Review article: cyclic vomiting syndrome in adults rediscovering and redefining an old entity

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1 Alimentary Pharmacology and Therapeutics Review article: cyclic vomiting syndrome in adults rediscovering and redefining an old entity R. A. Hejazi & R. W. McCallum Department of Internal Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA. Correspondence to: Dr R. W. McCallum, Department of Internal Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, 4800 Alberta Ave, El Paso, TX 79905, USA. Publication data Submitted 18 January 2011 First decision 3 February 2011 Resubmitted 10 May 2011 Accepted 12 May 2011 EV Pub Online 12 June 2011 This commissioned review article was subject to full peer-review. SUMMARY Background Cyclic vomiting syndrome is a disorder characterised by recurrent episodes of severe nausea and vomiting separated by symptom-free periods. Aims To review the history, epidemiology, clinical aspects, pathophysiology, diagnosis and treatments of adult cyclic vomiting syndrome as well as to identify areas for further clinical research and the unanswered questions in this field. Methods We conducted a PubMed search using such keywords as cyclic vomiting syndrome; nausea; vomiting; pathophysiology; diagnosis; treatment; trigger factors; gastric emptying test; autonomic nerve function test; gastrointestinal hormones; outcome and natural history and combined this information with the knowledge and extensive clinical research and publications from the authors. Results Available data show that in adult cyclic vomiting syndrome, severe epigastric and sometimes diffuse abdominal pain accompanies most cycles of nausea and vomiting interspersed with periods of symptomatic remission. Psychological disorders, specifically anxiety and depression are common, and gastric emptying is actually rapid in approximately 60% of patients and normal in the remainder. There is an impressive and sustained response to high-dose tricyclic antidepressants. In up to 15% who are regarded as poor responders to tricyclic antidepressants, a predictable profile can be identified related to co-existing psychological disorders, marijuana use, poorly controlled migraine headache or chronic narcotic use. Conclusions Cyclic vomiting syndrome in adults is an entity that is being increasingly recognised, but the need to educate Internists, Gastroenterologists and Emergency Department staff remains an ongoing challenge. Aliment Pharmacol Ther 2011; 34: doi: /j x

2 R. A. Hejazi and R. W. McCallum INTRODUCTION AND HISTORIC PERSPECTIVE Cyclic vomiting syndrome (CVS) is a disease characterised by recurrent episodes of incapacitating nausea and vomiting interspersed with relatively symptom-free intervals that might last anywhere from a few days to several months. Dr Samuel Gee first described cyclic vomiting syndrome (CVS) in 1882 when he reported this condition in a series of nine children. 1 Over the next 120 years, there has been periodic continuing evidence in the paediatric literature, 2 6 as well as scattered reports of adult CVS. 7 9 In 1988, Abell et al. 10 reported a series of eight adult patients with CVS and since then, the increasing number of reports of CVS in adults has reached the point where over the last 10 years, it is more dominant in the medical literature than paediatric CVS. 2 The major advances in describing and understanding paediatric CVS can be largely attributed to the contributions from the teams headed by Dr Li from Northwestern University and Children s Memorial Hospital and Dr David Fleisher at University of California at Los Angeles (UCLA) and University of Missouri, and their co-authors who have made extensive contributions to our understanding of CVS in children. Dr Fleisher and his group are also recognised as the early discoverers of CVS in adults and his experience in meticulously treating and documenting this entity in both in-patient and outpatient settings has laid the foundation for the advances that have occurred in pathophysiology and treatment, which we will review in this article. This virtual explosion in the recognition and diagnosis of CVS in adults has resulted in a literal sea change in the way nausea vomiting is now viewed in adults. It is estimated that CVS is the aetiology of unexplained vomiting in 3 14% (depending on different reports) of referred populations of patients being assessed in university medical centres in US for unexplained nausea 11, 12 vomiting. Wang et al. 13 first brought to our attention the major increase in hospitalisations that started occurring for nausea vomiting around the year 2000 (Figure 1). In their report, they proposed that gastroparesis was the main explanation for this observation. Another contributor was an increase in the entity gastritis detected by endoscopy during the vomiting admission. Other reasons can also be offered for this major increase in admission for vomiting: (i) The fact that cisapride (propulsid) a gastrointestinal (GI) motility agent was removed from the market in 2000 due to cardiac-related adverse events left many gastroparetics without this effective agent and hence symptoms returned; (ii) The FDA had just Figure 1 Common upper GI disorders related to hospitalisations in the United States: trends, characteristics, and outcomes, Adapted from Wang et al. 13 approved Humanitarian Device Exemption for Enterra therapy (neurostimulation or gastric electrical stimulation) for gastroparesis refractory to medical therapy and these patients had to be admitted to hospital to undergo surgery for the Enterra device and electrodes to be implanted; (iii) With the evolution of scintigraphy, the diagnosis of gastroparesis was being made in the setting of nonstandardised 1 or 2 h gastric emptying studies and with different meal components involved, all resulting in many false positive delayed gastric emptying or gastroparesis diagnosis. With the benefit of hindsight, we now can surmise that in the last 10 years beginning in 2000, cyclic vomiting was often being misinterpreted as gastritis as there was no obvious explanation for the vomiting except endoscopic findings of gastritis or oesophagitis. Also, we can now conclude that many patients assessed to be gastroparetic were misdiagnosed because they were not being studied with a standardised 4-h gastric emptying test and, in many cases, were studied during hospitalisations when narcotics were being administrated for abdominal pain, and gastric emptying was thus inhibited. Hence, cyclic vomiting in adults is actually the main contribution to this rising admission rate for vomiting that began to be recognised in the 2000s. METHODS We conducted a PubMed search using the such keywords as cyclic vomiting syndrome; nausea; vomiting; pathophysiology; diagnosis; treatment; trigger factors; gastric emptying test; autonomic nerve function test; gastrointestinal hormones; outcome and natural history, and combined this information with the knowledge and extensive clinical research and publications from the authors. 264 Aliment Pharmacol Ther 2011; 34:

3 Review: cyclic vomiting syndrome EPIDEMIOLOGY Cyclic vomiting syndrome affects approximately % of the paediatric population, with an incidence of new cases thought to be approximately 3 per children per year. 3 6 Although CVS has been well studied in paediatric populations, its prevalence in adults has been underappreciated and there is no information about the true prevalence of CVS in adults. In a large cohort of 549 patients who were referred to our GI motility centre for nausea vomiting and abdominal pain, CVS was diagnosed in 17 (3%) of the patients. 14 There is also a recent report that up to 14% of a referral population to a tertiary GI motility clinic was CVS. 12 As both cohorts were based at a tertiary referral setting then, the true incidence and prevalence of CVS in the general population could be different. Limited data are available on race in CVS patients. In a report of 162 adult patients with CVS, 89% of patients were Caucasian followed by 10% African- American and 1% Hispanics. 11 In a very recent study of epidemiology of functional GI disorders in a tertiary referral clinic in a predominantly Hispanic population in El Paso, Texas, the authors observed that although majority of patients were Caucasians (59%), Hispanic patients now accounted for 41% of the new CVS patients. 12 CVS is present in both genders with a slightly 7, 8, 11 male predominant pattern. DIAGNOSTIC CRITERIA Cyclic vomiting episodes are stereotypic for each individual patient and generally characterised by four phases: (i) Well phase where the person is without symptoms; (ii) Pre-emetic (prior to vomiting) phase characterised by pallor, intense sweating and intense nausea; (iii) Intense vomiting up to vomiting episodes essentially retching and dry heaving per day, which can lasting usually from 1 to 4 days or, in some cases, up to a week; (iv) Recovery phase where the patient s vomiting decreases, the nausea improves and the patient is able to take in liquids by mouth. 2, 15 (Figure 2). Diagnosis Diagnostic Criteria of CVS based on Rome III must include all the following: (i) Stereotypical episodes of vomiting regarding onset (acute) and duration (less than 1 week); (ii) Three or more discrete episodes in the previous year; (iii) Absence or infrequency of nausea and vomiting between episodes. These criteria must have been fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis. A recognised association is a personal or family history of migraine headaches 16 and this is actually listed as a supporting criterion. 16 Abdominal pain invariably accompanies the nausea and vomiting events something that is not the case in the typical paediatric setting. Over time, when the diagnosis is not made and no treatment is initiated, then there is the phenomenon of coalescence of cycles. Here, the remission time between attacks begins to change from months to weeks to the point of nearly weekly with very few good days. This is where confusion can begin regarding separation from gastroparesis, and hence gastroparesis often becomes the working diagnosis. There are other presentations of CVS that are not classic and should be regarded as forme frustes or part of the extended clinical spectrum of CVS. In the past, they have been referred to as psychogenic nausea and functional nausea and vomiting. Specifically, these characteristics of the extended spectrum of CVS refer to morning nausea or vomiting, which generally resolves during the day and where no other aetiologies are found. Often, sleeping through the nausea can overcome the symptom. It can interfere with being able to go to school or work. Another presentation is exercise-related nausea or vomiting, limited to specific energetic activities, and also accompanied by hints of morning nausea or vomiting. CLINICAL PRESENTATION The cardinal clinical features of the disease are discrete vomiting episodes accompanied by symptoms of nausea, Figure 2 Different phases of cyclic vomiting syndrome. Adapted from Fleisher et al. 15 Aliment Pharmacol Ther 2011; 34:

4 R. A. Hejazi and R. W. McCallum retching and abdominal pain. Published data on adults with CVS indicate duration of episodes lasting from a few hours to several days (1 14 days). 6 An observation in 45 CVS adult patients suggested a duration of attacks from few hours to 30 days and frequency varying from weekly episodes to every 3 months. 7 Essentially, most attacks are regarded as occurring out of the blue with no predictable preceding or trigger events. Common triggering factors proposed are similar for adults and children, and include psychological stress, excitement, motion sickness, lack of sleep, infection, physical exhaustion and certain food products (e.g. chocolate, cheese, monosodium glutamate) and menstrual cycles in some women, a phenomenon termed catamenial CVS. 17, 18 Abdominal pain often focused in the epigastrium but radiating diffusely accompanies these episodes in most patients. Between episodes, the majority of patients are relatively well, but if closely questioned, can have degrees of nausea and some abdominal pain episodes typically after meals. The average age at initial diagnosis is 5 years in children and about 31 years in adults 7 9, 11, 15, 19 with the age of onset around 22 years in adults. 11 Patients often remain undiagnosed for some time due to a lack of recognition of this clinical entity with reports suggesting a delay in diagnosis ranging from 8 to 21 years following disease onset. 4, 7, Patients initially present to emergency room (ER) physicians with an unexplained onset of vomiting and abdominal pain. It is generally attributed to food poisoning, stress, migraine headache or menstrual cycles. Patients generally will return to other ER settings and see other ER physicians who repeat similar theories and treatment regimens. In general, ER physicians may not recognise or immediately appreciate the entity of CVS in adults, resulting in a delay in diagnosis until such time that a detailed history by a specialist in the field can be obtained which can then elucidate the classic cycles necessary to make a diagnosis of CVS. DEMOGRAPHIC AND CLINICAL PROFILE In the next phase of this review article, we will describe associated conditions comorbidities and complications of CVS and discuss some hypothesised pathogeneses. See Table 1 for a summary of demographic and clinical profiles of adult CVS patients depicted in recent published studies. 8, 9, 11 Coexisting conditions observed in adults with CVS include migraine headaches, psychiatric disease, chronic marijuana use, gastro-oesophageal reflux disease, irritable bowel syndrome and diabetes mellitus. Migraine headaches and or a family history of migraines are reported in 39 82% of children and in 24 70% of adults with CVS. 2, 20, 21 However, with ongoing experience with larger numbers of adult CVS patients, migraine headache is actually present in a minority of 7, 11 adult patients, whereas others may have a remote history of migraine type headache. In addition, a family history of migraine particularly prominent in the maternal lineage is also prevalent among patients with CVS who themselves may not have migraine Migraine headache, abdominal migraine and CVS are postulated as manifestations of a common diathesis. Although this spectrum is not present in all migraine patients, individual patients may progress from one disorder to the other over time. Such terms as abdominal migraine and abdominal epilepsy are mentioned in the literature. 2 This is more likely for the paediatric onset population where reports suggest up to 80% correlation of migraine and CVS. 20, 22 In adults, this association is generally up to 25% 7 9, 11 and only accounts for a subset, some of whom may have had a paediatric onset anyway. The efficacy of antimigraine medications like tricyclic antidepressants to prevent or attenuate the severity and duration of cyclic vomiting episodes supports a common pathogenic link with migraines. 2, 7 Diabetes mellitus occurs in up to 13% 23 of CVS patients, which is actually more than the prevalence of diabetes in the general population regarded as approximately 8%. 24 Overall, the blood glucose control is quite good in the days leading up to an episode and there is no consistent evidence that cyclic vomiting could be part of diabetic ketoacidosis. However, optimal control of blood glucose is important when trying to minimise relapses of cyclic vomiting long term. Psychiatric disorders, including anxiety and depression, are frequent comorbid findings in patients with CVS. A subset of patients have panic attacks that may trigger relapses in two-thirds of adults. 7 9, 11, 25 Co-existing psychological disorders such as depression or anxiety are more common in the patients who are not responding to standard treatment with TCAs than in the responders. 11 It is still unknown whether mental illness contributes to the symptoms, or co-exists with CVS. Our experience indicates that TCAs are more effective in CVS patients without co-existing psychological disorders and depression. In a recent trial, 35% of patients who did not respond to TCAs in terms of clinical status had either depression or an anxiety disorder as a coexisting 266 Aliment Pharmacol Ther 2011; 34:

5 Review: cyclic vomiting syndrome Table 1 Demographic and clinical profile of adult CVS patients in three major published CVS cohorts Characteristic N (%) Hejazi et al. 11 Prakash et al. 9 Namin et al. 8 Gender Male 72 (55) 8 (47) 18 (58) Female 60 (45) 9 (53) 13 (42) Race N A N A Caucasian 117 (89) African-American 13 (10) Hispanic 2 (2) Others 0 Mean age (years) 34 4 (range 20 68) (range 18 62) Age of onset (years) Age of diagnosis (years) 28 3 N A N A Psychological disorder 18 (14) 4 (23)* Depression 8 (6) 24 (78) Anxiety disorder 10 (8) 26 (84) Migraine headache 30 (23) 4 (24) 4 (13) IBS 12 (9) N A 10 (32) Diabetes mellitus 10 (8) N A 2 (6) Cholecystectomy N A N A 7 (23) GI surgery N A 3 (17) 6 (19) GE reflux N A 9 (53) Smoking 36 (28) N A N A Chronic marijuana use 34 (26) None 13 (42) Chronic narcotic use 26 (20) None N A CVS, cyclic vomiting syndrome; GE reflux, gastro-oesophageal reflux; GI, gastrointestinal. * Chart notation of currently active anxiety state or affective disorder. diagnosis, and it was significantly more frequent in the nonresponders than in the responder group [ (11%), P < 0.05]. 11 This is evidence that the presence of a severe psychological disorder in CVS may need to be separately managed. In another study, Namin et al. 8 reported that half of their patients felt that they would attribute mental stress as a contributory factor for their attacks. However, the results of the Hamilton Rating Scale for Anxiety (HAM-A) indicated that 26 (84%) of these same patients were actually suffering from an anxiety disorder. In addition, the Zung Depression Inventory revealed depression in 78% of those patients with the majority being categorised as moderate or severe levels of depression. Marijuana use has been postulated as a contributing factor in some patients with CVS. 25 The typical history is that use begins recreationally during teenager years and some may continue smoking daily into adulthood. In a subset of these chronically exposed subjects, recurrent vomiting attacks develop. On the other hand, marijuana is also used by CVS patients intermittently for alleviating nausea vomiting symptoms and this approach along with hot showers and baths can be a useful technique for patients to overcome some attacks. 25, 26 However, there is literature indicating that in the group where chronic marijuana use predates the onset of CVS symptoms, the cessation of cannabis can lead to lessening or even termination of the cyclic emesis In studies where these patients were later re-exposed to marijuana in a randomised fashion, there was evidence 26, 28 that the re-exposure could provoke an attack. In one extensive experience, chronic marijuana was elicited in up to 42% of patients, mainly in males, but was thought to provoke a cycle of CVS in only a small subset (approx.5%). 8, 11 Therefore, the role of marijuana as a causative or triggering agent in CVS is still not clear. Nevertheless, patients should be encouraged to taper, decrease and try to stop marijuana and replace it if Aliment Pharmacol Ther 2011; 34:

6 R. A. Hejazi and R. W. McCallum necessary with antianxiety agents or substituted with marinol. It remains unknown whether chronic marijuana use can have deleterious effects on the endogenous cannabinoid system or if other constituents or contaminant of the marijuana related to the source of purchase can be inhaled, and accumulate in toxic quantities. 2 Also, cannabinoid preparations can inhibit gastric emptying of solid food in humans, 30 which may explain why its chronic use is not positive and suggests one mechanism for a provocative role for inducing cycles. Functional GI disease can be a comorbid disease in some CVS adult patients as irritable bowel syndrome (IBS) was found in 10 of 31 patients (32%) in one series 8 and 10% in other series. 11 THEORIES OF PATHOGENESIS Investigators have postulated possible pathophysiologies of CVS. Such theories include psychological or infectious stressors, which initiate central arousal and the cascade of hypothalamic pituitary adrenal (HPA) axis activation, to explain the role of a centrally acting mechanism of CVS. In this theory, it is hypothesised the corticotrophin releasing factor (CRF) signalling system is activated by stressors (e.g. infections, psychological, energy depletion) and plays an important role in mediating autonomic (sympathetic activation and vagal inhibition) alterations that impact on gut motility. 31 It is supported by data emphasising that various immunological, psychological or physical stresses can precipitate the episodic occurrence of emesis in 70% of children with CVS as well as morning predominance for the onset of symptoms. 4 Recent diagnostic investigations such as functional magnetic resonance imaging (fmri) and positron emission tomography (PET) studies showed evidence of altered responsiveness of central arousal circuits involving the amygdala, cingulated cortical subregions and pontine regions, including the periaqueductal grey region and the locus ceruleus complex in several functional GI disorders stress-sensitive disorders, including migraine headaches, which share altered responsiveness and modulation of central arousal circuits, including dysregulation of the periaqueductal grey (PAG) area. 32 Preliminary results from functional O-PET brain imaging in adult patients with CVS suggest alterations in brain areas that deal with heightened awareness and anxiety (the cingulated cortices) as well as those that deal with pain and pleasure (the inferior frontal cortex). 33 The tight linkage between migraine headache and CVS has suggested these diseases as a common pathophysiological mechanism with diverse manifestation attributed to more generalised underlying central nervous system disorder. 34, 35 It is hypothesised that CVS is a variant of migraine in that the headache may not be present, but an aura feeling or flashing lights in the eyes may be reported, which is part of the migraine spectrum. The role of the autonomic nervous system is evolving from studies that reported increases in sympathetic tone in children with CVS in tests of autonomic function including postural adjustment ratio, heart rate variability, tilt table and sudomotor testing In two recent reports, autonomic nerve dysfunction was common in adult CVS patients, being observed respectively in and 48% 40 of their cohorts. These dysautonomic features in patients with CVS led to the hypothesis that sympathetic autonomic imbalance may render patients more susceptible to over-respond to central emetic signals. 2 The presence of mitochondrial dysfunction that leads to cellular energy deficits and contributes to autonomic dysfunction was postulated as a possible pathophysiological mechanism in paediatric CVS. Defects in mitochondrial energy production due to mutations may predispose individuals to the onset of vomiting during periods of heightened demands for energy (e.g. stress, infections) These hypotheses are supported by reports of mitochondrial DNA (mtdna) heteroplasmic mutations (i.e. two species of mtdna present in the sample) and CVS and migraine-associated homoplasmic polymorphisms in the small (1 kda) mtdna control region of a subset of children with CVS To determine the mtdna polymorphism, a study was conducted in adults and children with CVS. In this study, a strong association of 16519T and 16519T+ 3010A polymorphism with childhood onset CVS and adult migraine was found, but no association was identified in the adult onset CVS population T polymorphism confers an increased risk for CVS in children with an odds ratio of 6.3 vs. only 1.6 in adults. 47 These data suggest that the previously reported 48 strong association of CVS with the and 3010 mtdna migraine-associated polymorphisms is restricted to paediatric-onset CVS and absent in adult-onset CVS. 47 Although these data suggest that paediatric-onset and adult-onset CVS cases are genetically distinct, the adultonset CVS may also be associated with energy metabolism 47 in ways that are yet to be discovered and will require future research. While we conclude that adult CVS may be genetically distinct from paediatric CVS, this study also suggested a strong association of adult CVS with co-morbid migraine and multiple other functional disorders Aliment Pharmacol Ther 2011; 34:

7 Review: cyclic vomiting syndrome Abnormal Gastric emptying (GE) has been hypothesised as one pathophysiological mechanism of CVS; initially, this was based on reports of rapid gastric emptying present between attacks in adults with CVS. 8, 49 Understanding the role of gastric emptying (GE) in CVS is very important as a means for distinguishing CVS patients from gastroparesis patients. It is key to realise the timing of the GE study in the clinical spectrum of CVS patient. Rarely can a GE be done during an acute attack or relapse of CVS. In the few reports in which it was accomplished, GE was inhibited and slow. 8 The vast majority of reports analyse GE data during the remission periods between acute attack and these will be summarised. In a study of 92 adults CVS, rapid gastric emptying was observed in 59% of patients, while 27% had normal GE and the remaining 14% had slow GE. 23 The presence of rapid GE in majority of CVS when studied during the remission phase of the disease is now a very important way of differentiating adult CVS from gastroparesis. Interestingly, in this rapid emptying group, there is a low grade of nausea and dyspepsia during the remission phase and up to 15% also had IBS symptoms, being attributed to the exaggerated gastro-colic reflex and a component of mild dumping syndrome. The subgroup with delayed GE could be explained by being studied during a hospitalisation where narcotics were being given or as out-patients when narcotics use was continuing or marijuana was being used. They should not to be confused with idiopathic gastroparesis, because when gastric emptying was repeated without influence from narcotics or marijuana, it was rapid or normal. This is a key clinical point in separating CVS from idiopathic gastroparesis. In a separate study, 545 patients were referred to a GI motility centre with nausea, vomiting, and 48 (9%) had rapid gastric emptying. Cyclic vomiting syndrome was the dominant aetiology of rapid GE in this population as summarised in Table Delayed GE has actually been reported during the actual vomiting phase in some patients when this test could be performed. 8 The explanation for this inhibition may relate to potential neuroendocrine mediators such as CRF and related downstream effector pathways cortisol production and prostaglandins E2 as well as autonomic alterations. These factors may initiate or sustain the vomiting in CVS 2 as well CRF is a potent inhibitor of gastric emptying and it was proposed that altered CRF receptor-mediated signalling plays a key role in triggering emesis in patients with CVS. 2 Interestingly, Table 2 Aetiology of rapid gastric emptying in 48 patients with dumping syndrome Female Male Total (%) Number of patients Cyclic vomiting syndrome (35) Nausea Vomiting in non-ulcer dyspepsia (25) Diabetes mellitus (13) Fundoplication Vagotomy (11) Diarrhoea and abdominal (11) pain of unknown origin (IBS) Gastric bypass (6) Adapted from Hejazi et al. 14 tricyclic antidepressants reduce the frequency of vomiting episodes and inhibit the promoter activity of the CRF gene. 31, 50, 51 A preliminary study reports elevated peripheral CRF levels in affected children during active vomiting episodes. 52 Could gastric motility abnormalities explain some of the symptoms between acute cycles? In addition to rapid gastric emptying, there are abnormalities on electrogastrography (EGG) in patients with CVS; specifically, tachygastria and blunting of the amplitude of waves in 8, 10 response to meal ingestion were reported. Ghrelin, a hormone locally produced in the gut mucosa and is released with a meal, has been postulated as a potential mechanism for rapid gastric emptying in humans. Acceleration of gastric emptying has been documented in humans. 53 In the first report addressing serum ghrelin levels in adult patients with CVS, mean fasting serum ghrelin levels in adult CVS patients were significantly elevated compared with the range for the normal subjects. Thirteen (59%) of CVS group had rapid GE (<50% retention at 1 h) and their mean ghrelin level was 1105 pg ml, higher when compared with 1016 pg ml in CVS patients with a normal GE (n = 9). These elevated serum ghrelin levels in adult CVS suggest a potential contribution for serum ghrelin in explaining the finding of the rapid GE observed in the majority of CVS patients when in the remission state. 54 It does not address what then provokes the CVS changes leading to a vomiting cycle and inhibition of gastric emptying. The question to be answered is why rapid GE suddenly becomes inhibited, as nausea and abdominal pain signal the onset of relapse cycle in these CVS patients. The central control mechanisms that could inhibit ghrelin Aliment Pharmacol Ther 2011; 34:

8 R. A. Hejazi and R. W. McCallum release while initiating nausea, vomiting and abdominal pain are areas for future research. Table 3 Differential diagnosis of cyclic vomiting syndrome Gastric disorders Peptic ulcer disease, gastroparesis Biliary tract dysmotility Pancreatitis, Intermittent small bowel obstruction Chronic intestinal pseudo-obstruction Malrotation with volvulus Extra-intestinal disorders Central nervous system abnormalities (e.g. mass and hydrocephalus) Renal disorders(e.g. nephrolithiasis, ureteropelvic junction obstruction) Hormonal and metabolic disorders (e.g. adrenocortocoid insufficiency, acute intermittent porphyria) DIAGNOSTIC TESTS AND DIFFERENTIAL DIAGNOSIS As CVS has no specific diagnostic feature, the lists of clinical disorders that mimic CVS are extensive and primarily related to the abdominal pain, which may be concentrated in the epigastrium and upper abdomen but also is diffusely radiating. This pain generally requires narcotics initially and can lead to many diagnostic adventures. The most important gastrointestinal diseases that should be ruled out are summarised in Table 3. Although no specific test can diagnose CVS, some initial screening studies and laboratory tests (complete blood count and differential, glucose, electrolytes, liver chemistries, pancreatic enzymes and pregnancy test), urinalysis, and plain flat and upright radiographic series are helpful to exclude some organic cause of chronic nausea vomiting and, if present, complications of CVS. Some patient may have a mildly elevated WBC and lactic acidosis secondary to severe vomiting, starvation and ketosis. Other specialised tests such as upper endoscopy, CT scan, gastric emptying study and hormonal testing generally follow. Sometimes, the gall-bladder is removed in the name of pain. Because of the delay in diagnosis related to many visits to the ER where abdominal pain control is being requested with narcotics, then the patient can develop a reputation as exhibiting drug-seeking behaviour. Patients miss more and more time from employment and their jobs and finance can be threatened because of their unreliability, as well as severe disruption in personal and family life. TREATMENT Treatment of CVS is based on identifying and avoidance of triggering factors, prophylactic drug therapy to prevent recurrent episodes, abortive treatment and or supportive care to ameliorate acute episodes, and psychological support of the patients and family. Avoidance of known triggering factors such as emotional stress, energy-depleting states (sleep deprivation, fasting and infection) and marijuana is crucial and some triggering foods (e.g. chocolate, cheese, monosodium glutamate and red wine) have been incriminated. As a pharmacological prophylaxis, tricyclic antidepressants (TCA) are shown to be effective in several studies. 7 9, 55 Historically, in the literature, amitriptyline has been the dominant TCA, and our experience is mainly with this agent. Tricyclic antidepressants should begin with a low initial dose (e.g. amitriptyline 10 mg at night) with incremental increases in dose to titrate to the desired therapeutic effect (range 1 2 mg kg day). Dose increases should be attempted by increments of 10 mg every 2 3 weeks (if tolerated) to quickly achieve the dose goal. There is no specific dose in mind but control of symptoms and prevention of cycles is the goal. In patients where amitriptyline cannot be tolerated, newer TCAs such as doxepin can be tried. 7 In migraine-associated CVS and in children with CVS, b-adrenoceptor antagonist propranolol and histamine (H1) serotonin receptor antagonist cyproheptadine added to TCA and or prescribed alone have controlled the symptoms and prevented attack successfully. 53 In adults, we recommend topiramate when a headache background is present in a dose of mg day to prevent migraine and this is added to the TCA. Other specific co-existing conditions can be managed by adding other medications: low-dose benzodiazepine (e.g. lorazepam 1 mg p.o. up to four times day) for decrease in anxiety and panic; antispasmodic (dicyclomine) for IBS-like related abdominal pain, particularly in those patients with rapid gastric emptying and an exaggerated gastro-colic reflex; proton pump inhibitors for gastro-oesophageal reflux symptoms attributed to contact with vomited contents; antiemetic agents such as ondansetron, promethazine, or prochlorperazine for back up nausea, and some may need abdominal pain management with non-narcotics e.g. tramadol, ketorolac and infrequently limited narcotic use. 270 Aliment Pharmacol Ther 2011; 34:

9 Review: cyclic vomiting syndrome TREATMENT DURING VOMITING EPISODE Treatment during the vomiting phase has the goals to prevent dehydration and terminate the cycles of nausea and vomiting and abdominal pain. This involves rehydration and antiemetic, antianxiety and or analgesic medications. Intravenous fluid replacement should be with 5 10% dextrose solution, and include potassium replacement. Anti emetic agents such as promethazine, diphenhydramine and 5-HT3 receptor antagonists such as ondansetron may be effective during the acute emetic phase when administered intravenously in high doses. Deep sedation and induced sleep are most highly effective for this entity and benzodizepines (e.g. lorazepam 1 2 mg i.v. every 3 h) should be the main approach to treating patients in the emergency room or if they require admission. Intravenous narcotics may be initially needed (e.g. morphine, hydromorphone hydrochloride). Intravenous diphenhydramine may also be complementary to promethazine and ondansetron in the hospital setting. LONG-TERM MANAGEMENT Treatment results with TCA s have been positive in more than 80% of our patients and significantly decreased the duration and frequency of episodes and emergency visits and hospitalisation in adult CVS patients. Their side effects seen in one-third of our patients were: dry mouth, somnolence, constipation, postural hypotension, chronic fatigue, blurred vision and mild hallucinations, and are generally well tolerated. 7 In addition, these side effects can be minimised by slowly increasing the dose by 10 mg every 2 4 weeks and decreasing the dose for a while if side effects occur. In our experience, only 3 4% of patients actually had to stop using TCAs. 7 We then rely on other TCAs such as nortriptyline and doxepin as substitutes with less adverse events, but still with therapeutic benefits. Amitriptyline blood levels can be useful in guiding the dosing regimen and also confirming that patients are definitely taking the agent. The normal therapeutic amitriptyline blood levels are , and a level >500 is regarded as a toxic level. To investigate the demographic and clinical characteristics of adult CVS patients not responding to standard TCA therapy, we performed a study of 132 adults (62 men) with cyclic vomiting syndrome followed for a mean of 1.6 years. Of these, 17 (eight men) patients were identified as nonresponders based on the criteria of unchanged, increased or minimally changed (<25%) frequency duration of episodes and or emergency department visits hospitalisations. In this study, nonresponse to standard therapy in adult CVS patients was observed in approximately 13% and was not explained by the level of dosing with TCA therapy. The main risk factors for nonresponse were: co-existing poorly controlled migraine headache, psychiatric disorder, chronic narcotic and marijuana use. 11 These issues should be addressed aggressively when symptom exacerbations continue during attempts to induce remission in cyclic vomiting syndrome with high-dose TCA therapy. In patients who cannot tolerate increased doses of TCA or are still breaking through or requiring hospitalisation, we recommend adding to the amitriptyline either levetiracetam (500 mg to up to 3000 mg day) or Zonisamide ( mg day). These medications were approved by the FDA for the treatment of epilepsy, but then tried with success in CVS. 56 They can be also used alone where they are regarded as second line therapy in adult CVS. Other novel pharmacological treatments for CVS focus on improving mitochondrial function. L-Carnitine is an amino acid-like compound whose primary function is to transport long chain fatty acids into mitochondria for oxidation. Oral L-carnitine (available as over the counter in US, doses up to 3 g day) has been reported to reduce the frequency of CVS attacks in some cases. 57, 58 Efficacy of co-enzyme Q10 (doses up to 300 mg day), a hydrophobic substance, serves as an electron carrier in the mitochondrial respiratory chain and as an antioxidant. Its efficacy in CVS has not been 59, 60 confirmed. FUTURE RESEARCH An important area for the future research is the question whether TCAs can be slowly tapered and the patient return to his her previous asymptomatic state. This is very relevant in young women who may be considering pregnancy because amitriptyline is listed as a class B drug regarding safety in pregnancy. Can there be a re-normalisation of brain-gut balance that abruptly changed at the time when CVS commenced? Can the previously balanced state be restored and the triggers which changed the equilibrium be aborted and can adaptation occur to the point that no pharmacological therapy is needed? These questions will need to be addressed and will be an important future area for research and clinical trials. Overall, this is all part of the bigger question: what is the long-term outcome of these adult patients with CVS? For now, the treatment message is to induce a remission and only then consider some tapering of the TCA dose in a very slow fashion. The drug is safe, whereas the relapses of CVS are severe and remission is the goal. Aliment Pharmacol Ther 2011; 34:

10 R. A. Hejazi and R. W. McCallum CONCLUSIONS The entity of cyclic vomiting in adults has evolved in the span of 25 years from being undiagnosed and not even thought of, from being termed abdominal epilepsy and abdominal migraine to now a fully accepted, well-defined problem with a unique clinical calling card separating it from the other clinical states that explain vomiting. The good news for clinicians is that it can be diagnosed in the office, ER or at the bed side by just listening carefully to the history of dramatic episodes interspersed with quiescent periods of varying length, with slow coalescence of the vomiting attacks over time if no treatment is started. Then confusion with gastroparesis begins, but is quickly resolved by doing a gastric emptying study confirming either rapid or normal GE clearly distinguishing it from gastroparesis. The best news, however, that is it is an immensely treatable problem where remission can be induced and sustained by chronic TCAs therapy, safe and well-tolerated agents. This treatment can restore lives that have been ravaged by undiagnosed CVS, a condition not responding to generic antiemetics and promotility agents. The challenge is to explain the dramatic onset of this condition in apparently normal adults, the central mechanisms as well as the biochemistry of the triggering events. Another question that is beginning to be addressed is to understand the long-term natural history. The take-home message, however, is that an old friend from the 19th century was resurrected, recognised, defined and re-discovered in adults in the 21st century. CVS has gone its own full cycle to become an important and increasingly diagnosed as well as treatable explanation for the combination of recurrent unexplained attacks of nausea, vomiting and abdominal pain. 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