NORD gratefully acknowledges Richard G. Boles, MD, Division of Medical Genetics and the Saban Research Institute, Childrens Hospital Los Angeles, and Division of Pediatrics, Keck School of Medicine at the University of Southern California, for assistance in the preparation of this report.
Cyclic vomiting syndrome (CVS) is a rare disorder characterized by recurrent, similar episodes of severe nausea and vomiting. An episode may last for a few hours to several days and then is followed by a period of time during which affected individuals are free of severe nausea and vomiting. This alternating pattern of disease and disease-free periods distinguishes cyclic vomiting syndrome from other similar disorders. Also, in cyclic vomiting syndrome, within each sufferer the episodes are similar. The associated nausea and vomiting can be severe enough to be incapacitating (e.g., individuals may be unable to walk or talk and/or be bedridden). Additional symptoms that are often present during an episode including dizziness, paleness of the skin (pallor), lack of energy (lethargy), abdominal pain and headaches. Oftentimes, nausea is the most disturbing symptom, and vomiting is infrequent. In some cases as children grow older, they may outgrow these episodes, although many of these children eventually develop migraines. Cyclic vomiting syndrome may affect children more often than adults. The exact cause of cyclic vomiting syndrome is unknown.
The hallmark of cyclic vomiting syndrome is recurrent episodes of severe nausea and vomiting. In children, these episodes usually last for several hours to a few days. In adults, episodes tend to occur less frequently, but usually last longer sometimes as long as 10 days. These recurrent, characteristic episodes are extremely similar in each individual, often occurring at the same time of day, with the same associated symptoms, severity, and duration as previous episodes. Episodes often occur at night or first thing in the morning. Affected individuals may only experience episodes several times a year or as frequently as several times a month. On occasion after years of cycling, episodes can “coalesce” together such that there is no symptom-free period.
The nausea and vomiting that characterize these episodes are often quite severe. Nausea can be persistent and intense. Affected children may experience bouts of rapid-fire, projectile vomiting as frequently as four or more times per hour with a peak pace of every 5-15 minutes. After the contents of the stomach are emptied, individuals may continue to dry heave. Nausea and vomiting can be so severe that affected individuals are unable to walk or talk and in some cases may make an affected individual appear unconscious or comatose. Episodes may cause affected individuals to withdraw from social interaction. Drinking water to induce vomiting and hence reduce nausea is common, and should not be confused with a psychogenic cause.
Additional symptoms may occur during an episode including paleness of the skin (pallor), lack of energy (lethargy), fever, and drooling. The emesis can be bilious (green or yellow) or non-bilious. Continuous vomiting may result in the loss of vital fluids (dehydration). Gastrointestinal abnormalities such as severe abdominal pain, diarrhea, and retching (gagging) are not uncommon. Affected individuals may have a reduced appetite and weight loss may also occur. Some affected individuals may exhibit a variety of migraine-like neurological symptoms including headaches, abnormal sensitivity to light (photophobia), increased sensitivity to sound (phonophobia), and dizziness or vertigo.
In many cases, affected individuals can identify a precipitating event or “trigger” that sets off an episode of cyclic vomiting syndrome. The most common trigger is infection, especially a common “cold” or inflammation of the sinuses (sinusitis). Additional triggers include stress, anxiety or excitement, overeating or eating just before going to bed, certain foods such as chocolate or cheese, physical exhaustion, lack of sleep and motion sickness. In women, menstruation may trigger an episode. Many adults with cyclic vomiting syndrome are prone to anxiety or panic attacks, which can trigger episodes.
The exact cause of cyclic vomiting syndrome is unknown. Although nausea and vomiting are the main features of cyclic vomiting syndrome, researchers now believe that the primary organ affected is the brain and that the symptoms of the disorder develop due to abnormalities in the normal interaction between the brain and the gut (brain-gut disorder).
Although the specific cause of cyclic vomiting syndrome is unknown, likely there are several causes. Researchers have noted a relationship between cyclic vomiting syndrome and migraines, and some theorize that cyclic vomiting syndrome may be a migraine variant. Many children with cyclic vomiting syndrome have a family history of migraines or develop migraines when they get older. Cyclic vomiting syndrome may be referred to as a type of “abdominal migraine” and the terms are sometimes used interchangeably. An abdominal migraine is a migraine variant in which there are recurrent episodes of abdominal pain. Vomiting may or may not accompany an abdominal migraine.
Additional factors that may be associated with the development of cyclic vomiting syndrome include dysfunction of the autonomic nervous system. The autonomic nervous system is the portion of the nervous system that controls or regulates certain involuntary body functions including heart rate, blood pressure, sweating, the production and release of certain hormones, and bowel and bladder control. Autonomic disturbances are common during episodes, including fever, tachycardia, high blood pressure and urinary retention (blockage). Vomiting itself is an autonomic disturbance. Autonomic or “functional” disturbances can also occur between episodes, such as reflex sympathetic dystrophy (a chronic pain condition), syncope (fainting), and disorders of gastrointestinal motility. The latter are particular common, and can include gastroesophageal reflux (GERD, explained below), delayed gastric emptying (resulting in bloating during meals), irritable bowel and/or constipation.
Additional conditions sometimes seen in individuals with cyclic vomiting syndrome include depression, anxiety, attention deficit hyperactivity disorder (ADHD), seizures, autistic spectrum disorders and learning disabilities.
Some research indicates that the dysfunction in the body’s response to stress may contribute or trigger episodes of cyclic vomiting syndrome. Affected individuals may experience altered release of corticotrophin-releasing factor (CRF) from the hypothalamus, the portion of the brain that controls the production and release of certain hormones. CRF is a stress hormone that stimulates the adrenal cortex, which controls the body’s response to stress. Some research has indicated that CRF may cause vomiting.
Researchers have also learned that, in most cases, blood and urine testing reveal signs of abnormal energy metabolism. In many of those cases, changes (mutations) of genetic material found in the DNA of mitochondria (mtDNA) play a role in the development of cyclic vomiting syndrome. Mitochondria, which are found by the thousands in the cells of the body, particularly in muscle and nerve tissue, produce the vast majority of energy that is required for the function of biological processes. As opposed to the genetic instructions of cellular chromosomes (nuclear DNA), which are found within the nucleus of each cell, mitochondrial genetic instructions are found outside of the nucleus of the cell. The exact role such mutations play in the development of cyclic vomiting syndrome is unknown.
Mutations affecting the genetic instructions for mitochondria (mtDNA) are inherited from the mother. MtDNA found in sperm cells typically is destroyed following fertilization. As a result, all human mtDNA comes from the mother. An affected mother will pass the mutation(s) on to all her children, but only her daughters will pass the mutation(s) on to their children. As a result, family members related entirely through women carry the same mtDNA genetic sequence. In half or more of CVS families, those relatives often suffer themselves from dysautonomic or functional-related symptoms, especially chronic pain (including migraine), bowel disorders, and depression.
The exact way the abovementioned factors and additional, as yet unidentified, factors interact to cause cyclic vomiting syndrome is unknown. Research is ongoing to determine the cause and underlying mechanisms that result in cyclic vomiting syndrome.
Cyclic vomiting syndrome affects females somewhat more often than males (55:45). It most commonly occurs in children between the ages of three and seven, although it can begin at any age, from early infancy through to old age. A diagnosis is often delayed for many years. Although cyclic vomiting syndrome may be seen more often in children, it is being recognized with greater frequency in adults. The incidence of cyclic vomiting syndrome is unknown, although it is not rare. Two studies in Scotland and Australia have suggested that as many as 2% of all school-aged children suffer from cyclic vomiting syndrome. However, researchers believe the disorder is underdiagnosed, making it difficult to estimate its true frequency in the general population. Cyclic vomiting syndrome was first described in the medical literature in 1806 in French, and 1882 in English.
A diagnosis of cyclic vomiting syndrome may be suspected based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic findings. The determination of cyclic vomiting syndrome can only be made after other causes of recurrent vomiting have been ruled out. There is no "test" to prove the presence of cyclic vomiting syndrome, although the presence of urine ketosis early in an episode is helpful. A variety of tests of may be used to rule out other, more common, causes of recurrent nausea and vomiting.
The treatment of cyclic vomiting syndrome is directed toward preventing, shortening or managing the episodes of nausea and vomiting. Treatment of this disorder is based upon experience and observation (empiric) as opposed to an evidence-based treatment regimen. Specific therapies must be tailored for each individual case.
To prevent episodes from occurring, some individuals have been treated with certain anti-migraine medications, especially amitriptyline, as well as cyproheptadine (in preschool-aged children) or propranolol. Anti-migraine therapies seem particularly effective for individuals with a family history of migraine.
Two studies each for coenzyme Q10 and L-carnitine have suggested that these mitochondrial-targeted cofactors can be helpful to prevent vomiting episodes. Both are natural substances that can be obtained in the United States without a prescription. Co-enzyme Q10 is involved in electron transport (energy production), and L-carnitine in fat transport and the clearing of metabolic waste products. In some cases, vomiting episodes become less frequent or halt altogether when these cofactors are used alone. One study suggested that their effects are synergistic (more powerful) in combination with amitriptyline. Side effects of these cofactors are rare and generally mild; L-carnitine can cause nausea and diarrhea, as well as a fish-like odor.
The drug, erythromycin, may also be used to reduce the severity of episodes, although not all experts agree. Erythromycin is a prokinetic drug that helps move ingested material through the gastrointestinal tract. Erythromycin may be used in individuals with cyclic vomiting syndrome who experience dysmotility (failure of the muscles of the GI tract to function normally). Drugs that prevent seizures (anticonvulsants), especially toparimate, have also been used to prevent episodes from occurring. Preventive drug therapy is usually recommended for individuals with equal to or more than one episode per two month period, especially if episodes are prolonged or severe.
Certain drugs may be used to stop an episode as it is about to begin (abortive therapy). In some cases, affected individuals can sense an episode coming on. Drugs used to treat nausea (anti-emetics) such as ondansetron or granisetron or certain anti-migraine drugs known as triptans may be used to stop an episode if they are administered at the onset of an episode. Other drugs that have been used to stop an oncoming episode include ibuprofen (Advil or Motrin) or drugs that reduce acid production in the stomach such as Zantac or Prilosec. About one-half of individuals with cyclic vomiting syndrome respond favorably, often including aborting episodes, to sugar-containing intravenous (IV) fluids. In particular, D10-containing (10% sugar) IV fluids are often helpful if given early. Sugar-containing drinks such as juices or sodas can also be helpful at home in many cases. Abortive therapy is generally used when episodes occur less frequently (i.e., less than once every 2 month) or when preventive therapy has not worked.
Since individuals respond to medications differently, no one therapy works for all affected individuals. Several attempts at different preventive and abortive therapies may be necessary until an effective regimen is found for an individual case. In particular, treatment failures are frequently the result of too little drug given too infrequently. For example, although most experts start at 0.5 mg per kg body weight per day, amitriptyline often requires 1 to 1.5 mg/kg/day for over a month or two in order to prevent vomiting episodes. Blood levels of amitriptyline can be obtained to check that the dose given is adequate and not excessive.
When preventive and abortive therapy does not work, supportive care during an episode may include bed rest in a dimly lit, quiet room. The administration of intravenous fluids to prevent complications such as dehydration may be necessary. Anti-nausea medications (especially ondansetron at 0.3 to 0.4 mg/kg/dose, maximium dose about 24 mg) and sedatives such as lorazepam may also be used. In severe episodes, hospitalization may be necessary.
Avoidance of known triggers (when possible) may also help reduce the frequency of episodes. The support of family is considered essential by researchers to help deal with the unpredictable, disruptive nature of cyclic vomiting syndrome and the likelihood of a delay in attaining the proper diagnosis.
Research into cyclic vomiting syndrome is ongoing. Researchers are studying substances that block the actions of corticotrophin-releasing factor thereby reducing the body’s stress response (CRF antagonists). Newer anti-migraine, anti-seizure and anti-nausea drugs are also being studied as potential treatment options for individuals with cyclic vomiting syndrome.
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