INTRODUCTION	Section 2 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Background: 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 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 rare.

Given that manifestations of Reye syndrome are not unique to Reye syndrome but also 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 any child with vomiting and altered mental status. Diagnostic criteria from the Centers for Disease Control and Prevention (CDC) are as follows:

• 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 8 or fewer WBCs per cubic millimeter (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 surviving patients with a diagnosis of Reye syndrome has revealed that many, if not most, had an underlying inborn error of metabolism (IEM). Many of these IEMs had not yet been described when Reye syndrome was diagnosed. 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, and toxic exposures that cause hepatocellular damage and encephalopathy.

Pathophysiology: 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. Malaria 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:

• In the US: The frequency, which peaked in the 1970s and early 1980s, is now <0.03-1 case per 100,000 persons younger than 18 years, though it may be as high as 6 cases per 100,000 with regional viral epidemics. The rate is <0.1% of children with viral illness treated with aspirin.

  Before the 1970s, most cases might have been diagnosed as encephalitis or drug intoxication. The dramatic decrease in the frequency of Reye syndrome since the 1980s is largely attributable the discoveries of and advances in diagnosis of IEM that mimic Reye syndrome and to decreased aspirin use in children. The decrease is most marked in patients older than 5 years. Overreporting of cases during the peak years that did not fully meet criteria and possible underreporting of cases in recent years by physicians who no longer consider the diagnosis may also account for the apparent decline.

  The CDC reported 1207 cases of Reye syndrome in patients younger than 18 years between December 1, 1980, and November 30, 1997. The peak incidence of 555 cases occurred in 1980. The rate declined to an average of 100 cases per year in 1985 and 1986. In 1987-1993, the maximum cases reported were 36 per year; 2 or fewer cases have been reported every year since 1994.

  The percentage of patients with a previous diagnosis of Reye syndrome is 0.4%. The percentage of patients who have a sibling with a Reye syndrome history is 2.9%.

  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.

• Internationally: In Australia, 49 cases of Reye syndrome were reviewed by using the scoring systems Gauthier and Hall developed. Of 26 survivors, 18 (69%) later received diagnoses of other conditions. Most had IEMs, and none of the 49 patients had indisputable Reye syndrome.

  A decreased frequency is observed; however, it is not uniformly associated with decreased aspirin use in children. Seasonal variation is not as pronounced worldwide as in the United States.

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.

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.

	CLINICAL	Section 3 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

History:

• According to CDC surveillance statistics from 1980 to 1997, 93% of 1160 patients had at least 1 viral illness in the 3 weeks preceding the onset of Reye syndrome.

• Illnesses included viral URTI or influenza in 73%, varicella in 21%, gastroenteritis in 14%, and other illness with exanthem 5%.

• Salicylates were detectable in the blood of 82% of patients.

• Influenza B (most common), influenza A, and varicella-zoster virus are most often involved.

• Parainfluenza, adenovirus, coxsackieviruses A and B, echovirus, Epstein-Barr virus, rubella virus, measles virus, cytomegalovirus, herpes simplex virus, parainfluenza viruses, and poliomyelitis viruses are less commonly involved than the pathogens listed above.

• Reye syndrome can occur after vaccination with live viral vaccines.

• Abrupt onset of pernicious vomiting occurs 12 hours to 3 weeks after viral illness; the mean is 3 days.

• Neurologic symptoms usually occur 24-48 hours after onset of vomiting. Lethargy is usually the first neurologic manifestation.

• Diarrhea and hyperventilation may be the first signs in children younger than 2 years.

• Irritability, restlessness, delirium, seizures, and coma occur.

• Obtain an appropriate history in any child who presents with symptoms similar to those of Reye syndrome to determine whether an IEM should be considered.

Physical:

• Signs and symptoms of Reye syndrome include protracted vomiting, with or without clinically significant dehydration, encephalopathy in afebrile patients with minimal or absent jaundice, and hepatomegaly in 50% of patients.

• Some authorities postulate that antiemetics mask early symptoms, and others propose that antiemetics may further predispose the individual to the disease.

• Lovejoy initially described clinical stages I-V, Hurwitz modified to stages 0-5 to include a nonclinical stage (stage 0). The CDC uses the Hurwitz classification and adds stage 6. Stage 0 does not meet the CDC case definition because it does not meet the criteria for encephalopathy. The stages are as follows:

• Stage 0 - Alert, abnormal history and laboratory findings conversant with Reye syndrome, no clinical manifestations

• Stage 1 - Vomiting, sleepiness, and lethargy

• Stage 2 - Restlessness, irritability, combativeness, disorientation, delirium, tachycardia, hyperventilation, dilated pupils with sluggish response, hyperreflexia, positive Babinski sign, and appropriate response to noxious stimuli

• Stage 3 - Obtunded, comatose, decorticate rigidity, and inappropriate response to noxious stimuli

• Stage 4 - Deep coma, decerebrate rigidity, fixed and dilated pupils, loss of oculovestibular reflexes, and dysconjugate gaze with caloric stimulation

• Stage 5 - Seizures, flaccid paralysis, absent deep tendon reflexes (DTRs), no pupillary response, and respiratory arrest

• Stage 6 - Patients who cannot be classified because they have been treated with curare or other medication that alters level of consciousness

Causes:

• Viral illness - Especially influenza B, influenza A, varicella-zoster virus)

• Toxins - Insecticides, herbicides, aflatoxins, paint, paint thinner, hepatotoxic mushrooms, hypoglycin in akee fruit, margosa oil

• Drugs - Salicylates, paracetamol, outdated tetracycline, valproic acid, zidovudine, didanosine, antiemetics

• Aspirin is the drug classically associated with Reye syndrome. The association with salicylates, though not universally accepted, was demonstrated in several epidemiologic studies around the world.

• An association with antiemetics, eg, phenothiazines, has been postulated but not substantiated.

• IEMs - Most commonly fatty-acid oxidation defects (particularly medium chain fatty acid oxidation defect [MCAD]), urea-cycle defects, and also amino and organic acidopathies and disorders of carbohydrate metabolism

• Recurrence of symptoms and precipitating factors, including prolonged fast, change in diet or metabolic stressor, and family members with similar symptoms, suggest IEM.

• IEMs may also account for the heterogeneity of disease manifestations in patients younger than 5 years who have received a diagnosis of Reye syndrome.

• IEMs may also explain why decreases salicylate use and decreases in the incidence of Reye syndrome have been greatest in patients older than 5 years.