Aetiology
The aetiology remains unknown. However, certain viruses, drugs, exogenous toxins, and metabolic disorders have been implicated. These include:[8]
Viral infections: influenza B (and less commonly influenza A), varicella-zoster, parainfluenza, adenovirus, Coxsackie virus, cytomegalovirus, herpes simplex virus, echovirus 2, and Epstein-Barr virus. CDC data in the US indicate that, among patients with a history of antecedent viral illness during the three week period prior to onset of Reye's syndrome, 73% had influenza-like illness, 21% had varicella-zoster infection, 14% had viral gastroenteritis, and 5% had viral exanthema.[5]
Drugs: acetylsalicylic acid, antiemetics, valproic acid, outdated tetracyclines, zidovudine, didanosine, and paracetamol. Aspirin is the drug classically associated with Reye's syndrome and has been studied the most.[5][13] However, studies have not clearly supported or refuted a cause-effect relationship in children.[8]
Toxins: aflatoxin, margosa oil, hypoglycin (found in unripe ackee fruit), various pesticides, polyethylene, and various insecticides.
An atypical response to an initial viral infection: in genetically predisposed individuals, it is postulated that exposure to certain exogenous agents triggers a sequence of events leading to mitochondrial dysfunction.[6]
Inborn errors of metabolism may mimic Reye's syndrome. These include urea cycle disorders, glycogen storage disease, organic acidaemias, primary carnitine deficiency, hereditary fructose intolerance, and fatty acid oxidation defects.[4]
Pathophysiology
The pathogenesis is unclear, but a preceding viral infection seems to be an initial factor involved in most cases.[5][14] In certain genetically predisposed individuals, this infection then disrupts mitochondrial function and lipid metabolism in numerous organs, particularly the liver, and also in the kidneys, and the brain, and in skeletal muscle tissues.[6] Damaged cells release cytokines and other mediators that facilitate metabolic changes, and possibly sensitise tissues for further injury by exogenous factors.[6]
In the liver specifically, this metabolic failure leads to decreased gluconeogenesis with increased fatty acid and ammonia production. This process may then be aggravated by the introduction of additional environmental factors, or by an underlying metabolic disorder. The resultant hypoglycaemia and hyperammonaemia may lead to cerebral oedema and increased intracranial pressure.
Classification
National Reye's syndrome surveillance system (US) (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.
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