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Cyclic Vomiting Syndrome

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].

- 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

- 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]

- 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

- 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

  • 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
  • SubsetsCyclic vomiting syndrome (CVS) plus two or more neuromuscular disorders in associationCatamenial CVS: associated with menstrual cycle (1)[B]
  • CVS has four distinct phases:Interepisodic: symptom-free periodProdromal: often marked by nausea with or without abdominal pain; able to take oral medications; minutes to hours (2)[B]Vomiting: nausea, vomiting, and retchingRecovery: 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 mechanismHeightened 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) → vomitingVomiting 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 dysfunctionAutonomic 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 periodEpisodic attacks of intense nausea and vomiting lasting 1 hour to 10 days and occurring at least 1 week apartStereotypical pattern and symptomsVomiting at least 4 times per hour for at least 1 hour during attackReturn to baseline between episodesNot attributable to another disorder
  • Rome III criteria for adultsStereotypical onset (acute) and duration (<1 week) of vomiting episodes≥3 discrete episodes in the prior yearAbsence of nausea and vomiting between episodesSupporting criterion: history or family history of migraine headaches
  • Adult hallmarksProminence of epigastric or diffuse abdominal painIncreased prevalence of anxiety and depressionNormal or rapid gastric emptyingSuccessful 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 examHypoglycemia, 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 effectsCyproheptadine (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)AdjunctsTopiriramate: 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 q6-8hLorazepam: 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

  • ProphylacticPhenobarbital (79%): 2 to 3 mg/kg/dayErythromycin (75%): 20 mg/kg/day divided BID-TIDValproic acid (not calculated): 10 to 40 mg/kg/dayLevetiracetam: 500 to 3,000 mg daily (5)[A]Zonisamide: 100 to 700 mg daily (5)[A]
  • AbortiveHydromorphone: 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 doseDiphenhydramine: 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.