NORD gratefully acknowledges Richard G. Boles, MD, Director, Neurabilities NeuroGenomics Program, Voorhees, NJ, for assistance in the preparation of this report.
Cyclic vomiting syndrome (CVS) is an uncommon disorder affecting both children and adults and characterized by recurrent episodes of severe nausea and vomiting. An episode may last for a few hours to several days and is then followed by a period of time during which affected individuals are relatively free of severe nausea and vomiting. Some can experience milder symptoms between attacks. This alternating pattern of disease and disease-free periods distinguishes cyclic vomiting syndrome from other gastrointestinal disorders. For each person who suffers from this condition, the episodes are similar to each other. The associated nausea and vomiting can be severe enough to incapacitate the individual who may be unable to walk or talk and/or be bedridden. Additional symptoms often present during an episode including dizziness, paleness of the skin (pallor), lack of energy (listlessness) and, abdominal pain and headaches. Oftentimes, nausea is the most disturbing symptom, more so than vomiting. Some affected children outgrow these episodes as they get older but for many others, CVS transitions into migraine headache. Cyclic vomiting syndrome may affect children more often than adults. The exact causes of cyclic vomiting syndrome remains unknown in many people, but a cause or risk factors can be determined in many others.
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 can last longer, even over a week. These recurrent, characteristic episodes are quite similar within each individual, often beginning at the same time of day, with similar 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 vomiting between severe attacks such that there is no symptom-free period.
The nausea and vomiting that characterize CVS episodes are often quite severe. Nausea can be persistent and intense. Unlike most other gastrointestinal disorders, the vomiting in CVS may not 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 prolonged hot showers 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 vomit may be 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. Stress is a common trigger, more commonly excitement/positive stress (birthdays, holidays) than negative stress. Additional triggers include infection, certain foods, alcohol, 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.
Although nausea and vomiting are the main features of cyclic vomiting syndrome, researchers now believe that the primary system affected is the nervous system, including the brain and peripheral nerves. There are more nerve cells (neurons) in the abdomen than in the head, and symptoms of the disorder develop due to abnormalities in the normal interaction between neurons in the brain and in the gut (thus, brain-gut disorder).
Although the specific cause of cyclic vomiting syndrome is unknown in many people, 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. Channelopathies caused by defects in cellular ion (salt) channels are a common cause for migraine and are recently being reported in abdominal migraine and CVS as well.
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/POTS (fainting) and disorders of gastrointestinal motility.
Dysmotility refers to abnormal motion through the gastrointestinal tract, either too fast, too slow or in the wrong direction. During CVS episodes, motion through the gut is very abnormal, and thus there is severe dysmotility. However, many CVS patients have lesser degrees of dysmotility between episodes. Different types of dysmotility that are common in people with CVS include gastroesophageal reflux (GERD), gastroparesis (low stomach motility causing delayed emptying of the stomach) and forms of irritable bowel disease (IBS: diarrhea, constipation, and/or bloating). Nausea is a common component of dysmotility and is especially common among adults. Thus, nausea (and occasionally vomiting) can be present between CVS episodes. However, during CVS episodes the nausea (and possibly vomiting) is far more intense than it is between episodes.
Additional conditions that occur more often 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 reveal signs of abnormal energy metabolism in most people with CVS. Changes (mutations) in the genetic material of mitochondrial genes may play a role in the development of CVS. Mitochondria provide most of the power for cells. As muscle and nerve tissue have very high energy requirements, defective mitochondrial energy production may lead to an energy shortage during stress that affects nerve function, especially the autonomic nerves that control the gut. This might lead to disease by reducing the capacity to produce sufficient energy during times of stress such as with fever, illness, hot weather (sweating), excitement and exercise.
Because the genetic instructions (blueprints) for mitochondria DNA (mtDNA) are inherited from the mother, an affected mother will pass the same mutation to all of her children. As a result, in some families disease is found primarily on the mother’s side – the siblings, the maternal aunts and uncles and the maternal grandmother – all of whom carry the same mtDNA genetic sequences. Only females will pass a mtDNA mutation 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), fatigue and anxiety/depression.
In other cases, CVS can be caused by abnormal genes for mitochondrial function in the nuclear DNA (not in the mtDNA) and can be inherited from either the mother or the father.
The exact manner that all the above mentioned and additional factors fit together in the puzzle to cause CVS is still unclear. 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 reported). Because CVS it is sometimes not recognized or misdiagnosed 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.
A diagnosis of cyclic vomiting syndrome may be suspected based upon a thorough clinical evaluation with the identification of characteristic findings. 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 causes of recurrent nausea and vomiting. In particular, it is important to rule out a physical/structural blockage of the intestines, including malrotation, with an upper gastrointestinal series of radiographs. Standard blood chemistries testing is important to detect abnormal levels of sodium and potassium (electrolytes) and well as pancreatitis (lipase).
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 as opposed to an evidence-based treatment regimen. Specific therapies should be tailored for each individual patient.
Prophylactic therapy is used to prevent 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 in preventing vomiting episodes. Both are natural substances that can be obtained in the United States and most other countries without a prescription. Co-enzyme Q10 assists in energy production (electron transport) and L-carnitine aids with fuel transport (fat transport) and the clearing of metabolic waste products. In some patients, vomiting episodes become less frequent when these cofactors are used alone. One study suggests that they work best in combination with amitriptyline, and recommends adjusting dosage of all three treatments based on blood levels. Side effects of these cofactors are rare and generally mild; L-carnitine can cause nausea and diarrhea as well as a fish-like odor. Co-enzyme Q10 is available in two forms, ubiquinone and ubiquinol. Studies have shown that ubiquinol is up to five times more bioavailable (absorbable from the intestines) as ubiquinone and is thus preferred. Given this bioavailability, ubiquinol is also more cost effective despite a higher unit cost.
Preventive drug therapy is usually recommended for individuals with equal to or more than one episode per two-month period, but can be considered in those with less frequent episodes 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. Aprepitant is recently being used more often for CVS.
Treatment of symptoms once they start 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 sugar-containing intravenous (IV) fluids. In particular, D10-containing (10% sugar) IV fluids may be helpful if given early, although this is not always available and D5-containing fluids at high rates can be substituted. 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 patient. 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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