Cyclic Vomiting Syndrome



Fig. 23.1
The four phases of CVS with the corresponding goals of treatment are shown. (Reprinted from Fleisher DR, Gornowicz B, Adams K, et al. Cyclic Vomiting Syndrome in 41 adults: the illness, the patients, and problems of management. BMC Med 2005)



Patients will typically return to normal health in between episodes. Episodes can occur at any time of the day, but usually start in the middle of the night or early in the morning. Episodes are often triggered by physical and/or psychological stress. This stress can be either positive (holidays or birthdays) or negative such as the death of a loved one or job loss. In women, episodes may occur around the menstrual period and is referred to as catamenial CVS.

The exact cause of CVS is not known but there are several theories that researchers are exploring. CVS is thought to be a functional gastrointestinal disorder (FGID) . There are nerves that connect the brain and the gut with the brain functioning like a “supercomputer.” Patients with FGIDs have increased sensitivity of the nerves in the gastrointestinal tract (visceral hypersensitivity) where even normal food, fluid, and gas in the gut can provoke pain due to miscommunication between the brain and the gut (malfunction of the brain-gut axis) resulting in symptoms. Recent studies with imaging techniques like functional MRI scans have shown that patients with CVS have alterations in the networks in the brain that are associated with nausea, vomiting, and emotion. There is some evidence that patients with CVS have certain problems with the production of chemicals in the body called endocannabinoids (marijuana-like substances that we all produce in our bodies) that can result in nausea and vomiting.

Further, dysfunction of genes in the mitochondria (the powerhouses of our cells that help drive energy production) may be associated with CVS in children but this has not been seen in adults [2]. There is no proof that CVS is hereditary though several studies show that various functional disorders like migraine, IBS, and fibromyalgia tend to cluster in families [35]. In summary, we do not know what causes CVS but ongoing research has provided us with some clues. Your children may be more predisposed to getting migraines and/or CVS than the general population but there is no definite evidence to prove this.



Brief Review of the Literature



Epidemiology


Cyclic vomiting syndrome (CVS) is a chronic functional gastrointestinal disorder that was first described in children in 1882 [6]. Initially thought to be a pediatric disorder, it is now being diagnosed increasingly in adults. The prevalence of CVS in children is about 1–2% [7]. The incidence of CVS in Ireland was 3.15 cases 100,000 children per year. The prevalence of CVS in adults has not been systematically studied. CVS affects mostly Caucasians usually in their second and third decade of life and both males and females are affected with some conflicting data on gender preponderance. CVS is also associated with multiple functional disorders such as anxiety, depression, and dysautonomia similar to other FGIDs.


Pathophysiology


The pathophysiology of CVS is unknown; however, mitochondrial DNA polymorphisms and altered endocrine and/or autonomic stress responses have been implicated. CVS has a strong association with migraine headaches with 43% percent of adults having a personal history and 64% a family history of migraine headaches. A strong matrilineal inheritance of both migraines and other functional GI disorders suggests the presence of mitochondrial dysfunction in CVS. This prompted studies that revealed that mitochondrial DNA single nucleotide polymorphisms (mtDNA SNPs) 16,519T and 3010A increased the odds of CVS 17-fold in children with CVS compared to normal healthy subjects [2]. However, the prevalence of these mitochondrial DNA SNPs was not increased in adults with CVS compared to historical controls [4]. These studies did reveal a high degree of matrilineal inheritance of multiple functional disorders in a subset of adults with CVS compared to historical controls. Future studies examining this relationship are warranted.

CVS is thought to be a centrally mediated disorder supported by studies using functional magnetic resonance imaging (fMRI) techniques that showed differences in functional connectivity in areas that are associated with nausea, mood, and pain processing [8]. There are a number of statistically significant differences in functional connectivity between patients with CVS and healthy controls seen in the right dorsolateral prefrontal cortex, left and right inferior temporal gyrus, and left postcentral gyrus. Nausea network analysis also showed that after emotional stress, there were significant differences observed between patients with CVS and healthy controls in connections between the right premotor area and right middle cingulate cortex and between the right superior temporal gyrus and right perigenual anterior cingulate cortex. These areas are involved in emotion and pain processing and these findings suggest that patients with CVS may have a differential response to stress as opposed to healthy individuals.

Autonomic dysregulation and heightened sympathetic activity have also been implicated in CVS. Sympathetic nervous system dysfunction was seen in 40-90% of patients with CVS with either postural orthostatic dysfunction, sudomotor dysfunction, or both [9]. Rapid gastric emptying, a surrogate marker for autonomic dysfunction, was present in 57% of patients in one study. Rashed et al. and To et al. demonstrated heightened sympathetic cardiovascular tone in patients with CVS. The successful use of dexmedetomidine, an alpha2-adrenergic agonist, to treat CVS corroborates this hypothesis.

Stress is a major trigger for CVS episodes and hypothalamic-pituitary-adrenal (HPA) axis dysfunction has been implicated in CVS. In some patients, increased ACTH and cortisol levels were noted while the patients exhibited hypertension and lethargy. This was first described by Sato and is thought to be a subset of CVS. Tache et al. showed that corticotrophin-releasing factor (CRF) causes gastric stasis and/or emesis in animals [10]. More recently, salivary cortisol and salivary alpha amylase (a surrogate marker for sympathetic nervous system activity) were elevated in patients with CVS who used marijuana during an episode as opposed to nonusers. Approximately 40% of patients with CVS use marijuana to alleviate nausea and anxiety and stimulate appetite. Though the active ingredient in marijuana , ∆9-tetrahydrocannabinol (THC), has antiemetic properties, chronic marijuana use has been associated with cyclic vomiting [11, 12]. Recently, the Rome Foundation established criteria for cannabinoid hyperemesis syndrome, which has symptoms similar to CVS except for the chronic use of marijuana [13]. Further studies are needed to elucidate the exact relationship between marijuana, the endocannabinoid system and CVS.



What Is Cannabinoid Hyperemesis? I Use Marijuana for My Symptoms, Which Helps with Nausea and Appetite and Reduces My Levels of Stress. Is Marijuana Helpful or Harmful in This Disorder?



The Role of Marijuana and the Endocannabinoid System in CVS



Suggested Response to the Patient


Cannabinoid hyperemesis syndrome (CHS) is a disorder that is thought to be due to chronic marijuana use. This syndrome resembles CVS except for the history of heavy prolonged marijuana use. Patients with this disorder often take very hot showers or baths for relief of symptoms This is referred to as “compulsive hot-water bathing .” It is generally thought that vomiting episodes will get better and resolve with abstinence from marijuana. However, marijuana is stored in the fat cells in the body and with heavy use it can take up to 3 months for this marijuana to be removed completely from the body. Further, patients without marijuana use also report compulsive hot-water bathing making it very difficult to make the diagnosis of CHS.

This is in contrast to studies that show that marijuana helps control nausea and vomiting and stimulates appetite. Many patients also use marijuana to relieve anxiety. One reason for this discrepancy may be that marijuana that is obtained commercially has more than 500 chemicals in it and the concentration of THC in marijuana is very high which could result in it having the opposite effect. So, until further studies are done, it is best that patients with CVS avoid marijuana and discuss alternative options to manage anxiety, nausea, and vomiting.


Brief Review of the Literature



Chronic Marijuana Use and the Role of the Endocannabinoid System in CVS

Cannabinoid hyperemesis syndrome (CHS) is a chronic disorder that . is characterized by recurrent episodes of nausea and vomiting that are indistinguishable from CVS. Experts coined this term based on studies showing an association between cyclic vomiting and chronic marijuana use (for several years). Compulsive hot-water bathing was observed in 72% of patients with chronic pathognomonic of marijuana use. However, this pattren of bathing is not pathognomonic and is reported in 42% of non-marijuana users with CVS. Recently, the Rome Foundation established clinical criteria for making the diagnosis of CHS (Table 23.1) [13].


Table 23.1
Rome IV criteria for cannabinoid hyperemesis syndrome

















Must include all of the following:

• Stereotypical episodic vomiting resembling cyclic vomiting syndrome (CVS) in terms of onset, duration, and frequency

• Presentation after prolonged excessive cannabis use

• Relief of vomiting episodes by sustained cessation of cannabis use

Supportive remarks

May be associated with pathologic bathing behavior (prolonged hot baths or showers)


aCriteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis

The cause for the compulsive hot-water bathing pattern is not known but it is proposed that this could be due to the effects of marijuana on the limbic system and thermoregulatory systems in the brain. Chronic marijuana use is seen mostly in young males; a retrospective study of 82 patients with CVS showed that 37% of patients with CVS used marijuana in comparison to 11% in functional vomiting and 13% in irritable bowel syndrome. A recent Internet survey showed that about 80% of patients with CVS used marijuana and reported relief of nausea, vomiting, and anxiety. These patients also stated that it improved appetite and overall well-being [14]. In contrast to these data, which were by patient report, multiple case series report the association of chronic heavy marijuana use with cyclic vomiting. Allen et al. described ten patients who had a pattern of cyclic vomiting and a compulsive hot-water bathing pattern associated with chronic marijuana use [11]. The largest series of cyclic vomiting associated with chronic marijuana use included 98 patients. Follow-up was available only in ten patients of which three (30%) did not abstain from cannabis use and continued to have symptoms. Symptoms resolved in six patients (60%) who stopped using marijuana but the longest duration of follow-up was only 1–3 months [15]. Lack of long-term follow-up is a major limitation of these studies and there is still no clear data that prove causation.The diagnosis of CHS can be challenging, as it is often difficult to convince patients to abstain from marijuana especially given its legalization in many states in the USA and purported health benefits. Further, many patients who abstain from marijuana use continue to have CVS episodes. Of historical interest, even Charles Darwin appears to have had CVS and was prescribed hydrotherapy though there is no indication that he used marijuana [16].

The major psychoactive ingredient in marijuana is ∆9-tetrahydrocannabinol (THC) . However, the cannabis plant contains almost 500 different chemicals aside from THC including cannabidiol, cannabichromene, cannabidivarin, and terpenoids. Marijuana that is obtained illegally in the USA, UK, and other countries has almost exclusively THC and seldom other phytocannabinoids. THC binds to two G-protein coupled receptors called cannabinoid receptors 1 and 2 (CB1 and CB2), which are densely distributed in the central and peripheral nervous system. These receptors are activated endogenously by two ligands called endocannabinoids [N-arachidonylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG) , which modulate the stress response and play an important role in nausea and vomiting. These ligands, their corresponding receptors, and degrading enzymes are collectively referred to as the endocannabinoid signaling system (ECS) . The ECS plays an important role in the modulation of stress, nausea, and vomiting [18]. CB1 agonists inhibit vomiting and CB1-receptor antagonists can cause vomiting. This is in contrast to data that suggests that THC causes cyclic vomiting. One possible explanation could be that chronic THC exposure downregulates and desensitizes CB1 receptors.

A recent study in patients with CVS showed a significant increase in endocannabinoid-related lipids during an episode of CVS, which correlated with poor sleep quality and nausea. The same study also showed a significantly higher salivary cortisol (surrogate for HPA axis activity) and salivary alpha amylase concentration (marker for sympathetic nervous system activity) during an episode of CVS in marijuana users compared to nonusers [18]. These results could be due to a heightened response of the HPA axis and the sympathetic nervous system with chronic marijuana use but it is also possible that marijuana use attenuated the stress response in CVS. Future studies should help clarify the effects of chronic marijuana use and the role of the endocannabinoid system in CVS. This should present us with unique opportunities to develop targeted therapies for CVS.


Do I Need Further Testing, Such as Lab Tests, Imaging or Endoscopic Procedures? Pitfalls in Diagnosis: How to Avoid Unnecessary Testing and Making the Correct Diagnosis



Suggested Response to the Patient


CVS is a clinical diagnosis, meaning that the key to diagnosis is based upon a careful review of the patient’s presenting symptoms and clinical history. There are no blood tests or imaging studies that will definitively diagnose CVS. This level of diagnostic uncertainty can understandably be frustrating. Instead, physicians must rule out life-threatening causes of recurring nausea and vomiting such as blockages in the gastrointestinal tract, twisting or rotation of the intestines, masses in the brain, along with disorders of the pancreas that can mimic CVS.

In order to rule out these disorders, basic laboratory tests to assess liver and kidney function, upper endoscopy (EGD) and routine imaging of the abdomen are usually performed. If they return normal and symptoms are consistent with CVS, further diagnostic testing is generally not required and treatment for CVS should be initiated.

Further genetic testing or in-depth testing for hormonal disorders or disorders of metabolism need not be performed unless there is a high index of clinical suspicion, or if there is no response to therapy. Typically these types of metabolic disorders affect children at a younger age. Clues to such metabolic disorders are episodes, which are always precipitated by fasting, intercurrent illness, or a high-protein meal [19]. If these symptoms are present, appropriate workup with blood and urine tests and referral to a metabolic specialist may be indicated. Imaging of the brain is usually not necessary unless neurologic symptoms or abnormal physical exam findings are present or if there is a history of trauma to the head.


Brief Review of the Literature


As with other functional GI disorders, there are no biochemical markers to make a diagnosis of CVS. The diagnosis of CVS is based on the Rome IV criteria for CVS and is included in Table 23.2 [13].


Table 23.2
Rome IV criteria for cyclic vomiting syndrome





















• Stereotypical episodes of vomiting regarding onset (acute) and duration (less than 1 week)

– Abrupt in onset

– Occurring at least 1 week apart

• 3 or more discrete episodes in the prior year

– Two episodes in the past 6 months

– Absence of nausea and vomiting between episodes

– But other milder symptoms can be present between episodes

• No metabolic, gastrointestinal, central nervous system, structural, or biochemical disorders

The Rome IV criteria differ from Rome III in that a provision was made to include patients with a coalescent pattern of symptoms. Patients usually return to normal health in between episodes but in some instances can coalesce with nausea and dyspepsia in between episodes. It is important to recognize this phenomenon and obtaining a careful history is vital in making an accurate diagnosis.

The differential diagnosis for CVS is quite broad ranging from structural, metabolic, and endocrinologic diseases. Such considerations include anatomic obstruction (malrotation with intermittent volvulus), intermittent small bowel obstruction, peptic ulcer disease, pancreatitis, intestinal pseudo-obstruction, intracranial mass, hyperemesis gravidarum, cannabinoid hyperemesis, disorders of fatty acid oxidation, urea cycle defects, acute intermittent porphyria, diabetes with ketoacidosis, and Addison’s disease. The majority of these conditions in adults are quite rare, and assaying for each and every one of them should be avoided except when clinical suspicion is high. Indications for a more extensive workup include an abnormal neurological exam, attacks precipitated solely by fasting, intercurrent illness and a high-protein diet suggesting metabolic disorders, a family history of metabolic disorders, or nonresponse to adequate therapy for 3–6 months.

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Jan 31, 2018 | Posted by in ABDOMINAL MEDICINE | Comments Off on Cyclic Vomiting Syndrome

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