Reye's Syndrome

This is a rare syndrome, characterized by encephalopathy and fatty degeneration of the liver, usually after an influenza like illness or varicella. It has been reported after gastroenteritis and even live-virus vaccines. The most likely mechanism is a toxic interaction of salicylate on mitochondria that have been sensitized by the viral infection.

• The incidence of Reye's syndrome is falling in both the UK and USA.¹
  • There were 52 cases in the UK during the 5 years 1991-1996 compared with 276 reported cases in the 5 years up to 1986.
  • NHS Direct gives the incidence as less than 1 in 100,000 children per year.²
  • The Health Promotion Agency kept surveillance of Reye's disease from 1981 but ceased in 2001 when the numbers had fallen dramatically. However, there are still are still sporadic cases, often associated with use of aspirin in children. Continued vigilance is required.³
• It is most common in January to March when flu like illnesses are most prevalent.
• An association has been shown to exist between Reye's syndrome and the use of aspirin during the prodromal illness. The falling incidence is lauded as a public health success⁴ informing the public about the dangers of giving aspirin to children under 12, but Reye's syndrome can occur in older children and even adults. Teenagers should also be advised to use ibuprofen and paracetamol rather than aspirin.
• The usual presentation is between 5 and 14 years with a median of 7. It is rare over 18 but can occur in the first year of life, especially in black children. In black children, about two thirds are under 1 years old, compared with about one eighth of white children.⁵
• It seems likely that in the early days, the disease was under-diagnosed, whereas in the 1970s and 1980s diagnoses may have been excessive.⁶ Such unreliability makes it difficult to assess the true change in incidence of the disease.
• Retrospective re-evaluation of surviving patients diagnosed with Reye's syndrome has revealed that many, if not most of these patients have an underlying inborn error of metabolism.⁷ Errors include amino and organic acidopathies, urea cycle defects, disorders of carbohydrate metabolism, and fatty-acid oxidation defects, which may mimic Reye's syndrome.
• This has led to debate about the aetiology of Reye's syndrome, including if it is truly a distinct entity and not just a variety of metabolic disorders.⁸ It is certainly true that since the ban on the use of aspirin under the age of 12 in 1986 it has declined and it is argued that better diagnosis of metabolic abnormalities will not account for all this.⁹
• In 2002 the ban on aspirin was raised to 16 years old.¹⁰

A few days after apparent recovery from a viral URTI or chicken pox, the typical patient abruptly deteriorates, initially developing protracted vomiting, listlessness, lethargy and drowsiness. The patient may continue to deteriorate, developing delirium and confusion, combative behaviour and stupor, with sluggish pupillary responses; sometimes progressing to seizures, coma, and death. Liver function is impaired, sometimes with slight hepatomegaly, but without jaundice. About half have an enlarged liver.

The diagnostic criteria for Reye's syndrome are:

• Acute non-inflammatory encephalopathy with an altered level of consciousness
• Hepatic dysfunction with a liver biopsy showing fatty metamorphosis or a more than 3-fold increase in ALT, AST and/or ammonia levels
• No other explanation for cerebral oedema or hepatic abnormality
• Cerebrospinal fluid (CSF) with 8 or fewer WBCs per cubic millimetre
• Brain biopsy with cerebral oedema without inflammation

Infants and young children sometimes present atypically, eg without vomiting and have a poorer prognosis. Diarrhoea and hyperventilation may be the first signs in children under 2 years.

The original staging was 1 to 5¹¹ but now it is 0 to 6.¹² Staging is valuable to aid management and for retrospective assessment of prognosis.

0. No clinical abnormality but there are biochemical abnormalities suggestive of the disease
1. Lethargic, sleepy, vomiting, difficult to arouse
2. Delirium, combative, with semi-purposeful motor responses. Tachycardia, hyperventilation, sluggish pupillary response, extensor Babinski sign.
3. Unrousable, predominately flexor motor responses (decorticate)
4. Unrousable, predominately extensor responses, fixed dilated pupils (decerebrate)
5. Unrousable, flaccid paralysis, seizures, absent tendon reflexes, unresponsive pupils, respiratory arrest
6. Cannot be classified because of treatment with curare or other medication that alters level of consciousness

• Glucose. Hypoglycaemia must be identified and treated, especially in those under 1 year old.
• Transaminases are abnormally elevated. SGOT and SGPT when markedly elevated, strongly suggest a diagnosis of Reye's Syndrome
• Blood ammonium
• INR
• CT or MRI of the head may reveal cerebral oedema but often it is normal
• EEG
• Lumbar puncture (if intracranial pressure not elevated) is usually required to exclude other causes
• Liver biopsy (if performed) shows swollen, pleomorphic mitochondria, poor gluconeogenesis and ureagenesis. Coagulation defects must be corrected before biopsy.

• Meningitis
• Encephalitis
• Diabetes. There may be ketonuria in Reye's syndrome due to vomiting
• Toxic ingestion, poisoning or drug overdose
• Head injury
• Renal or hepatic failure
• Inherited metabolic disorders (oxidation defects, urea cycle disorders, and other organic acidurias)

Successful management of the disease depends on early diagnosis.

• Maintain airway and brain oxygenation and correct any hypoglycaemia with IV glucose and set up a 10% glucose infusion
• Monitor and control blood chemistry and avoid dehydration
• Keep the patient quiet
• Consult expert colleagues and arrange admission to paediatric ITU

Stage 2 or worse needs referral to a tertiary centre where intracranial pressure (ICP) can be monitored and lowered with appropriate therapy.

• Control fever
• Anticonvulsants may be required to treat seizures and vitamin K to correct bleeding
• Hyperammonaemia may be treated with sodium phenylacetate/sodium benzoate or haemodialysis
• Elevate the head of the bed and avoid over-hydration to prevent raised ICP

In stages 3,4 and 5:

• Continuously monitor and treat ICP
• Central venous pressure, arterial pressure, and/or end-tidal carbon dioxide
• Treat seizures with phenytoin
• Correct coagulation defects if PTT exceeds 16 seconds

Between 65 and 75% of patients admitted during stage 1 or 2 make a full recovery, and their mortality rate is currently around 20%. 10 to 20% have a persistent neurological deficit with a range from slight to profound. Ammonia level is the best predictor, with approximately 3% of patients experiencing neurological sequelae if levels are less than 45 μg/dL and 11%, if more than 45 μg/dL.¹ Prognosis is worse in younger children (<5) and the more advanced the illness, death rates rising to 85% in stage 5.

There appears to be good evidence that the avoidance of aspirin in children with febrile illness has had a dramatic effect on the incidence of Reye's disease although the evidence of the association is not conclusive.⁴ It is important to avoid aspirin where possible and where alternatives exist, probably until the age of 16 or even 18. Kawasaki disease is usually treated with high dose aspirin and Reye's disease following this has been reported.¹³ As always, it is a matter of balancing risks and benefits.

Reports of the syndrome appeared as early as 1929,¹⁴ but it was not until 1963 that an Australian pathologist named Ralph Douglas Reye at the Royal Alexandra Hospital for Children in Sydney wrote his paper describing a group of children with common abnormalities, lethargy, belligerence, and excessive vomiting.¹⁵

Dr. Reye died suddenly in 1977 a day after his mandatory retirement at age 65. His obituary in The Medical Journal of Australia was less than two lines but now his name is on every bottle of aspirin.