Cyclic Vomiting Syndrome

NASPGHAN

1. At least five attacks in any interval, or a minimum of three attacks during a 6-month period

2. Episodic attacks of intense nausea and vomiting lasting 1 h–10 days and occurring at least 1 week apart

3. Stereotypical pattern and symptoms in the individual patient

4. Vomiting during attacks occurs at least 4 times/h for at least 1 h

5. Return to baseline health between episodes

6. Not attributed to another disorder

Rome III

1. Two or more periods of intense nausea and unremitting vomiting or retching lasting hours to days

2. Return to usual state of health lasting weeks to months

All respective criteria must be met to meet consensus definitions for both NASPGHAN and Rome III

The continuum between CVS and migraine was suggested by Whitney in 1898 and corroborated by other authors including us in 1998 [4, 5]. In a cross-sectional school survey in Scotland, Abu-Arafeh described a developmental progression from CVS to abdominal migraine and migraine headaches (median ages 5, 9, and 11 years, prevalences 1.9, 4, and 11 %, respectively) [6]. This suggestion of a natural history that begins with CVS and ends with migraines reproduces initial reports by Barlow in 1984 who labeled this progression as the “periodic syndrome” [7]. Although some experience all three phases, the majority trade CVS for migraines by age 10. We estimate that 75 % will develop migraine headaches by age 18 years.

The lack of a specific The International Classification of Diseases (ICD) 9 code and use of persistent vomiting (536.2) have hindered establishment of the true prevalence of CVS. ICD 10 will have a specific code and enable proper epidemiologic surveys. Typical misdiagnoses, including gastroenteritis, gastroesophageal reflux, food poisoning, and eating disorders, often delay accurate diagnosis by a median 2.6 years. In our consecutive series, CVS was second only to gastroesophageal reflux as a cause of recurrent vomiting [8]. Two school-based surveys (not clinical exam) estimated the frequency to be 2 % in Scottish and Turkish children, and the incidence of new cases of CVS was reported to be 3.15 per 100,000 children per year in Irish children [6, 9]. In our series, the average age of onset of CVS is 4.8 years, with a predominance in girls over boys (57:43; Table 25.2).

Table 25.2

Epidemiology and demographics. (Sunku and Li [3], with kind permission from Springer Science + Business Media)

Features
Age of onset	4.8 years
Delay in diagnosis	2.6 years
Prevalence	2 %
Incidence	3.15/100,000
Female to male ratio	57:43
Migraine association	39–87 %

Recently, pathophysiologic connections have been made with mitochondrial disease, autonomic dysfunction and the stress response. Current research, including our own, is focused on the identification of neuroendocrine mechanisms mediating vomiting in these patients.

Cyclic Versus Chronic Patterns of Vomiting

An important clinical clue to the diagnosis of CVS is the pattern of vomiting. Based on temporal pattern, children with recurrent vomiting can be delineated into cyclic and chronic groups . The cyclic group has an intense, but intermittent pattern of vomiting with peak emesis of ≥ 4/h and ≤ 2 episodes per week [10]. The chronic group has a low-grade, daily pattern of emesis with < 4 emesis/h and > 2 episodes per week [10]. Two thirds of all children with recurrent vomiting fit into the chronic or continuous pattern of vomiting. These children rarely appear acutely ill or become dehydrated. Conversely, the cyclic pattern is associated with more intense vomiting and affected children more often require IV hydration (62 vs. 18 %) compared with the chronic group [8] (Table 25.3).

Table 25.3

Characteristics of chronic and cyclic vomiting. (Reprinted with permission from Ref. [11], Table 20.3, p. 292)

	Chronic pattern	Cyclic pattern
Time of onset	Daytime	Nighttime or early morning
Peak number of emeses/h	< 4 emeses	≥ 4 emeses
Frequency of recurrence	> 2 episodes/week	≤ 2 episodes/week, typically 2–4 weeks
Family history of migraine	Uncommon (14 %)	Common (82 %)
Ill-appearing	No	Yes (pale, lethargic)
Headaches	Infrequent (19 %)	More frequent (41 %)
Photophobia	Infrequent (4 %)	More frequent (18 %)
Vertigo	Infrequent (7 %)	More frequent (24 %)
Intravenous hydration	Uncommon (18 %)	Common (58 %)
Esophagitis on EGD	Common (59 %)	Uncommon (15 %)

EGD esophagogastroduodenoscopy

These two patterns are also important because both of these groups differ in symptom and diagnostic profile. In those with the cyclical vomiting pattern, non-GI disorders including neurologic (including abdominal migraine) , renal, endocrine, and metabolic ones predominate over GI disorders by a ratio of 5:1 [10, 12]. In contrast, in the chronic group, GI disorders (mostly peptic disease) predominate over non-GI causes for vomiting by a ratio of 7:1 [10, 12] (Table 25.4). This implies the need to center the diagnostic work-up on extraintestinal disorders in children who present with the cyclic vomiting pattern, while on upper GI (UGI) tract disorders in the chronic vomiting pattern .

Table 25.4

Differential diagnosis of cyclic vomiting. ([11], Table 20.4, p. 293)

	Chronic pattern	Cyclic pattern
Gastrointestinal	Peptic injury (GERD esophagitis, gastritis, duodenitis)	Anatomic (malrotation, volvulus, duplication cyst)
	Eosinophilic gastroenteritis/esophagitis
	Celiac disease
	Giardiasis
	Inflammatory bowel disease	Pseudo-obstruction
		Cholelithiasis/gallbladder dyskinesia
	Chronic appendicitis
	Pancreatitis
Infectious	Chronic sinusitis	Sinusitis/other infections may be a trigger
Genitourinary	Pyelonephritis, pregnancy	Acute hydronephrosis due to uretopelvic junction obstruction or stones
Metabolic	Rare	Mitochondrial disorders (MELAS)
		Organic acidemias
		Aminoacidurias
		Fatty acid oxidation defects
		Urea cycle defects
		Acute intermittent porphyria
Endocrine	Adrenal hyperplasia	Addison’s disease
		Diabetic ketoacidosis
		Pheochromocytoma
Neurological	Chiari malformation	CVS, migraine (headaches/abdominal)
	Subtentorial neoplasm	Familial dysautonomia
Psychiatric	Münchausen by proxy (rare)	Münchausen by proxy (rare)
	Functional vomiting	Bulimia nervosa

GERD gastroesophageal reflux disease, CVS cyclic vomiting syndrome, MELAS mitochondrial encephalomyopathy, lactic acidosis, and stroke

Clinical Patterns

CVS has a distinctive on–off temporal pattern of vomiting that serves as an essential criterion for diagnosis. CVS is distinguished by the “on” pattern of discrete, recurrent, and severe episodes of vomiting that are stereotypical within the individual as to time of onset (usually early morning), duration (hours or days), and symptomatology (pallor, listlessness). The “off” pattern occurs during week- or month-long intervals when the child resumes completely normal or baseline health (e.g., if there is other chronic disease), although 12 % may have interepisodic symptoms of daily nausea and/or mild vomiting [12]. During the episodes, the most common symptoms are listlessness (93 %) and pallor (91 %) and others include low-grade fever or hypothermia, intermittent flushing, diaphoresis, drooling, and diarrhea. Although found in significantly higher frequency than in patients with GI disorders (gastroesophageal reflux disease, GERD), fewer than half have migraine features of headache, photophobia, and phonophobia.

The duration of episodes generally ranges from hours to days with a median duration of 27 h. Episodes are always self-limited despite a few that may last longer than 1 week. Forty-nine percent of patients have “cyclic” intervals predictable within a week, most commonly 4 weeks, and the remainder have “sporadic,” unpredictable attacks. Forty-two percent have onset of their episodes early morning or upon awakening (1–8 a.m). Many have a remarkably rapid onset (1.5 h) and resolution (6 h) from the last emesis to the point of being able to eat and be playful. The 67 % with a prodrome have pre-emesis pallor, diaphoresis, abdominal pain, and headache, but rarely visual disturbances of a classical migraine aura.

The vomiting in CVS is uniquely rapid fire and peaks at a median frequency of 6 times an hour and 15 times per episode. The vomiting is typically projectile and contains bile (80 %), mucus, and occasionally blood, the latter usually the result of prolapse gastropathy. The bilious nature often raises concern for an obstructive lesion. The intense nausea differs from that in emesis from GI disorders in that it persists even after complete evacuation of gastric contents as if independent of gastric feedback. Many describe nausea as the most distressing symptom, only relieved during sleep. Due to the unrelenting nausea, during episodes, these children appear much more debilitated when compared to those with gastroenteritis, often curled into a fetal position, listless, and withdrawn to the point of being unable to walk or interact. Anorexia, nausea, midline abdominal pain, and retching are the most common GI symptoms.

Certain unusual observed behaviors during CVS episodes can raise questions about an underlying psychiatric disorder. There are children who drink compulsively and then vomit and describe that that maneuver dilutes the bitter bile and aids in evacuating it. Others take prolonged, scalding hot showers or baths until the hot water supply is exhausted. Nearly all turn their rooms into a darkened cave in order to avoid lights and sounds that trigger more nausea. Many are hyperesthetic to motion, odor, taste, and even to parental touch and attempt to shut out all external stimuli.

Various recurring stressors are recognized to precipitate CVS episodes in 76 % of patients. These include psychological (44 %), infectious (31 %), and physical triggers. The psychological stress is more often of an excitatory nature such as holidays, birthdays, outings, and vacations. Episodes may be triggered by various infections including upper respiratory infections, sinusitis, strep throat, and flu. The largest fraction (32 %) has a seasonal clustering of episodes with more during the winter and fewer during the summer. Although this pattern correlates with the school year, we can only speculate that less school-related stress, less exposure to infections, and longer duration of sleep helps. Dietary factors include foods rich in amines, aged cheese, chocolate, monosodium glutamate, and fluctuating caffeine intake (23 %). Lack of sleep from excess physical exhaustion from travel, sports, sleepovers, or a sleep disorder (24 %), and menses (catemenial CVS—22 %) are also common inciting events. Environmental triggers include changes in barometric pressures in weather fronts. One subgroup with a precisely timed interval every 60 days (predictable within a week) and an absence of identifiable triggers is especially refractory to therapy.

Pathophysiology

In the absence of a defined etiopathogenesis, CVS remains classified as an idiopathic disorder. Recent investigations support the contributory roles of mitochondrial DNA (mtDNA) mutations and dysfunction, hypothalamic–pituitary–adrenal (HPA) axis activation, and autonomic nervous system (ANS) dysfunction. CVS is a functional brain–gut disorder perhaps mediated through altered brain stem modulation of effector signals.

Mitochondrial Dysfunction

In two series, a striking maternal inheritance pattern was recognized for migraines in 64 and 54 % of probands with CVS [13, 14]. Evidence of mitochondrial dysfunction was first provided using nuclear magnetic resonance (NMR) to establish decreased ATP production in peripheral muscle in migraineurs [15]. This mitochondrial pathogenesis gained substantial support following the recent identification of two tandem mtDNA polymorphisms, 16519T and 3010A with impressive odds ratios of 17 and 15 in CVS and migraine in haplotype H, respectively [16]. Because the mutations are found in the control region rather than the enzyme sequence, the structure to function relationship is unclear. However, elevated lactate, ketones, and Krebs cycle intermediates during the early part of the attacks are consistent with mitochondrial dysfunction. In addition, clinical trials and open-label experience show promising effects of mitochondrial supplements coenzyme Q10, l-carnitine, and riboflavin in the treatment of migraines and CVS in children [17, 18].

Neuroendocrine

Stressors, both psychological (excitement, panic) and physical (fever, lack of sleep), are common triggers of attacks of CVS. An activated HPA axis during episodes of CVS was first described by Wolfe, Adler, and later in greater detail by Sato. They documented elevated levels of adrenocorticotropic hormone (ACTH), antidiuretic hormone, cortisol, catecholamines, and prostaglandin E2 [19, 20]. This finding may partially explain the symptoms of hypertension and profound lethargy in this subset of patients. Attenuation of CVS symptoms occurred after use of high-dose dexamethasone by Wolfe and Adler and indomethacin and clonidine by Sato et al. [21].

These findings have focused attention upon one potential role of corticotropin-releasing factor (CRF) as a brain–gut neuroendocrine mediator of foregut motility. Taché et al. have shown that psychological or physiologic stressors induce CRF release from the hypothalamus which stimulates inhibitory motor neurons via CRF-R2 receptors in the dorsal motor nucleus of the vagus that delays gastric emptying, independent of downstream effects of ACTH and cortisol secretion [22]. Preliminary data demonstrate increased peripheral CRF levels during episodes of CVS, but whether this acts to trigger emesis or occurs in response to the stress of the illness is not clear. The new entity of cannabis-induced hyperemesis syndrome which probably represents a variant of CVS raises the possibility that the endocannabinoid system plays a role in CVS. CB1 receptor activation attenuates the stress response and reduces nausea and increases the appetite well-known effects of tetrahydrocannabinol (THC). Interestingly, a growing number of case reports suggest that frequent high dose use may alter the ligand–receptor relationship and result in a cannabis-triggered CVS [23]. This unique response suggests that in some patients altered endocannabinoid signaling may trigger attacks. Conversely, there may be therapeutic potential in other CB1 receptor agonists.

Autonomic Dysfunction

Most of the prominent symptoms of CVS are expressed through the ANS. The peripheral vasoconstriction, hypersalivation, diaphoresis, tachycardia, and listlessness are prominent manifestations of nausea that persist throughout the episode typically unrelieved by evacuation of the stomach. Chelminsky reported autonomic dysfunction in the form of postural orthostatic tachycardia syndrome (POTS) was identified on a small series of children with CVS recently [24]. They noted that treatment of the POTS appeared to help reduce the frequency of CVS episodes. We recently found an overall prevalence of POTS in 19 % our CVS patients, and when we limited the cohort to adolescents > 11 years in whom POTS is known to be more common, the rate was 38 %.

Four formal studies of the ANS function in children and adults with CVS reveal a consistent pattern of heightened sympathetic tone with normal parasympathetic tone [24]. Interestingly, studies of gastric emptying in adults reveal rapid emptying when well. However, whether this finding extends to children is unknown.

Subtypes of CVS and Comorbidities

Migraines

An association with migraines was identified over a century ago [4, 25] . The current association occurs in 83 % of those with CVS who have a positive family history of migraines or migraines themselves. In addition, there is a progression from CVS to migraine headaches with advancing adolescent age. In the absence of definitive diagnostic tests for migraines and CVS, strong link is further supported by similar symptomatology (e.g., pallor, lethargy, nausea, photophobia, phonophobia) and positive responses in both groups to anti-migraine therapy. These migraine-associated CVS patients generally have milder episodes, a greater association with psychological stress, and significantly higher response rates to anti-migraine therapy (79 vs. 36 %) [26, 27].

Sumatriptan (a selective 1B/1D serotonin agonist) is one anti-migraine drug that can abort episodes if administered early on especially via the nasal route (52 %). This action on serotonin receptors with similar rates of response to patients with migraine headaches suggests a central role of action presumably by decreasing cerebrovascular dilatation. Until we have a clearer delineation of mechanisms involved in migraine and CVS, we cannot be certain if the CVS patients who do not fit under the migraine umbrella have dissimilar pathophysiologic cascades.

CVS +

In Boles’ series, 25 % had coexisting neurological findings of developmental delay, seizures, hypotonia, and skeletal myopathy as well as cognitive and cranial nerve dysfunction [28]. These children classified as CVS+ were found to have an earlier age of onset for CVS and a threefold- to eightfold-higher prevalence of dysautonomic (neurovascular dystrophy) and constitutional (growth retardation) manifestations than CVS patients without neurological findings.

Cannabis

There is a group of adolescents and adults with CVS who use marijuana to alleviate nausea and vomiting that instead may aggravate CVS symptoms , and has been labeled as cannabis-induced hyperemesis. It is more likely cannabis-triggered CVS [23]. There are now more than 100 patients described, mostly young males and heavy users over several years. One series of nine patients reports termination of bouts of emesis after cessation of chronic use of marijuana with exacerbation upon resumption of smoking cannabis.

< div class='tao-gold-member'>

Only gold members can continue reading. Log In or Register to continue