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Reye Syndrome
Kattie Hoy, MD
image BASICS
DESCRIPTION
  • A serious, acute noninflammatory encephalopathy associated with cerebral edema and fatty infiltration of the liver classically noted in children taking aspirin during a viral infection (1,2)
  • Occurs primarily in children and adolescents, with an average age of 6 years (2)
  • Reye syndrome (RS) is typically biphasic, often initially presenting with symptoms of viral or bacterial infection (i.e., in order of association influenza A or B, varicella, parainfluenza, measles, adenovirus, coxsackieviruses, parechovirus, CMV, EBV, HIV, hepatitis A or B, Mycoplasma, and Chlamydia), 1 to 5 days without symptoms, followed by onset of severe vomiting, altered mental status, and signs of acute encephalopathy (2,3).
  • RS is currently very rare since warning statements by the CDC and American Academy of Pediatrics in 1982 were issues for use of aspirin in children, followed by black box warning in 1986 against use of aspirin in children and teenagers with recent viral illness (4,5).
  • System(s) affected: gastrointestinal, nervous, muscular, and cardiac (6)
  • Synonym(s): white liver disease
EPIDEMIOLOGY
Incidence
  • Predominant age (1,2)
    • 3 months to 12 years, but can occur at any age
    • Peak incidence at 6 years of age
  • Predominant sex: male = female (2)
  • Currently very rare. In the United States, <0.1/100,000 annually since 1989 (Autret). Prior to issued warnings about aspirin use in children, the United States documented 555 case reports in 1980. Most recent U.S. statistics noted no >2 cases per year between 1994 and 1997 (1).
  • Mortality rate 20-40%, male > female (5,7)
ETIOLOGY AND PATHOPHYSIOLOGY
Specific etiology is unknown but appears to be secondary to multiple synergistic factors causing acute mitochondrial injury from significant inhibition of fatty acid oxidation limiting gluconeogenesis causing hypoglycemia, elevated ammonia, acute transaminitis, and hepatic fatty infiltration (1,8).
Genetics
Possible genetic factors that lead to predisposition for development of RS but currently no known genetic pattern (3)
RISK FACTORS
  • Pediatric age group
  • Prodromal illnesses
    • Viral: influenza A and B, varicella, parainfluenza, measles, adenovirus, coxsackievirus, parechovirus, EBV, CMV, HIV, hepatitis A and B, or rotavirus
    • Bacterial: Mycoplasma, Chlamydia, Salmonella, Shigella (3)
  • Use of preparations containing aspirin, salicylates, and/or salicylamides (1).
  • Other exogenous agents with less significant association: valproic acid, aflatoxin in Thailand, bongkrekate in Indonesia, margosa oil in Southern Asia, unripe ackee fruit in Jamaica, hopentanate in Japan, and insecticides in Canada (1)
GENERAL PREVENTION
  • Avoid salicylates in children with viral illnesses because the drug appears to act as a cofactor in susceptible individuals (1).
  • A physician should be consulted before giving any child aspirin or antinausea medicines (containing salicylates) during a viral illness, especially influenza A (5).
  • Recognize early symptoms of the disease for prompt initiation of supportive treatment (7).
image DIAGNOSIS
RS is a diagnosis of exclusion (1).
  • CDC diagnostic criteria (5)
    • Acute noninflammatory encephalopathy with an altered level of consciousness
    • Hepatic dysfunction with liver biopsy showing fatty change or an over 3-fold increase in AST, ALT, and/or ammonia levels
    • No other explanation for cerebral edema or hepatic abnormality
    • Cerebral spinal fluid with white blood cells 8/mm3 of fewer
    • Brain biopsy showing cerebral edema without inflammation
  • RS clinical staging system (5)
    • I: vomiting, somnolence, lethargy
    • II: confusion, delirium, combativeness, hyperreflexia, hyperventilation
    • III: obtundation, predominantly flexor motor responses, decorticate, intact pupillary reflex
    • IV: coma, seizures, predominant extensor motor responses, decerebrate posturing, fixed pupils
    • V: coma, flaccid paralysis, loss of deep tendon reflexes, seizures, respiratory arrest, isoelectric EEG, pupils unresponsive
PHYSICAL EXAM
  • Hyperpnea, somnolence, altered mental status
  • Various stages of neurologic deficits pending stage of syndrome
  • Hepatomegaly usually present; icterus absent or only seen moderately; sometimes intracranial pressure elevation (3)[A]
DIFFERENTIAL DIAGNOSIS
  • Acute encephalopathy without hepatic abnormalities
    • Encephalitis
    • Meningitis
    • Drug overdose
    • Poisoning
    • Psychiatric illness
    • Diabetes mellitus
  • Reye-like syndrome: acute toxic encephalopathy with hepatic abnormalities due to either metabolic disorders or drug or toxin ingestions, including the following (3):
    • Inherited metabolic disorders: organic acidurias with defects in hepatic fatty acid oxidation; fatty acid metabolism defects
    • Acyl-CoA dehydrogenase, carnitine deficiency
      • Urea cycle defects
      • Carbamoyl phosphate synthetase, ornithine transcarbamylase
      • Fructosemia
    • The most commonly diagnosed metabolic disorder in association with RS is medium-chain acylcoenzyme A dehydrogenase deficiency.
    • Toxin ingestions
DIAGNOSTIC TESTS & INTERPRETATION
  • Over 3-fold elevations of AST, ALT, and/or ammonia (5)
  • Hypoglycemia (8)
  • Possible coagulopathy with abnormal bleeding time, PT, PTT, and/or platelet count (7)
  • Mixed respiratory alkalosis and metabolic acidosis (3)
  • MRI findings of cerebral edema with signal alteration in many areas including brainstem, thalami, temporal lobe, parasagittal cortex, cerebellar, and subcortical white matter (9)[C]
Follow-Up Tests & Special Considerations
Usually complete resolution of lesions on T2-weighted images except in areas of thalamus, which can take many months to resolve (9)[C]
Diagnostic Procedures/Other
  • Lumbar puncture with CSF pressure measurement (5)
  • Liver biopsy (5,7)
  • Brain biopsy (5)
Test Interpretation
  • Liver biopsy notes variably sized multiple intracellular and extracellular vacuoles representing microvesicular steatosis. Hepatocytes also display nuclear pyknosis and fragmentation. The mitochondria are distorted with destroyed cristae (10).
  • Brain biopsy with cerebral edema without inflammation (5)
  • Increased CSF pressure without pleocytosis (<8 leukocytes/mm3) (5)
Pediatric Considerations
  • It is essential to make the diagnosis as early as possible and start appropriate supportive measures immediately as progression to more severe stage is associated with higher mortality (7).
  • Must investigate for inborn errors of metabolism in any patient suspected to have RS as well as other etiology due to RS being a diagnosis of exclusion (1).
P.917

image TREATMENT
GENERAL MEASURES
  • Supportive care dictated by the severity of illness (5)[A]
  • IV glucose and frequent monitoring of serum glucose to treat hypoglycemia (7)[B].
  • Hyperventilation, mannitol, glycerol, and corticosteroids to control intracranial pressure (7)[B]
  • Vitamin K, fresh frozen plasma, and platelets as needed for treatment of coagulopathy (7)[B]
  • Mechanical ventilation as needed
  • Dialysis to remove toxins and toxic metabolites (7)[B]
MEDICATION
  • All treatment is supportive and may include the following (7)[B]:
    • Glucose 10-15% IV
    • Vitamin K
    • For increased intracranial pressure
      • Mannitol
      • Dexamethasone
      • Glycerol
  • Contraindications: NSAIDs such as diclofenac and mefenamic acid may complicate clinical picture so should not be used (3)[A].
  • Precautions: Mannitol and poor renal output may result in vascular overload and pulmonary edema.
  • Resveratrol used in animals studies showed protection against the oxidative stress occurring in RS but has yet been researched in clinical practice (10).
SURGERY/OTHER PROCEDURES
Liver transplant (11)[C]
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Medical emergency requiring immediate hospitalization and frequent monitoring, often in an intensive care setting (3)[A]
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Complete bed rest until recovery is noted and able to return to normal activity as tolerated.
Patient Monitoring
Depends on specific residual effects. may require care of physicians; nurses; psychologists; and/or physical, occupational, and/or speech therapists (7)[B]
DIET
NPO during the acute phase
PATIENT EDUCATION
  • National Reye Syndrome Foundation, P.O. Box 829, Byron, OH 43506-0829 (800) 233-7393; www.reyessyndrome.org
  • National Institutes of Health: http://www.ninds.nih.gov/disorders/reyes_syndrome/reyes_syndrome.htm
PROGNOSIS
  • Overall prognosis is related to degree of cerebral edema and ammonia level on admission, correlated with severity of stage (7)[B].
  • Outcomes range from a mild illness without progression and complete resolution to a critical illness with significant lasting sequelae or death (7)[B].
  • Possible neurologic sequelae include brain damage and disability, problems with attention, concentration, speech, language, and fine and gross motor skills.
  • Sequelae are more common with higher stages.
REFERENCES
1. Glasgow JF. Reye’s syndrome: the case for a causal link with aspirin. Drug Saf. 2006;29(12):1111-1121.
2. Autret-Leca E, Jonville-Béra AP, Llau ME, et al. Incidence of Reye’s syndrome in France: a hospital-based survery. J Clin Epidemiol. 2001;54(8):857-862.
3. Pugliese A, Beltramo T, Torre D. Reye’s and Reye’s-like syndromes. Cell Biochem Funct. 2008;26(7):741-746.
4. Bennett CL, Starko KM, Thomsen HS, et al. Linking drugs to obscure illnesses: lessons from pure red cell aplasia, nephrogenic systemic fibrosis, and Reye’s syndrome. A report from the Southern Network on Adverse Reactions (SONAR). J Gen Intern Med. 2012;27(12):1697-1703.
5. Degnan LA. Reye’s syndrome: a rare but serious pediatric condition. US Pharm. 2012;37(3): HS6-HS8.
6. Gosalakkal JA, Kamoji V. Reye syndrome and Reye-like syndrome. Pediatr Neurol. 2008;39(3):198-200.
7. Wulur H, Kho LK. Treatment of Reye’s syndrome at Sumber Waras Hospital. Acta Paediatr Jpn. 1990;32(4):435-442.
8. Tein I. Impact of fatty acid oxidation disorders in child neurology: from Reye syndrome to Pandora’s box. Dev Med Child Neurol. 2015;57(4):304-306.
9. Singh P, Goraya JS, Gupta K, et al. Magnetic resonance imaging findings in Reye syndrome: case report and review of the literature. J Child Neurol. 2011;26(8):1009-1014.
10. Abdin A, Sarhan N. Resveratrol protects against experimental induced Reye’s syndrome by prohibition of oxidative stress and restoration of complex I activity. Can J Physiol Pharmacol. 2014;92(9):780-788.
11. Cağ M, Saouli AC, Audet M, et al. Reye syndrome and liver transplantation. Turk J Pediatr. 2010;52(6):662-664.
Additional Reading
&NA;
  • 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.
  • Fischer H. Aspirin and Reye’s syndrome. Pediatrics. 2001;107(1):214.
  • Glasgow JF, Middleton B. Reye syndrome—insights on causation and prognosis. Arch Dis Child. 2001;85(5):351-353.
  • Monto AS. The disappearance of Reye’s syndrome—a public health triumph. N Engl J Med. 1999;340(18):1423-1424.
  • Schrör K. Aspirin and Reye syndrome: a review of the evidence. Paediatr Drugs. 2007;9(3):195-204.
  • Whitten R, Milner DA Jr, Yeh MM, et al. Liver pathology in Malawian children with fatal encephalopathy. Hum Pathol. 2011;42(9):1230-1239.
See Also
&NA;
Encephalitis, Viral; Hepatic Encephalopathy
Codes
&NA;
ICD10
G93.7 Reye’s syndrome
Clinical Pearls
&NA;
  • RS is a rare, acute noninflammatory encephalopathy largely affecting children and adolescents.
  • Associations include antecedent viral/bacterial infection and aspirin use.
  • Most current cases of RS are actually Reye-like syndromes, caused by an inborn error of metabolism or a toxin exposure.
  • All current treatment is supportive.
  • Acetaminophen is first choice to treat fever followed by ibuprofen, in children.
  • Prognosis is related to the degree of cerebral edema and ammonia level on admission and ranges from complete resolution to persistent neurologic sequelae or death.