Reye’s syndrome in Pediatrics

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https://www.ncbi.nlm.nih.gov/books/NBK526101

Reye's syndrome in pediatrics

Reye's syndrome is a rare, rapidly progressive, potentially fatal disorder characterized by:

Acute non-inflammatory encephalopathy with cerebral edema
Acute hepatic mitochondrial dysfunction with fatty liver, typically microvesicular steatosis
Usually follows a viral illness, classically influenza A/B or varicella
Strong epidemiologic association with aspirin or other salicylate exposure in children with viral fever

It is now uncommon because aspirin is avoided for fever/viral infections in children. CDC's salicylate advisory supports this warning.

Pathogenesis

The central mechanism is generalized mitochondrial dysfunction. Impaired mitochondrial oxidative phosphorylation and fatty-acid metabolism cause:

Failure of hepatic energy metabolism
Impaired urea cycle function leading to hyperammonemia
Impaired gluconeogenesis leading to hypoglycemia
Microvesicular fatty change in the liver
Cerebral edema and progressive encephalopathy

The proposed trigger is a combination of viral illness, salicylate exposure, and possible underlying susceptibility. Disorders of fatty-acid oxidation and other inborn errors of metabolism can produce a similar "Reye-like" presentation and must be investigated.
Yamada's Textbook of Gastroenterology, 7th ed., pp. 2037-2038.

Typical clinical presentation

Usually seen in a previously well child, often 4-12 years old, during recovery from a febrile viral infection.

Viral prodrome: fever, upper-respiratory symptoms, influenza, or varicella.
After about 3-7 days: persistent, profuse vomiting.
Rapid neurologic deterioration:
- Lethargy, irritability, confusion
- Delirium or agitation
- Hyperventilation
- Seizures
- Stupor and coma in severe disease

Physical signs

Mild to moderate hepatomegaly
Usually no jaundice
Dehydration
Hyperreflexia
Features of raised intracranial pressure in advanced disease

Adams and Victor's Principles of Neurology, 12th ed., pp. 1148-1149.

Investigations

Finding	Typical result
Blood glucose	Hypoglycemia, especially in younger children
Serum ammonia	Raised, may be marked
AST/ALT	Elevated, commonly 3-fold or more
Bilirubin	Normal or minimally elevated
PT/INR	Prolonged due to hepatic dysfunction
Blood gas	Often early respiratory alkalosis; metabolic abnormalities may follow
CSF	Raised pressure but typically normal cells and protein
CT/MRI brain	Cerebral edema, mainly to assess complications/exclude alternatives
Liver histology	Panlobular microvesicular steatosis, little inflammation or necrosis

A clinical definition includes acute non-inflammatory encephalopathy, evidence of hepatic dysfunction such as elevated transaminases or hyperammonemia, and no better explanation.
Tietz Textbook of Laboratory Medicine, 7th ed., p. 2001.

Diagnosis

Diagnosis is clinical and by exclusion. Suspect it in a child with:

Recent viral illness + salicylate exposure + persistent vomiting + encephalopathy + hyperammonemia/hypoglycemia/liver dysfunction.

Important alternatives to exclude:

Sepsis, meningitis, encephalitis
Acute liver failure and viral hepatitis
Toxic ingestion, especially salicylates, acetaminophen, valproate
Urea-cycle defects
Fatty-acid oxidation disorders, especially MCAD deficiency
Mitochondrial disorders
Organic acidemias
Diabetic ketoacidosis and other metabolic causes of coma

Very young age, recurrent episodes, developmental symptoms, family history of unexplained illness, or no viral prodrome make an inherited metabolic disorder more likely than true Reye's syndrome. NIH clinical review

Management

This is a pediatric emergency requiring PICU care.

Immediate management

ABC stabilization and careful neurologic monitoring
Check bedside glucose immediately and correct hypoglycemia with IV dextrose
Controlled IV fluids and electrolyte correction
Treat cerebral edema and raised intracranial pressure according to PICU protocol
Elevate head of bed, avoid hypoxia/hypercapnia and excessive stimulation
Intubation and controlled ventilation if consciousness is impaired or ICP is raised
Treat seizures
Correct coagulopathy when clinically indicated
Manage hyperammonemia with specialist metabolic/hepatology/PICU input
Investigate for toxins and metabolic disease concurrently

Treatment is supportive, particularly directed at maintaining glucose and reducing intracranial pressure. Merck's pediatric review

Prevention

Do not give aspirin or salicylate-containing medicines to children or teenagers with influenza, chickenpox, or other viral febrile illnesses, unless a specialist has specifically prescribed it.
Use age-appropriate acetaminophen/paracetamol or ibuprofen for fever or pain when suitable.
Be alert to hidden salicylates in combination cold remedies and bismuth-containing products.
Aspirin may still be specifically prescribed in conditions such as Kawasaki disease, but this requires medical supervision.

High-yield exam points

Viral illness + aspirin + vomiting + encephalopathy + liver dysfunction
No or mild jaundice despite liver involvement
Hyperammonemia, hypoglycemia, prolonged PT/INR, elevated AST/ALT
Histology: microvesicular fatty liver
Main cause of death: cerebral edema with raised intracranial pressure
Must rule out inborn errors of metabolism, especially fatty-acid oxidation and urea-cycle disorders
Management: PICU supportive care, glucose, control of ICP, management of ammonia and coagulopathy
Prevention: avoid aspirin/salicylates in children with viral illness

Recent PubMed searching did not identify a relevant systematic review specific to Reye's syndrome in the past two years.

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