Reye Syndrome 

Reye syndrome is characterized by acute noninflammatory encephalopathy and hepatic failure. In 1963, R. D. K. Reye first described this syndrome as a distinct entity in Australia, and, a few months later, G. M. Johnson described it in the United States. Cases with identical manifestations have been described as early as 1929.

Although the etiology of Reye syndrome is unknown, the condition typically occurs after a viral illness, particularly an upper respiratory tract infection (URTI), influenza, varicella, or gastroenteritis, and it is associated with the use of aspirin during the illness. The discovery of inborn errors of metabolism and identification of toxins that have manifestations similar to those of Reye syndrome and a dramatic decrease in the use of aspirin among children have made the diagnosis and occurrence of Reye syndrome exceedingly rare.

Given that manifestations of Reye syndrome are not unique to Reye syndrome but also are seen in other conditions and given that no test is specific for Reye syndrome, the diagnosis must be one of exclusion. A high index of suspicion is critical for diagnosis. With the recognition that Reye syndrome is rare, the diagnosis should be considered in the differential diagnosis in any child with vomiting and altered mental status. Diagnostic criteria from the Centers for Disease Control and Prevention (CDC) are as follows:^{[1, 2]}

• Acute noninflammatory encephalopathy with an altered level of consciousness
• Hepatic dysfunction with a liver biopsy showing fatty metamorphosis or a more than 3-fold increase in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and/or ammonia levels
• No other explanation for cerebral edema or hepatic abnormality
• CSF with WBCs (usually lymphocytes) 8/mm³ or fewer (8 X 10⁹/L or fewer)
• Brain biopsy with cerebral edema without inflammation

Early recognition and treatment are essential to prevent death and to optimize the likelihood of recovery without neurologic impairment.

When the criteria were developed, specific testing for other conditions was not required. Retrospective reevaluation of patients with a diagnosis of Reye syndrome who survived has revealed that many, if not most, had an underlying inborn error of metabolism (IEM). Many of these IEMs had not even been described when the diagnosis of Reye syndrome was made. Inborn errors that may mimic Reye syndrome include fatty-acid oxidation defects, amino and organic acidopathies, urea-cycle defects, and disorders of carbohydrate metabolism. Future discovery of other IEMs may ultimately explain even more of these cases. Additional etiologies that may mimic Reye syndrome include viral infections, neuromuscular diseases, adverse drug reactions, and toxic exposures to chemicals and plants that cause hepatocellular damage and encephalopathy.

The pathogenesis is unclear, but it appears to involve mitochondrial dysfunction that inhibits oxidative phosphorylation and fatty-acid beta-oxidation in a virus-infected, sensitized host. The host has usually been exposed to mitochondrial toxins, most commonly salicylates (>80% of cases). Some have postulated that salicylates stimulate the expression of inducible nitric oxide synthase (iNOS) because of findings of iNOS stimulation in African children with fatal malaria, a disease that causes symptoms similar to those of Reye syndrome and is often treated with aspirin.

Histologic changes include cytoplasmic fatty vacuolization in hepatocytes, astrocyte edema and loss of neurons in the brain, and edema and fatty degeneration of the proximal lobules in the kidneys. All cells have pleomorphic, swollen mitochondria that are in reduced number, along with glycogen depletion and minimal tissue inflammation. Hepatic mitochondrial dysfunction results in hyperammonemia, which is thought to induce astrocyte edema, resulting in cerebral edema and increased intracranial pressure (ICP).

Frequency

United States

National surveillance for Reye syndrome began in 1973. The peak incidence of 555 cases reported to the CDC was in 1979-1980. Between December 1, 1980, and November 30, 1997, 1207 cases of Reye syndrome in patients younger than 18 years were reported.^[3] During that period, the incidence rate was 0.15-0.88 cases per 100,000 children per year and as high as 6 cases per 100,000 during regional outbreaks of influenza. Cases have declined since 1980 when the government began issuing warnings about the association between Reye syndrome and aspirin. In 1985 and 1986, an average of 100 cases per year were reported. In 1987-1993, the maximum cases reported were 36 per year, with a range of 0.03-0.06 cases per 100,000 per year; 2 or fewer cases have been reported every year since 1994.

Before the 1970s, most cases that met criteria for Reye syndrome are thought to have been diagnosed as encephalitis or drug intoxication. The dramatic decrease in the frequency of Reye syndrome since the 1980s is largely attributable to the decrease in aspirin use in children and discoveries of and advances in diagnosis of IEM and the identification of toxins and drugs that produce symptoms that mimic Reye syndrome. In addition, overreporting of cases during the peak years that did not fully meet criteria and possible underreporting of cases in recent years by physicians who do not consider the diagnosis may also account for the apparent decline.

Seasonal occurrence initially peaked from December to April, which correlated with the peak occurrence of viral respiratory infections, particularly influenza. Since 1990, the seasonal variation has been less pronounced than this initial observation.

International

In the United Kingdom, 597 cases were reported between 1981 and 1996. The incidence of Reye syndrome decreased from a high in 1983-1984 of 0.63 per 100,000 children younger than 12 years to 0.11 cases per 100,000 in 1990-1991 after warnings of the association between Reye syndrome and aspirin were issued in 1986. Of the 597 cases, 155 were later reclassified, 76 as having an IEM.^[4]

Similar rates have been reported from other countries.

Mortality/Morbidity

• The mortality has decreased from 50% to less than 20% as a result of early diagnosis, recognition of mild cases, and aggressive therapy.
• Death is usually due to cerebral edema or increased ICP, but it may be due to myocardial dysfunction, cardiovascular collapse, respiratory failure, renal failure, GI bleeding, status epilepticus, or sepsis.
• Patients who survive may have complete recovery, though neurologic impairment is common.

Race

The racial distribution of Reye syndrome in the United States, according to CDC surveillance statistics in 1980-1997 is 93% white; 5% African American; and the remainder Asian, American Indian, and Native Alaskan.^[3]

Sex

Reye syndrome is equally distributed between the sexes.

Age

The peak ages are 5-14 years, with a median of 6 years and a mean of 7 years.

• Reye syndrome rarely occurs in newborns or in children older than 18 years.
• In African Americans, 67% of patients are younger than 1 year compared with only 12% in white patients.