Hyperammoniacal Encephalopathy

Reye syndrome

Reye syndrome is an acute metabolic encephalopathy associated with hepatic dysfunction characterized by ‘fatty metamorphosis’.

It was named after the Australian doctor [Ralph Douglas Kenneth Reye (1912-1977)] who described it in 1963 and has a mortality rate of about 20-40%.

It is has been an extremely rare diagnosis since the 1980s.

The disappearance of Reye Syndrome is attributed to our increased ability to diagnose IEMs that cause Reye-like syndromes and successful public health campaigns to stop the use of aspirin in children with febrile illnesses. Reye syndrome hardly ever affects adults.

The CDC 1990 clinical case definition for Reye Syndrome is ‘an illness that meets all of the following criteria‘:

• Acute, noninflammatory encephalopathy that is documented clinically by:
  • an alteration in consciousness and, if available,
  • a record of the CSF containing less than or equal to 8 leukocytes/cu.mm or a histologic specimen demonstrating cerebral edema without perivascular or meningeal inflammation
• Hepatopathy documented by either:
  • a liver biopsy or an autopsy considered to be diagnostic of Reye syndrome or
  • a threefold or greater increase in the levels of the serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT), or serum ammonia
• No more reasonable explanation for the cerebral and hepatic abnormalities

Findings on the history include:

• Recent viral illness or vaccination:
  • especially influenza A or B, and varicella zoster (chicken pox)
• Recent salicylate use (e.g. aspirin):
  • over 80% of cases report aspirin use in the previous 3wks
• Vomiting:
  • often with an abrupt onset within few days (12h to 3 weeks) of the resolution of the viral illness
• Neurological symptoms
  • Onset heralded by repetitive vomitingLethargy, irritability, restlessness, delirium, seizures, loss of brainstem reflexes, decorticate or decrebrate coma and flaccid paralysis.

Findings on physical examination include:

• Protracted vomiting ± dehydration
• Afebrile with encephalopathy (see neurological symptoms)
• hepatomegaly (~50%) but with minimal or absent jaundice

The severity of Reye syndrome is described using a 6 stage classification ranging from 0 (alert, wakeful) to V (flaccid non-responsive coma).

The exact mechanisms leading to Reye syndrome are obscure.

It is thought to result when a sensitized virus-infected host is exposed to an agent that causes mitochondrial dysfunction.

This combination of insults leads to inhibition of oxidative phosphorylation and fatty-acid beta-oxidation and the resulting metabolic derangement manifests as neurological and hepatic dysfunction. The most important precipitating agents is thought to be:

Aspirin (and other salicylates)

The actions of the CDC and FDA in the early 1980’s led to the widespread banishment of aspirin from general use in children. Some experts still question whether aspirin has a causal role in the disorder as not every case of Reye syndrome involves aspirin exposure and only about about 1/1000 children using aspirin get the disorder. In my view, however, the relative disappearance of this terrible disease since the discontinuation of widespread aspirin use in children should not be trivialized. Other drugs and toxins might also act as triggers of mitochondrial dysfunction — paracetamol, valproate, and antiemetics have all been cited as potential culprits.

There is no specific treatment for Reye syndrome.

Standard supportive care and monitoring should be provided, generally in an ICU-level setting.

• Attend to ABCs
• Treat hypoglycemia
• Treat seizures — e.g. benzodiapines, phenytoin
• Treat vomiting — antiemetics e.g. ondansetron
• Appropriate fluid management
• Correct hyperammonaemia
  • Consider use of ammonia detoxicants (sodium phenylacetate and sodium benzoate) that prevent ammonia production from glycine and glutamine.
• Prevent and treat raised intracranial pressure
• Treat severe metabolic acidosis
• Correct coagulopathy
• Prevent and treat other potential causes and complications, e.g. sepsis, multiple organ dysfunction syndrome (MODS), SIADH, diabetes insipidus.