Reye's Syndrome
Summary
Reye's Syndrome (RS) is a rare, life-threatening acute encephalopathy associated with fatty degeneration of the viscera (specifically the liver). It is classically triggered by the use of Salicylates (Aspirin) to treat a viral fever (Influenza B or Varicella) in children. Since the association was discovered in the 1980s and Aspirin was contraindicated in less than 16s, the incidence has plummeted. It is now a diagnosis of exclusion, with most "Reye-like" presentations actually being Inborn Errors of Metabolism (IEM). [1,2]
Clinical Pearls
Diagnosis of Exclusion: In the modern era, a child presenting with "Reye's Syndrome" almost certainly has an underlying metabolic disorder, such as MCAD Deficiency (Medium-chain acyl-CoA dehydrogenase deficiency) or a Urea Cycle Defect. These conditions can be unmasked by viral stress and mimic RS perfectly.
Anicteric Hepatitis: The hallmark of RS is liver failure (Coagulopathy, High ALT, High Ammonia) WITHOUT Jaundice. If the child is yellow, it is likely viral hepatitis, not Reye's.
The Kawasaki Exception: Kawasaki Disease is the ONLY indication for high-dose Aspirin in children. These children are at risk of RS if they catch Flu/Chickenpox. They should receive the annual Influenza vaccine and Varicella vaccine to mitigate this risk.
Demographics
- Incidence: Historically common, now rare (less than 1 per million).
- Age: Peak 4-12 years.
- Seasonality: Winter/Spring (correlating with Flu outbreaks).
Risk Factors
- Viral Infection: Influenza A/B, Varicella (Chickenpox).
- Salicylates: Aspirin (Acetylsalicylic acid). Also found in Pepto-Bismol and some herbal remedies (Willow bark).
Mitochondrial Dysfunction
- Trigger: Viral cytokines + Salicylates act synergistically to damage mitochondria.
- Liver: Inhibition of mitochondrial Beta-Oxidation of fatty acids.
- Fat accumulation (Microvesicular Steatosis).
- Glycogen depletion -> Hypoglycaemia.
- Urea Cycle failure -> Hyperammonaemia.
- Brain: Hyperammonaemia + Free Fatty Acids cause astrocyte swelling -> Cerebral Oedema -> Raised ICP -> Death.
Prodrome
- Viral illness (URTI or Chickenpox) improving for 3-5 days.
Acute Onset
- Stage 1: Profuse, pernicious vomiting. Lethargy. Sleepiness.
- Stage 2: Disorientation, Aggression, Delirium, Hyperreflexia.
- Stage 3: Coma, Decorticate posturing.
- Stage 4: Fixed dilated pupils, Decerebrate posturing.
- Stage 5: Flaccidity, Seizures, Respiratory arrest.
- General: Hepatomegaly (firm/smooth). NO Jaundice.
- Neurological: Examine pupils and reflexes for signs of coning.
- Skin: Check for Varicella scars (chickenpox marks).
Biochemistry
- Glucose: Low (Hypoglycaemia). Crucial to treat.
- Ammonia: Markedly elevated (>100 µmol/L). Correlates with prognosis.
- LFTs: ALT/AST rise (3-30x normal). Bilirubin Normal.
- Clotting: PT/APTT prolonged (Liver failure).
Metabolic Screen (To rule out IEM)
- Plasma Amino Acids.
- Urine Organic Acids.
- Acylcarnitine profile/FFA.
Imaging
- CT Head: Cerebral Oedema (loss of sulci). No mass lesion.
Biopsy (Definitive but rarely done now)
- Liver Biopsy: Pan-lobular Microvesicular Steatosis (tiny fat droplets in cells). By contrast, alcohol/obesity cause Macrovesicular fat.
Management Algorithm
CHILD WITH ENCEPHALOPATHY + VOMITING
↓
CHECK GLUCOSE, AMMONIA, LFTs
(Rule out Meningitis with LP if safe)
↓
SUSPECT REYE'S / METABOLIC EROR
↓
1. STABILISATION (ABCDE)
- Intubate if GCS < 8
- Correct **Hypoglycaemia** (10% Dextrose)
- Vitamin K / FFP for clotting
↓
2. REDUCE AMMONIA
- Sodium Phenylbutyrate / Sodium Benzoate
- CVVH (Dialysis) if levels critical
↓
3. TREAT CEREBRAL OEDEMA
- Head up 30°
- Mannitol / Hypertonic Saline
- Fluid restriction (careful balance)
Specific Therapy
- There is no specific cure. Treatment is supportive.
- Review Meds: Stop all salicylates and anti-emetics (which may mask symptoms).
- Cerebral Herniation: Main cause of death.
- Neurological Deficit: Intellectual disability, Cranial nerve palsies.
- Pancreatitis: Rare.
- Mortality: 20-40% (Depends on stage at diagnosis).
- Survival: Recovery is rapid if treated early. Liver function returns to normal.
- Sequelae: Neuropsychological deficits in 30% of Stages 3-5.
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| Encephalopathy | RCPCH | Approach to the comatose child. metabolic screen mandatory. |
| Aspirin Warning | MHRA / FDA | Do not use salicylates in less than 16s. |
Landmark Evidence
1. The US Surgeon General Warning (1980)
- Based on CDC case-control studies showing a strong link between Aspirin use in varicella/flu and Reye's. Led to labelling changes and near-eradication of the disease.
What is Reye's Syndrome?
It is a sudden, severe illness that damages the liver and brain. It happens mostly in children recovering from a virus (like Flu or Chickenpox) who have taken Aspirin.
Why is Aspirin dangerous for kids?
For reasons we don't fully understand, the combination of the virus and the chemical in Aspirin shuts down the liver's "batteries". The liver stops clearing toxins, and levels of ammonia build up in the blood, causing the brain to swell.
What should I look for?
If your child seems to be getting better from a cold but then suddenly starts vomiting repeatedly and acting confused, sleepy, or aggressive, seek help immediately.
Prevention
The golden rule: Never give Aspirin to a child under 16 unless a heart specialist has told you to. Use Paracetamol or Ibuprofen instead.
Primary Sources
- Belay ED, et al. Reye's syndrome in the United States from 1981 through 1997. N Engl J Med. 1999.
- Glasgow JF. Reye's syndrome: the case for a causal link with aspirin. Drug Saf. 2006.
Common Exam Questions
- Diagnosis: "Child with vomiting, confusion, high ammonia, normal bilirubin?"
- Answer: Reye's Syndrome (or Urea Cycle defect).
- Pathology: "Liver biopsy finding?"
- Answer: Microvesicular Steatosis.
- Pharmacology: "Drug implicated?"
- Answer: Aspirin (Salicylates).
- Exceptions: "When can you give aspirin to a child?"
- Answer: Kawasaki Disease.
Viva Points
- Hypoglycaemia Mechanism: The liver is full of fat and mitochondria are failing, so Gluconeogenesis (making new sugar) and Glycogenolysis (releasing stored sugar) stop. Distinguishes it from simple viral encephalitis (where sugar is usually normal/high due to stress).
- Differential: Why rule out IEM? Because MCAD deficiency is treatable (avoid fasting) and genetic (implications for siblings). Reye's is sporadic.
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.