Cyclic Vomiting Syndrome: Pearls and Pitfalls

Author: Brit Long MD (@long_brit, EM Chief Resident at SAUSHEC, USAF) // Edited by: Alex Koyfman MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Stephen Alerhand MD (@SAlerhand)

A 28 year-old male presents with 14 hours of repeated bouts of emesis. He has a history of chronic, recurrent headaches, but has never seen a physician for the headaches. The emesis is non-bloody and non-bilious. He has had no diarrhea or fevers, but has had some minor abdominal cramping associated with the vomiting. He states this has happened four times prior to this current episode.

His vital signs are normal, and the physical exam reveals dry mucosa with no abdominal tenderness or peritoneal signs. You order ondansetron, a liter of normal saline, and a basic metabolic panel as you begin to think about the differential. Are there any other tests including labs or imaging that could help?

Background

Cyclic vomiting syndrome (CVS) was first described in the 1800’s. It is defined by recurrent episodes of vomiting, with episodes of normal health in between.^1-3

But first, why is this disease important? Unfortunately, the disease can be disabling. Social functioning, work, and education often suffer due to the recurrent episodes. Patients may have up to 10 ED visits per year, with over 5 ED visits before actual diagnosis. Approximately 93% of patients will not be diagnosed in the ED!¹ Unfortunately, close to 32% of patients will be completely disabled by the time of diagnosis.² A little knowledge can go a long way, as many providers do not understand what this disease entails.

The incidence of CVS varies. One study consisting of predominantly Caucasian pediatric patients found a prevalence of 0.04%.³ Other studies consisting of pediatric patients have demonstrated prevalence of 0.5% to 2.3%.^3-5 The median age in these studies was 4.8 years, but ages affected include those as young as 6 days to those at the other end of life (73 years).⁶ In children, the average age of diagnosis is 9.6 years, with onset of symptoms at 5.3 years. In adults, the average age of first symptom onset is 21 years, but most are not diagnosed until age 34. Females are slightly more affected than males. Caucasians are more commonly affected.^4-7

Unfortunately, the pathophysiology is not currently well understood. There are several proposed brain-gut mechanisms, with an association with migraine headaches.^3-6 Sympathetic hyper-responsiveness and autoimmune dysfunction may contribute.⁸ The stress response mediated by the hypothalamic-pituitary-adrenal axis is also correlated with CVS.^8,9 Mutations in mitochondrial DNA may also be associated, particularly in pediatric patients.¹⁰ Cannabis use has received recent attention, as chronic abuse can increase the risk of CVS.¹¹

History

As discussed above, CVS is defined by recurrent stereotypical episodes of vomiting with episodes of normal health in between the vomiting. However, adult patients often lose this cyclic pattern, with 63% developing nausea in between episodes.^2-4

The peak rate of emesis is usually 6 per hour.¹² In pediatric patients, greater than 4 episodes of emesis per hour demonstrated a sensitivity of 92% and specificity of 100% for the diagnosis.¹³ Symptoms usually begin early in the morning or upon waking, with a prodrome of nausea that is soon followed by vomiting within one hour. The episodes peak and then decline over the following 8 hours. The nausea is severe and not completely relieved by vomiting.^3,4 Other symptoms are common such as abdominal pain, present in 60%-80% of patients, which may be severe and mimic an acute abdomen.^12,14 Fever and/or diarrhea can occur in 1/3 of patients, and pediatric patients often experience decreased activity and pallor during the episodes.³ CVS episodes are often associated with headache (43%), vertigo (26%), and photophobia (38%).^3,6,12

Children usually have 12 cycles per year, with adults having 4 cycles per year. Nausea between episodes is more common in adults. Children have shorter episodes when compared to adults (1-2 days vs. 3-6 days). ^2,3,6,12

Most pediatric patients will identify the trigger, which is most commonly infection (41%). Other stressors include psychological, physical exhaustion, specific foods (cheese, chocolate), motion sickness (9%), and sleep deprivation (18%).^3,6 Adults less commonly have a trigger.

Official criteria differ for pediatric and adult patients.

Pediatric – North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN): 1) At least 5 episodes, or a minimum of 3 over 6 months. 2) Episodes of nausea/vomiting lasting 1 hr to 10 days, with 1 week in between. 3) Stereotypical pattern and symptoms. 4) Return to baseline health in between episodes. 5) Symptoms not due to another disorder.¹⁴

Adult – Rome III criteria: 1) Stereotypical episodes of vomiting with acute onset lasting less than 1 week. 2) At least 3 episodes per year. 3) Absence of nausea/vomiting between episodes. 4) No other disorder accounts for symptoms (GI, metabolic, CNS, biochemical).¹⁵

Red Flags

This is where the emergency physician shines. Signs of an alternative diagnosis include severe headache, gait abnormality or other focal neurologic deficit, confusion, GI bleeding, localized abdominal pain, weight loss, progressive worsening, or a change in the typical episode pattern.^3,13,15 Remember, it is very common for these patients to experience generalized abdominal pain.

Workup

Currently, no diagnostic markers have been identified for CVS. Due to the risk for volume loss and severe emesis, a renal function panel, lipase, urinalysis, and liver function panel can assist providers in the evaluation for other conditions. However, these tests will likely be normal. Physicians should be on the lookout for red flags such as severe abdominal pain, bilious vomiting, abnormal neurologic findings, severe headache, abnormal mental status, and progressively worsening symptoms/episodes. Emesis should be non-bloody with no bilious material. The abdominal pain is often cramping in nature and improves between episodes. Severe pain that does not improve is not characteristic and suggests another diagnosis.^6,14-16

Metabolic disorders are associated with a presentation before age 2 years, vomiting with other illness/fasting/increased protein intake, any neurologic findings, and any laboratory finding such as hypoglycemia or acid-base disturbance.¹⁷ If concern for metabolic disease exists in the pediatric patient, other labs including serum pH (VBG), ammonia, amino acids, ketones, and lactate should be obtained.

The vast differential creates a conundrum for physicians in terms of imaging. Various modalities including endoscopy, upper GI radiography with small bowel follow-through, CT, gastric emptying study, and ultrasound have all been proposed. The majority of studies have looked at pediatric cohorts. One study found that UGI radiography with follow-through as most cost-effective.¹⁸ This is one study we often cannot obtain in the ED. The clinician at the bedside should tailor the workup to the patient. If concerned about neurologic pathology, head CT should be obtained. If the patient has diffuse pain or localized pain that does not improve, abdominal/pelvic CT is warranted. Overall, the tests with highest yield are endoscopy, head CT, small bowel radiography, and abdominal CT.¹⁷ Due to the high prevalence of abdominal pain in adult patients (approaching 80%), abdominal CT is often needed if the patient has not been diagnosed with CVS. If the patient states this is a typical exacerbation and no other red flags are present, imaging may be deferred.¹⁵

Treatment

If no etiology is found based on studies, empiric treatment involves 1) trigger avoidance, 2) abortive therapy, and 3) supportive care.

• Triggers: Many patients will know what causes their episodes, whether diet or psychological. Sleep deprivation and infections are other triggers. Unfortunately, avoidance is not always practical. ^14,15,19 If the condition is associated with cannabis, the patient should be counseled on the effects of the drug and the need to reduce use.

• Abortive therapy: Medications to treat an acute episode include ondansetron, promethazine, prochlorperazine, and the triptans.¹⁹ Intravenous administration is best, but many of the agents can also be provided subcutaneously, rectally, or intranasally. Ondansetron with a benzodiazepine or diphenhydramine works better than just ondansetron alone. Doses of ondansetron 0.3-0.4 mg/kg should be used. Triptans such as sumatriptan can be given subcutaneously or intranasally and have a 46% rate of improvement. Prophylactic therapy can also be used for patients with episodes that occur over one time per month or are severe and disabling.^14,20 Many of these agents are used in migraine prophylaxis! Tricyclics (amitriptyline) are often first-line, with 80% of patients improving. Zonisamide, cyproheptadine, levetiracetam, coenzyme Q10, propranolol, phenobarbital, and erythromycin are other prophylactic agents.⁶

• Supportive therapy: IV fluids with glucose can decrease illness severity by close to 40%! Provide sedative agents (such as diphenhydramine, chlorpromazine, or lorazepam) and place the patient in a quiet, dark room. Adequate sleep and hot showers can also assist in symptom relief. ^6,15,17

Patients unlikely to respond to treatment include those with chronic opiate use, psychiatric disease, and chronic marijuana use. ^22-24

Perhaps most importantly, patients and family members should contact the Cyclic Vomiting Syndrome Association. This international group provides numerous resources for patients including conferences, local support groups, and coping mechanisms.²³

Prognosis

The majority of pediatric patients will outgrow CVS by early teenage years. Unfortunately, patients often go on to develop migraine headaches, with 75% of pediatric patients affected by age 18 years. Most adults will respond well to prophylactic therapy and experience a decrease in their symptom severity and episode frequency.²²

What about cannabis hyperemesis syndrome?

This condition is characterized by patients who smoke large amounts of marijuana chronically, endure daily vomiting episodes, and have improvement of symptoms with bathing/showering using hot water. If trying to differentiate CVS and cannabis hyperemesis, the patient must stop using marijuana for at least one week. If symptoms resolve, cannabis hyperemesis is likely.²⁴

Summary

CVS is defined by stereotypical, recurrent episodes of emesis. Patients will often experience abdominal pain associated with the episodes. Evaluation for red flags is key including severe headache, gait abnormality or other focal neurologic deficit, confusion, GI bleeding, localized abdominal pain, weight loss, progressive worsening, or a change in the typical episode pattern. There is no established diagnostic workup including labs and imaging, and evaluation should be tailored to the patient and presentation. Treatment includes avoidance of triggers, aborting the acute episode, and supportive therapy.

References/Further Reading

1. Venkatesan T, Tarbell S, Adams K, McKanry J, Barribeau T, Beckmann K, et al. A survey of emergency department use in patients with cyclic vomiting syndrome. BMC Emerg Med. 2010 Feb 24. 10:4.
2. Fleisher DR, Gornowicz B, Adams K, Burch R, Feldman EJ. Cyclic Vomiting Syndrome in 41 adults: the illness, the patients, and problems of management. BMC Med. 2005 Dec 21. 3:20.
3. Li BU, Balint JP. Cyclic vomiting syndrome: evolution in our understanding of a brain-gut disorder. Adv Pediatr. 2000. 47:117-60.
4. Cullen KJ, MacDonald WB. The periodic syndrome: its nature and prevalence. Med J Aust. 1963 Aug 3. 50(2):167-73.
5. Abu-Arafeh I, Russell G. Prevalence and clinical features of abdominal migraine compared with those of migraine headache. Arch Dis Child. 1995 May. 72(5):413-7.
6. Li BU, Misiewicz L. Cyclic Vomiting Syndrome: a brain-gut disorder. Gastroenterol Clin N Am. 2003. 32:997-1019.
7. Gordan N. Recurrent vomiting in childhood, especially of neurological origin. Dev Med Child Neurol. 1994 May. 36(5):463-7.
8. Sato T, Uchigata Y, Uwadana N, et al. A syndrome of periodic adrenocorticotropin and vasopressin discharge. J Clin Endocrinol Metab. 1982 Mar. 54(3):517-22.
9. Tache Y. Cyclic vomiting syndrome: the corticotropin-releasing-factor hypothesis. Dig Dis Sci. 1999 Aug. 44(8 Suppl):79S-86S.
10. Venkatesan T, Zaki EA, Kumar N, Sengupta J, Ali M, Malik B, et al. Quantitative pedigree analysis and mitochondrial DNA sequence variants in adults with cyclic vomiting syndrome. BMC Gastroenterol. 2014 Oct 21. 14:181.
11. Parker LA, Rock EM, Limebeer CL. Regulation of nausea and vomiting by cannabinoids. Br J Pharmacol. 2011 Aug. 163(7):1411-22.
12. Li BU, Fleisher DR. Cyclic vomiting syndrome: features to be explained by a pathophysiologic model. Dig Dis Sci. 1999 Aug. 44(8 Suppl):13S-18S.
13. Pfau BT, Li BU, Murray RD, et al. Differentiating cyclic from chronic vomiting patterns in children: quantitative criteria and diagnostic implications. Pediatrics. 1996 Mar. 97(3):364-8.
14. Li BU, Lefevre F, Chelimsky GG, et al. North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition consensus statement on the diagnosis and management of cyclic vomiting syndrome. J Pediatr Gastroenterol Nutr. 2008 Sep. 47(3):379-93.
15. Venkatasubramani N, Venkatesan T, Li BUK. Extreme Emesis: Cyclic Vomiting Syndrome. Practical Gastroenterology. September 2007. 31:21-34.
16. Li BU, Murray RD, Heitlinger LA, et al. Heterogeneity of diagnoses presenting as cyclic vomiting. Pediatrics. 1998 Sep. 102(3 Pt 1):583-7.
17. Li BU. Cyclic vomiting syndrome and abdominal migraine: periodic syndromes with gastrointestinal symptoms. Int Semin Pediatr Gastroenterol Nutr. 2000. 9(3):1-8.
18. Olson AD, Li BU. The diagnostic evaluation of children with cyclic vomiting: A cost-effectiveness assessment. Pediatr. 2002.141:724-8.
19. Ozdemir HH, Bulut S, Berilgen MS, Kapan O, Balduz M, Demir CF. Resistant cyclic vomiting syndrome successfully responding to chlorpromazine. Acta Medica (Hradec Kralove). 2014. 57(1):28-9.
20. Li BU. Cyclic vomiting syndrome: a pediatric Rorschach test. J Pediatr Gastroenterol Nutr. 1993 Nov. 17(4):351-3.
21. Li BU. Cyclic vomiting: new understanding of an old disorder. Contemp Pediatr. 1996. 13:48-62.
22. Hejazi RA, Lavenbarg TH, Foran P, McCallum RW. Who are the non-responders to standard treatment with tricyclic antidepressant agents for cyclic vomiting syndrome in adults? A large single center experience. Aliment Pharmacol Ther. 2009 Oct 10.
23. Cyclic Vomiting Syndrome Association. http://cvsaonline.org
24. Simonetto DA, Oxentenko AS, Herman ML, Szostek JH. Cannabinoid hyperemesis: a case series of 98 patients. Mayo Clin Proc 2012; 87:114.