What is Reye syndrome?

What is Reye Syndrome

Reye syndrome is a rare but life-threatening acute metabolic encephalopathy affecting children and adolescents, characterized by the combination of non-inflammatory brain swelling with altered consciousness and acute liver dysfunction with fatty infiltration, typically occurring after a viral illness—particularly when aspirin has been used. 1

Core Clinical Definition

Reye syndrome presents as a biphasic illness with three essential diagnostic components 1:

• Acute non-inflammatory encephalopathy with depressed or altered level of consciousness
• Hepatic dysfunction demonstrated by either fatty metamorphosis on liver biopsy OR more than threefold elevation of ALT/AST
• Elevated ammonia levels 24-48 hours after mental status changes (the most frequent laboratory abnormality)

Clinical Presentation

The syndrome follows a characteristic temporal pattern 1:

• Initial phase: Protracted vomiting in an afebrile patient following viral illness (typically influenza B or varicella)
• Neurological phase: Begins 24-48 hours after vomiting onset, with lethargy as the first manifestation
• Physical findings: Minimal or absent jaundice, hepatomegaly in 50% of patients
• Young children (<2 years): May present with diarrhea and hyperventilation as initial signs

Etiology and Risk Factors

The cause remains incompletely understood, but key associations include 1, 2:

• Aspirin exposure: Clear epidemiological association with salicylate use during viral illness (82% of cases had detectable blood salicylate levels)
• Viral triggers: Influenza (particularly influenza B) and varicella are most commonly implicated
• Dramatic decline: Cases dropped from 555 in 1980 to fewer than 36 annually after 1987 following aspirin warnings

Critical caveat: Many children diagnosed with Reye syndrome actually have underlying inborn errors of metabolism 1, 3. Recent data shows 71% of children presenting with Reye syndrome phenotype have a confirmed inherited metabolic disorder, including urea cycle disorders (51%), fatty acid oxidation defects (24%), and mitochondrial disorders 3.

Diagnostic Workup

Beyond the core triad, additional findings include 1:

• CSF analysis: May show increased opening pressure but WBCs <9/ml (usually lymphocytes)
• Head CT: May reveal cerebral edema but often normal
• EEG: Slow wave activity in early stages, flattened waves in advanced stages
• Metabolic screening: Essential in all cases to rule out treatable inborn errors of metabolism 2, 3

Prognosis and Outcomes

Mortality and morbidity data 1:

• Overall case fatality rate: 31% historically, now reduced to less than 20% with earlier diagnosis and aggressive therapy
• Highest risk groups: Children under 5 years (relative risk 1.8) and those with serum ammonia >45 μg/dL (relative risk 3.4)
• Survivors: Among those who recover, 26% have residual neurological deficits, 43% achieve full recovery

Management Principles

There is no specific treatment 1:

• Metabolic support: Correction of metabolic imbalance with continuous hypertonic glucose infusion
• Intracranial pressure management: Reduction with intermittent hypertonic mannitol
• Specialist consultation: Advice from metabolic medicine specialist is essential
• Intensive care: All patients require ICU admission; 23% may need continuous venovenous hemodialysis 3

Modern Clinical Context

Any infant or child suspected of having Reye syndrome should undergo extensive investigation to rule out treatable inborn metabolic disorders that can mimic this presentation 2, 3. The recommendation for systematic Next-Generation Sequencing study reflects that standard metabolic tests can be inconclusive 3. True idiopathic Reye syndrome is now extremely rare, making the differential diagnosis of metabolic disorders paramount.