Reye syndrome is a rapidly worsening
brain disease
Central nervous system diseases or central nervous system disorders are a group of neurological disorders that affect the structure or function of the human brain, brain or spinal cord, which collectively form the central nervous system (CNS). Th ...
.
[ Symptoms of Reye syndrome may include ]vomiting
Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.
Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...
, personality changes, confusion, seizure
A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...
s, and loss of consciousness
Unconsciousness is a state in which a living individual exhibits a complete, or near-complete, inability to maintain an awareness of self and environment or to respond to any human or environmental stimulus. Unconsciousness may occur as the re ...
.[ While ]liver toxicity
Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury (DILI) is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdr ...
typically occurs in the syndrome, jaundice
Jaundice, also known as icterus, is a yellowish or, less frequently, greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving ...
usually does not.[ Death occurs in 20–40% of those affected with Reye syndrome, and about a third of those who survive are left with a significant degree of ]brain damage
Brain injury (BI) is the destruction or degeneration of brain cells. Brain injuries occur due to a wide range of internal and external factors. In general, brain damage refers to significant, undiscriminating trauma-induced damage.
A common ...
.
The cause of Reye syndrome is unknown.[ It usually begins shortly after recovery from a ]viral infection
A viral disease (or viral infection) occurs when an organism's body is invaded by pathogenic viruses, and infectious virus particles (virions) attach to and enter susceptible cells.
Examples include the common cold, gastroenteritis, COVID-19, t ...
, such as influenza
Influenza, commonly known as the flu, is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These sympto ...
or chickenpox
Chickenpox, also known as varicella ( ), is a highly contagious disease caused by varicella zoster virus (VZV), a member of the herpesvirus family. The disease results in a characteristic skin rash that forms small, itchy blisters, which ...
. About 90% of cases in children are associated with aspirin
Aspirin () is the genericized trademark for acetylsalicylic acid (ASA), a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and inflammation, and as an antithrombotic. Specific inflammatory conditions that aspirin is ...
(salicylate
Salicylic acid is an organic compound with the formula HOC6H4COOH. A colorless (or white), bitter-tasting solid, it is a precursor to and a metabolite of acetylsalicylic acid (aspirin). It is a plant hormone, and has been listed by the EPA To ...
) use.[ Inborn errors of metabolism are also a risk factor.][ The syndrome is associated with changes on blood tests such as a high blood ammonia level, low blood sugar level, and prolonged ]prothrombin time
The prothrombin time (PT) – along with its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) – is an assay for evaluating the Coagulation#Extrinsic pathway, extrinsic pathway and Coagulation#Common pathway, ...
.[ Often, the liver is enlarged in those who have the ]syndrome
A syndrome is a set of medical signs and symptoms which are correlated with each other and often associated with a particular disease or disorder. The word derives from the Greek language, Greek σύνδρομον, meaning "concurrence". When a sy ...
.[
Prevention is typically by avoiding the use of aspirin in children.][ When aspirin was withdrawn for use in children in the US and UK in the 1980s, a decrease of more than 90% in rates of Reye syndrome was observed.][ Early diagnosis of the syndrome improves outcomes.][ Treatment is supportive;] mannitol
Mannitol is a type of sugar alcohol used as a sweetener and medication. It is used as a low calorie sweetener as it is poorly absorbed by the intestines. As a medication, it is used to decrease pressure in the eyes, as in glaucoma, and to l ...
may be used to help with the brain swelling.[
The first detailed description of Reye syndrome was in 1963 by Australian pathologist Douglas Reye.] The syndrome most commonly affects children. It affects fewer than one in a million children a year. The general recommendation to use aspirin in children was withdrawn because of Reye syndrome, with use only recommended in Kawasaki disease
Kawasaki disease (also known as mucocutaneous lymph node syndrome) is a syndrome of unknown cause that results in a fever and mainly affects children under 5 years of age. It is a form of vasculitis, in which medium-sized blood vessels become in ...
.[
]
Signs and symptoms
Reye syndrome progresses through five stages:
* Stage I
** Vasoconstrictive rash on palms of hands and feet
** Persistent, heavy vomiting
Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.
Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...
that is not relieved by not eating
** Generalized lethargy
Lethargy is a state of tiredness, sleepiness, weariness, fatigue, sluggishness, or lack of energy. It can be accompanied by depression, decreased motivation, or apathy. Lethargy can be a normal response to inadequate sleep, overexertion, overw ...
** Confusion
In psychology, confusion is the quality or emotional state of being bewildered or unclear. The term "acute mental confusion"
** Nightmare
A nightmare, also known as a bad dream, Retrieved 11 July 2016. is an unpleasant dream that can cause a strong emotional response from the mind, typically fear but also despair, anxiety, disgust or sadness. The dream may contain situations o ...
s (possible symptom)
** No fever
Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...
usually present
** Headache
A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...
s
* Stage II
** Deep lethargy
Lethargy is a state of tiredness, sleepiness, weariness, fatigue, sluggishness, or lack of energy. It can be accompanied by depression, decreased motivation, or apathy. Lethargy can be a normal response to inadequate sleep, overexertion, overw ...
** Delirium
Delirium (formerly acute confusional state, an ambiguous term that is now discouraged) is a specific state of acute confusion attributable to the direct physiological consequence of a medical condition, effects of a psychoactive substance, or ...
** Confusion
** Combative behavior
** Stupor
Stupor is the lack of critical mental function and a level of consciousness, in which an affected person is almost entirely unresponsive and responds only to intense stimuli such as pain. The word derives from the Latin '' stupor'' ("numbness, in ...
** Hyperventilation
Hyperventilation is irregular breathing that occurs when the rate or tidal volume of breathing eliminates more carbon dioxide than the body can produce. This leads to hypocapnia, a reduced concentration of carbon dioxide dissolved in the blo ...
** Fatty liver
Fatty liver disease (FLD), also known as hepatic steatosis and steatotic liver disease (SLD), is a condition where excess fat builds up in the liver. Often there are no or few symptoms. Occasionally there may be tiredness or pain in the upper r ...
(found on biopsy
A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, an interventional radiologist, or an interventional cardiology, interventional cardiologist. The process involves the extraction of sampling (medicine), sample ...
)
** Hyperactive reflexes
* Stage III
** Continuation of Stage I and II symptoms
** Possible coma
A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to Nociception, respond normally to Pain, painful stimuli, light, or sound, lacks a normal Circadian rhythm, sleep-wake cycle and does not initiate ...
** Possible cerebral edema
Cerebral edema is excess accumulation of fluid ( edema) in the intracellular or extracellular spaces of the brain. This typically causes impaired nerve function, increased pressure within the skull, and can eventually lead to direct compres ...
** Possible seizures
A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...
** Rarely, respiratory arrest
Respiratory arrest is a serious medical condition caused by apnea or respiratory dysfunction severe enough that it will not sustain the body (such as agonal breathing). Prolonged apnea refers to a patient who has stopped breathing for a long period ...
** Decorticate posturing
* Stage IV
** Seizures
** Decerebrate posturing
** Deepening coma
A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to Nociception, respond normally to Pain, painful stimuli, light, or sound, lacks a normal Circadian rhythm, sleep-wake cycle and does not initiate ...
** Dilated pupils with minimal response to light
** Loss of oculocephalic reflexes
** Minimal but still present liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
dysfunction
* Stage V
** Very rapid onset following stage IV
** Areflexia
** Deep coma
** Dilated, nonreactive pupils
** Isoelectric EEG
Electroencephalography (EEG)
is a method to record an electrogram of the spontaneous electrical activity of the brain. The bio signals detected by EEG have been shown to represent the postsynaptic potentials of pyramidal neurons in the neoc ...
** Respiratory arrest
Respiratory arrest is a serious medical condition caused by apnea or respiratory dysfunction severe enough that it will not sustain the body (such as agonal breathing). Prolonged apnea refers to a patient who has stopped breathing for a long period ...
** Seizures
A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...
** Multiple organ failure
Multiple organ dysfunction syndrome (MODS) is altered organ function in an acutely ill patient requiring immediate medical intervention.
There are different stages of organ dysfunction for certain different organs, both in acute and in chronic ...
** Flaccidity
** Hyperammonemia
Hyperammonemia, or high ammonia levels, is a metabolic disturbance characterised by an excess of ammonia in the blood. Severe hyperammonemia is a dangerous condition that may lead to brain injury and death. It may be primary or secondary.
Ammoni ...
(above 300 mg/dL of blood)
** Death
Death is the end of life; the irreversible cessation of all biological functions that sustain a living organism. Death eventually and inevitably occurs in all organisms. The remains of a former organism normally begin to decompose sh ...
Causes
The cause of Reye syndrome is unknown.[ It usually begins shortly after recovery from a ]viral infection
A viral disease (or viral infection) occurs when an organism's body is invaded by pathogenic viruses, and infectious virus particles (virions) attach to and enter susceptible cells.
Examples include the common cold, gastroenteritis, COVID-19, t ...
, such as influenza
Influenza, commonly known as the flu, is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These sympto ...
or chickenpox
Chickenpox, also known as varicella ( ), is a highly contagious disease caused by varicella zoster virus (VZV), a member of the herpesvirus family. The disease results in a characteristic skin rash that forms small, itchy blisters, which ...
.[ About 90% of cases in children are associated with ]aspirin
Aspirin () is the genericized trademark for acetylsalicylic acid (ASA), a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and inflammation, and as an antithrombotic. Specific inflammatory conditions that aspirin is ...
(salicylate
Salicylic acid is an organic compound with the formula HOC6H4COOH. A colorless (or white), bitter-tasting solid, it is a precursor to and a metabolite of acetylsalicylic acid (aspirin). It is a plant hormone, and has been listed by the EPA To ...
) use.[ Inborn errors of metabolism are also a risk factor.][
The association with aspirin has been shown through ]epidemiological
Epidemiology is the study and analysis of the distribution (who, when, and where), patterns and Risk factor (epidemiology), determinants of health and disease conditions in a defined population, and application of this knowledge to prevent dise ...
studies. The diagnosis
Diagnosis (: diagnoses) is the identification of the nature and cause of a certain phenomenon. Diagnosis is used in a lot of different academic discipline, disciplines, with variations in the use of logic, analytics, and experience, to determine " ...
of Reye syndrome greatly decreased in the 1980s, when genetic testing
Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
for inborn errors of metabolism was becoming available in industrialized countries. A retrospective study of 49 survivors of cases diagnosed as Reye syndrome showed that the majority of the surviving patients had various metabolic disorder
A metabolic disorder is a disorder that negatively alters the body's processing and distribution of macronutrients, such as proteins, fats, and carbohydrates. Metabolic disorders can happen when abnormal chemical reactions in the body alter the ...
s, particularly a fatty-acid oxidation disorder medium-chain acyl-CoA dehydrogenase deficiency.
Aspirin
There is an association between taking aspirin
Aspirin () is the genericized trademark for acetylsalicylic acid (ASA), a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and inflammation, and as an antithrombotic. Specific inflammatory conditions that aspirin is ...
for viral illnesses and the development of Reye syndrome, but no animal model of Reye syndrome has been developed in which aspirin causes the condition.
The serious symptoms of Reye syndrome appear to result from damage to cellular mitochondria
A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...
, at least in the liver, and there are a number of ways that aspirin could cause or exacerbate mitochondrial damage. A potential increased risk of developing Reye syndrome is one of the main reasons that aspirin has not been recommended for use in children and teenagers, the age group for which the risk of lasting serious effects is highest.
In some countries, oral mouthcare product Bonjela (not the form specifically designed for teething) has labeling cautioning against its use in children, given its salicylate
Salicylic acid is an organic compound with the formula HOC6H4COOH. A colorless (or white), bitter-tasting solid, it is a precursor to and a metabolite of acetylsalicylic acid (aspirin). It is a plant hormone, and has been listed by the EPA To ...
content. There have been no cases of Reye syndrome following its use, and the measure is a precaution. Other medications containing salicylates are often similarly labeled as a precaution.
The Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention (CDC) is the National public health institutes, national public health agency of the United States. It is a Federal agencies of the United States, United States federal agency under the United S ...
(CDC), the U.S. Surgeon General, the American Academy of Pediatrics
The American Academy of Pediatrics (AAP) is the largest professional association of pediatricians in the United States. It is headquartered in Itasca, Illinois, and maintains an office in Washington, D.C. The AAP has published hundreds of poli ...
(AAP) and the Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) recommend that aspirin and combination products containing aspirin not be given to children and teenagers under 19 years of age during episodes of fever-causing illnesses. Hence, in the United States
The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...
, it is advised that the opinion of a doctor or pharmacist should be obtained before anyone under 19 years of age is given any medication containing aspirin (also known on some medicine labels as acetylsalicylate, salicylate
Salicylic acid is an organic compound with the formula HOC6H4COOH. A colorless (or white), bitter-tasting solid, it is a precursor to and a metabolite of acetylsalicylic acid (aspirin). It is a plant hormone, and has been listed by the EPA To ...
, acetylsalicylic acid
Aspirin () is the Generic trademark, genericized trademark for acetylsalicylic acid (ASA), a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and inflammation, and as an antithrombotic. Specific inflammatory conditions ...
, ASA, or salicylic acid).
Current advice in the United Kingdom
The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Northwestern Europe, off the coast of European mainland, the continental mainland. It comprises England, Scotlan ...
by the Committee on Safety of Medicines is that aspirin should not be given to those under the age of 16 years, unless specifically indicated in Kawasaki disease
Kawasaki disease (also known as mucocutaneous lymph node syndrome) is a syndrome of unknown cause that results in a fever and mainly affects children under 5 years of age. It is a form of vasculitis, in which medium-sized blood vessels become in ...
or in the prevention of blood clot
A thrombus ( thrombi) is a solid or semisolid aggregate from constituents of the blood (platelets, fibrin, red blood cells, white blood cells) within the circulatory system during life. A blood clot is the final product of the blood coagulatio ...
formation.
Diagnosis
Differential diagnosis
Causes for similar symptoms include
* Various inborn metabolic disorders
A metabolic disorder is a disorder that negatively alters the body's processing and distribution of macronutrients, such as proteins, fats, and carbohydrates. Metabolic disorders can happen when abnormal chemical reactions in the body alter the ...
* Viral encephalitis
Viral encephalitis is inflammation of the brain parenchyma, called encephalitis, by a virus. The different forms of viral encephalitis are called viral encephalitides. It is the most common type of encephalitis and often occurs with viral meningiti ...
* Drug overdose
A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014. or poison
A poison is any chemical substance that is harmful or lethal to living organisms. The term is used in a wide range of scientific fields and industries, where it is often specifically defined. It may also be applied colloquially or figurati ...
ing
* Head trauma
A head injury is any injury that results in trauma to the skull or brain. The terms ''traumatic brain injury'' and ''head injury'' are often used interchangeably in the medical literature. Because head injuries cover such a broad scope of inj ...
* Liver failure
Liver failure is the inability of the liver to perform its normal synthetic and metabolic functions as part of normal physiology. Two forms are recognised, acute and chronic (cirrhosis). Recently, a third form of liver failure known as acute- ...
due to other causes
* Meningitis
Meningitis is acute or chronic inflammation of the protective membranes covering the brain and spinal cord, collectively called the meninges. The most common symptoms are fever, intense headache, vomiting and neck stiffness and occasion ...
* Kidney failure
Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...
* Shaken baby syndrome
Treatment
Treatment is supportive.[ ]Mannitol
Mannitol is a type of sugar alcohol used as a sweetener and medication. It is used as a low calorie sweetener as it is poorly absorbed by the intestines. As a medication, it is used to decrease pressure in the eyes, as in glaucoma, and to l ...
may be used to help with the brain swelling.[
]
Prognosis
Documented cases of Reye syndrome in adults are rare. The recovery of adults with the syndrome is generally complete, with liver and brain function returning to normal within two weeks of onset.
In children, mild to moderate to severe permanent brain damage is possible, especially in infants. Over thirty percent of the cases reported in the United States from 1981 through 1997 resulted in fatality.
Epidemiology
Reye syndrome occurs almost exclusively in children. While a few adult cases have been reported over the years, these cases do not typically show permanent neural or liver damage. Unlike in the United Kingdom, the surveillance for Reye syndrome in the United States is focused on people under 18 years of age.
In 1980, after the CDC began cautioning physicians and parents about the association between Reye syndrome and the use of salicylates in children with chickenpox or virus-like illnesses, the incidence of Reye syndrome in the United States began to decline, prior to the FDA
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
's issue of warning labels on aspirin in 1986. In the United States between 1980 and 1997, the number of reported cases of Reye syndrome decreased from 555 cases in 1980 to about two cases per year since 1994. During this time period 93% of reported cases for which racial data were available occurred in whites and the median age was six years. In 93% of cases a viral illness had occurred in the preceding three-week period. For the period 1991–1994, the annual rate of hospitalization due to Reye syndrome in the United States was estimated to be between < 0.3 – 1 per million population less than 18 years of age.
During the 1980s, a case-control study carried out in the United Kingdom also demonstrated an association between Reye syndrome and aspirin exposure. In June 1986, the United Kingdom Committee on Safety of Medicines issued warnings against the use of aspirin in children under 12 years of age and warning labels on aspirin-containing medications were introduced. United Kingdom surveillance for Reye syndrome documented a decline in the incidence of the illness after 1986. The reported incidence rate of Reye syndrome decreased from a high of 0.63 per 100,000 population less than 12 years of age in 1983–1984 to 0.11 in 1990–1991.
From November 1995 to November 1996 in France, a national survey of pediatric departments for children under 15 years of age with unexplained encephalopathy
Encephalopathy (; ) means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of overall brain dysfunction; this syndrome ...
and a threefold (or greater) increase in serum aminotransferase
Transaminases or aminotransferases are enzymes that catalyze a transamination reaction between an amino acid and an α- keto acid. They are important in the synthesis of amino acids, which form proteins.
Function and mechanism
An amino acid c ...
and/or ammonia
Ammonia is an inorganic chemical compound of nitrogen and hydrogen with the chemical formula, formula . A Binary compounds of hydrogen, stable binary hydride and the simplest pnictogen hydride, ammonia is a colourless gas with a distinctive pu ...
led to the identification of nine definite cases of Reye syndrome (0.79 cases per million children). Eight of the nine children with Reye syndrome were found to have been exposed to aspirin. In part because of this survey result, the French Medicines Agency reinforced the international attention to the relationship between aspirin and Reye syndrome by issuing its own public and professional warnings about this relationship.
History
The syndrome is named after Douglas Reye, who, along with fellow physicians Graeme Morgan and Jim Baral, published the first study of the syndrome in 1963 in ''The Lancet
''The Lancet'' is a weekly peer-reviewed general medical journal, founded in England in 1823. It is one of the world's highest-impact academic journals and also one of the oldest medical journals still in publication.
The journal publishes ...
''. In retrospect, the occurrence of the syndrome may have first been reported in 1929. Also in 1964, George Johnson and colleagues published an investigation of an outbreak of influenza B that described 16 children who developed neurological problems, four of whom had a profile remarkably similar to Reye syndrome. Some investigators refer to this disorder as Reye-Johnson syndrome, although it is more commonly called Reye syndrome. In 1979, Karen Starko and colleagues conducted a case-control study in Phoenix, Arizona, and found the first statistically significant link between aspirin use and Reye syndrome. Studies in Ohio and Michigan soon confirmed her findings pointing to the use of aspirin during an upper respiratory tract or chickenpox
Chickenpox, also known as varicella ( ), is a highly contagious disease caused by varicella zoster virus (VZV), a member of the herpesvirus family. The disease results in a characteristic skin rash that forms small, itchy blisters, which ...
infection as a possible trigger of the syndrome. Beginning in 1980, the CDC cautioned physicians and parents about the association between Reye syndrome and the use of salicylates in children and teenagers with chickenpox or virus-like illnesses. In 1982, the U.S. Surgeon General issued an advisory, and in 1986, the Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
required a Reye syndrome-related warning label for all aspirin-containing medications.
References
External links
NINDS Reye's Syndrome Information Page
{{DEFAULTSORT:Reye's Syndrome
Ailments of unknown cause
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Pediatrics
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