The cause of Reye syndrome is unknown, but many cases seem to follow infection with influenza A or B Influenza Influenza is a viral respiratory infection causing fever, coryza, cough, headache, and malaise. Mortality is possible during seasonal epidemics, particularly among high-risk patients (eg, those... read more or varicella Chickenpox Chickenpox is an acute, systemic, usually childhood infection caused by the varicella-zoster virus (human herpesvirus type 3). It usually begins with mild constitutional symptoms that are followed... read more . Using salicylates (generally aspirin) during such illness increases the risk by as much as 35-fold. This finding has led to a marked decrease in salicylate use in the US since the mid-1980s (except when specifically indicated, such as in Kawasaki disease Kawasaki Disease Kawasaki disease is a vasculitis, sometimes involving the coronary arteries, that tends to occur in infants and children between the ages of 1 year and 8 years. It is characterized by prolonged... read more ) and a corresponding decrease in the incidence of Reye syndrome from several hundred annual cases to about 2. The syndrome occurs almost exclusively in children < 18 years. In the US, most cases occur in late fall and winter.
The disease affects mitochondrial function, causing disturbance in fatty acid and carnitine metabolism. Pathophysiology and clinical manifestations are similar to a number of inherited metabolic disorders of fatty acid transport and mitochondrial oxidation ( see Introduction to Inherited Disorders of Metabolism Introduction to Inherited Disorders of Metabolism Most inherited disorders of metabolism (also called inborn errors of metabolism) are caused by mutations in genes that code for enzymes; enzyme deficiency or inactivity leads to Accumulation... read more ).
Symptoms and Signs of Reye Syndrome
The disease varies greatly in severity but is characteristically biphasic. Initial viral symptoms (upper respiratory infection or sometimes chickenpox) are followed in 5 to 7 days by pernicious nausea and vomiting and a sudden change in mental status. The changes in mental status may vary from a mild amnesia, weakness, vision and hearing changes, and lethargy to intermittent episodes of disorientation and agitation, which can progress rapidly to deepening stages of coma manifested by
Decorticate and decerebrate posturing
Fixed dilated pupils
Focal neurologic findings usually are not present. Hepatomegaly occurs in about 40% of cases, but jaundice is absent.
Complications of Reye syndrome
Increased intracranial pressure
Syndrome of inappropriate ADH secretion Syndrome of inappropriate antidiuretic hormone secretion (SIADH) Hyponatremia is decrease in serum sodium concentration 136 mEq/L ( 136 mmol/L) caused by an excess of water relative to solute. Common causes include diuretic use, diarrhea, heart failure, liver... read more
Bleeding diatheses (especially gastrointestinal)
Poor temperature regulation
Uncal herniation and death
Diagnosis of Reye Syndrome
Clinical findings in association with laboratory testing
Reye syndrome should be suspected in any child exhibiting the acute onset of an encephalopathy (without known heavy metal or toxin exposure) and pernicious vomiting associated with hepatic dysfunction. Liver biopsy provides the definitive diagnosis, showing microvesicular, fatty changes, and is especially useful in sporadic cases and in children < 2 years. The diagnosis may also be made when the typical clinical findings and history are associated with the following laboratory findings: increased liver transaminases (aspartate aminotransferase, alanine aminotransferase > 3 times normal), normal bilirubin, increased blood ammonia level, and prolonged prothrombin time.
Head CT or MRI is done as for any child with encephalopathy. If head CT or MRI is normal, a lumbar puncture Lumbar Puncture (Spinal Tap) Lumbar puncture is used to do the following: Evaluate intracranial pressure and cerebrospinal fluid (CSF) composition (see table Cerebrospinal Fluid Abnormalities in Various Disorders) Therapeutically... read more can be done. Cerebrospinal fluid (CSF) examination usually shows increased pressure, < 8 to 10 white blood cells/mcL, and normal protein levels; the CSF glutamine level may be elevated. Hypoglycemia and hypoglycorrhachia (a very low concentration of CSF glucose) occur in 15% of cases, especially in children < 4 years; they should be screened for metabolic disease. The condition is staged from I to V according to severity.
Signs of metabolic derangement include elevated serum amino acid levels, acid-base disturbances (usually with hyperventilation, mixed respiratory alkalosis–metabolic acidosis), osmolar changes, hypernatremia, hypokalemia, and hypophosphatemia.
The differential diagnosis of coma and liver dysfunction includes
Potentially treatable inborn abnormalities of urea synthesis Urea Cycle Disorders Urea cycle disorders are characterized by hyperammonemia under catabolic or protein-loading conditions. There are many types of urea cycle and related disorders (see the table) as well as many... read more (eg, ornithine transcarbamylase deficiency) or fatty acid oxidation Overview of Fatty Acid and Glycerol Metabolism Disorders Fatty acids are the preferred energy source for the heart and an important energy source for skeletal muscle during prolonged exertion. Also, during fasting, the bulk of the body’s energy needs... read more (eg, systemic carnitine deficiency Carnitine Deficiency Carnitine deficiency results from inadequate intake of or inability to metabolize the amino acid carnitine. It can cause a heterogeneous group of disorders. Muscle metabolism is impaired, causing... read more , medium chain acyl-CoA dehydrogenase deficiency Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) In these processes, there are numerous inherited defects, which typically manifest during fasting with hypoglycemia and metabolic acidosis; some cause cardiomyopathy and muscle weakness. Beta-oxidation... read more )
Acute encephalopathy caused by salicylism Aspirin and Other Salicylate Poisoning Salicylate poisoning can cause vomiting, tinnitus, confusion, hyperthermia, respiratory alkalosis, metabolic acidosis, and multiple organ failure. Diagnosis is clinical, supplemented by measurement... read more , other drugs (eg, valproate), or poisons; viral encephalitis Encephalitis Encephalitis is inflammation of the parenchyma of the brain, resulting from direct viral invasion or occurring as a postinfectious immunologic complication caused by a hypersensitivity reaction... read more or meningoencephalitis
Illnesses such as idiopathic steatosis of pregnancy and tetracycline liver toxicity may show similar light microscopic findings.
Prognosis for Reye Syndrome
Outcome is related to the duration of cerebral dysfunction, severity and rate of progression of coma, severity of increased intracranial pressure, and degree of blood ammonia elevation. Progression from stage I to higher stages is likely when the initial blood ammonia level is > 100 mcg/dL (> 60 mcmol/L) and the prothrombin time is ≥ 3 seconds longer than that of the control. In fatal cases, the mean time from hospitalization to death is 4 days. Fatality rates average 21% but range from < 2% among patients in stage I to > 80% among patients in stage IV or V.
Prognosis for survivors usually is good, and recurrences are rare. However, the incidence of neurologic sequelae (eg, intellectual disability, seizure disorders, cranial nerve palsies, motor dysfunction) is as high as 30% among survivors who developed seizures or decerebrate posturing during illness.
Treatment of Reye Syndrome
Treatment of Reye syndrome is supportive, with particular attention paid to control of increased intracranial pressure and blood glucose because glycogen depletion is common.
Treatment of elevated increased intracranial pressure includes intubation, hyperventilation, fluid restriction of 1500 mL/m2/day, elevating the head of the bed, osmotic diuretics, direct increased intracranial pressure monitoring, and decompressing craniotomy. Infusion of 10 or 15% dextrose is common to maintain euglycemia. Coagulopathy may require fresh frozen plasma or vitamin K.
Other treatments (eg, exchange transfusion, hemodialysis, barbiturate-induced deep coma) have not been proved effective but are sometimes used.
Reye syndrome of acute encephalopathy and hepatic dysfunction, typically occurring after viral infection (particularly with salicylate use), has become rare since routine use of aspirin in children has been reduced.
Diagnosis is by exclusion of similarly manifesting infectious, toxic, and metabolic disorders; liver biopsy may help confirm it.
Treatment is supportive, particularly with measures to lower increased intracranial pressure.