A greater frequency of mitochondrial polymorphisms (16519T and 3010A) has recently been identified in pediatric patients with CVS, compared with controls,16–18 but it was not found in Asian pediatric populations or in adults.19,20 This variability may be due to the small sample sizes, involuntary bias during patient recruitment, and the differences in allelic frequencies between the different ethnicities.

The endocannabinoid signaling system plays an important role in CVS.21,22 This system is formed by endogenous ligands, N-arachidonoylethanolamide, 2-arachidonylglycerol (endocannabinoids), and two cannabinoid G-protein coupled receptors (cannabinoid receptor type 1 [CNR1] and type 2 [CNR2]), which regulate gastrointestinal motility.23,24 The CNR1 and CNR2 receptor agonists prevent vomiting, and in contrast, the CNR1 receptor antagonists cause vomiting. The polymorphisms in the CNR 1 rs806380 gene are associated with a greater risk for CVS. In addition, the serum concentration of endocannabinoid-related lipids, N-oleoylethanolamine and N-palmitoylethanolamide, is higher in the symptomatic phase of CVS and those lipids are positively correlated with several CVS symptoms. These data support the hypothesis that chronic cannabis use causes an increase in stress responses during CVS,21 and show that the variations in the endocannabinoid pathway lead to a higher risk of developing CVS.

The autonomous nervous system plays an outstanding role in emesis. A series of brainstem nuclei receive information from the vagus and sympathetic afferent nerves during emetic stimulation. Efferent signals are created that start the stereotyped and coordinated muscle actions involved in vomiting. Many adults with CVS have sympathetic nervous system dysregulation.10,25,26 Studies have reported increases in sympathetic tone in patients with CVS, recorded through various tests of autonomic function, such as postural adjustment ratio, heart rate variability, tilt table test, and sudomotor tests.10,27–29 The most frequent finding in these reports was an adrenergic anomaly, in addition to coexisting abnormalities of vagal cholinergic function. Based on these studies that describe dysautonomic characteristics in patients with CVS, researchers have posited the hypothesis that this imbalance can cause patients to be more susceptible to producing an uncontrolled response to central emetic signals.27

During the inter-episodic phase of the disease, patients with CVS can present with accelerated gastric emptying in up to 59% of cases.30 In fact, accelerated gastric emptying can be an indirect marker of the underlying autonomic dysregulation in CVS. Importantly, the presence of delayed gastric emptying should not be interpreted as gastroparesis, especially in the context of typical episodic vomiting. Therefore, carrying out gastric emptying tests for diagnosing CVS is not recommended.

This observed dysregulation of the autonomous nervous system has implications in the treatment of CVS, such as vagal neuromodulation with percutaneous electrical nerve field stimulation,31 which improves symptoms, modulating the vagal function in patients with gut-brain axis gastrointestinal disorders and those with CVS.32 In addition, neuromodulation has been shown to predominantly benefit the subgroup of patient that have deficient vagal function.33

Homeostasis cannot completely explain the autonomic changes that accompany purely cognitive and emotional events. A more complete conceptual framework for autonomic control that accounts for them is known as allostasis.34 Allostatic regulation requires “central commands” that orchestrate changes in autonomic and motor activity. These central orders can ultimately proceed from the cerebral cortex and a network of central nuclei essential for autonomic regulation. In the framework of allostatic regulation, cognitive events, the anticipation of behavioral changes, and physiologic needs and the associations learned, shape the autonomic control patterns through changes in neuronal activity. Sleep deprivation, mood disorders, chronic stress, and early adverse life events can lead to allostatic regulation alteration through neural plasticity. Such maladaptive neural plasticity could lead to abnormal patterns of autonomic and neuroendocrine acitivity.35,36 The fact that vomiting and retching during the emetic phase of CVS are mainly produced when the stomach is empty, implies that the allostatic feedback mechanisms are disordered, which could give rise to a reduced threshold for vomiting and retching, regardless of physiologic necessity or peripheral information. This neural system could be abnormally developed to be activated through a low threshold in the presence of mental and/or physiologic stimuli, possibly analogous to anticipatory tachypnea patterns in patients with panic attacks.37 The prediction of this model would be that any factor that acutely alleviates stress or anxiety in patients with CVS could improve centrally driven vomiting patterns.

Neuronal hyperexcitability can be a common link between CVS and other central nervous system (CNS) disorders.38–40 Hyperexcitability can be a consequence of genetic variants in the structure and function of the ion channel and/or neurotransmitter receptors or can be the result of an aberrant development of neuronal circuits. Studies that describe alterations in the functional connectivity of the cerebral networks, particularly within the networks that involve the amygdala and insular cortex, can better explain the role of brain anomalies in CVS.41 In a case-control study, patients with CVS showed increased functional integrity of salience intrinsic connectivity to the middle/posterior insula, a key region of the brain for nausea and viscerosensory processing.41 It is possible that this neuronal hyperexcitability and a lower threshold for triggering specific patterns within the CNS predispose to the triggering of stereotypic vomiting episodes in CVS.

Cannabis has been used for centuries for both recreational and medicinal purposes. Its active ingredient is Δ 9-tetrahydrocannabinol (THC), a CNR1 agonist, and cannabidiol. THC acts on the CNR1, but cannabidiol has no psychotropic activity and acts on the 5-hydroxytryptamine 1A (5-HT1A) receptors.42 There is clinical data showing that cannabis has antiemetic properties and is frequently used by patients with CVS to alleviate the symptoms of nausea and vomiting, lack of appetite, and stress.14 Contrastingly, several case series on cannabinoid hyperemesis syndrome (CHS) have implied that the chronic use of cannabis causes vomiting.43–45 Approximately 20% of patients with CHS use cannabis ≥ 4 times a week, whereas the rest are occasional users. How cannabis use perpetuates symptoms is CHS must be determined. Cannabinoid use is independently associated with increases of sympathetic nerve flow.46,47 This influence on sympathetic activity occurs through the inhibition of the activity of the descending gamma-aminobutyric acid (GABA)ergic neurons.48–51 Since this descending GABAergic input ultimately inhibits the activity of the rostral ventrolateral medulla (rVLM) neurons,52 the chronic cannabinoid inhibition of this input would be thought to increase the activity of the target rVLM neurons (Fig. 2). The GABAergic reduction in the nucleus of the solitary tract could lower the vomiting threshold.

Figure 2.

Inhibition of descending GABAergic neuronal activity due to chronic cannabis consumption.

(0.13MB).

Experts consider that CHS is a subgroup of CVS. Based on similar clinical presentations and the lack of objective tests that demonstrate causality, it is hypothesized that chronic cannabis use can unmask symptoms in genetically predisposed individuals and cause hyperemesis.14 In addition, THC concentration in cannabis products has increased exponentially over time, which could also explain the paradoxical effects of cannabis use being an antiemetic at low doses and proemetic in high concentrations.53

Catamenial CVS is characterized by its association with the onset of menstrual periods. This subtype highlights the role of the hormonal influence on CVS, and said association is described in case series.54–56 A similar association between migraine and menstrual periods suggests a pathophysiologic parallelism.57 This triggering mechanism can reflect the sensitivity to the decrease of estrogens that is produced right before menstruation. Treatment with gonadotropin-releasing hormone (GnRH) analogues, estrogen supplements, oral contraceptives with low estrogen doses or progesterone alone achieves satisfactory prevention, suggesting the importance of maintaining adequate hypothalamic-pituitary axis regulation in CVS.58,59 The recognition of this subtype highlights the importance of a deeper understanding of the pathologic mechanisms of CVS, consequently providing highly efficacious personalized treatment.

We underline the importance of CHS as the differential diagnosis of CVS, given that the pharmacologic treatment will be different for each entity. The majority of patients with CVS arrive at the emergency room with episodes of vomiting, nausea, and abdominal pain.60 These symptoms are the same as those suffered by the patient with CHS, and so clinical differentiation can be difficult. The fact that intensity and chronicity of cannabis use are greater in CHS is a key differentiation point. In addition, symptom relief following abstinence helps define CHS, according to the Rome IV criteria (Table 1).

Anxiety and depression are frequent comorbidities of CVS. A study found a 47% prevalence of anxiety in children with CVS.11 In adults, the prevalence of anxiety varies widely, from 15% to 84%, and was significantly associated in a multivariate analysis.61,62 Similarly, up to 78% of adults with CVS have been reported to present with mild-to-severe depression.62 Although the direct pathophysiologic mechanisms of anxiety or depression in CVS remain nuclear, the elevated incidence of these disorders suggests that emotional regulation plays an important role in the pathophysiology and development of CVS. For example, a considerable number of patients with CVS have indicated “anticipatory anxiety” as a possible triggering factor, as well.11,63 Patients that do not tolerate uncertainty also experience a greater negative impact on quality of life, regardless of the true frequency of the attacks of CVS experienced.64 These patients can especially benefit from cognitive-behavioral therapy. Lastly and interestingly, patients with CVS frequently have panic attacks. Both panic disorder and CVS follow a similar temporality pattern and share clinical signs of sympathetic nervous system activation, suggesting they can share certain pathophysiologic mechanisms.63 Different experts posit that previous adverse experiences or chronic stress can be risk factors for developing CVS,65 given that such events can affect neuronal processing and alter allostatic regulation, predisposing certain patients to the syndrome.65–67 Due to the high prevalence of mood disorders in CVS, recent clinical guidelines suggest offering some type of “mind-body” therapy, such as meditation, relaxation therapies, or even cognitive-behavioral therapy, to the majority of patients.68

Although there is currently little scientific evidence for establishing a relation between specific foods and CVS, the consumption of chocolate, cheese, and monosodium glutamate has been described as a possible trigger of CVS attacks.60,69 Curiously, those same foods have long been associated with migraine,70 and several mechanisms can explain the associations. Specific smells and possibly flavors can precipitate migraines, and the neuronal codification of those stimuli may contribute to starting an attack of CVS.71 The possibility that food allergies can act as triggers for CVS has also been suggested. In a case series of patients with this CVS phenotype, the episodes were resolved by avoiding the food whose specific sensitivity was confirmed through tests.72 Even though such tests are still limited, they suggest that environmental exposures, especially those related to ingested foods, can be relevant therapeutic goals.

The differential diagnosis is broad because symptoms can be due to gastrointestinal (malrotation, gastroparesis), intracranial (intracranial masses, hydrocephaly), or abdominal (renal colic) disorders, or to metabolic (fatty acid oxidation or urea cycle disorders, mitochondrial dysfunction) or drug/toxin (CHS) alterations.77 Laboratory, radiographic, and endoscopic tests detect a substantial number of these differential diagnoses.

Acute hepatic porphyrias should be considered in the evaluation of all patients, especially 15 to 50-year-old women with recurrent intense abdominal pain accompanied by nausea, vomiting, and neuropathy. These entities are congenital metabolism errors of the blood group and include acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and 5-aminolevulinic acid dehydratase deficiency porphyria.78 Acute intermittent porphyria is the most common type, with an estimated prevalence of one per 100,000 inhabitants.79,80

All patients with hepatic porphyrias should be advised to avoid triggers, such as stress, excessive alcohol and/or tobacco use, and calorie deprivation, given that they are factors that induce messenger RNA and delta-aminolevulinate synthase 1 protein expression in the hepatocytes.81–84 This differential diagnosis is mentioned in numerous articles, and a recent study on the prevalence of acute hepatic porphyrias in patients diagnosed with CVS was recently evaluated. Acute hepatic porphyria was not detected in any of the 234 patients analyzed.85

It is necessary to avoid the triggers identified by the patient (insomnia, fasting, stress). In addition, the presence of mood disorders should be looked for, to correctly refer the patient to a psychologist or psychiatrist. Anxiety, panic, and depression disorders are frequent in adults with CVS62,63 and the symptoms of said disorders can influence the precipitation of CVS episodes.

Migraine is closely related to CVS.1,86 The prevalence of migraine in adults with CVS varies from 13% to 70%.63,87 In addition, 57% of adult patients with CVS (with or without migraine) have a first and/or second degree relative with migraine or migraine variants.63 Whether the treatment of migraine independently improves the evolution of CVS is not clear but many medications are efficacious prophylactic therapies (such as tricyclic antidepressants [TADs] and antiepileptics) or abortive therapies (such as triptans) for both conditions. Anecdotally, when CVS and migraines coexist, both have been observed to respond to TADs, but at different doses, obliging the physician to increase the amount of the drug, even when symptoms of one of the disorders have disappeared.

Given that chronic cannabis consumption is associated with the lack of treatment response, its use should be suspended.88 Patients usually benefit from a multidisciplinary approach that includes the gastroenterologist, psychologist/psychiatrist, and nursing personnel familiarized with the syndrome.

A unique characteristic of CVS is the conduct of bathing with warm water that provides temporary symptom relief.89 Even though this behavior is associated with cannabis use, it is also observed in 50% of patients that do not use cannabis.75

During the inter-episodic phase, treatment is prophylactic and is recommended in patients with moderate/severe disease, i.e., in patients with > 4 episodes per year of nausea and severe vomiting that make the patient seek help at the emergency service or require hospitalization. TADs are the first-line drugs for CVS prophylaxis and have been shown to reduce the duration, severity, and frequency of episodes, as well as the number of emergency room visits and hospitalizations.90 Amitriptyline, the TAD of choice, is usually started at a low dose of 25mg and is gradually increased to a target dose of approximately 100mg at night in adults. TADs can cause a prolonged QT interval, and so an electrocardiogram should be taken at the start and during the titration of the TAD to monitor it.91

In patients that do not tolerate TADs, anticonvulsants, such as zonisamide or levetiracetam, can be considered. In a noncontrolled study of 20 patients that did not tolerate TADs and that were started on zonisamide (mean dose of 400mg/day) or levetiracetam (mean dose of 1,000mg/day), 75% had a moderate clinical response, whereas 20% had complete symptom remission.92 Topiramate, another anticonvulsive and antimigraine agent, can also be used as prophylactic treatment.93 It is usually started with 25mg per day and the dose is increased 25mg every week, until reaching 100mg per day. Topiramate can slightly increase the risk for kidney stones, therefore optimized liquid intake should be recommended to patients. It can also cause a decrease in bicarbonate levels, and so patients should be supplemented if levels are shown to be low.

Aprepitant is a highly selective high-affinity antagonist of substance P/neurokinin 1 receptors.94 It binds to the receptors of the nucleus of the solitary tract that mediate the emetic motor reflex. It has been utilized to prevent chemotherapy-induced vomiting, as well as postoperative nausea and vomiting. Even though the plasma half-life is nine to 13hours, clinical effects can last for three to five days.95 The significant inhibitors and inducers of the CYP3A4 system increase and decrease serum aprepitant levels, respectively, and should be avoided if possible.96 It should be used with caution in patients with severe liver disease. A clinical trial was conducted on the prophylactic use of aprepitant for treating children and adolescents presenting with CVS that was refractory to conventional treatment.97 The trial included adolescents weighing more than 60kg that were treated with 125mg twice a week. In an intention-to-treat analysis, 82% of the patients had complete resolution or partial response (> 50% decrease in frequency and intensity) of episodes at 12 months. According to those criteria, 19% had complete response and 63% had partial response. Based on the data in children and adolescents and the clinical experience of experts, aprepitant is currently recommended as an alternative prophylactic treatment in patients that do not respond to or do not tolerate standard therapy with amitriptyline or topiramate. The suggested dose is 125mg twice a week for adults weighing > 60kg, and 80mg twice a week for adults weighing 40-60kg. Aprepitant is expensive, which should be considered when prescribing it.

Its use is recommended as monotherapy or in combination with prophylactic medications. Its recommendation is based on studies that signal mitochondrial dysfunction as part of the pathogenesis of CVS.98,99 Patients with migraine show reduced mitochondrial respiratory complex function, which most likely is present in CVS as well, albeit there are no studies confirming that assumption.100

Coenzyme Q10 (Co-Q10) is a natural hydrophobic compound derived from steroids that acts as an electron transporter between complex 1 or 2 and complex 3 of the mitochondrial respiratory chain. A retrospective study compared the efficacy of Co-Q10 with amitriptyline in children with CVS.101 Prophylactic treatment with Co-Q10 showed an overall efficacy of 68%, with no side effects.101 A dose of 10mg/kg of Co-Q10 per day, divided into two doses, until reaching 200mg twice a day, is recommended. For refractory cases, the suggestion is to measure Co-Q10 levels in blood and increase the dose to reach a serum level of 3mg/L.

Despite prophylaxis, patients with CVS can have intermittent vomiting attacks that need to be treated at the emergency service. A survey of adults with CVS showed that the median number of visits to the emergency room due to disease-related symptoms was 15 (range: 1-200). Relevantly, many patients tend to receive only a partially efficacious treatment due to lack of awareness of the disorder.112,113 Thus, all patients with CVS are recommended to have an individualized treatment plan for improving results (Table 3).114

During the acute phase, a combination of antiemetics and benzodiazepine sedation appears to be the best option because the latter drugs are used for alleviating anxiety and promoting sleep. First-generation antihistamines, such as injectable diphenhydramine, can be used.115,116

In patients with abdominal pain, the analgesic of choice is intravenous ketorolac. If the pain is severe, treatment with opioids should be considered. If the pain is refractory to those treatments, the use of intravenous ketamine in infusion has recently been described as an option.117–119

In addition, enabling the patient to rest in a quiet and darkened environment and maintaining good hydration with crystalloid solutions, even when the patient shows no signs of dehydration, appear to be beneficial. Altogether, this is the preferred approach for ending the emetic phase of CVS.113

The increasing understanding of the pathophysiology of CVS has brought about advances in its treatment. It is widely known that the vagus nerve plays an important role in nausea, vomiting, and pain.120 Some of the vagal nerve branches are situated in the external ear and directly project from there to the brainstem, together with other cranial nerves.121 Auricular stimulation with transcutaneous electrical nerve stimulation is efficacious in pediatric patients with gut-brain axis gastrointestinal disorders and is currently approved by the US Food and Drug Administration for the treatment of irritable bowel syndrome in children. Typical treatment is four weeks of auricular neurostimulation with four electrodes attached to the auricle that administer nonpainful wavelength frequencies.32 A recent study that evaluated the efficacy of auricular neurostimulation in children with CVS showed a decrease in abdominal pain and improvement in anxiety and sleep.122

Studies on migraine have shown that the calcitonin gene-related peptide is released during an acute migraine attack and sumatriptan normalizes its levels.123 This led to the production of calcitonin gene-related peptide antagonists and the use of monoclonal antibodies against the receptor of said peptide. Several studies have shown they are efficacious for reducing the number of days of both episodic and chronic migraines.124 Their role has not been studied in CVS, but given their shared pathophysiology, they should be taken into account for future projects.

The main goal of this trial is to compare the frequency of vomiting episodes per year observed during the first year after starting treatment with coenzyme Q10 with the frequency observed the year prior to starting treatment, in children with CVS. The trial is currently in development.