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Reye Syndrome, Pediatric

Basics

Description

- Mitochondrial injury of unknown etiology in a viral-infected host results in dysfunction of oxidative phosphorylation and fatty acid oxidation. - Mitochondrial toxins, usually salicylates, exacerbate the condition when ingested after mitochondrial injury. - Multiple factors may sometimes be involved, including complex metabolic problems affecting the mitochondria. - Postmortem - Liver: grossly yellowish-white due to increased triglyceride levels; foamy cytoplasm with increased microvesicular fat, decreased glycogen - Brain: marked edema with increased intracellular fluid and loss of neurons - Abnormal-looking mitochondria can be detected in many tissues. - Multiple organ involvement may be present in fatty acid oxidation or other defects.

- Slight liver enlargement without jaundice - Absence of focal neurologic signs - Neurologic exam varies with stage of disease: - Stage 0: alert, wakeful - Stage 1: difficult to arouse, lethargic, sleepy - Stage 2: delirious, combative, with purposeful or semipurposeful motor responses - Stage 3: unarousable, with predominantly flexor motor responses, decorticate - Stage 4: unarousable, with predominantly extensor motor responses, decerebrate - Stage 5: unarousable, with flaccid paralysis, areflexia, and pupils unresponsive - Stage 6: treated with curare or equivalent drug and therefore unclassifiable

  • Acute encephalopathy and fatty degeneration of the liver which may be idiopathic or secondary
  • "Classic " пїЅ Reye syndrome is associated with aspirin (acetylsalicylic acid) therapy, whereas Reye-like syndromes are due to metabolic disorders or other etiologies.Acute, noninflammatory encephalopathy that is documented clinically by (a) an alteration in consciousness and, if available, (b) a record of the CSF containing ≤8 leukocytes/mm3 or a histologic specimen demonstrating cerebral edema without perivascular or meningeal inflammationLiver enlargement documented by either (a) a liver biopsy or an autopsy considered to be diagnostic of Reye syndrome or (b) a 3-fold or greater increase in the levels of the serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT), or serum ammoniaNo more reasonable explanation for the cerebral and hepatic abnormalities

Epidemiology

  • Peak incidence age 6 years
  • Most children range from 4 to 12 years of age.
  • Association with ingestion of aspirin-containing medicines by children with varicella or influenza B
  • In 1982, the U.S. Surgeon General issued an advisory on the use of salicylates and Reye syndrome.
  • Reye-like illness is often associated with fatty acid oxidation defects and other inborn errors of metabolism.

Incidence

  • Peak incidence of 555 cases in children in the United States in 1980
  • From 1994 to 1997, there were no more than 2 cases of Reye syndrome annually.
  • Reye-like illness due to metabolic causes should be suspected now in all cases with this presentation.

Pathophysiology

  • Mitochondrial injury of unknown etiology in a viral-infected host results in dysfunction of oxidative phosphorylation and fatty acid oxidation.
  • Mitochondrial toxins, usually salicylates, exacerbate the condition when ingested after mitochondrial injury.
  • Multiple factors may sometimes be involved, including complex metabolic problems affecting the mitochondria.
  • PostmortemLiver: grossly yellowish-white due to increased triglyceride levels; foamy cytoplasm with increased microvesicular fat, decreased glycogenBrain: marked edema with increased intracellular fluid and loss of neuronsAbnormal-looking mitochondria can be detected in many tissues.Multiple organ involvement may be present in fatty acid oxidation or other defects.

Diagnosis

History

  • Prodromal illness: upper respiratory infection (73%) " пїЅinfluenza B, influenza A, and varicella
  • Abrupt-onset vomiting within 47 days of initial illness
  • Natural history: neurologic deterioration in which delirium may progress to seizures, coma, or death
  • Underlying history of inborn errors of metabolism or family history of conditions like medium-chain acyldehydrogenase deficiency should be sought.

Physical Exam

  • Slight liver enlargement without jaundice
  • Absence of focal neurologic signs
  • Neurologic exam varies with stage of disease:Stage 0: alert, wakefulStage 1: difficult to arouse, lethargic, sleepyStage 2: delirious, combative, with purposeful or semipurposeful motor responsesStage 3: unarousable, with predominantly flexor motor responses, decorticateStage 4: unarousable, with predominantly extensor motor responses, decerebrateStage 5: unarousable, with flaccid paralysis, areflexia, and pupils unresponsiveStage 6: treated with curare or equivalent drug and therefore unclassifiable
  • Organomegaly may be present in Reye-like illness.

Diagnostic Tests & Interpretation

Lab

  • Ammonia test: Result may be normal at the onset of vomiting. Serum level >45 g/dL suggests higher mortality.
  • CSF: normal except for elevated intracranial pressure
  • Hypoglycemia is often present.
  • Ketonemia may be present.

Imaging

EEG: characteristic of metabolic encephalopathy with generalized slow-wave abnormalities пїЅ пїЅ

Diagnostic Procedures/Other

  • Liver and muscle function testing: elevated levels of transaminases, creatinine kinase, lactate dehydrogenase, and ammonia; increased PT
  • Metabolic workup: Abnormalities of organic and amino acids may be present if symptoms are caused by a metabolic disorder.
  • Cultured fibroblasts for fatty acid oxidation defects

Differential Diagnosis

  • It is important to distinguish between so-called classic Reye syndrome, associated with aspirin (acetylsalicylic acid) therapy, and Reye-like syndromes, often due to metabolic disorders and other causes as mentioned subsequently. All cases who present with Reye syndrome should be investigated for metabolic disorders.
  • Metabolic diseases: In a report by Hou et al., Reye-like syndrome was secondary to hereditary organic acidemias (n = 13), urea cycle defects (n = 4), mitochondrial disorders (n = 3), fulminant hepatitis (n = 2), tyrosinemia (n = 1), and valproate-associated hepatotoxicity (n = 1). In the United Kingdom, 12% of Reye syndrome cases between 1981 and 1996 were subsequently reclassified as metabolic disorders.
  • CNS infections (e.g., meningitis, encephalitis)
  • Toxins
  • Drug ingestion (e.g., salicylates, valproate)

Alert

Failure to recognize early and control or prevent cerebral edema is associated with increased mortality. пїЅ пїЅ

Treatment

General Measures

Vitamin K, fresh frozen plasma, and platelets as needed for treatment of secondary coagulopathy пїЅ пїЅ

Inpatient Considerations

Initial Stabilization

  • Should be tailored based on severity of presentation
  • IV glucose to counteract effects of glycogen depletion
  • Fluid restriction in patients with cerebral edema (1,500 mL/m2/day), along with mannitol to increase serum osmolality and induce cerebral dehydration

Ongoing Care

Follow-up Recommendations

Cerebral function at presentation is the best predictor of outcome. Evaluate for metabolic diseases if not done already. пїЅ пїЅ

Prognosis

  • Most patients suffer only mild illness without progression.
  • Patients with milder disease (stages 0, 1, 2) tend to recover completely.
  • Patients with stage 3 disease are equally likely to recover completely or die.
  • Patients with stage 4 or 5 disease usually do not survive.

Complications

  • Elevated intracranial pressure secondary to cerebral edema
  • Cardiovascular collapse
  • Overall mortality of 31%

Additional Reading

  • Belay пїЅ пїЅED, Bresee пїЅ пїЅJS, Holman пїЅ пїЅRC, et al. Reye 's syndrome in the United States from 1981 through 1997. N Engl J Med. 1999;340(18):1377 " пїЅ1382. пїЅ пїЅ[View Abstract]
  • Chow пїЅ пїЅEL, Cherry пїЅ пїЅJD, Harrison пїЅ пїЅR, et al. Related articles, reassessing Reye syndrome. Arch Pediatr Adolesc Med. 2003;157(12):1241 " пїЅ1242. пїЅ пїЅ[View Abstract]
  • Duerksen пїЅ пїЅDR, Jewell пїЅ пїЅLD, Mason пїЅ пїЅAL, et al. Co-existence of hepatitis A and adult Reye 's syndrome. Gut. 1997;41(1):121 " пїЅ124. пїЅ пїЅ[View Abstract]
  • Glasgow пїЅ пїЅJF, Middleton пїЅ пїЅB. Reye syndrome " пїЅinsights on causation and prognosis. Arch Dis Child. 2001;85(5):351 " пїЅ353. пїЅ пїЅ[View Abstract]
  • Gosalakkal пїЅ пїЅJA, Khamoji пїЅ пїЅV. Reye syndrome and Reye like syndrome. Pediatr Neurol. 2008;39(3):198 " пїЅ200. пїЅ пїЅ[View Abstract]
  • Green пїЅ пїЅCl, Blitzer пїЅ пїЅMG, Shapira пїЅ пїЅE. Inborn errors of metabolism and Reye 's syndrome: differential diagnosis. J Pediatr. 1988;113(1, Pt 1):156 " пїЅ159. пїЅ пїЅ[View Abstract]
  • Hou пїЅ пїЅJW1, Chou пїЅ пїЅSP, Wang пїЅ пїЅTR. Metabolic function and liver histopathology in Reye-like illnesses. Acta Paediatr. 1996;85(9):1053 " пїЅ1057.
  • Schr пїЅ пїЅr пїЅ пїЅK. Aspirin and Reye syndrome: a review of the evidence. Paediatr Drugs. 2007;9(3):195 " пїЅ204. пїЅ пїЅ[View Abstract]
  • van Bever пїЅ пїЅHP, Quek пїЅ пїЅSC, Lim пїЅ пїЅT. Aspirin, Reye syndrome, Kawasaki disease, and allergies: a reconsideration of the links. Arch Dis Child. 2004;89(12):1178. пїЅ пїЅ[View Abstract]

Codes

ICD09

ICD10

SNOMED

  • 74351001 Reye 's syndrome (disorder)

FAQ

  • Q: Is Reye syndrome fatal?
  • A: пїЅ пїЅ пїЅ30% of children will die, usually due to cerebral edema. Mortality rates are best predicted by neurologic state at the onset of presentation.
  • Q: How can the neurologic findings of Reye syndrome be differentiated from those of meningitis?
  • A: Aside from elevated intracranial pressure, the lumbar taps of patients with Reye syndrome are at best unremarkable. Elevated leukocyte count is not seen in these cases.
  • Q: What additional recommendations are suggested for children on chronic aspirin therapy?
  • A. When annual influenza vaccine supply is limited, according to the CDC, vaccination efforts should focus on delivering vaccination to specific subpopulations, including children "receiving long-term aspirin therapy and who therefore might be at risk for experiencing Reye syndrome after influenza virus infection. " пїЅ