Landscape of cyclic vomiting syndrome: from bedside to bench, past to present

Abstract

Investigations into mechanisms of cyclic(al) vomiting syndrome (CVS) began at the bedside more than a century ago. The modern era started with the formation of the Cyclic Vomiting Syndrome Association in 1993 that helped initiate robust efforts in education, advocacy, family-physician conferences, scientific symposia, dedicated clinical programs, therapeutic guidelines and research. Even today, bedside clues continue to emerge with the recent description of cannabinoid hyperemesis syndrome (CHS) and subsequent evidence of a perturbed endocannabinoid system. The clinical picture of CVS has evolved from that of a straightforward emetic disorder related to migraine requiring short-term antiemetics or prophylactic anti-migraine therapy, to a complicated, heterogenous one with multiple comorbid associations (anxiety, dysautonomia) and endophenotypes (migraine, Sato, CHS). This expanded view has important therapeutic implications which necessitates managing the comorbidities which can in turn impact the disease itself and proffered promising evidence that behavioral management (meditation) and vagal neuromodulation appear efficacious with few untoward effects, perhaps by reestablishing autonomic (parasympathetic) balance. The pathophysiologic picture now appears to be inscribed on an autonomic polyvagal design but multiple additional pathways interact, some confirmed (NK1, CB1, HPA axis, PPM1D gene, biological calendar, estrogen), and others, possible (TRPV-1, CGRP, GDF-15, mitochondrial dysfunction, impaired cation transport). CVS and its cousin CHS continue to challenge clinicians and perplex investigators and in the current era require not only a critical mass of specific pathway expertise but also syncretic biopsychosocial thinking to integrate these disparate threads. We may have reached such a tipping point at this Symposium.

Introduction

The history of investigation into potential mechanisms of cyclic(al) vomiting syndrome began from bedside observations of its puzzling presentation. Consequently, clinicians throughout the 20^th century viewed the disorder through their own rose-colored glasses, variably considering cyclic vomiting syndrome (CVS) as a migraine, epileptic, metabolic, psychological or autonomic disorder [1]. Even today, new clues to pathophysiology continue to emerge from the bedside. For example, the advent a CVS-type illness following prolonged daily recreational use of cannabis has implicated the endocannabinoid system, likely altered CB1 receptor physiology and CN1 polymorphisms. Hence, the bedside vantagepoint continues to be a wellspring of potential mechanistic insights. We review the history of investigative efforts as the backstory, reprise the salient clinical features that have spurred past and current pathophysiologic thinking, and provide an up-to-date picture in 2024.

History

What is now known as CVS was initially described by Heberden in French in 1806 and the seminal and still apt description was recorded by Samuel Gee in English in 1882 at St. Barthomew’s Hospital in central London [2]. The 19^th Century encompassed the most famous, then undiagnosed, sufferer and ‘survivor’ in history, namely Charles Darwin [3–4]. Over the next 110 years, sporadic articles variably considered it to be a ‘periodic’ migraine manifestation, metabolic ‘ketonemic’ vomiting, neurologic ‘abdominal migraine’ or ‘abdominal epilepsy’, psychogenic ‘gastric neurosis’ and disorder of autonomic function [1]. In 1993, David Fleisher characterized the phenomenology in a large series of 71 pediatric patients [5]. That same year, Kathleen Adams RN (see Dedication), the parent of an affected child, founded the Cyclic Vomiting Syndrome Association in the US with David Fleisher and B U.K. Li as initial medical advisors. Ms. Adams many-fold efforts ushered in the current era of progress through patient education and support, biannual family-professional conferences, concerted advocacy, and extensive collaboration with academic physicians (Table 1).

Table 1.

Recent clinical and research progress in CVS

1993	Formation of Cyclic Vomiting Syndrome Association (K Adams, D Fleisher, BUK Li)
1993	Detailed description of 71 pediatric CVS cases (D Fleisher)
1994-5	International Symposium and Proceedings in J Pediatr Gastroenterol Nutr (BUK Li, ed.)
1998-9	2nd International Symposium and Proceedings in Dig Dis Sci (BUK Li, RM Issenman, SK Sarna eds.)
2004	First report of cannabinoid hyperemesis syndrome (JH Allen et al.)
2005	First description of 41 adult CVS cases (D. Fleisher et al.)
2006-8	First conference and clinical review of adult CVS (T. Abell et al.)
2008	Consensus Statement on the Diagnosis and Management of Pediatric CVS (B U.K. Li et al.)
2019	Guidelines on the Management of CVS in Adults (T. Venkatesan et al.)
2022-4	3rd International Symposium and Proceedings in Neurogastroenterol Motil (T. Venkatesan, BUK Li eds.)
2024	NASPGHAN 2024 Guidelines for management of cyclic vomiting syndrome. (K. Karrento et al.)

Prior to 1993, occasional published reports on CVS appeared less than annually. In 1994, we assembled those who had published on CVS or abdominal migraine at the First International Symposium on CVS in London in order to define diagnostic criteria, characterize phenomenology, review treatment and establish the diagnostic label – cyclic(al) vomiting syndrome [6]. Within two years of publication of the Proceedings, the first mentions of CVS occurred at national North American Society of Pediatric Gastroenterology Hepatology and Nutrition (NASPGHAN) and American Gastroenterological Association conferences and led to talks and sessions. In 1998, the Second Symposium brought together diverse clinical experts and basic scientists (most unfamiliar with CVS) to brainstorm, representing central mediation of emesis, migraine, gastrointestinal motility, autonomic nervous system, neuroendocrinology (corticotrophin releasing hormone, anti-diuretic hormone), mitochondrial metabolism, serotonin receptor pharmacology, and channelopathies. The resulting collaboration resulted in two funded R21 National Institutes of Health grants and a steady rise in annual publications (Figure 1) [7].

Figure 1. Increase in literature on CVS and CHS since 1993.

CVS and its cousin cannabinoid hyperemesis syndrome (CHS) remain perplexing without a delineated pathophysiology or trial-tested therapies. Despite those challenges, substantial progress has been made over the past 30 years. We established the first dedicated, multidisciplinary pediatric CVS program including gastroenterology, nursing, psychology and neurology at Children’s (now Lurie) Memorial Hospital in Chicago in 2001. The Consensus Statement (guidelines) on diagnosis and treatment of pediatric CVS was published in 2008 [8]. Recognition of CVS in adults led to an inaugural conference and a published scientific review in adults and the founding first dedicated, multidisciplinary adult program all at the Medical College of Wisconsin at Milwaukee in 2006 [9,10]. CHS was first described in 2004 and relevant annual publications now equal in number those on CVS (Figure 1) [11]. Publication of the first adult treatment guidelines in 2019 fast forwards us to these Proceedings of the Third International Symposium on CVS and CHS [12]. Update of the pediatric guidelines on diagnosis and treatment of CVS and revision of the Rome V diagnostic criteria for CVS and CHS will be completed in 2025 and 2026 respectively [13].

Just as we brought clinicians, clinical/translational and basic scientists together at the Second International Symposium, we followed the same broad-based multidisciplinary format to the Third International Symposium on CVS and CHS held in Columbus, Ohio in 2022 which was supported in part by an NIH R-13 grant. The plethora of experts represent the diverse aspects of the gut-brain network in both CVS and CHS: central mediation of emesis, endocannabinoid system, migraine pathways, autonomic regulation of the GI tract, functional imaging and transcranial mapping, sleep disorders, biobehavioral responses and the polyvagal platform.

Bedside clues to potential mechanisms

We review salient features of the clinical presentation that continue to provide numerous, sometimes befuddling, clues from which to pursue pathophysiology and treatment. We have divided these bedside clues into Clinical Characteristics, Clinical Course and Clinical Endophenotypes (Table 2).

Table 2.

Bedside clues to potential mechanisms

Category	Clinical manifestation	Potential mechanism/implication
Clinical patterns
Temporal patterns	cyclic	unknown biological calendar
	sporadic	stress-triggered episodes
	early morning onset	CRH-based circadian susceptibility?
Acute symptoms	pallor, lethargy, ↑ HR, salivation	maximally aroused nausea state
	persistent retching on empty stomach centrally-driven, PAG-mediated?
	hot water bathing behavior	TRPV-1 antiemetic response
Age of onset	pediatric-onset ~ 5 years	may resolve, but progresses to migraine
	adolescent-onset 11-18 years	more likely to extend into adulthood
	adult-onset ~ 35 years	longer episodes, ↑interictal symptoms
Triggers	psychological/physiological stressors	possibly CRH-mediated
Clinical subtypes
Migraine-related	family history in ∼ 80% children progression from CVS to migraines	largest subgroup, CGRP effective? developmental progression – pubertal?
Epilepsy	nonspecific EEG findings Panayiotopolous Syndrome	CVS responds to anticonvulsants overlap, possible misdiagnosis
Dysautonomic	acute autonomic symptoms progression to CVS + nausea/POTS	↑ sympathetic drive
		↓ parasympathetic control (↓ vagal efficiency) vagal neuromodulation appears effective
Comorbid anxiety	affects > 50%	CBT and meditation appear effective
	panic anxiety may trigger episodes	elicits sympathetic response
CVS+	neurodevelopmental delay	newly-described Jansen-de Vries syndrome
Mitochondrial	fatigue, mt supplements help	mtDNA SNPs, but exact mechanism unknown
Sato-variant	hypertension + ↑↑ HPA axis	hypothalamic surge, most severe subtype
Catamenial	with onset of menses	sensitivity to rapid estrogen decline
Cannabinoid hyperemesis risk	prolonged cannabis exposure	↓ CB1R numbers, CNR1 polymorphisms →↑ CVS
	hot water bathing helps	TRPV-1 mediated anti-emetic effect
	topical capsaicin helps	TRPV-1 mediated anti-emetic effect

Clinical characteristics

- High intensity vomiting and retching

Recurring discrete bouts of emesis remain the core feature of CVS. What is unusual is its high peak frequency of 6–12 emeses per hour (every 5–10 min), an unmatched pace that can continue for hours [14]. For the clinician, each individual acute bout with vomiting (100%) and diarrhea (30%) may mimic acute gastroenteritis or Bacillus cereus poisoning for which it is often misdiagnosed. The salient clinical question is ‘has this occurred before’ usually goes unasked and the repetitive pattern is missed. Once the gastric contents are emptied, the guttural retching can persist at a similar frequency that indicates the originating locus is central rather than gastric. That nearly all parents (98%) recognize their child’s episodes to be stereotypical as time of onset, duration, associated symptoms, in the absence of concomitantly ill family members, supports an endogenous rather than exogenous (e.g. viral) source.

If the penultimate causal defect is central, then where? Welch, extrapolating from nuclear magnetic resonance studies in migraine, proposed the periacqueductal grey area as a potential site of aberrant regulation of descending autonomic (vagal) efferent signals to the proximal gut [15]. Andrews and Levinthal have both proposed that the hypothetical emetic threshold is reduced by susceptibilities and acute and chronic stressors that permit the vomiting and retching to feed forward in a highly dysfunctional manner [16,17].

- Cyclic vs. sporadic episodes

Despite the name ‘cyclic’ or ‘cyclical’, only half of affected children have predictable intervals between cycles. The other half have unpredictable or sporadic episodes that are more often triggered by physiologic (infection, sleep deprivation) or psychological (birthday excitement, family disruption) perturbations. In the ‘cyclic’ or regularly cycled group, the most common interval is monthly even in boys and premenarchal girls [18]. There is a cyclic subgroup, nick-named ‘long-cycle calendar-timed’, that has unusually long yet precise intervals > 1 month (e.g. 63 days) that suggests an internal biological calendar. However, it remains unclear where a calendar of such lengthened cycles resides. See section on Triggering Events below.

- Early morning onset

The most common time of episode onset is in the early morning hours or upon awakening, not unlike migraines and epilepsy. This timing suggests either a relationship to the sleep-related cycles (e.g. REM), disrupted sleep patterns, or even to hypnagogic states. Sleep hygiene has been used to as a lifestyle modification in both migraines and CVS. Taché raised the possibility that central corticotropin-releasing hormone (CRH), which has a circadian peak in the early morning hours, acts either as a susceptibility factor or trigger [19]. CRH is secreted in response physical or behavioral stressors inhibits upper gut motility via CRH-R2 and enhances distal gut motility via CRH-R1, both symptoms found in CVS. Peripheral CRH levels have been found in higher concentrations during CVS episodes but whether of central or peripheral origin remains unclear [20]

- Episode symptoms

Acute episodes of CVS, in addition to core gastrointestinal symptoms nausea (72%), vomiting (100%), abdominal pain (80%) and diarrhea (28%), have a plethora of autonomic symptoms including pallor (87%), lethargy (91%), tachycardia, hypothermia, mydriasis, hypersalivation, [1]. Many patients report the nausea as unabating, even more troublesome than vomiting, without the usual temporary relief following emesis, ending only as the entire episode ends. Severe listlessness and incapacitation often render patients in so-called ‘conscious coma’ but in fact they can hear, despite being unable to walk or respond verbally. In episodes, children may have to be carried by their parents and adults may have to crawl to reach the commode to vomit. Whether this state of heightened autonomic arousal or storm represents a synergistic accumulation of stimulatory input or the effects of allostatic adaption to chronic stress or a specific inborn error of autonomic regulation is unknown and is discussed further under Dysautonomia below.

- Hot water bathing behavior

CVS and CHS episodes are both accompanied by unusual hot water bathing (hydrotherapy) behavior used for temporary (onset and offset within 10 minutes) symptomatic relief of nausea and vomiting [21]. One resourceful family, recognizing that their hot water tank lasted only an hour, resorted to checking into a hotel each time with its inexhaustible supply. This predilection for very hot water is no longer considered a pathognomonic feature CHS as half (48%) of adults as well as children with CVS also manifest this behavior [22]. Interestingly, in acute emetic attacks in CHS, temporary symptomatic relief can also be achieved with topically-applied capsaicin [23,24]. Water temperatures > 43C activate TRPV-1 receptors which not only mediate nocioception but can also act as a central antiemetic. This temperature is within the upper tolerable range. Interestingly, both TRPV-1 and CBR1 receptors are co-localized on the same afferent neurons, and although the respective ligands do not cross-react with the other receptor, both may interact in these emetic disorders. [25]

Clinical course

- Three ages of onset

There appears to be three overlapping ages of onset of CVS: pediatric-onset (median age 5), adolescent-onset (11–18) and adult-onset (mid 30’s) that may differ in natural history, outcome and possibly in pathophysiology. CVS can even begin in infancy (2%) and after age 70. The pediatric and adult-onset patterns appear to have two major differences: affected children are less likely to have coalescent (interictal) symptoms than adults (12% vs. 36%) and have much shorter episodes (2 vs 6 days) [1,9]. Episode duration appears to lengthen as the child ages into adulthood: from 1.8 to 2.3 to 2.9 days in infant/toddler, childhood and adolescent, and longer in adults [26]. Although most children outgrow CVS during adolescence, by age 18 approximately 75% are predicted to develop migraines in a developmental tradeoff [1,27]. A similar developmental pattern observed when motion sickness abates at the onset of puberty and migraines begin [28]

Although the teenage-onset group is less well characterized, some insight has been gained from delineation of adult CVS into two groups: pediatric-onset and adult onset. In a large series (n=101), one-third (29%) began before age 18 (average 13.4 years) suggesting that those beginning during adolescence may be at higher risk for persistence into adulthood [29]. Those with childhood onset were more likely female, had a greater delay in diagnosis but were less likely to develop chronic opioid or tobacco use. Mitochondrial SNPs found in children were less common in adults, suggesting that the other pathophysiologic factors may be involved [30–32].

- Triggering events

In both children and adults with CVS, most can identify episode triggers including both behavioral and physiologic stressors. In children, 76% of parents most often identify a trigger; most often a stressor (51%), which can be either noxious (53%) or positive excitement (47%). Others include infections (37%), fatigue (30%), dietary (18%) and menses in 22% of post-menarcheal girls [5,33]. In adults, 63–87% report specific triggers including noxious stress (67–69%), excitement stress (50–59%), menses (70%), infection (15%) and anticipatory or panic anxiety (17%) [9,29]. In the sporadically occurring CVS, all such events become afferent input into the stress cascade but whether directly activating CRH or whether the theoretical emetic threshold is lower by other factors such as CNR1 polymorphisms, cellular energy deficits, or impaired parasympathetic control is unclear. Cannabis is discussed below in Cannabis-triggered CVS

- Comorbid conditions

Two decades ago, CVS was viewed simply as a recurrent emetic disorder, which between episodes, one returned to normal health. That clinical picture has changed dramatically as recent studies in both children and adults have revealed a plethora of interictal co-morbid conditions that profoundly affect quality of life (QoL). In school-aged children, anxiety (59%) and depression (14%) are especially prominent [34]. Other comorbid symptoms include chronic fatigue or limited stamina (52%), sleep disturbances (48%), constipation or irritable bowel syndrome (41%), functional daily nausea (12–18%), postural orthostatic syndrome (14% overall or 38% of tested adolescents and complex regional pain syndrome (10%) [35]. Adults also have prevalent comorbid anxiety (47%) and depression (49%), migraine (43–70% self, 57–64% familial) POTS in 35% of adults) and dysautonomia (14%) [9,29,36]. In children, co-morbid anxiety and coping ability anxiety is the strongest determinant of quality of life (QoL) even more than the quantitative severity of episodes! [37]. These comorbid associations in CVS are not unlike psychiatric comorbidities also documented in adults with DGBIs [38].

- Iatrogenesis

For clinicians, there are two cautionary tales in CVS, often repeated over testing and unneeded surgical procedures. Until the first Consensus Statement on pediatric diagnosis in 2008, the standard approach was to complete an exhaustive wide-ranging evaluation to exclude GI (radiographic, endoscopic), neurologic (radiographic, EEG), renal (radiographic), metabolic and endocrine (serum) causes of vomiting despite the low yield. In our initial series three decades ago, 12% of those with an ‘cyclic’ vomiting patten were found to have an underlying disorder whereas more recently after diagnostic criteria were established, only 4% had a change in management resulting from an extensive evaluation costing $6,125 per patient [39,40]. Amongst 41 adults, invasive testing entailed 1.5 upper endoscopies, 1.1 upper GI radiographs, 1.0 abdominal /pelvic ultrasonography studies and 0.8 abdominal CTs, and 0.6 colonoscopies per patient. In addition, 22 nondiagnostic surgical procedures included 10 cholecystectomies, five laparotomies and two appendectomies all with normal results [9].

Clinical endophenotypes

- Migraines-related

CVS has been viewed as a migraine equivalent and part of the migraine-related periodic syndrome since 1898 [33,41]. This association is based upon similar patterns of episodic attacks and accompanying symptoms (e.g. pallor, listlessness), common progression to or coincident migraines, and therapeutic response to anti-migraine agents [1]. The relationship is further bolstered by a striking positive family history (72–80%) or personal migraines (42%) in children with CVS in contrast to those with GI disorders (14%) who had the same prevalence as the general population. In adult CVS, 43–70% had migraines and 57–64% had a family migraine history [9,29]. A matrilineal inheritance pattern for migraines found in 64% of children and 83% of adults suggested a mitochondrial link addressed in Mitochondrial Dysfunction.

As part of the ‘periodic syndrome’ children can have CVS, abdominal migraine or migraine headache either sequentially or concomitantly. Suggesting an overall sequential progression, one cross-sectional school-based study found the mean ages of onset and current age of CVS, abdominal migraine and migraine headaches to be 5, 7 and 8 and 9.6, 10.3 and 11.5 years respectively [42–44]. In our cohort, most often CVS progresses directly from CVS to migraines. Notably, children who have more than one migraine conditions in tandem may require different dosages (e.g. requiring dose escalation) to manage all effectively.

Migraine-associated CVS comprised 90% of a consecutive cohort of 100 affected children, the largest subgroup [35]. We found that pediatric CVS patients that do not have a migraine association had higher episode severities and lower response rates to anti-migraine agents, the first indication that CVS was comprised of different endophenotypes [33].

- Epilepsy

In the 1950s, some pediatric neurologists focused on spike and wave patterns seen in CVS patients and labeled it ‘abdominal epilepsy’ [1]. Subsequent studies revealed these findings to be nonspecific and found in children with recurrent abdominal pain. A few have suggested that the response to topiramate in children with CVS may be guided by an abnormal EEG, however it is known that migraines generally respond to topiramate [45]. Nevertheless, citing the relationships between migraine, CVS and epilepsy, Levinthal has suggested the presence of a modifiable neuronal threshold which, when exceeded, may result in emesis and for which anticonvulsants could be useful [17].

Several seizure disorders can mimic CVS and present specific diagnostic challenges. Panayiotopoulos Syndrome, also known as benign occipital epilepsy or autonomic seizures, shares many characteristics with CVS [46,47]. The peak age is 4–5 years, equal in girls and boys, lasting 1–2 years from onset, occasionally up to age 14. The time of onset is usually nocturnal and the duration of attacks are 15–30 minutes occasionally up to 2 hours with complete resolution. Besides emesis (75%) with nausea and retching, autonomic symptoms include pallor, mydriasis, hypothermia, hypersalivation, and incontinence. Neurological manifestations include prodromal aura and headache, unresponsiveness, lateral gaze (60%) usually without classic motor manifestations. Treatment simply involves education without use of chronic anticonvulsants. Temporal lobe epilepsy is a rare mimic of CVS that is associated with a temporary lack of awareness with staring, overpowering emotions (fear), repetitive movements with occasional vomiting [48].

- Dysautonomia

Virtually all acute symptoms of CVS may be viewed as an autonomic storm raging out of control as described above under Episode Symptoms. Perhaps one comparable but unrelated model is Riley-Day familial dysautonomia in which a monogenetic mutation in ELP1 obtunds baroreceptor feedback and can present with vomiting episodes [49]. In CVS, there appears to be substantial overlap with autonomic disorders. Chelimsky reported a small series of children with CVS who had tilt table-induced tachycardia consistent with postural orthostatic tachycardia syndrome (POTS) and suggested that treatment of POTS could reduce episodes with the caveat that the treatments (lifestyle modifications and β-blockers) of both conditions overlap [50]. In our large pediatric cohort, we found that 38% of screened adolescents had evidence of POTS [35]. In adults, Venkatesan reported that 35% met criteria for POTS [36]. Recently, amongst a large cohort of children with CVS 40% during their mid-teens evolved into chronic nausea associated with documented dysautonomia [51].

Earlier results of autonomic testing in both children and adults found evidence of heightened sympathetic tone [36,52]. However, more recent work by Kolacz indicate that the underlying defect may be impaired parasympathetic downregulation of sympathetic system based upon two heart rate variability measures: respiratory sinus arrhythmia and vagal efficiency (dynamic metric) [53]. Moreover, this polyvagal model can explain why vagal neuromodulation is effective in treating CVS and which is supported by the observation that low vagal efficiency was associated with a positive therapeutic response due presumably to restored parasympathetic regulation of sympathetic drive [54]. The large remaining question is whether autonomic dysfunction undergirds all of CVS, but only becomes clinically evident during adolescence (e.g. POTS), or whether this malfunction is acquired in select CVS patients during adolescence and young adulthood that form a substantial subset of CVS.

- Developmental delay

CVS can be associated with neuromuscular dysfunction, a subtype coined ‘CVS+’ by Boles, including cognitive, skeletal, cranial nerve and seizures disorders. In his series, likely biased by his genetics practice, CVS+ accounted 25% of patients whereas other series report only 1–2% [9,55]. In the author’s clinical experience, CVS has been diagnosed in a handful of patients with Angelman and VACTERL syndrome, however whether this association was due to ascertainment bias (e.g. self-referrals from parent groups) is unclear.

Jansen-de Vries Syndrome (JvDS) was recently described in 2017 and is associated with cognitive delay, hypotonia, short stature and periodic vomiting and caused by de novo truncating mutations in the PPM1D gene (protein phosphatase Mg²⁺/Mn²⁺ dependent 1D) [56–57]. Global neurodevelopmental delay affects 97%, hypotonia 74%, feeding difficulty (G-tubes) and constipation, and cyclic vomiting in one abstract was noted in 60%. The dysmorphic features include broad mouth and forehead and upturned nose most noticeable in toddlers, with short stature, small hands and feet and myopia. The prominent behavioral changes include anxiety (64%) and a hypersocial affect (68%) and some have autism and ADHD. In a child with CVS and unexplained neurodevelopmental delay, genetic screening for JvDS should be strongly considered.

- Mitochondrial dysfunction

Circumstantial evidence for mitochondrial dysfunction in CVS emerged from several clinical and genetic lines of evidence. In CVS, there are common comorbid symptoms of chronic fatigue and dysautonomia [35,36] and a striking maternal inheritance of familial migraines [ 29,33,58]. Boles found two mitochondrial DNA polymorphisms (3010A when present in those with 16519T) strongly associated with both CVS and migraine in Haplotype H (Caucasians) [59]. He also provided preliminary evidence that prophylactic mitochondrial supplements (CoQ10, riboflavin) can be efficacious [60]. However, a simple mitochondrial pathogenic model remains elusive. Both mtSNPs reside in the control region rather the respiratory chain peptide sequences therefore begging the structure-to-function relationship. Through WES and WGS, Boles has suggested that nuclear susceptibility plays a perfect storm role. Gene variants in SCN4A, CACNA1A, RYR2, TRAP1, MEFV and others (17) in a CVS cohort were noted in significantly higher frequency than other susceptibility genes [61,62]. The common theme is that these candidate genes involve either cation transport or energy metabolism and propose that ensuing vagal hyperexcitability could cause CVS episodes. This polygenic scenario could contribute to the substantial diversity in endophenotypes, their associated comorbidities and therapeutic responses. However, these findings and their therapeutic implications need further validation.

- Sato-variant (hypothalamic surge)

The Sato-variant was found in 6% of an affected pediatric cohort presents with a distinct clinical and neuroendocrine profile with hallmark intra-episodic hypertension, profound lethargy and an overactivated hypothalamic-pituitary-adrenal axis. This unique variant first described by Wolff in 1964, Sato documented the accompanying neuroendocrine profile with marked elevations of ACTH, cortisol, catecholamines, antidiuretic hormone (ADH), and prostaglandin E₂ in the early phase of episodes [63–65]. Although not measured, CRH atop the cascade is presumably elevated as well and has been suggested as an inciting mediator [19]. The elevated cortisol, epinephrine, norepinephrine and antidiuretic hormone account for the hypertension. Some develop hyponatremia from the excess anti-diuretic hormone, and diuresis may precede the end of the episode. There is no evidence of a neural crest tumor (e.g. pheochromocytoma) and the hypertension resolves between episodes. In a sub-analysis, the Sato-variant had more emeses per episode (92 vs.26) and longer episode duration (144 vs. 36 hours) than other CVS children and appears to be the most severe endophenotype [1]. Anecdotally, parenteral dexamethasone, perhaps acting via feedback inhibition, has been used to treat the refractory cases.

- Catamenial CVS

Catamenial CVS is a subtype (9% of a large cohort) that parallels menstrual migraine and typically starts just prior to or during the first day or two of menses [35,66]. This ‘estrogen-sensitive’ subtype has been strongly suggested to be triggered by the precipitous pre-menstrual decline in estrogen. Analogous to menstrual migraine, this group can be managed by either low estrogen birth control or long-acting depot medroxyprogesterone acetate to abolish menstrual cycles rather than conventional anti-migraine therapy [67]. This subtype is not considered a separate entity from CVS but simply a estrogen-triggered variant of CVS that is best treated with hormonal therapy.

- Cannabis-trigger CVS

Cannabinoid hyperemesis syndrome (CHS) was first described by Allen et al. in South Australia in 2004 [11]. All were young adult males, some beginning in adolescence, who had phenotypic CVS that appeared to be triggered by prolonged (median 6 years), high-dose (daily or multiple times per week) recreational cannabis use, and complete cessation completely resolved symptoms when followed up to 4 years [11,68,69]. CHS also occurs in adolescents, more often in girls who used daily cannabis over 1–4 years [70,71]. Although there is nearly complete phenotypic overlap, even the CHS criteria include ‘resembling CVS’, a recent paper on adolescents discovered a few differences. Comparing CHS and CVS groups the cannabinoid group were older (18.1 vs. 14.5 years), had higher systolic blood pressures, and almost unanimously positive urine drug screen (86% vs. 3%); the latter provides further support for its confirmatory diagnostic use [72]. Whether CHS is a distinct entity from CVS remains controversial but amongst CVS mavens there is an informal consensus that CHS represents an endophenotype of CVS with a cannabinoid trigger.

An important source of confusion is that some CVS patients use cannabis intermittently during episodes to quell the nausea. Together with the toxic effect of long-term use in CHS strongly suggests a biphasic response to cannabis: a therapeutic effect at low-dose, episodic use and an adverse one with daily, long-term (multi-year) usage. A clear history of excessive rather than sporadic use, possibly buttressed by a positive urine toxicology screen, is critical for correctly differentiating the two on the front-line. Nevertheless, a link between altered CB1 receptor physiology both CHS and CVS, is highly tenable. Excessive exposure to cannabis reduces the number of CB1 receptors in both animals and humans, and, in that setting, THC may displace endogenous ligands resulting in weakened suppression of emesis [73,74]. In a large adult CVS cohort, Venkatesan has also identified CN1 (gene for CB1) polymorphisms that may render individuals more likely to develop CVS or respond to treatment [75]. Hence, a perturbed endocannabinoid system either through endogenous (genetic) and/or exogenous (excess THC) factors appears to be involved in both CHS and CVS. There are several relevant papers in these Proceedings.

- Where we are today

This updated bedside perspective reveals a newfound heterogeneity of clinical complexity (co-morbidities) and CVS endophenotypes to an illness that twenty years ago was viewed simply as a recurrent vomiting disorder related to migraines. At this Third Symposium, the inclusion of CHS added endocannabinoids to the Rorschach mix of mechanisms. In addition, the unexpected responses to hot water hydrotherapy and capsaicin may open other therapeutic avenues such as use of TRPV-1 antagonists. In addition, CGRP receptors for migraine therapy and central GDF-15 emetic pathways were completely unknown at the Second Symposium.

Unfortunately, no magic therapeutic bullets have emerged from the many case series, clinician experience and very few clinical trials. Amongst the wide array of therapeutic responses, there is a known high placebo rate, ranging from some patients who respond to mitochondrial supplements alone, others to cognitive behavioral therapy or meditation, and a promising vagal neuromodulation approach. This expanded view of the disorder necessitates management of a wide array of comorbid associations which may in turn help the primary disorder, for example, treating anxiety with CBT or POTS with extra fluids, salt and mineralocorticoids.

CVS is comprised of multiple endophenotypes despite having a final common pathway that leads to episodes of unrelenting, dysfunctional vomiting. This heterogeneity signifies not only heterogeneity of treatment responses, but may lead us towards subcategorization, risk stratification and differential treatment strategies for each. The largest subgroup is clearly migraine-related but the others including Sato-variant, catamenial CVS, CVS+ (and syndromic CVS), dysautonomia, cannabis-triggered may have different proximal pathways. Further, by the fact that the percent in subgroups add up to > 100%, a single individual may fall into more than one subtype that suggests synergistic effects between these mechanisms. Perhaps we can imagine a day when identified biomarkers for these endophenotypes – genetic, metabolomic, autonomic – enable us to prospectively select appropriate therapeutic approaches based upon robust classification and therapeutic evidence.

Where does leave us today? With the multiscreen view emerging from the Third Symposium, can we weave the spotlighted pathophysiologic threads into a comprehensive mechanistic tapestry? Perhaps not yet, but we can clearly see the threads and begin to integrate them even if not in a tight coherent pattern. Porges provides the polyvagal biobehavioral framework as the underlying vagal grid of allostatic adaptation to chronic stress that over time leads to parasympathetic dysfunction. In this emerging textile, there appear to be many fibers that impinge synergistically upon the emetic pathways including CRH and HPA axis, NK1, 5HT₃, GDF-15, CB1, TRPV-1, CGRP, estrogen each with a place in the final fabric. And, there appear to be significant susceptibility strands that impact the fabric including mitochondrial and nuclear polymorphisms, genetic syndromes, migraine, unknown biological calendar, unknown age-related developmental factors, anxiety and panic anxiety, mixed in with chronic maladaptive responses to biobehavioral stress, HPA surges, and excess THC exposure. Finally, is there one penultimate neurological locus where a critically lowered emetic threshold permits unstopped feed-forward emesis to proceed? It seems like an impossible tapestry to weave but the bedside vantagepoint a quarter of a century after the Second Symposium has greatly clarified the extent and complexity we continue to confront in CVS and now CHS.

One of the most interesting therapeutic insights from this Third Symposium is that meditation, cognitive behavioral therapy, and vagal neuromodulation seem effective in CVS perhaps by temporarily restoring parasympathetic/vagal effectiveness. Such approaches, by restoring homeostatic balance, would seem to offer significant advantages over pharmacotherapy, which by nature of its unidirectional effects can cause a plethora of side effects, many currently encountered by patients. As we step forward from this Third Symposium, with a new perspective and fresh set of early and mid-career investigators, we anticipate the gut-brain tapestry envisioned here will shed further insight into mechanisms not only of CVS and CHS, but other DGBI as well. The future of CVS is bright!

Key points:

• Formation of the Cyclic Vomiting Syndrome Association in 1993 spurred significant collaborative efforts in clinical and scientific investigation into cyclic vomiting syndrome (CVS).

• The bedside view is complex but continues to provide insights into CVS due to its multifaceted presentation, multiple comorbidities, and numerous subtypes (e.g. cannabinoid hyperemesis syndrome).

• CVS is expressed clinically as an autonomic storm, but how the evident threads – migraine, HPA axis, endocannabinoid system, cellular energetics, anxiety and biological calendars – fit together remains to be determined.

Abbreviations:

AM

abdominal migraine

ANS

autonomic nervous system

CB1

cannabinoid receptor 1

CBT

cognitive behavioral therapy

CGRP

calcitonin gene-related peptide

CHS

cannabinoid hyperemesis syndrome

CNR1

cannabinoid receptor gene 1

CRH

corticotropin-releasing hormone

CVS

cyclic vomiting syndrome

CVS+

cyclic vomiting syndrome + neurodevelopmental delay

HPA

hypothalamic-pituitary-adrenal

mt

mitochondrial

PAG

periaqueductal grey

SNP

single nucleotide polymorphisms

TRPV-1

Transient receptor potential vanilloid 1