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.
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 for 8 days. These recurrent, characteristic episodes are extremely similar within each individual, often beginning at the same time of day, with the same severity, duration and associated symptoms, as in previous episodes. Episodes often occur in the early morning hours or upon awakening 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 with daily nausea and mild vomiting between severe attacks 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. Unlike most other gastrointestinal disorders, the vomiting in CVS does not typically relieve the nausea. 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. Symptoms can be so severe that affected individuals are unable to walk or talk and in some cases may appear unconscious or comatose. Episodes may cause affected individuals to withdraw from social interaction. The behavior of drinking water to dilute the bile and induce vomiting and hence reduce nausea is common, and should not be confused with a psychogenic cause. More commonly described in adults but also occurring in children, many take continuous prolonged hot shower or baths to alleviate the nausea.
Additional symptoms may occur during an episode including paleness of the skin (pallor), lack of energy (lethargy), fever, and drooling. The emesis is typically bilious (green or yellow). Repetitive vomiting may cause loss of vital fluids (dehydration). Gastrointestinal symptoms such as severe abdominal pain, diarrhea, and retching (gagging) are not uncommon. Affected individuals have a reduced appetite and weight loss may occur. Some 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.
Many affected individuals can identify a precipitating event or “trigger” that sets off an episode of CVS. In children, stress is the most trigger, more commonly excitement (birthdays, holidays) than negative stress. Additional triggers include infection, certain foods such as monosodium glutamate, chocolate or cheese, physical exhaustion, lack of sleep, motion sickness, and incoming weather fronts. In adolescents and 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, there are likely to be several contributing causes. Researchers have found a strong relationship between CVS and migraines, and some theorize that CVS is a migraine variant. Most children with CVS have a family history of migraines or have migraines themselves (> 80%). CVS has been referred to as “abdominal migraine” and the terms are sometimes used interchangeably. An abdominal migraine is a migraine variant in which there are recurrent episodes of predominating abdominal pain. Vomiting may or may not accompany an abdominal migraine.
Additional factors that may be associated with the development of CVS include dysfunction of the autonomic nervous system. The autonomic nervous system is the 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 “functional” disturbances are common during episodes, including fever, pallor, tachycardia, high blood pressure and urinary retention. Vomiting itself is an autonomic disturbance. Autonomic 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 often seen in those with CVS include anxiety, depression, attention deficit hyperactivity disorder (ADHD), seizures, autistic spectrum disorders and learning disabilities.
Some research indicates that the body’s response to stress may be overactive and contribute or trigger episodes of CVS. Affected individuals may have increased release of corticotrophin-releasing factor (CRF) from the hypothalamus. 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 inhibit the stomach pumping.
Researchers have also learned that blood and urine testing reveals signs of abnormal energy metabolism. Changes (mutations) in genetic material found in the mitochondrial DNA (mtDNA) may play a role in the development of CVS but reducing the capacity to produce sufficient energy during times of stress such as fever, illness, hot weather (sweating), excitement and aerobic exercise. Because mitochondria (cell’s power plant) in particular power muscle and nerve tissue, defective mitochondrial energy production may lead to a energy shortage during stress that affects nerve function, especially the autonomic nerves that control the gut.
Because the genetic instructions (blueprints) for mitochondria (mtDNA) are inherited from the mother, an affected mother (with migraines) will pass the same mutation(s) on to all her children. For example, the migraines are found primarily on the mother’s side – the siblings, the maternal aunts and uncles and the maternal grandmother – and the all carry the same mtDNA genetic sequences. Only her daughters will pass the mutation(s) on to their children. 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 (GE reflux or constipation), and depression.
The exact manner that all the above mentioned and additional factors fit together in the puzzle to cause CVS is still unknown. Research is ongoing to determine the cause and underlying mechanisms that result in CVS.
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 (73 is the oldest). Because it is not recognized or misdiagnoses as stomach flu, a correct diagnosis is often delayed for many years. Although CVS is found more often in children, it is being recognized with greater frequency in adults. The incidence of CVS is unknown, although it is not rare. Two studies in Scotland and Australia have suggested that as many as 2% of all Caucasian school-aged children suffer from CVS. However, researchers believe the disorder is underdiagnosed, making it difficult to estimate its true frequency in the general population. CVS 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 diagnostic criteria are currently based upon the consensus criteria of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition and the Rome IV Committee. The determination of CVS 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 may be helpful. A variety of tests of may be used to rule out other, more common, causes of recurrent nausea and vomiting, including an upper gastrointestinal radiograph.
The treatment of cyclic vomiting syndrome is directed toward preventing, shortening or managing the episodes of nausea and vomiting and reducing symptoms of abdominal pain. Treatment of this disorder is based upon experience and observation (empiric) as opposed to an evidence-based treatment regimen. Specific therapies should be tailored for each individual case.
To prevent (prophylactic therapy) episodes from occurring, some individuals are 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 suggest 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 assists in energy production (electron transport) and L-carnitine aids with fuel transport (fat transport) and clearing of metabolic waste products. In some cases, vomiting episodes become less frequent when these cofactors are used alone. One study suggests that their effects are best used 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.
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. Although not all experts agree, erythromycin may also be used to reduce the severity of episodes, especially in individuals with CVS and poor stomach pumping. Drugs that prevent seizures (anticonvulsants), especially toparimate and phenobarbital have also been used to prevent episodes from occurring. 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. Certain drugs may be used to stop an episode as it is about to begin (abortive therapy). Some affected individuals can sense (e.g. nausea) an episode coming on (warning phase). Drugs used to treat vomiting (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 beginning of an episode. About one-half of individuals with CVS respond favorably to attempts to abort or lessen the severity of episodes using to sugar-containing intravenous (IV) fluids. In particular, D10-containing (10% sugar) IV fluids may be helpful if given early. Sugar-containing drinks such as juices or sodas can also be helpful at home.
Since individuals respond to medications differently, no one therapy works for all affected individuals. Several attempts using 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 target 0.5 mg per kg body weight per day, amitriptyline is often required 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-vomiting medications (especially ondansetron at 0.3 to 0.4 mg/kg/dose, maximum dose about 24 mg), ketorolac used for pain and lorazepam for sedation may also be used. When children or adults are asleep, they don’t experience nausea. Deep sleep may also reset their system and shorten the episode. In severe episodes, hospitalization may be necessary.
Avoidance of known triggers (when possible) may also help reduce the frequency of episodes. Treatment of underlying commonplace anxiety using cognitive behavioral therapy and stress management (deep breathing) is often the key to improvement and rehabilitation back to school. The support of family is considered essential by clinicians to help deal with the unpredictable, disruptive nature of CVS and the likelihood of a delay in attaining the proper diagnosis.
Research into cyclic vomiting syndrome is ongoing. Newer anti-migraine, anti-seizure and anti-vomiting drugs are also being studied as potential treatment options for individuals with CVS.
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