Reye's syndrome (RS) is characterized by acute noninflammatory encephalopathy and hepatic failure. Although the etiology of Reye syndrome is unknown, the condition typically occurs after a viral illness, particularly an upper respiratory tract infection (URTI), influenza, varicella (chicken pox), or gastroenteritis, and it is associated with the use of aspirin during the illness. The discovery of inborn errors of metabolism that have manifestations similar to those of Reye syndrome and a dramatic decrease in the use of aspirin among children have decreased the incidence of the condition.

Given that manifestations of Reye syndrome are not unique to Reye syndrome but also seen in other conditions, and given that no test is specific for Reye syndrome, the diagnosis must be one of exclusion. A high index of suspicion is critical for diagnosis. The diagnosis should be considered in any child with vomiting and altered mental status. Diagnostic criteria from the Centers for Disease Control and Prevention (CDC) are as follows:

• Acute noninflammatory encephalopathy with an altered level of consciousness
• Hepatic dysfunction with a liver biopsy showing fatty metamorphosis or a more than 3-fold increase in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and/or ammonia levels
• No other explanation for cerebral edema or hepatic abnormality
• CSF with 8 or fewer WBCs per cubic millimeter (8 X 109/L or fewer)
• Brain biopsy with cerebral edema without inflammation

Early recognition and treatment are essential to prevent death and to optimize the likelihood of recovery without neurologic impairment.

Pathophysiology
The pathogenesis is unclear, but it appears to involve mitochondrial dysfunction that inhibits oxidative phosphorylation and fatty-acid beta-oxidation in a virus- infected, sensitized host. The host has usually been exposed to mitochondrial toxins, most commonly salicylates (Aspirin) in greater than 80% of cases.

Frequency/Mortality/Morbidity
The frequency, which peaked in the 1970s and early 1980s, is now <0.03-1 case per 100,000 persons younger than 18 years, though it may be as high as 6 cases per 100,000 with regional viral epidemics. The rate is <0.1% of children with viral illness treated with aspirin. The CDC reported 1207 cases of RS in patients younger than 18 years between December 1, 1980, and November 30, 1997. The peak incidence of 555 cases occurred in 1980. The rate declined to an average of 100 cases per year in 1985 and 1986. In 1987-1993, the maximum cases reported were 36 per year. The percentage of patients with a previous diagnosis of RS is 0.4%. The percentage of patients who have a sibling with a RS history is 2.9%. Seasonal occurrence initially peaked from December to April, which correlated with the peak occurrence of viral respiratory infections, particularly influenza. Since 1990, the seasonal variation has been less pronounced than this initial observation.

The mortality has decreased from 50% to less than 20% as a result of early diagnosis, recognition of mild cases, and aggressive therapy. Death is usually due to cerebral edema or increased ICP, but it may be due to myocardial dysfunction, cardiovascular collapse, respiratory failure, renal failure, GI bleeding, status epilepticus, or sepsis. Patients who survive may have complete recovery, though neurologic impairment is common.

History
According to CDC surveillance statistics from 1980 to 1997, 93% of 1160 patients had at least 1 viral illness in the 3 weeks preceding the onset of Reye syndrome. Illnesses included viral URTI or influenza in 73%, varicella in 21%, gastroenteritis in 14%, and other illness with exanthem 5%. Salicylates were detectable in the blood of 82% of patients. Influenza B (most common), influenza A, and varicella-zoster virus (chicken pox) 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.

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.

Physical
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.

Lovejoy initially described clinical stages I-V, 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 conversant 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

Causes

• Viral illness - Especially influenza B, influenza A, varicella-zoster virus)
• Toxins - Insecticides, herbicides, aflatoxins, paint, paint thinner, hepatotoxi
• mushrooms, hypoglycin in akee fruit, margosa oil
• Drugs - Salicylates, paracetamol, outdated tetracycline, valproic acid, zidovudine, didanosine, antiemetics
• Aspirin is the drug classically associated with Reye syndrome. The association with salicylates, though not universally accepted, was demonstrated in several epidemiologic studies around the world.

Lab and Imaging Studies
Above shows a section of liver showing small, clear vesicles consistent with microvesicular steatosis (hematoxylin and eosin; original magnification, x400).

On liver function testing, ammonia levels are as much as 1.5 times normal (up to 1200 mcg/dL) 24-48 hours after the onset of mental status changes is the most frequent laboratory abnormality. Ammonia levels may return to the reference range in stages 4 and 5. Levels of transaminases, ALT, and AST increase to 3 times normal but may return to the reference ranges by stages 4 or 5. Bilirubin levels are >2 mg/dL (usually <3 mg/dL) in 10-15% of patients. If direct bilirubin is more than 15% of total. If the total is >3 mg/dL, consider other diagnoses. The prothrombin time (PT) and activated partial thromboplastin time (aPTT) are prolonged >1.5-fold in >50% of patients.

Other labs: Lipase and amylase levels are elevated. Serum bicarbonate levels are decreased secondary to vomiting. BUN and creatinine levels are elevated. Expect hypoglycemia, particularly in children younger than 1 year. A serum glucose test is indicated for all children with altered mental status.

Head CT scanning may reveal cerebral edema, but the results are usually normal.

Treatment
In a child with vomiting and altered mental status, a glucose level should be immediately checked and treated if abnormal. Because no specific treatment exists the child must be carefully monitored. Supportive care is based on the stage, with aggressive treatment to correct or prevent metabolic abnormalities, particularly hypoglycemia and hyperammonemia, and to prevent or control cerebral edema. Care by stage is as follows:

Stages 0-1
Keep the patient quiet. Frequently monitor vital signs and laboratory values.
Correct fluid and electrolyte abnormalities, acidemia, and hypoglycemia. If the patient is initially hypoglycemic, administer dextrose 25% as an intravenous (IV) bolus at a dose of 1-2 mL/kg. If the initial pH is less than 7.2, consider the administration of bicarbonate (somewhat controversial) up to 1 mEq/ kg/h; avoid rapid correction or overcorrection. Maintain fluids, electrolytes, serum pH, albumin, serum osmolality, urine output, and glucose values. Overhydration may precipitate cerebral edema. Use colloids (e.g.: albumin) as necessary to maintain intravascular volume. Dehydration may compromise cardiovascular volume and reduce cerebral perfusion.

Stage 2
Continuous cardiorespiratory monitoring, placement of arterial lines and urine catheters to monitor urine output, and ECG and/or EEG are standard care.
Correct hyperammonemia. The US Food and Drug Administration (FDA) has not approved any medication to treat hyperammonemia specifically due to Reye syndrome. Sodium phenylacetate/sodium benzoate (Ammonul), a medication that treats hyperammonemia is FDA approved for the treatment of acute hyperammonemia and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle. Use furosemide (Lasix) to control fluid overload, and administer insulin to maintain euglycemia. In addition, administer ondansetron (Zofran) 0.15 mg/kg (not to exceed 8 mg q8h) during the first 15 minutes of the initial dose. If the ammonia level is more than 500 mcg/dL or if the patient's condition fails to respond to the initial dose of sodium phenylacetate/sodium benzoate, start dialysis, preferably hemodialysis. Prevent increased ICP. Elevate the head of the bed and avoid overhydration and use of hypo-osmotic fluids.

Stages 3-5
Continuously monitor ICP (intracranial pressure), central venous pressure, arterial pressure, and/or end-tidal carbon dioxide. Manage the airway with rapid-sequence intubation and ventilation as appropriate for raised ICP. Treat increased ICP by following standard guidelines. Treat seizures with phenytoin 10-20 mg/kg IV as a loading dose followed by 5 mg/kg/d IV divided every 6 hours or fosphenytoin dosed as 10-20 mg/kg phenytoin equivalents (PEs).
Correct coagulopathy (PT >16 seconds), particularly if an intracranial bolt and/or liver biopsy is required. In rare cases, an exchange transfusion is required.

Medical-Legal Considerations
The number one cause of RS in a child is treating a viral illness with Aspirin. No healthcare practitioner should recommend that Aspirin be given to an ill child. Other potential problems resulting in litigation include: Failure to identify hypoglycemia and treat it; failure to recognize that progression of disease may be extremely rapid; overhydrating the patient with exacerbation of cerebral edema; failure to aggressively treat cerebral edema (the major cause of morbidity and mortality).