Basics
Description
- Acute encephalopathy and fatty degeneration of the liver which may be idiopathic or secondary
- "Classic " � 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 inflammation
- Liver 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 ammonia
- No 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.
- 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.
Diagnosis
History
- Prodromal illness: upper respiratory infection (73%) " �influenza 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, 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
- 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 � �
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. � �
Treatment
General Measures
Vitamin K, fresh frozen plasma, and platelets as needed for treatment of secondary coagulopathy � �
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. � �
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 � �ED, Bresee � �JS, Holman � �RC, et al. Reye 's syndrome in the United States from 1981 through 1997. N Engl J Med. 1999;340(18):1377 " �1382. � �[View Abstract]
- Chow � �EL, Cherry � �JD, Harrison � �R, et al. Related articles, reassessing Reye syndrome. Arch Pediatr Adolesc Med. 2003;157(12):1241 " �1242. � �[View Abstract]
- Duerksen � �DR, Jewell � �LD, Mason � �AL, et al. Co-existence of hepatitis A and adult Reye 's syndrome. Gut. 1997;41(1):121 " �124. � �[View Abstract]
- Glasgow � �JF, Middleton � �B. Reye syndrome " �insights on causation and prognosis. Arch Dis Child. 2001;85(5):351 " �353. � �[View Abstract]
- Gosalakkal � �JA, Khamoji � �V. Reye syndrome and Reye like syndrome. Pediatr Neurol. 2008;39(3):198 " �200. � �[View Abstract]
- Green � �Cl, Blitzer � �MG, Shapira � �E. Inborn errors of metabolism and Reye 's syndrome: differential diagnosis. J Pediatr. 1988;113(1, Pt 1):156 " �159. � �[View Abstract]
- Hou � �JW1, Chou � �SP, Wang � �TR. Metabolic function and liver histopathology in Reye-like illnesses. Acta Paediatr. 1996;85(9):1053 " �1057.
- Schr � �r � �K. Aspirin and Reye syndrome: a review of the evidence. Paediatr Drugs. 2007;9(3):195 " �204. � �[View Abstract]
- van Bever � �HP, Quek � �SC, Lim � �T. Aspirin, Reye syndrome, Kawasaki disease, and allergies: a reconsideration of the links. Arch Dis Child. 2004;89(12):1178. � �[View Abstract]
Codes
ICD09
ICD10
SNOMED
- 74351001 Reye 's syndrome (disorder)
FAQ
- Q: Is Reye syndrome fatal?
- A: � � �30% 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. " �