Description^1,2

This is a rare syndrome, characterised by an acute, life-threatening, non-inflammatory encephalopathy and fatty degeneration of the liver with minimal or no clinical signs of liver involvement. In classic Reye's syndrome, there is a severe but self-limiting disturbance of mitochondrial structure and associated enzymatic disturbances usually lasting about 6 days. This is accompanied by an intense, acute catabolic state associated with cerebral oedema in the absence of encephalitis or meningitis.

This condition appears to be a very rare complication of common viral infections. It often occurs after an unremarkable viral infection, particularly following influenza B, influenza A and varicella infections. It has also been reported after gastroenteritis and even live-virus vaccines. Measles has not been implicated. It is thought to come about as a result of interactions between viral and toxic environmental factors, with the most likely mechanism being an interaction of toxic substances on mitochondria that have been sensitised by the viral infection.

The most intensively investigated toxic factor has been salicylate (usually in the form of aspirin). This has been because of epidemiological associations (aspirin is involved in > 80% of cases² although this has not been geographically universal) and because of histopathological similarities between liver changes in Reye's syndrome and in those found in acute salicylate poisoning. However, this proposed aetiology does not explain the encephalopathy, the cause of which remains unknown.

Other drugs that have been used in patients who have developed Reye's syndrome have included outdated tetracycline, valproic acid, zidovudine, didanosine and anti-emetics. Reye or Reye-like syndromes have also been associated with insecticides, herbicides, aflatoxins, paint, paint thinner, margosa oil, hepatotoxic mushrooms, hypoglycin in ackee fruit (Jamaican vomiting sickness) and herbal medications with atractyloside (a diterpenoid glycoside found in the extracts of the tuber of Callilepis laureola - impila poisoning).

Reye-like illnesses have also been described whereby there is a similar pathological picture but associated with inherited metabolic disorders such as urea cycle defects, alpha-1 antitrypsin deficiency, fructosaemia etc. Fatty acid metabolism disorders seem to be more implicated. The number of these disorders reported to present with a Reye-like syndrome is increasing. Cystic fibrosis is one of these conditions. 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.³ 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.⁴ In 2002 the ban on aspirin was raised to 16 years old.⁵

Epidemiology

• 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 (see Reye-like syndrome above).⁷
• The incidence of Reye's syndrome is falling in the UK:⁵
  • 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. There have been no recorded cases in England and Wales since 2001.⁸
  • NHS Direct gives the incidence as less than 1 in 100,000 children per year.⁸
  • 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 sporadic cases, often associated with use of aspirin in children. Continued vigilance is required, particularly in the light of the current 'flu pandemic when individuals are more likely to forget advice about withholding aspirin from children.
• 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 success⁹ informing the public about the dangers of giving aspirin to children under 12. However 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 7.² It is rare over 18 but can occur in the first year of life.
• In black children, about two thirds are under 1 years old, compared with about one eighth of white children.¹⁰
• The sex incidence is equal.¹

Presentation¹

• This syndrome usually occurs in a child with an unremarkable medical history, a few days after the recovery phase of an unexceptional viral illness. Most frequently, this is an upper respiratory tract infection, influenza, varicella, or gastroenteritis. Other viral illnesses may be associated.²
• The typical patient abruptly deteriorates, typically about 3 days after apparent improvement. Initially there is protracted vomiting (rarely, this may be absent), followed by listlessness, lethargy and drowsiness 24 hours to 48 hours later. This is associated with tachypnoea.
  

  Use of anti-emetics has been linked to the aetiology and may complicate the presentation by masking the vomiting aspect of the presentation.

• The first sign in younger patients (under the age of 2) may simply be diarrhoea and tachypnoea.²
• The patient may continue to deteriorate, with more prominent neurological symptoms. Initially this may be a withdrawn state. It is followed by delirium and confusion, combative behaviour and stupor. There may be visual hallucinations.
• There may be sluggish pupillary responses but ophthalmological features of raised intracranial pressure are not always present.
• The clinical deterioration can continue, sometimes progressing to seizures and coma. Decerebrate posturing, opisthotonos, dilated/unequal pupils, deep rapid respirations, variations in pulse and, finally, a flaccid apnoeic state precede death.

Liver function is impaired, sometimes with slight hepatomegaly but without jaundice. The course of the illness may vary (4-60 hours) and the neurological status may stabilise or improve (spontaneously or with therapy) at any stage short of brain death.

In infants, the presentation is with more predominant respiratory symptoms and signs (tachypnoea, respiratory distress, hyperinflation and apnoea) ± temperature instability. Hypoglycaemia and hepatomegaly are more common and vomiting is usually absent. The history of a preceding viral infection is less common.

Investigations

Biochemistry¹

• Biochemical evidence of liver dysfunction is always found.¹ Transaminases are markedly elevated. Elevated bilirubin is less common.
• The prothrombin time is usually very slightly prolonged. Check INR.
• Ammonia levels may be up to 1.5 times the normal level.
• Hypoglycaemia must be identified and treated - it is a feature of severe cases, particularly in children under the age of 2.
• Measurements should also be made of urea and electrolytes, bicarbonate, magnesium, calcium and phosphate levels.¹ Serum osmolality should be checked as should blood ammonia and creatinine phosphokinase levels.
• There are a number of metabolic events that occur secondary to Reye's syndrome and these may be reflected in the blood biochemistry, e.g. very high serum concentrations of glucocorticoids, growth hormones, glucagon, fatty acids and glycerol. Lipase and amylase levels will also be elevated.
• Lactate dehydrogenase may be high or low.
• Urine specific gravity is raised and 80% of patients have ketonuria.²

Other investigations

As the patient stabilises following the acute phase, inherited disorders of metabolisms should be actively sought and ruled out.

Diagnosis²

The diagnosis is one of exclusion as there are no specific tests. However, diagnostic criteria for Reye's syndrome have been proposed:

• 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 a maximum of 8 x 10⁹/L white blood cells
• Brain biopsy: cerebral oedema without inflammation

Differential diagnosis

A child presenting with Reye's syndrome has to be assumed to have an inborn error of metabolism (particularly if under the age of 4) until proven otherwise.¹ Other differentials to consider when presented with these cases include:

• Meningitis
• Encephalitis
• Hepatitis
• Salicylate poisoning
• Other toxic ingestion, poisoning or drug overdose
• Diabetes. (There may be ketonuria in Reye's syndrome due to vomiting)
• Hypoglycaemia
• Head injury
• Renal or hepatic failure

Staging of Reye's syndrome

The original staging was 1 to 5 but now it is 0 to 6.¹¹ 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's 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.

Management

Successful management of the disease depends on early diagnosis. It is aimed at preventing, correcting and minimising metabolic abnormalities and controlling increased intracranial pressure. Early recognition and treatment are essential to prevent death and life-long neurological impairments.²

Important aspects of management are outlined here but not appropriate (or possible) in primary care. The remit of the general practitioner is to recognise the condition early and refer urgently.

• It is worth noting that the patient should be kept as quiet as possible; unnecessary handling or stimulation raises the intracranial pressure.
• Establish and maintain the patient's airway, breathing and circulation as needed.
• Check the glucose level, particularly if the patient is younger than 1 year, has an altered mental status or both. Administer dextrose to manage hypoglycemia.

There is no specific treatment for Reye's syndrome.² Treatment is supportive. On admission, some of the steps taken in initial management will include:

• Maintaining airway and brain oxygenation.
• Immediately correcting any hypoglycaemia with IV glucose and setting up a 10% glucose infusion. Blood sugar levels should be between 11 mmol/L and 22 mmol/L (i.e. higher than normal).
• If the blood pressure is normal, the head and upper trunk should be elevated at a 40° angle and over-hydration avoided.
• Monitoring and controlling blood chemistry and avoid dehydration.
• Ondansetron may be cautiously used to control the vomiting. Antacids may also be prescribed.
• Hyperammonaemia may be treated with sodium phenylacetate/sodium benzoate or haemodialysis
• Controlling fever.
• Anticonvulsants (e.g. phenytoin) may be required to treat seizures (if they are used in the acute phase, they are likely to be required for a number of months after recovery).
• Correction of coagulation defects if PTT exceeds 16 seconds; vitamin K may be needed to correct bleeding.
• Expert colleagues should be consulted early and admission to paediatric ITU sought.

Stage 2 or worse needs referral to a tertiary centre where intracranial pressure (ICP) can be monitored and lowered with appropriate therapy. Other parameters (central venous pressure, blood biochemistry abnormalities, coagulopathies, seizures etc.) will also need to be carefully managed.

Complications²

• Brain herniation with its complications
• Acute respiratory failure
• Cardiovascular collapse
• Aspiration pneumonia
• GI bleeding
• Pancreatitis
• Acute renal failure
• Sepsis
• Death

Prognosis

Prognosis has improved greatly with improvements in early diagnosis, recognition of milder cases and aggressive treatment.² If cerebral oedema is controlled, there is complete recovery.¹ Between 65% and 75% of patients admitted during stages 1 or 2 make a full recovery.

The 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.¹² Prognosis is worse in younger children (< 5) and in more advanced illness, death rates rising to 85% in stage 5. Other factors suggesting a poor prognosis include:¹

• Rapid progression of symptoms to grade 4 encephalopathy
• Creatinine phosphokinase > 10 times normal
• AST:ALT ration less than 1
• Marked slowing on EEG
• High non-esterified fats
• High long chain dicarboxylic acids
• Hypoproteinaemia unresponsive to fresh frozen vitamin K and FFP²

Prevention

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.⁹ It is important to avoid aspirin where possible and where alternatives exist, probably until the age of 16 or even 18. Kawasaki's disease is usually treated with high-dose aspirin and Reye's disease following this has been reported but is very rare indeed (1 in 200,000 children with Kawasaki's disease in one Japanese study).¹³ As always, it is a matter of balancing risks and benefits but varicella and influenza vaccines may be considered for these children.

Footnote

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 fewer than two lines but now his name is on every bottle of aspirin.