Reye Syndrome, Emergency Medicine

Basics

Description

Reversible clinicopathologic syndrome of unknown etiology
Primary mitochondrial injury
Decreased enzyme activity:
- Krebs cycle
- Gluconeogenesis
- Urea biosynthesis
Fatty infiltration:
- Liver:
  - Hyperammonemia due to decreased conversion from ammonia to urea
  - Hepatorenal syndrome may be the end result.
  - Rapid recovery of liver function in survivors
- Brain:
  - Encephalopathy of unclear etiology
  - Cytotoxic edema
  - Deteriorating level of consciousness reflects increasing intracranial pressure (ICP).
  - Herniation is the most common cause of death.
  - Normal recovery of neurologic function in survivors
- Skeletal and myocardial muscle
- Fatty infiltration and distorted mitochondria
<10% of cases occur before the age of 1 yr:
- Average age is 7 yr
- Peak age is 4 " 11 yr
- Extremely rare in age >18 yr.
Regional differences:
- Highest incidence in the Midwestern states
- Lower incidence in the states of the Southeast and far West
More common in whites than in blacks
Peak incidence in winter and early spring
Reye-like syndrome:
- Describes conditions resulting in defects in urea and fatty acid metabolism, toxicologic injury, and impaired gluconeogenesis

Etiology

Not known with certainty
Multifactorial causes have been epidemiologically implicated:
- Antecedent viral syndrome
- Influenza A or B
- Varicella
- Diarrhea illness
- Genetic predisposition
- Exposure to salicylates
- Other undefined factors

Diagnosis

Signs and Symptoms

Usually the patient is afebrile.
Tachycardia
Hyperventilation

History

Biphasic history marked by an infectious phase (viral illness or prodrome) followed by an encephalopathic stage
Profuse and repeated vomiting:
- Typically 4 " 5 days after the start of the viral illness
Marked behavioral changes, including delirium and combativeness, disorientation, and hallucination

Physical Exam

No focal neurologic signs
Hepatomegaly in 40% of cases
Pancreatitis
Clinical staging of Reye syndrome with Lovejoy classification:
- Stage 0:
  - Wakeful
- Stage I:
  - Vomiting
  - Lethargy
  - Sleepiness
- Stage II:
  - Disorientation
  - Delirium
  - Combative/stuporous
  - Hyperventilation
  - Hyperreflexia
  - Appropriate response to noxious stimuli
- Stage III:
  - Obtunded
  - Coma
  - Hyperventilation
  - Inappropriate response to noxious stimuli
  - Decorticate posturing
  - Preservation of pupillary light reflexes
  - Preservation of oculovestibular light reflexes
- Stage IV:
  - Deeper coma
  - Decerebrate rigidity
  - Loss of oculovestibular reflexes
  - Dilated, fixed pupils
  - Disconjugate eye movements in response to caloric stimulation
- Stage V:
  - Seizures
  - Absent deep tendon reflexes
  - Respiratory arrest
  - Flaccid paralysis
  - No papillary response
Infants: Atypical presentation:
- Tachypnea
- Apnea
- Irritability
- Seizures
- Hypoglycemia

Essential Workup

Establish the presence of encephalopathy and liver abnormalities.
Lab testing to assess for characteristic biochemical abnormalities
Liver biopsy confirms the diagnosis.

Diagnosis Tests & Interpretation

Lab

Liver function tests:
- ≥3 rise in aspartate aminotransferase, alanine aminotransferase
- Serum ammonia level >1.5 " 3 normal:
  - Transient 24 " 48 hr after mental status changes
  - Level >300 Όg/dL is associated with poor prognosis.
- Serum bilirubin should be normal or slightly elevated.
Hypoglycemia may be present, especially in infants.
Elevated BUN
Ketonuria
The prothrombin time may be prolonged due to decreased liver-dependent clotting factors (II, VII, IX, X).
Normal platelet count and blood smear
Negative toxicology screen

Imaging
Head CT scan:

May show diffuse cerebral edema
Edema is diffuse, and lumbar puncture is not contraindicated.

Diagnostic Procedures/Surgery

Lumbar puncture:
- Perform after head CT
- Measure opening pressure
- <8 leukocytes/mm3
Percutaneous liver biopsy:
- Useful in patients with atypical presentation (1 yr old, recurrent, familial)

Differential Diagnosis

Inborn errors of metabolism:
- Disorders of the urea cycle
- Disorders of fatty acid oxidation
- Systemic carnitine deficiency
- Organic acidemias
- Disorders of the electron transport chain
Hypoglycemia
Toxin exposure:
- Toxic encephalopathy without liver dysfunction (Gall syndrome)
- Lead
- Hydrocarbons
Drug intoxication:
- Acetaminophen
- Salicylates
- Ethanol
Infection:
- Sepsis
- Meningitis
- Encephalitis
- Varicella hepatitis
Trauma, head

Treatment

Pre-Hospital

Decreased mental status:
- Glucose
- Narcan
Coma:
- Assist respirations with bag-valve mask.

Initial Stabilization/Therapy

Place on a cardiorespiratory monitor.
Supplemental oxygen
Rapid-sequence intubation if airway management required
Glucose if mental status is altered:
- 10% glucose solution IV
- Rate of 2/3 maintenance requirement after dehydration is corrected
- Follow serum glucose hourly; maintain glucose 125 " 175 mg/dL.
Avoid early overhydration.

Ed Treatment/Procedures

Institute treatment before the liver biopsy.
Vitamin K:
- Indicated if prothrombin time is elevated.
Fresh-frozen plasma:
- To control bleeding
- To correct a severe coagulopathy
Interventions aimed at lowering ICP:
- Stage III or greater
- Stage II with serum ammonia >300 Όg/L:
  - Intubation using rapid-sequence protocol
  - Hyperventilation
  - Fluid restriction
  - Barbiturate coma
Osmotically active agents:
- Mannitol
- Furosemide
Monitor ICP:
- Subarachnoid bolt
- Intraventricular cannula

Medication

D50W: 1 " 2 mL/kg/dose (0.5 " 1 g/kg) IV for age >3 yr
D25W: 2 " 4 mL/kg/dose (0.5 " 1 mg/kg) IV for age of <3 yr; maintenance infusion 10% dextrose solution at a rate of 2/3 maintenance
Fresh-frozen plasma: 10 mL/kg/dose q12 " 24h IV or PRN
Lasix: 1 mg/kg IV
Mannitol: 0.25 " 1 g/kg IV q4 " 6h
Pentobarbital: 3 " 5 mg/kg IV slowly while monitoring BP; maintenance infusion 1 " 2 mg/kg/h; maintain level at 2 " 5 mg/L
Vitamin K: 1 " 2 mg/dose IV slowly (infants and children); 2 " 10 mg/dose IV (adolescents)

Follow-Up

Disposition

Admission Criteria

All children with suspected Reye syndrome should be admitted to the ICU.
Hospital capable of ICP monitoring

Discharge Criteria
Hospital discharge criteria are individualized for each case:

Mental status and lab values have improved and stabilized.

Issues for Referral
Close follow-up with specialists in gastroenterology (hepatology) and neurology

Followup Recommendations

Long-term psychological and neuropsychological testing

Pearls and Pitfalls

Aspirin and salicylates are found in many medications and combination products.
All efforts must be directed at identifying other possible causes of illness in the patient with suspected Reye syndrome.
Monitoring and control of intracranial pressure is a key component of treatment.

Additional Reading

Gosalakkal JA, Kamoji V. Reye syndrome and Reye-like syndrome. Pediatr Neurol. 2008;39:198 " 200.
Hurwitz ES. Reye syndrome. In: Feigin RD, Cherry JD, Demmler-Harrison GJ, et al., eds. Feigin & Cherrys Textbook of Pediatric Infectious Diseases. 6th ed. Philadelphia, PA: WB Saunders; 2009:693 " 694.
National Reye's Syndrome Foundation. Available at www.reyessyndrome.org. Accessed on January 28, 2013.
Pugliese A, Beltramo T, Torre D. Reye's and Reye's-like syndromes. Cell Biochem Funct. 2008;26:741 " 746.
Schr Άr K. Aspirin and Reye syndrome: A review of the evidence. Paediatr Drugs. 2007;9:195 " 204.

Codes

ICD9

331.81 Reyes syndrome

ICD10

G93.7 Reyes syndrome

SNOMED

74351001 Reyes syndrome (disorder)

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