be effective for some patients with CVS (5)[A].
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
- Dehydration requiring >2 L of IV fluids
- Failure of outpatient management
- Increased anion gap that reflects severe dehydration or metabolic decompensation
- IV fluids or IV medications
- Lorazepam 1 to 2 mg IV q3h main approach to induce sleep most effective in acute crisis (5)[A]
IV Fluids
Replacement of ongoing losses; 5-10% dextrose-containing fluids or normal saline with added potassium to attenuate any metabolic crisis (5)[A]
Nursing
- Decrease stimulation; avoid noise and bright light.
- Supportive care
- Encourage relaxation techniques.
- Avoid unnecessary interruptions during sleep.
Discharge Criteria
- Vomiting and electrolyte imbalances resolved
- Pain managed with oral analgesia
- Euvolemia
- Appropriate oral intake
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Weekly appointments for severe cases
- Monitor for hypokalemia, acid-base disturbances, and ketosis if ongoing emesis.
- Regular outpatient visits for support
DIET
- Foods rich in carbohydrates, vitamins, and minerals
- A low-amine diet may help for prophylaxis in children.
- Limit fats and spicy foods.
- Avoid trigger foods: chocolate, cheese, and monosodium glutamate.
- Regular meal schedules
- Maintain good hydration.
PATIENT EDUCATION
- A vomiting diary to note patterns helps to identify potentially avoidable triggers in 75% of children.
- Stress management
- Good sleep hygiene
- Regular, moderate exercise
- Cyclic Vomiting Syndrome Association Web site: www.cvsaonline.org
PROGNOSIS
- Usually lasts 2.5 to 5.5 years
- Vomiting resolves in 70% of children with CVS. However, many children will continue to have somatic symptoms, including headache and abdominal pain.
- 35% develop recurrent/migraine headaches.
- 50-75% treated prophylactically are asymptomatic at 1 year.
- 13% are nonresponsive to therapy. Risk factors for nonresponders include poorly controlled migraines, psychiatric conditions, chronic narcotic use, and marijuana use (5)[A].
COMPLICATIONS
Occur during vomiting phase:
- Dehydration and hypovolemic shock
- Electrolyte derangement, including the syndrome of inappropriate antidiuretic hormone
- Hematemesis
- Peptic esophagitis
- Mallory-Weiss tear
- Weight loss
REFERENCES
11 Venkatesan T, Zaki EA, Kumar N, et al. Quantitative pedigree analysis and mitochondrial DNA sequence variants in adults with cyclic vomiting syndrome. BMC Gastroenterol. 2014;14:181.22 Fleisher DR. The cyclic vomiting syndrome described. J Pediatr Gastroenterol Nutr. 1995;21(Suppl 1):S1-S5.33 Cooper CJ, Said S, Bizet J, et al. Rapid or normal gastric emptying as new supportive criteria for diagnosing cyclic vomiting syndrome in adults. Med Sci Monit. 2014;20:1491-1495.44 Moses J, Keilman A, Worley S, et al. Approach to the diagnosis and treatment of cyclic vomiting syndrome: a large single-center experience with 106 patients. Pediatric Neurol. 2014;50(6):569-573.55 Hejazi RA, McCallum RW. Cyclic vomiting syndrome: treatment options. Exp Brain Res. 2014;232(8):2549-2552.
ADDITIONAL READING
- Boles RG. High degree of efficacy in the treatment of cyclic vomiting syndrome with combined co-enzyme Q10, L-carnitine and amitriptyline, a case series. BMC Neurol. 2011;11:102.
- Fleisher DR. Empiric guidelines for the management of cyclic vomiting syndrome. http://cvsaonline.org/pdfs/2008%20Empiric%20Guidelines%202045-3.pdf. Accessed 2015.
- Hejazi RA, Reddymasu SC, Namin F, et al. Efficacy of tricyclic antidepressant therapy in adults with cyclic vomiting syndrome: a two-year follow-up study. J Clin Gastroenterol. 2010;44(1):18-21.
- Hikita T, Kodama H, Kaneko S, et al. Sumatriptan as a treatment for cyclic vomiting syndrome: a clinical trial. Cephalalgia. 2011;31(4):504-507.
- Hikita T, Kodama H, Nakamoto N, et al. Effective prophylactic therapy for cyclic vomiting syndrome in children using valproate. Brain Dev. 2009;31(6):411-413.
- Lee LY, Abbott L, Mahlangu B, et al. The management of cyclic vomiting syndrome: a systematic review. Eur J Gastroenterol Hepatol. 2012;24(9):1001-1006.
- Li BU, Lefevre F, Chelimsky GG, et al. North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition consensus statement on the diagnosis and management of cyclic vomiting syndrome. J Pediatr Gastroenterol Nutr. 2008;47(3):379-393.
- Pareek N, Fleisher DR, Abell T. Cyclic vomiting syndrome: what a gastroenterologist needs to know. Am J Gastroenterol. 2007;102(12):2832-2840.
CODES
ICD10
- G43.A0 Cyclical vomiting, not intractable
- G43.A1 Cyclical vomiting, intractable
ICD9
- 536.2 Persistent vomiting
- 346.20 Variants of migraine, not elsewhere classified, without mention of intractable migraine without mention of status migrainosus
SNOMED
cyclical vomiting syndrome (disorder)
CLINICAL PEARLS
- CVS is more common in children than adults. The average age of diagnosis is 5 years.
- A food diary helps identify patterns and triggers for vomiting cycles.
- Proper sleep hygiene, stress management, and appropriate diet help mitigate symptoms.
- Treatment in the vomiting phase often requires a combination of pharmacologic and psychosocial interventions.
- Long-term prophylaxis can help reduce frequency and duration of recurrent vomiting cycles. Amitriptyline is the drug of choice in patients over the age of 5.