Cyclic vomiting syndrome (CVS) is a chronic functional disorder of unknown etiology that is characterized by paroxysmal, recurrent episodes of vomiting and was first described in children by Samuel Gee in 1882. Although this was initially thought to occur mostly in children, it is being recognized with increasing frequency in adults. CVS is characterized by episodes or cycles of severe nausea and vomiting that last for hours, or even days, that alternate with intervals with no symptoms.
Although the pathophysiology is unknown, various mechanisms such as corticotropin-releasing factor (CRF) and a heightened sympathetic response may play a role. Data also suggest a strong genetic component, with evidence of mitochondrial heteroplasmies that predispose to cyclic vomiting syndrome and other related disorders, such as migraine and chronic fatigue syndrome.
Each episode of CVS is similar to previous ones, meaning the episodes tend to start at the same time of day, last the same length of time, and occur with the same symptoms and level of intensity. Although CVS can begin at any age, in children it starts most often between the ages of 3 and 7. Episodes can be so severe that a person has to stay in bed for days, unable to go to school or work.
The exact number of people with CVS is unknown, but medical researchers believe more people may have the disorder than commonly thought. Because other more common diseases and disorders also cause cycles of vomiting, many people with CVS are initially misdiagnosed until other disorders can be ruled out. CVS can be disruptive and frightening not just to people who have it but to family members as well.
The Four Phases of CVS
There are 4 phases in CVS:
Symptom-free interval phase. This phase is the period between episodes when no symptoms are present.
Prodrome phase. This phase signals that an episode of nausea and vomiting is about to begin. Often marked by nausea―with or without abdominal pain―this phase can last from just a few minutes to several hours. Sometimes, taking medicine early in the phase can stop an episode in progress. However, sometimes there is no warning; a person may simply wake up in the morning and begin vomiting.
Vomiting phase. This phase consists of nausea and vomiting; an inability to eat, drink, or take medicines without vomiting; paleness; drowsiness; and exhaustion.
Recovery phase. This phase begins when the nausea and vomiting stop. Healthy color, appetite, and energy return.
What triggers CVS?
Many people can identify a specific condition or event that triggered an episode, such as an infection. Common triggers in children include emotional stress and excitement. Anxiety and panic attacks are more common triggers in adults. Colds, allergies, sinus problems, and the flu can also set off episodes in some people.
Other reported triggers include eating certain foods such as chocolate or cheese, eating too much, or eating just before going to bed. Hot weather, physical exhaustion, menstruation, and motion sickness can also trigger episodes.
What are the symptoms of CVS?
A person who experiences the following symptoms for at least 3 months―with first onset at least 6 months prior―may have CVS:
- vomiting episodes that start with severe vomiting―several times per hour―and last less than 1 week
- three or more separate episodes of vomiting in the past year
- absence of nausea or vomiting between episodes
A person with CVS may experience abdominal pain, diarrhea, fever, dizziness, and sensitivity to light during vomiting episodes. Continued vomiting may cause severe dehydration that can be life threatening. Symptoms of dehydration include thirst, decreased urination, paleness, exhaustion, and listlessness. A person with any symptoms of dehydration should see a health care provider immediately.
How is CVS diagnosed?
CVS is hard to diagnose because no tests―such as a blood test or x ray―can establish a diagnosis of CVS. A doctor must look at symptoms and medical history to rule out other common diseases or disorders that can cause nausea and vomiting. Making a diagnosis takes time because the doctor also needs to identify a pattern or cycle to the vomiting.
Pathophysiology
The etiology and pathophysiology in cyclic vomiting syndrome are not unknown. Over the last decade, studies have proposed several potential brain-gut mechanisms. Migraine-related mechanisms have been proposed, and patients with cyclic vomiting syndrome have a significantly higher prevalence of family members with migraine headaches (82% vs 14% of control subjects with a chronic vomiting pattern). Furthermore, 28% of patients with cyclic vomiting syndrome whose vomiting subsequently resolved developed migraine headaches. Finally, 80% of affected patients with family histories positive for migraine respond to antimigraine therapy.
Mitochondrial DNA (mtDNA) mutations may be involved in the pathogenesis of cyclic vomiting syndrome. Boles et al have demonstrated that, among children with cyclic vomiting syndrome and neuromuscular disease, 86% have a history of migraines on the matrilineal side. Boles and colleagues also reported a large mitochondrial DNA deletion in a single child with cyclic vomiting syndrome and have identified additional mutations concentrated in the D-loop, a hypervariable locus of the control region, in other children with cyclic vomiting syndrome.
In children with cyclic vomiting syndrome, two mtDNA polymorphisms (16519T and 3010A) are expressed with a high degree of frequency and may serve as a surrogate marker for predisposition to the disease. The mtDNA polymorphism, 16519T, was found to be 6 times more common in pediatric cyclic vomiting syndrome than in control populations.
Another common mtDNA polymorphism, 3010A, was noted to increase the odds ratio for developing cyclic vomiting syndrome in subjects with 16519T as much as 17 times. These mtDNA polymorphisms may account for the clustering of functional conditions and symptoms in the same individuals and families. Unlike pediatric cyclic vomiting syndrome, adult-onset cyclic vomiting syndrome is not associated with these mtDNA polymorphisms, suggesting a degree of genetic distinction.
Children with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome are known to have both severe migraines and episodic vomiting, as in cyclic vomiting syndrome. Several children with cyclic vomiting syndrome, including 4 members of an Italian family, have been reported to have various mitochondrial mutations. Sympathetic hyperresponsivity and autonomic dysfunction also appear to contribute to the pathogenesis of cyclic vomiting syndrome. Many associated symptoms, such as pallor, flushing, fever, lethargy, salivation, and diarrhea, are mediated by the autonomic nervous system.
Several studies support altered autonomic function in cyclic vomiting syndrome. Rashed et al and To et al demonstrated a heightened sympathetic cardiovascular tone in patients with cyclic vomiting syndrome. Kasawinah et al reported the successful use of dexmedetomidine, an alpha-2 adrenergic agonist, to treat cyclic vomiting syndrome. In a small study involving 6 children with cyclic vomiting syndrome, all patients had sympathetic autonomic dysfunction, affecting mainly the vasomotor and sudomotor systems. Symptoms developed during tilt testing in half of these patients, suggesting that these findings may play a role in the pathophysiology of this disorder.
To evaluate this association with autonomic dysfunction, a cross-sectional study using the Ohio dysautonomia (ODYSA) questionnaire was administered to 21 patients with cyclic vomiting syndrome (3 children) and 46 patients with migraines. Both the cyclic vomiting syndrome and the migraine groups had similar comorbid conditions, with fibromyalgia noted in 38% of subjects with cyclic vomiting syndrome, orthostatic intolerance noted in 47% of subjects with cyclic vomiting syndrome, functional dyspepsia in 9.5% of subjects with cyclic vomiting syndrome, and complex regional pain syndrome in 24% of subjects with cyclic vomiting syndrome. The limitation of this study was the findings were not corroborated with either a physical examination or standard autonomic function test findings. However, the findings of orthostatic intolerance are of clinical significance because the use of pharmacological therapy such as fludrocortisone and beta blockers may be considered in these patients.
The stress response, mediated by the hypothalamic-pituitary-adrenal (HPA) axis, can also potentially induce episodes of cyclic vomiting syndrome. Infectious, psychological, and physical stressors are known triggers of episodes. Sato et al documented increased levels of adrenocorticotropic hormone (ACTH) and cortisol, associated with extreme lethargy and hypertension, before the onset of vomiting. Furthermore, Taché has definitively shown that central CRF induces gastric stasis, emesis, or both in animals. Therefore, CRF may be a potential brain-gut mediator of cyclic vomiting syndrome that directly connects stress and vomiting. If this theory holds true, CRF receptor antagonists currently in development could theoretically ablate the vomiting by blocking the CRF receptor's vagally mediated actions.
How these pathways fit together is still unclear. Li and Misiewicz have proposed that heightened neuronal excitability due to enhanced membrane ion permeability (ion channelopathy), mitochondrial energy deficits (due to dysfunction), or hormonal state (eg, menstrual periods) may be present.
Both physical (infection) and psychologic stressors (excitement) can initiate a known cascade that releases hypothalamic CRF, the suspected neuroendocrine trigger, resulting in vomiting. Altered brainstem regulation of these autonomic signals may be the necessary abnormality that allows the dysautonomia to feed forward and become self-sustained for days on end.
Mitochondrial DNA (mtDNA) mutations may be involved in the pathogenesis of cyclic vomiting syndrome. Boles et al have demonstrated that, among children with cyclic vomiting syndrome and neuromuscular disease, 86% have a history of migraines on the matrilineal side. Boles and colleagues also reported a large mitochondrial DNA deletion in a single child with cyclic vomiting syndrome and have identified additional mutations concentrated in the D-loop, a hypervariable locus of the control region, in other children with cyclic vomiting syndrome.
In children with cyclic vomiting syndrome, two mtDNA polymorphisms (16519T and 3010A) are expressed with a high degree of frequency and may serve as a surrogate marker for predisposition to the disease. The mtDNA polymorphism, 16519T, was found to be 6 times more common in pediatric cyclic vomiting syndrome than in control populations.
Another common mtDNA polymorphism, 3010A, was noted to increase the odds ratio for developing cyclic vomiting syndrome in subjects with 16519T as much as 17 times. These mtDNA polymorphisms may account for the clustering of functional conditions and symptoms in the same individuals and families. Unlike pediatric cyclic vomiting syndrome, adult-onset cyclic vomiting syndrome is not associated with these mtDNA polymorphisms, suggesting a degree of genetic distinction.
Children with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome are known to have both severe migraines and episodic vomiting, as in cyclic vomiting syndrome. Several children with cyclic vomiting syndrome, including 4 members of an Italian family, have been reported to have various mitochondrial mutations. Sympathetic hyperresponsivity and autonomic dysfunction also appear to contribute to the pathogenesis of cyclic vomiting syndrome. Many associated symptoms, such as pallor, flushing, fever, lethargy, salivation, and diarrhea, are mediated by the autonomic nervous system.
Several studies support altered autonomic function in cyclic vomiting syndrome. Rashed et al and To et al demonstrated a heightened sympathetic cardiovascular tone in patients with cyclic vomiting syndrome. Kasawinah et al reported the successful use of dexmedetomidine, an alpha-2 adrenergic agonist, to treat cyclic vomiting syndrome. In a small study involving 6 children with cyclic vomiting syndrome, all patients had sympathetic autonomic dysfunction, affecting mainly the vasomotor and sudomotor systems. Symptoms developed during tilt testing in half of these patients, suggesting that these findings may play a role in the pathophysiology of this disorder.
To evaluate this association with autonomic dysfunction, a cross-sectional study using the Ohio dysautonomia (ODYSA) questionnaire was administered to 21 patients with cyclic vomiting syndrome (3 children) and 46 patients with migraines. Both the cyclic vomiting syndrome and the migraine groups had similar comorbid conditions, with fibromyalgia noted in 38% of subjects with cyclic vomiting syndrome, orthostatic intolerance noted in 47% of subjects with cyclic vomiting syndrome, functional dyspepsia in 9.5% of subjects with cyclic vomiting syndrome, and complex regional pain syndrome in 24% of subjects with cyclic vomiting syndrome. The limitation of this study was the findings were not corroborated with either a physical examination or standard autonomic function test findings. However, the findings of orthostatic intolerance are of clinical significance because the use of pharmacological therapy such as fludrocortisone and beta blockers may be considered in these patients.
The stress response, mediated by the hypothalamic-pituitary-adrenal (HPA) axis, can also potentially induce episodes of cyclic vomiting syndrome. Infectious, psychological, and physical stressors are known triggers of episodes. Sato et al documented increased levels of adrenocorticotropic hormone (ACTH) and cortisol, associated with extreme lethargy and hypertension, before the onset of vomiting. Furthermore, Taché has definitively shown that central CRF induces gastric stasis, emesis, or both in animals. Therefore, CRF may be a potential brain-gut mediator of cyclic vomiting syndrome that directly connects stress and vomiting. If this theory holds true, CRF receptor antagonists currently in development could theoretically ablate the vomiting by blocking the CRF receptor's vagally mediated actions.
How these pathways fit together is still unclear. Li and Misiewicz have proposed that heightened neuronal excitability due to enhanced membrane ion permeability (ion channelopathy), mitochondrial energy deficits (due to dysfunction), or hormonal state (eg, menstrual periods) may be present.
Both physical (infection) and psychologic stressors (excitement) can initiate a known cascade that releases hypothalamic CRF, the suspected neuroendocrine trigger, resulting in vomiting. Altered brainstem regulation of these autonomic signals may be the necessary abnormality that allows the dysautonomia to feed forward and become self-sustained for days on end.
How is CVS treated?
Treatment varies, but people with CVS generally improve after learning to control their symptoms. People with CVS are advised to get plenty of rest and sleep and to take medications that prevent a vomiting episode, stop one in progress, speed up recovery, or relieve associated symptoms.
Once a vomiting episode begins, treatment usually requires the person to stay in bed and sleep in a dark, quiet room. Severe nausea and vomiting may require hospitalization and intravenous fluids to prevent dehydration. Sedatives may help if the nausea continues.
Sometimes, during the prodrome phase, it is possible to stop an episode from happening. For example, people with nausea or abdominal pain before an episode can ask their doctor about taking ondansetron (Zofran) or lorazepam (Ativan) for nausea or ibuprofen (Advil, Motrin) for pain. Other medications that may be helpful are ranitidine (Zantac) or omeprazole (Prilosec), which help calm the stomach by lowering the amount of acid it makes.
During the recovery phase, drinking water and replacing lost electrolytes are important. Electrolytes are salts the body needs to function and stay healthy. Symptoms during the recovery phase can vary. Some people find their appetite returns to normal immediately, while others need to begin by drinking clear liquids and then move slowly to solid food.
People whose episodes are frequent and long-lasting may be treated during the symptom-free intervals in an effort to prevent or ease future episodes. Medications that help people with migraine headaches, such as propranolol (Inderal), cyproheptadine (Periactin), and amitriptyline (Elavil), are sometimes used during this phase, but they do not work for everyone. Taking the medicine daily for 1 to 2 months may be necessary before one can tell if it helps.
The symptom-free interval phase is a good time to eliminate anything known to trigger an episode. For example, if episodes are brought on by stress or excitement, a symptom-free interval phase is the time to find ways to reduce stress and stay calm. If sinus problems or allergies cause episodes, those conditions should be treated. During an episode, anti-migraine drugs such as sumatriptan (Imitrex) may be prescribed to stop symptoms of migraine headache. However, these agents have not been studied for use in children.
What are the complications of CVS?
The severe vomiting that defines CVS is a risk factor for several complications:
- Dehydration. Vomiting causes the body to lose water quickly. Dehydration can be severe and should be treated immediately.
- Electrolyte imbalance. Vomiting causes the body to lose important salts it needs to keep working properly.
- Peptic esophagitis. The esophagus—the tube that connects the mouth to the stomach—becomes injured from stomach acid moving through it while vomiting.
- Hematemesis. The esophagus becomes irritated and bleeds, so blood mixes with vomit.
- Mallory-Weiss tear. The lower end of the esophagus may tear open or the stomach may bruise from vomiting or retching.
- Tooth decay. The acid in vomit can hurt teeth by corroding tooth enamel.
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