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Reye Syndrome

by Elizabeth J. Palumbo, MD

Reye syndrome is a rare form of acute encephalopathy and fatty infiltration of the liver that tends to occur after some acute viral infections, particularly when salicylates are used. Diagnosis is clinical. Treatment is supportive.

The cause of Reye syndrome is unknown, but many cases seem to follow infection with influenza A or B or varicella. 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 juvenile idiopathic arthritis and Kawasaki disease) 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 yr. 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 Inherited Disorders of Metabolism).

Symptoms and Signs

The disease varies greatly in severity but is characteristically biphasic. Initial viral symptoms (URI 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

  • Progressive unresponsiveness

  • Decorticate and decerebrate posturing

  • Seizures

  • Flaccidity

  • Fixed dilated pupils

  • Respiratory arrest

Focal neurologic findings usually are not present. Hepatomegaly occurs in about 40% of cases, but jaundice is absent.

Complications

Complications include

  • Electrolyte and fluid disturbances

  • Increased intracranial pressure (ICP)

  • Diabetes insipidus

  • Syndrome of inappropriate ADH secretion

  • Hypotension

  • Arrhythmias

  • Bleeding diatheses (especially GI)

  • Pancreatitis

  • Respiratory insufficiency

  • Hyperammonemia

  • Aspiration pneumonia

  • Poor temperature regulation

  • Uncal herniation and death


Diagnosis

  • Clinical findings in association with laboratory testing

  • Liver biopsy

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 yr. The diagnosis may also be made when the typical clinical findings and history are associated with the following laboratory findings: increased liver transaminases (AST, ALT > 3 times normal), normal bilirubin, increased blood ammonia level, and prolonged PT.

Head CT or MRI is done as for any child with encephalopathy. If head CT or MRI is normal, a lumbar puncture (see Lumbar puncture (spinal tap)) can be done. CSF examination usually shows increased pressure, < 8 to 10 WBCs/μL, 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 yr; 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.

Differential diagnosis

The differential diagnosis of coma and liver dysfunction includes sepsis or hyperthermia (especially in infants); potentially treatable inborn abnormalities of urea synthesis (eg, ornithine transcarbamylase deficiency) or fatty acid oxidation (eg, systemic carnitine deficiency, medium chain acyl-CoA dehydrogenase deficiency); phosphorus or carbon tetrachloride intoxication; acute encephalopathy caused by salicylism, other drugs (eg, valproate), or poisons; viral encephalitis or meningoencephalitis; and acute hepatitis. Illnesses such as idiopathic steatosis of pregnancy and tetracycline liver toxicity may show similar light microscopic findings.


Prognosis

Outcome is related to the duration of cerebral dysfunction, severity and rate of progression of coma, severity of increased ICP, and degree of blood ammonia elevation. Progression from stage I to higher stages is likely when the initial blood ammonia level is > 100 μg/dL (> 60 μmol/L) and the PT is 3 sec 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

  • Support measures

Treatment is supportive, with particular attention paid to control of ICP and blood glucose because glycogen depletion is common. Treatment of elevated ICP includes intubation, hyperventilation, fluid restriction of 1500 mL/m 2 /day, elevating the head of the bed, osmotic diuretics, 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.

Key Points

  • 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 ICP.

Drugs Mentioned In This Article

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  • ACHROMYCIN V

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