Reye Syndrome Clinical Presentation

• According to CDC surveillance statistics from 1980-1997, 93% of 1160 patients had at least 1 viral illness in the 3 weeks preceding the onset of Reye syndrome.^[3] Illnesses included viral upper respiratory illness or influenza in 73%, varicella in 21%, gastroenteritis in 14%, and other illness with exanthem 5%.^[3] Salicylates were detectable in the blood of 82% of patients.^[3]
• Influenza B (most common), influenza A, and varicella-zoster virus are most often involved.
• Parainfluenza, adenovirus, coxsackieviruses A and B, echovirus, Epstein-Barr virus, rubella virus, measles virus, cytomegalovirus, herpes simplex virus, parainfluenza viruses, and poliomyelitis viruses are less commonly involved than the pathogens listed above.
• Reye syndrome can occur after vaccination with live viral vaccines.
• Abrupt onset of pernicious vomiting occurs 12 hours to 3 weeks after viral illness; the mean is 3 days.
• Neurologic symptoms usually occur 24-48 hours after onset of vomiting. Lethargy is usually the first neurologic manifestation.
• Diarrhea and hyperventilation may be the first signs in children younger than 2 years.
• Irritability, restlessness, delirium, seizures, and coma occur.
• Obtain an appropriate history in any child who presents with symptoms similar to those of Reye syndrome to determine whether an IEM should be considered.

Signs and symptoms of Reye syndrome include protracted vomiting, with or without clinically significant dehydration, encephalopathy in afebrile patients with minimal or absent jaundice, and hepatomegaly in 50% of patients. Some authorities postulate that antiemetics mask early symptoms, and others propose that antiemetics may further predispose the individual to the disease.

Lovejoy initially described clinical stages I-V,^[5] Hurwitz modified to stages 0-5 to include a nonclinical stage (stage 0). The CDC uses the Hurwitz classification and adds stage 6. Stage 0 does not meet the CDC case definition because it does not meet the criteria for encephalopathy. The stages are as follows:

• Stage 0 - Alert, abnormal history and laboratory findings consistent with Reye syndrome, no clinical manifestations
• Stage 1 - Vomiting, sleepiness, and lethargy
• Stage 2 - Restlessness, irritability, combativeness, disorientation, delirium, tachycardia, hyperventilation, dilated pupils with sluggish response, hyperreflexia, positive Babinski sign, and appropriate response to noxious stimuli
• Stage 3 - Obtunded, comatose, decorticate rigidity, and inappropriate response to noxious stimuli
• Stage 4 - Deep coma, decerebrate rigidity, fixed and dilated pupils, loss of oculovestibular reflexes, and dysconjugate gaze with caloric stimulation
• Stage 5 - Seizures, flaccid paralysis, absent deep tendon reflexes (DTRs), no pupillary response, and respiratory arrest
• Stage 6 - Patients who cannot be classified because they have been treated with curare or other medication that alters level of consciousness

Viral illness and salicylates are the most well-documented causes of Reye syndrome. For other drugs and toxins, whether the syndrome produced is Reye syndrome or a Reye-like syndrome is unclear. Several IEMs appear to cause Reye-like syndromes.

Viral illness

Especially influenza B, influenza A, varicella-zoster virus

Salicylates

Aspirin is the drug classically associated with Reye syndrome. The association with salicylates was demonstrated in several epidemiologic studies around the world. Fewer than 0.1% of children who took aspirin developed Reye syndrome, but greater than 80% of patients diagnosed with Reye syndrome had taken aspirin in the past 3 weeks.

The association was questioned based on bias and limitations of the studies, but recommendations by government health agencies that children not be treated with salicylates resulted in immediate and dramatic decrease in the incidence of Reye syndrome.

A causal relationship between Reye syndrome and salicylates has not been definitively established, but an in vitro study demonstrates that salicylates decrease beta-oxidation of the long-chain fatty acid, palmitate, by cultured fibroblasts from children who recovered from Reye syndrome compared to controls.^[6] Recognition of structural similarity between aspirin metabolites and enzyme substrates for the mitochondrial trifunctional enzyme important in B-oxidation led to identification of the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) component of the enzyme as the target of salicylate inhibition. Absence of inhibition of beta-oxidation by salicylates in fibroblasts from patients with LCHAD deficiency substantiated the finding.

Paracetamol, outdated tetracycline, valproic acid, zidovudine, didanosine, and antiemetics are associated with Reye or Reye-like syndrome.

An association with antiemetics, such as phenothiazines, has been postulated but not substantiated.

Reye or Reye-like syndrome include 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).

IEMs

IEMs produce Reye-like syndromes. Most commonly, fatty-acid oxidation defects (particularly medium-chain fatty-acid oxidation defect [MCAD]), urea-cycle defects are found, but amino and organic acidopathies, primary carnitine deficiency, and disorders of carbohydrate metabolism are also found.

Recurrence of symptoms and precipitating factors, including prolonged fast, change in diet or metabolic stressor, and family members with similar symptoms, suggest IEM. The percentage of patients with a previous diagnosis of Reye syndrome is 0.4%. The percentage of patients who have a sibling with a Reye syndrome history is 2.9%. It is likely that at least of some of these patients had IEM rather than Reye syndrome.

IEMs may also account for the heterogeneity of disease manifestations in patients younger than 5 years, especially those younger than 1 year, who have received a diagnosis of Reye syndrome. IEMs, rather than true Reye syndrome in patients younger than 5 years, may also explain why decreases in salicylate use and decreases in the incidence of Reye syndrome have been greatest in patients older than 5 years.

Preexisting failure to thrive, neurologic abnormalities, dysfunction, and decompensation out of proportion to intercurrent illnesses also suggest IEM.