CYCLIC VOMITING SYNDROME

C. Prakash Gyawali, MDProfessor of Medicine

Washington University in St. Louis

Case

Symptoms began at age 19 yr5-6 day episodes of recurrent, severe vomiting with

stereotypical course every 3-6 monthsFrequent hospitalizations with attacks because of

dehydrationAsymptomatic between episodesMultiple endoscopies and abdominal imaging studies

26 year old male

Definition and Clinical Features

Cyclic Vomiting Syndrome

Recurrent stereotypical periods of acute nausea and vomiting (at least 3 episodes in past year)

Symptom-free intervals lasting weeks to months

No structural or metabolic explanation for the symptoms

Personal history or family history of migraines is supportive of diagnosis

Adapted from: Rome III criteria, 2006

Functional Vomiting• One or more episodes of vomiting a week• No evidence of eating disorder, rumination or major

psychiatric disease• Absence of

– self induced vomiting– chronic cannabinoid use– CNS abnormalities– metabolic syndromes

• Chronic: symptom onset at least 6 months before diagnosis, criteria fulfilled for past 3 months

Adapted from: Rome III criteria, 2006

CVS in an Adult GI Practice

<1% of out-patient referrals0.04-1.9% prevalenceAll age groups, ethnicities

Prakash C & Clouse RE Am J Gastroenterol 1999; Pareek N, Am J Gastroenterol 2007

Delay in Diagnosis of CVS

0

4

8

12

16

0

4

8

12

16

20

<12 years at onset>12 years at onset

Before 1995Since 1995

Year

sYears

Prakash C, Staiano A, Rothbaum RJ, Clouse RE Am J Gastroenterol 2001

Outcome of ER Visits

Venketasan T, BMC Emergency Medicine 2010;10:4

Phases of Adult CVS

Prakash C & Clouse RE Am J Gastroenterol 1999

Episode Inter-episode period

Age at onset35 ±4 yr

Episode duration6 ± 1 days

Inter-episode time3.1 ± 0.5 months

Prodrome Recovery

Associated Clinical Features of CVS

Prodrome30%

NauseaLethargyAnorexia

Epigastric painHeadache

Precipitants~50%

InfectionsMenses

PregnancyLarge meals

Stress

Alleviants<50%

SleepDark room

Associated symptoms >70%

AnxietyAbdominal pain

PhotophobiaPhonophobia

Social withdrawalHeadache

Prakash C & Clouse RE AJG 1999; Pareek N AJG 2007

Clinical characteristic Prevalence

Extensive invasive testing All subjects

At least one hospitalization

All subjects

Esophageal damage from vomiting

59%

Surgical exploration with intervention

18%

Other Features of CVS in Adults

Prakash C & Clouse RE Am J Gastroenterol 1999

Associated Conditions

CVS General Population

Migraine 11-40% 9-20%IBS 67% 10-20%Headache 52% unknownMotion sickness 46% unknownSeizure disorder 5.6% 0.5-1%

Prakash C & Clouse RE Am J Gastroenterol 1999; Pareek N, Am J Gastroenterol 2007

Migraine diathesis

CVS Abdominal migraine

Migraine headache

Family history of migraine

40-82% 65% 62%

Prevalence 0.4-1.9% 1.7-2.7% 5-20%Vomiting 100% 30-70% 40-70%Abdominal pain 5-80% 100% 10-55%Headache 35-60% 30-50% 100%

Matrilineal inheritanceAbnormal adrenergic tone

Pareek N, Am J Gastroenterol 2007

Mechanisms

PredispositionsMechanismsSympathetic autonomic

imbalance

Abnormal gastric motor response

Mitochondrial dysfunction

Defective cellular energy productionTriggers

Stimulation of arousal mechanisms

Vomiting response during periods of heightened

cellular energy demand

Episode of cyclic vomiting syndromeprodrome, vasomotor symptoms,

nausea, vomiting, exhaustionCRF release, HPA axis activation

Investigation

Exclusion of Organic Disease

• Complete blood count• Complete metabolic profile• Pancreatic enzymes• Urine analysis• Pregnancy test• Cross-sectional imaging (abdomen, brain)• Contrast studies• Endoscopy• EEG

leukocytosis

erosive esophagitis

Autonomic Dysfunction

Venkatesan et al, Neurogastroenterol Motil 2010;22:1303-e339

Exaggerated cardiovascular responses and heart rate variability to postural change (To 1999)

Gastric Emptying in CVS

Hejazi RA et al, Neurogastroenterol Motil 2010;22:1298

narcoticsmarijuanadiabetes

GET may fluctuate depending on phase of illness – rapid during remission, variable during episodes

Management

Management Goals

Fleisher DR et al, BMC Medicine 2005;3:20

Abortive Management: Prodrome• Lifestyle Changes/Relaxation Techniques

– Decrease stress (dark, quiet room)– Hot bath or hot shower

• Antimigraine therapies– 5-HT1D agonist (sumatriptan, zolmitriptan, frovatriptan)

• Antiemetics– 5-HT3 antagonists (ondansetron, granisetron)– Antihistamines (diphenhydramine)– Phenothiazines (promethazine, prochlorperazine)

• Anxiolytics– Benzodiazepines (lorazepam)

• Other - High carbohydrate liquids, ibuprofen

Abell TL et al, NGM 2008;20:269-284

Abortive Management: Emetic PhaseClass Example

Supportive Dark, quiet surroundings

Hydration IV fluids D100.45NS, 1.5 x maintenance

Antiemetics 5HT3 antagonists Ondansetron

Phenothiazines Promethazine, prochlorperazine

Antihistamines Diphenhydramine

D2 antagonists Metoclopramide, domperidone

Anxiolytics Benzodiazepines Lorazepam

Analgesics NSAIDs Ketolorac parenteral

Opioids Hydromorphone IV/PCA, fentanyl

Antimigraine 5HT1B/1D agonist Sumatriptan parenteral

Acid suppression Proton pump inhibitors Omeprazole, esomeprazole

Abell TL et al, NGM 2008;20:269-284

Response of Vomiting Syndromes to Low-Dose TCAs

0

20

40

60

80

CVS Functional vomiting

Subjects (%)

Completeremission

Partialresponse

Noimprovement

Prakash C & Clouse RE 1999

p=0.02 between groups

88% reported improvement in CVS symptoms with TCA therapy- Hejazi R, McCallum R, et al, JCG 2010

Characteristics of Non-Responders

Hejazi et al, APT 2010;31:295-301

Newer Antiepileptic Drugs for Cyclic Vomiting Syndrome

Clouse RE, Sayuk G, Prakash C. Clin Gastroenterol Hepatol 2007

Abortive & Maintenance Treatments

• Ondansetron (Zofran)• Lorazepam (Ativan)• Sumatriptan (Imitrex)• Promethazine

(Phenergan)• Diphenhydramine

(Benadryl)• Erythromycin• Narcotic analgesics

• Tricyclic antidepressants

• Propranolol (Inderal)• Cyproheptadine

(Periactin)• Antiepileptics• Topiramate• Valproate• Phenobarbital

Abortive treatments Maintenance treatments

Experimental Therapies

• Mitochondrial Stabilization– L-Carnitine 330 mg, 2-3 pills 2-3 times a day– Co-enzyme Q10, upto 10 mg/kg/day

• Autonomic dysfunction– α receptor antagonist: Phentolamine,

dextromedetomidine• Antiemetic

– NK1 receptor antagonist: aprepitant (Emend)– Granisetron patch (Sancuso)

Abell TL et al, Neurogastroenterol Motil 2008;20:269-284

Prodrome30%

SumatriptanOther triptans

SedativesAnalgesics

Precipitants~50%

Treat if possible

Alleviants<50%

SleepDark room

Associated symptoms >70%

Analgesics for painSedatives for anxiety

AntiemeticsIV fluids with dextrose

Prakash C & Clouse RE AJG 1999; Pareek N AJG 2007

sedatives anxiolytic* β-blockerclonidine

anxiety level

*sertraline, venlafaxine, paroxetine

hemodynamic reactivity

Provide Support Information & Simplify Measures for Acute Treatment

CVSA-USA/Canada

www.cvsa.org

“…carries the diagnosis of cyclic vomiting syndrome.”

“…symptoms typically respond to intravenous…”

“…prompt treatment can avoid hospitalization…”

“…avoid imaging and other investigation…”

CVS occurs in adults, and onset can be at any age

Rest, quiet environment, social stability over the diagnosis are important (including simple measures to expedite emergency medical care)

Standard antiemetics and anti-migraine treatments can be helpful in breaking episodes; scheduled benzodiazepines are administered early

Careful use of tricyclic antidepressants is the most successful prophylaxis

Summary