Consensus diagnostic criteria for cyclical vomiting syndrome (CVS) comprise (i) a history of three or more periods of intense, acute nausea, and unremitting vomiting lasting hours to days, with intervening symptom-free intervals, lasting weeks to months and (ii) exclusion of metabolic, gastrointestinal or central nervous system structural or biochemical disease (1). Individuals with specific physical etiologies (for example intestinal malrotation) are excluded although the distinction between functional and physical etiologies is becoming blurred in some areas. CVS affects children, typically aged 2-7 years, usually resolving in adolescence; it is described in older children and adults (2).
PHYSIOLOGY OF EMESIS
Three phases of emesis are recognized: A prodromal (pre-ejection) phase, an ejection phase with retching and vomiting and a post-ejection phase.
This phase, which may be short or absent, is characterized by the sensation of nausea and consistently associated with elevation of plasma vasopressin (ADH), sometimes to levels above those required for maximal antidiuresis and disturbed gastric antral myoelectrical activity (tachygastria). Other, probably secondary, endocrine changes include increased plasma concentrations of adrenaline, adrenocorticotrophic hormone (ACTH), growth hormone and prolactin. Autonomic nervous system mediated changes include sympathetically mediated tachycardia, cutaneous vasoconstriction and sweating (“cold sweating”), vagally mediated relaxation of the proximal stomach and salivation. Prior to the onset of retching a vagally mediated retrograde giant contraction originating in the lower small intestine sweeps small intestinal contents back into the stomach.
Retching usually precedes vomiting. The function of retching is unknown as are the factors which regulate the number of retches in a burst and whether a vomit follows retching. Vomiting is brought about by coordinated rhythmic contraction of the diaphragm, external intercostals and abdominal muscles, compressing the stomach and ejecting gastric contents through the mouth.
Relatively little is known about how normal bodily functions recover after an episode of emesis and what determines if and when one emetic episode is followed by another. This is of particular significance in CVS.
The autonomic and somatic motor components of retching and vomiting are coordinated in the brainstem and do not require more rostral regions of the brain (3). This contrasts with the subjective sensation of nausea which requires projection of the “emetic signal” to “higher” regions of the brain. The nucleus tractus solitarius (NTS) in the dorsal brainstem is implicated in the coordination of the emetic response and receives inputs from the vestibular system, area postrema and abdominal vagal afferents. There is evidence that these inputs interact and there is considerable clinical utility in the notion that the various emetogenic inputs into the NTS act cumulatively until a critical “emetic threshold” is exceeded and emesis is induced. In individuals the pathways may have different “set” levels of sensitivity determined genetically, developmentally or by previous experience. This framework can be used to explain both physical and functional causes of emesis. Examples include allergen induced release of local mediators within the foregut to activate 5-hydroxytryptamine3 (5-HT3), neurokinin1(NK1) and protease activated (PAR-2) receptors on vagal afferents in food allergy and direct inputs into the NTS by the vestibular apparatus in motion induced emesis (involving M3 and M5 cholinergic muscarinic receptors and histamine H1 receptors) (4).
CLINICAL FEATURE OF CVS
Up to 2% of children are affected by episodes of recurrent emesis with normality between episodes (5). In CVS vomiting reaches its highest intensity during the first hours of the attack. The duration and other characteristics of each vomiting episode vary considerably between individuals, although for each individual the general features of each attack are often stereotyped. In over 75% the onset of emesis is at a characteristic time of day (commonly in the night or early hours of the morning). A triggering factor is identifiable in 80% including infection (∼40%), psychologic stresses (∼35%), food products, including chocolate, cheese, and monosodium glutamate, physical exhaustion or lack of sleep (15-20%), atopic events (10-15%), motion sickness (∼10%), and menstruation (10-15%). Emesis is usually preceded by an apparently short prodrome with intense nausea and extreme pallor. During this period cortisol and ACTH levels are high and hypertension is common (6). The frequency and intensity of vomiting commonly peaks in the first hour after its onset (median frequency 6 times/hour) and declines over the ensuing 4-8 hours, the whole episode lasting a median of 41 hours, although occasionally days (7). Nausea remains intense and is not relieved by emesis. Abdominal pain is present in up to 80% of patients and maybe associated with fever and/or diarrhea (7). Other symptoms/signs may include abnormal posturing (Parkinsonian or fetal positioning), social withdrawal, lethargy which may be profound (patients may be unable to walk or talk, or may appear semi-comatose), pallor and excessive salivation. Rapid dehydration as a result of emesis is frequent; an associated potent antidiuretic stimulus is a consistent feature causing peripheral vasoconstriction and compounding hyponatraemia. The central neuropharmacology of this phase of CVS is incompletely understood.
Recent data point to maternal inheritance of CVS in a large percentage of cases and demonstrate mitochondrial DNA control region sequence variation in many affected individuals. Family studies document that mothers and sometimes maternal grandmothers of affected individuals have a higher incidences of migraine, depression or anxiety, irritable bowel and hypothyroidism (8). The much higher prevalence of migraine in families of children with CVS (∼82% vs 14% of controls) has recently been explained by the demonstration that mitochondrial DNA control region sequence variations seen in CVS are also prevalent in individuals with non-prodromic migraine (9).
INVESTIGATION OF CYCLICAL VOMITING
“Idiopathic” CVS is mimicked by a large variety of disorders; a systematic approach to the investigation of recurrent vomiting is necessary to exclude physical diseases which require disease specific treatment. The temporal pattern of emesis in non-CVS vomiting may differ from that seen in “idiopathic” CVS. Having less than 4 emeses per hour at peak and more than 2 episodes per week has been suggested to indicate chronic vomiting, as opposed to cyclical vomiting, and hence suggest other pathology (10). An algorithm illustrating the general approach to investigation is depicted in Figure 1.
Investigations should include (especially during a vomiting episode to pick up mild or intermittent defects) blood and urine screening for metabolic, endocrine and other disorders (electrolytes, pH, glucose, lactate, ammonia, amino acids, carnitine species, δ amino laevulinic acid, amylase; urinary ketones and organic acids, urine microscopy and culture), exclusion of anatomic problems with upper GI contrast studies and abdominal/renal ultrasound, and exclusion of clinically silent brainstem pathologies with cranial MRI. Exclusion of inflammatory pathologies of the GI tract by intestinal biopsy and formal exclusion of vestibular disease is worthwhile. These, and other, conditions modulate the sensitivity of the NTS to other pro-emetic stimuli and require treatment as appropriate.
TREATMENT OF IDIOPATHIC CVS
The approach depends upon the stage of the vomiting cycle (11). Management in stage I (between episodes) involves avoidance of/reducing the risk of precipitating factors. Examples include avoidance of foods known to induce a cycle and stress management where this is a precipitant. Pharmacological therapies might include agents which influence menstrual periods or motion sickness if these are implicated. Empiric trials of other preventative agents might include pizotifen, propranolol, amitryptilline, or clonidine. Emerging treatments include pyridoxine and 5-hydroxytryptophan.
Management in stage II (prodrome) may be limited by its short duration and by delayed gastric emptying which limits oral drug bioavailability. Acute use of agents which block 5HT3 receptors has aborted episodes in some individuals if administered in a form which gains access to the systemic circulation - for example sub-lingual, rectal or intravenous administration. Lorazepam may potentiate this effect. In individuals who experience a prodrome before the onset of gastric stasis the addition of a neurokinin 1 antagonist (an antagonist of the action of substance P at its receptor - for example Aprepitant©) and a glucocorticoid (dexamethasone) will be additive. Treatment of hypertension during this phase is imperative. Increasingly, nitroglycerin patches, administered transdermally, are being used with efficacious results.
Management of stage III (established vomiting) is both supportive (to actively manage fluid and electrolyte balance and to actively manage hypertension) and aimed at terminating the episode. Intravenous fluids are required in severe cases to correct electrolyte and water loss and prevent hypoglycaemia. Sustained high concentrations of circulating ADH in some individuals will render them at risk of fluid overload during IV therapy. Strict fluid balance monitoring and daily weights are therefore imperative. Monitoring of urine and blood osmolality will facilitate detection of SIADH.
Combined use of intravenous 5HT3 receptor blockade and a benzodiazepine (for example lorazepam) with or without IV dexamethasone may terminate an emetic episode. Both lorazepam and dexamethasone potentiate the anti-emetic efficacy of 5HT3 receptor blockade. Sumatriptan succinate, a 5-HT1D agonist might also be efficacious when administered intranasally or subcutaneously. Parenteral chlorpromazine is highly efficacious as it is both anti-emetic, antihypertensive and sedative, but it should not be given until IV rehydration is complete. It is customary to give IV histamine H2 blockers or proton pump inhibitors during this period to reduce gastric acid production. With the increasing implication of mitochondrial genomic events in CVS monitoring of acid-base balance and blood glucose is imperative.
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