Approach

The diagnosis of Reye's syndrome is usually made based on history and laboratory testing. Reye's syndrome should be considered in any child presenting with profuse, protracted vomiting and altered mental status, ranging from personality changes to coma. Data from the US suggest that Reye's syndrome mainly affects white children aged 5 to 14 years.[5]

There is no definitive test to confirm the diagnosis of Reye's syndrome. Because Reye's-like illnesses can be caused by many different disease entities, a low threshold for the diagnosis of Reye's syndrome should aid in quickly ruling in or out other aetiologies. Any patient in whom the diagnosis of Reye's syndrome is suspected should undergo additional investigations for inborn errors of metabolism in consultation with a geneticist, a gastroenterologist, and other specialists as appropriate.

History

The usual course of Reye's syndrome is biphasic. It is important to consider a diagnosis of Reye's syndrome in children recovering from a recent viral infection (e.g., influenza, varicella-zoster infection, or viral gastroenteritis). The patient typically has a prodromal illness that is not of unusual severity.[16] During recovery from the prodromal illness, the patient develops an acute onset of profuse vomiting followed by a change in mental status. These symptoms occur about 1 to 3 weeks after the viral illness, and the change in mental status usually follows the onset of emesis by about 1 to 2 days. Seizures may occur in late stages of disease.

History should also be obtained for any recent exposure to aspirin or salicylate-containing medications; 82% of patients have had exposure.[5] However, the causal relationship between Reye's syndrome and aspirin exposure has not been clearly established. Other drugs and toxins implicated include antiemetics, valproic acid, outdated tetracyclines, zidovudine, didanosine, paracetamol, aflatoxin, margosa oil, hypoglycin (found in unripe ackee fruit), various pesticides, polyethylene, and various insecticides.

Clinical examination and stages

The US National Reye's Syndrome Surveillance System has described increasing stages of severity (modified from Hurwitz):[2]

  • Stage 1: Lethargic, vomiting

  • Stage 2: Irritable, delirious, hyper-reflexive, positive Babinski's sign, dilated/sluggish pupils, responsive to pain

  • Stage 3: Decorticate posturing, obtunded, unresponsive to pain

  • Stage 4: Decerebrate posturing, comatose, fixed/dilated pupils

  • Stage 5: Areflexia, flaccid paralysis, unresponsive pupils, seizures, respiratory failure

  • Stage 6: Patient cannot be classified as he/she has been treated with curare or another medication that alters the level of consciousness.

The patient is usually afebrile. The only physical findings may be hepatomegaly, present in only 50% of patients at presentation, and hyperventilation. Jaundice, fever, and signs of meningeal inflammation suggest other diagnoses. Pupillary responses may be helpful in assessing disease severity (stage). Raised intracranial pressure is clinically suggested by irritability and vomiting.

Initial laboratory investigations

Baseline serum chemistry, glucose, LFTs, ammonia level, coagulation studies (serial PT, PTT, and INR), platelet and fibrinogen levels, urine/serum toxicology screen, and urinalysis should constitute the initial approach to these patients.[17]

Findings include:

  • significantly elevated ammonia and transaminases with normal bilirubin levels, hypoglycaemia, metabolic acidosis, negative toxicology screens, and urine ketosis.

  • hypoglycaemia, a possible feature at presentation, particularly in younger children (<3 years old). Ammonia levels are usually at least 1.5 to 20 times elevated at the time of presentation.[18] Levels >250 micromol/L (>350 micrograms/dL) can be associated with increased mortality.[19]

A blood gas should be considered if the patient has significant altered mental status or if the patient is electively intubated.

Subsequent tests

Neurological tests

  • For patients with a mental status change, a lumbar puncture (LP), a CT scan of the head, and an EEG should also be considered, although these are not required for diagnosis.

  • As a patient with Reye's syndrome may have elevated intracranial pressure, the risk of performing an LP should be evaluated.[17]​ CSF studies are typically normal with negative cultures. If the CSF shows an elevated WBC count, aetiologies other than Reye's syndrome are more likely.

  • CT head will most probably be normal, but may show cerebral oedema without a bleed or a mass.

  • EEG may also be ordered, and typically shows non-specific, generalised slowing and flattening of waves.

Liver biopsy

  • In select patients, a liver biopsy is indicated (infants <1 year old, children with recurrent episodes, familial cases, or atypical cases: for example, absence of prodromal illness).[20] Biopsy reveals no significant inflammation; histochemical studies show abundant small fat droplets within hepatocytes; ultrastructural studies demonstrate hepatic mitochondrial changes.

  • Findings can also help rule out metabolic disorders, toxic liver disease, and hepatitis.

Additional tests

It is important to rule out inborn errors of metabolism that cause similar symptoms, particularly in younger children, children who have had similar episodes in the past, and children with a history or a family history of hypoglycaemic episodes, particularly after stress. Consultation with a metabolic specialist is recommended to direct further laboratory testing.

Inborn errors of metabolism may also show metabolic acidosis, hyperammonaemia, and a low blood sugar. If the bilirubin level is elevated, an alternative aetiology other than Reye's syndrome is more likely.

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