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Pediatrics, Reye Syndrome

Author: Debra L Weiner, MD, PhD, Attending Physician, Division of Emergency Medicine, Children's Hospital, Boston; Assistant Professor, Department of Pediatrics, Harvard Medical School
Contributor Information and Disclosures

Updated: Feb 3, 2009

Introduction

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 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.

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, 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.

Clinical

History

• According to CDC surveillance statistics from 1980-1997, 93% of 1160 patients had at least 1 viral illness in the 3 weeks preceding the onset of Reye syndrome.³   
  • Illnesses included viral upper respiratory illness or influenza in 73%, varicella in 21%, gastroenteritis in 14%, and other illness with exanthem 5%.³
  • Salicylates were detectable in the blood of 82% of patients.³
• 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,⁵ 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 consistent 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 and salicylates are the most well-documented causes of Reye syndrome. For other drugs and toxins, whether the syndrome produced is Reye syndrome or a Reye-like syndrome is unclear. Several IEMs appear to cause Reye-like syndromes.
• Viral illness - Especially influenza B, influenza A, varicella-zoster virus
• Drugs  
  • Salicylates
    • Aspirin is the drug classically associated with Reye syndrome. The association with salicylates was demonstrated in several epidemiologic studies around the world. Fewer than 0.1% of children who took aspirin developed Reye syndrome, but greater than 80% of patients diagnosed with Reye syndrome had taken aspirin in the past 3 weeks.
    • The association was questioned based on bias and limitations of the studies, but recommendations by government health agencies that children not be treated with salicylates resulted in immediate and dramatic decrease in the incidence of Reye syndrome. 
    • A causal relationship between Reye syndrome and salicylates has not been definitively established, but an in vitro study demonstrates that salicylates decrease beta-oxidation of the long-chain fatty acid, palmitate, by cultured fibroblasts from children who recovered from Reye syndrome compared to controls.⁶ Recognition of structural similarity between aspirin metabolites and enzyme substrates for the mitochondrial trifunctional enzyme important in B-oxidation led to identification of the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) component of the enzyme as the target of salicylate inhibition. Absence of inhibition of beta-oxidation by salicylates in fibroblasts from patients with LCHAD deficiency substantiated the finding.
    • Paracetamol, outdated tetracycline, valproic acid, zidovudine, didanosine, and antiemetics are associated with Reye or Reye-like syndrome.
    • An association with antiemetics, such as phenothiazines, has been postulated but not substantiated.
  • Reye or Reye-like syndrome include insecticides; herbicides; aflatoxins; paint; paint thinner; margosa oil; hepatotoxic mushrooms; hypoglycin in ackee fruit (Jamaican vomiting sickness); and herbal medications with atractyloside, a diterpenoid glycoside found in the extracts of the tuber of Callilepis laureola (impila poisoning).
• IEMs: IEMs produce Reye-like syndromes. Most commonly, fatty-acid oxidation defects (particularly medium-chain fatty-acid oxidation defect [MCAD]), urea-cycle defects are found, but amino and organic acidopathies, primary carnitine deficiency, and disorders of carbohydrate metabolism are also found.  
  • Recurrence of symptoms and precipitating factors, including prolonged fast, change in diet or metabolic stressor, and family members with similar symptoms, suggest IEM. 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%. It is likely that at least of some of these patients had IEM rather than Reye syndrome.
  • IEMs may also account for the heterogeneity of disease manifestations in patients younger than 5 years, especially those younger than 1 year, who have received a diagnosis of Reye syndrome. IEMs, rather than true Reye syndrome in patients younger than 5 years, may also explain why decreases in salicylate use and decreases in the incidence of Reye syndrome have been greatest in patients older than 5 years.
  • Preexisting failure to thrive, neurologic abnormalities, dysfunction, and decompensation out of proportion to intercurrent illnesses also suggest IEM.

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