Cyclic Vomiting Syndrome (CVS)

Definition

Recurrent self limited sterotypical vomiting episodes that reveal no etiology despite appropriate evaluation
NASPGHAN (must have the following to meet Dx)

5 or more episodes of vomiting ever or 3 or more episodes within 6mo
Sterotypical episodes with protracted nausea and vomiting lasting 1hr - 10 days
Minimum of 1wk with return to baseline between episodes
Episodes = Vomiting 4 or more times/hr for at least 1 hr
No other explanation for symptoms

Rome IV

2 or more periods of intense, unremitting vomiting and paroxysmal vomiting lasting hrs - days within 6 mo timeframe
Episodes are sterotypical for each patient
Episodes are seperated by weeks to months with return to baseline between episodes
No other explanation for symptoms despite appropriate medical evaluation

Background

Incidence

F>M (55:45)

Affects Whites >> Other Races

Median age of onset ~ 5yo (Dx usually confirmed after 2.6yrs)

Conditions seen with CVS:

Anxiety/depression
Constipation or irritable bowel syndrome
Postural orthostatic tachycardia syndrome (POTS)
Fatigue
Complex regional pain syndrome
Paroxysmal and daily nausea
Sleep disorders

Triggers

Stressors (vacations, outings, intercurrent illness, menstruation, fasting, and anxiety)
Fatigue and poor sleep
Infections like chronic sinusitis
Food triggers: MSG, chocolate, and aged cheese

Clinical Features

1. Pallor
2. Lethargy
3. Anorexia
4. Protracted and severe nausea
5. Abdominal pain
6. Mild-to-severe dehydration
7. Hyperesthesia and allodynia (pain from stimulus that should only cause sensation)
8. Excess salivation
9. Headache
10. Photosensitivity
11. Phonosensitivity

DDx

Gastrointestinal:

eosinophilic esophagitis
gastritis
chronic appendicitis
malrotation
pseudo-obstruction

Central nervous system:

brainstem neoplasm
Chiari malformation

Biliary:

biliary dyskinesia
recurrent pancreatitis
familial dysautonomia

Renal:

acute hydronephrosis from uteropelvic junction obstruction (Dietl crisis with flank pain)

Metabolic:

methylmalonic academia
partial ornithine transcarbamylase deficiency
medium-chain acyl-coenzyme A dehydrogenase deficiency
acute intermittent porphyria

Endocrine:

Addison disease
diabetes mellitus
pheochromocytoma

Diagnosis (target evaluation to avoid unnecessary testing)

In all children age 2-18yrs meeting criteria for CVS, obtain:

Electrolytes
BUN
Creatinine
Glucose

UGI series to r/o malro

Bilious vomiting, hematemesis, and abdominal tenderness:

Abd US/pelvis and esophagogastroduodenoscopy
ALT, GGT, and lipase (amylase also if during an episode)
Abd US during an acute episode in refractory cases to r/o Dietl Crisis

If attack is precipitated from Fasting, High Protein meal, or intercurrent illness:

Recommend metabolic testing prior to administration of IV fluids (serum glucose, electrolytes for anion gap, lactate, ammonia, carnitine, amino acids, urinary ketones, and organic acids)

Abnormal Neuro exam (profound altered mental status, motor asymmetry, abnormal gait/ataxia or eye movements)

MRI Brain + metabolic workup

Child <2yo

Metabolic and Neuro workup

Consider:

urinary delta-aminolevulinic acid
porphobilinogen (acute intermittent porphyria)
epinephrine
norepinephrine
urine catecholamines (pheochromocytoma)

Some experts use NextGen sequencing for mitochondrial mutations

SNP 16519 T and 3010A

Related nuclear genes -affecting mitochondrial function

RYR2

Treatment

No established guidelines, only expert opinion /concensus
Multidimensional approach

lifestyle modification
avoiding triggers
stress reduction
prophylactic medications
abortive/rescue medications during acute episodes

Prophylaxis

for patients with >1 episode /4 wks or severe episodes >2 days

Age <5yrs

1st Choice: cyproheptadine 0.25-0.5mg/kg/day div BID (or once QHS)

may increase sleepiness and increase appetite

2nd Choice: propranolol 0.25-1.0 mg/kg/day div 10mg BID or TID

Age >5yrs

1st Choice: Amitriptyline 0.25-0.5mg/kg nightly QHS and increase weekly by 5-10mg until 1.0-1.5mg/kg

Closely monitor corrected QT interval before starting the medication and 7-10days after reaching peak dose (or nortriptyline-liquid formulation)
may increase sleepiness, constipation, mood changes, and arrhythmias

2nd Choice: Propranolol 0.25-1.0mg/kg/day (mostly 10mg twice daily or 3 times daily)

Other options:

Anticonvulsants (recommend neurologist supervision):

phenobarbitol 2mg/kg QHS
Topiramate
Valproic acid
gabapentin
Levetiracetam

Mitochondrial supplements

Coenzyme q10 (10mg/kg/day div BID - Max = 300mg BID)
L-carnitine (50-100mg/kg/day div BID - Max = 1.5g BID)

Abortive Therapy

Antimigraine agents

Triptans (nasal or subcutaneous)
Antiemetics:

5HT3: ondansetron or granisetron (parenteral, rectal, topical)

NK1 antagonist - aprepitant

Analgesics: risk of converting from intermittent to chronic daily pattern

ketorolac (NSAID)
hydromorphone (narcotic)

Sedatives:

diphenhydramine
lorazepam
chlorazepam+diphenhydramine

Hydration

oral or IV (D10)

ER management

Individualized written protocol

Place child in quiet / dark room (avoid excess stimulation)
Monitor vitals closely (q4-6hrs)
Strict I/O's charted
Hydration

IVF D10 0.45NS+KCl @ 1.5 maintenance
Oral fluids as tolerated

Antiemetics: ondansetron 0.3mg/kg q6hrs IV
Analgesics: ketorolac 1.0mg/kg/dose <20mg every 8hrs IV

Criteria for inpatient admission

dehydration >5%
Intractable emesis
no urine output >12hrs
increased anion gap >18

If all inpatient Rx fails,

consider: IV dexamethasone or Dihydroergotamine (DHE) under expert supervision

Additional information

Pathophysiology

Not fully understood
Migraine Diathesis (>80%) - similar response to migraine therapy in most patients

Hypothesized that CVS, Abdominal Migraine, and Migraine Headaches may represent age dependent phases of migraine diathesis with median age of onset as follows

CVS - 5yrs
Abd migraine - 9yrs
Migraine Headaches -11yrs

Autonomic dysfunction

increased sympathetic and normal parasympathetic tone
Assoc w/ POTS

Mitochondrial dysfunction

increased lactic acid with episodes
Mitochondrial mutations associated with CVS, 16519T and 3010A

Brain - Gut (increased hypothalamic-pituitary-adrenal axis) hypothesis: SATO variant and Corticotrophin releasing factor (inhibits foregut)
Food Sensitivity: elimination of food allergens has shown improvement in some patients
Hormonal: response of hormonally sensitive catamenial CVS to low-dose estrogen or medroxyprogesterone injection

SATO variant

Varient of CVS. Surge in hypothalamic axis associated with hypertension abd elevated adrenocorticotropic hormone, ADH, cortisol, and catecholamine levels

References:

Chelimsky TC, Chelimsky GG. Autonomic abnormalities in cyclic vomiting syndrome. J Pediatr Gastroenterol Nutr. 2007;44:326-330.
Li B, 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;47:379-393.
Li B, Williams SE. Cyclic vomiting syndrome: clinical features and comorbidities. Contemp Pediatr. 2012;29:34.Li B, Kovacic K. Vomiting and nausea. In: Wyllie R, Hyams JS, and Kay M, eds. Pediatric Gastrointestinal and Liver Disease, 5th ed. Philadelphia, PA: Elsevier; 2016, pp. 84-103.
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. Pediatr Neurol.2014;50:569-573.
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.