What is Reye Syndrome
Reye syndrome is a rare but life-threatening childhood acute encephalopathy coupled with liver dysfunction that typically follows a viral illness—particularly influenza B—and is strongly associated with aspirin use during that illness. 1
Definition and Core Features
Reye syndrome is characterized by three cardinal features that define the diagnosis 1:
- Acute non-inflammatory encephalopathy with altered level of consciousness (no inflammatory cells in CSF or neural tissue)
- Hepatic dysfunction demonstrated by either fatty metamorphosis on liver biopsy OR more than threefold elevation in ALT/AST
- Elevated ammonia levels appearing 24–48 hours after mental status changes (the most frequent laboratory abnormality)
The syndrome presents with protracted vomiting and encephalopathy in afebrile patients with minimal or absent jaundice, and hepatomegaly occurs in approximately 50% of cases 1.
Clinical Presentation and Timeline
The illness follows a biphasic pattern 2:
- Phase 1: Prodromal viral illness (frequently influenza A or B, or varicella)
- Phase 2: Neurological symptoms begin 24–48 hours after onset of vomiting, typically 3–5 days after the viral illness when the child appears to be recovering 1, 2
Lethargy is usually the first neurological manifestation in older children 1. In children younger than two years, diarrhea and hyperventilation may be the first signs rather than typical vomiting and lethargy 1.
Etiology and Risk Factors
The cause remains incompletely understood, but the evidence points to innate susceptibility coupled with aspirin taken for relief of viral symptoms 1. The pathophysiology involves a mitochondrial metabolism disorder leading to metabolic failure of multiple tissues, especially the liver 3.
Influenza B is particularly implicated, though influenza A also causes cases 1. There was a dramatic fall in incidence following warnings about aspirin use in children beginning in 1980 1, 4. After a peak of 555 cases in 1980, there have been no more than 36 cases per year since 1987 in the United States 4.
Children on long-term aspirin treatment for medical conditions may be at increased risk if they develop influenza infection 1.
Diagnostic Workup
Key laboratory findings include 1:
- Metabolic acidosis (always present)
- Elevated ammonia (most frequent abnormality, appears 24-48 hours after mental status changes)
- Elevated transaminases (>3-fold increase in ALT/AST)
- Detectable blood salicylate levels (found in 82% of reported cases) 4
Imaging and other studies 1:
- Head CT may reveal cerebral edema but results are usually normal
- EEG may show slow wave activity in early stages and flattened waves in advanced stages
- CSF may have increased opening pressure with WBCs <9/ml (usually lymphocytes)
Critical Differential Diagnosis
Any infant or child suspected of having Reye syndrome should undergo extensive investigation to rule out treatable inborn metabolic disorders that can mimic Reye syndrome, as many children have an underlying inborn error of metabolism 1, 4. This is especially important now that true Reye syndrome has become very rare 4.
Management Approach
There is no specific treatment for Reye syndrome 1. Management focuses on:
- Correction of metabolic imbalance
- Reduction of intracranial pressure
- Advice from a specialist in metabolic medicine should be requested 1
Prognosis and Outcomes
The overall case fatality rate is 31%, though mortality has fallen from 50% to less than 20% as a result of earlier diagnosis and more aggressive therapy 1, 4.
Risk factors for poor outcomes include 4:
- Age under 5 years (relative risk 1.8)
- Serum ammonia >45 μg/dL (relative risk 3.4)
The prognosis is directly related to the stage at presentation and the rapidity and adequacy of intensive care treatments 3.
Prevention
Aspirin should be avoided in children and adolescents with viral illnesses, particularly influenza and varicella 4, 2, 5. Since 1986, the FDA has required warning labels on all aspirin products about the association with Reye syndrome 2. Special attention should be directed toward educating adolescents and parents of older children, as the syndrome is now more prevalent in older adolescents who may self-medicate 2, 5.