Continuing Education Activity

Reye syndrome is a rare and potentially fatal pediatric illness defined as acute noninflammatory encephalopathy with fatty liver failure. Australian pathologist R.D.K. Reye first described this syndrome in 1963. National surveillance of Reye syndrome began in the United States in the early 1970s and led to strict warnings regarding aspirin use in children. Reye syndrome typically presents in children as vomiting and confusion with rapid progression to coma and death. This activity reviews the cause, pathophysiology and presentation of Reye syndrome and stresses the importance of the interprofessional team in its management.

Objectives:

• Identify the etiology of Reye syndrome.
• Recall the presentation of reye syndrome.
• List the treatment and management options available for Reye syndrome.
• Discuss interprofessional team strategies for improving care and outcomes in patients with Reye syndrome.

Introduction

Reye syndrome is a rare and potentially fatal pediatric illness defined as acute noninflammatory encephalopathy with fatty liver failure. Australian pathologist R.D.K. Reye first described this syndrome in 1963. National surveillance of Reye syndrome began in the United States in the early 1970s and led to strict warnings regarding aspirin use in children. Reye syndrome typically presents in children as vomiting and confusion with rapid progression to coma and death. This syndrome often begins in the days following recovery from a viral illness during which aspirin was administered. Inborn errors of metabolism (especially fatty acid metabolism), medication reactions and toxins may also predispose or cause the development of Reye syndrome. This diagnosis is based on clinical signs as well as laboratory testing. However, there is no test specific to Reye syndrome.[1][2]

Etiology

Reye syndrome is most commonly precipitated by viral pathogens such as influenza A and B as well as varicella. Center for Disease Control and Prevention (CDC) surveillance data between 1980 and 1997 found that cases of Reye syndrome were preceded by influenza infection 73%, varicella infection 21%, and gastroenteritis infections 14% of the time. Serum salicylate concentrations were detectable in 82% of cases. Less commonly associated viral associations are seen with coxsackie, parainfluenza, Epstein-Barr (EBV), cytomegalovirus (CMV), adenovirus and hepatitis. Bacterial pathogens such as Chlamydia, Bordetella pertussis, Mycoplasma, and Shigella have also been associated with the development of Reye syndrome. Epidemiologic studies found a link between use of salicylate and development of Reye syndrome. While less than 0.1% of children who took aspirin developed Reye syndrome, more than 80% of children diagnosed with Reye syndrome had taken aspirin in the preceding 3 weeks. This data led to recommendations against the use of aspirin in children in 1980. The number of reported cases of Reye syndrome fell dramatically following the widespread warnings against the use of aspirin in children.[3][4]

Epidemiology

Reye syndrome is a rare diagnosis with fewer than 2 cases reported annually since 1994. However, the true incidence may not be known for reporting cases to the CDC is no longer mandated. The peak age of onset is 5 to 14 years of age; however, cases have been reported in children less than one year of age. Gender has not been reported as a risk factor. There is seasonal variation with the majority of cases being reported from December through April.

National surveillance of Reye syndrome began in 1973. The CDC reported 555 cases between 1979 and 1980. Between December 1980 through November 1997, the CDC reported 1207 cases of Reye syndrome in the United States. The incidence fell from an average of 100 cases per year in 1985 and 1986 to an average of 36 cases per year between 1987 and 1993. Incidence has fallen off sharply since 1991 with 0.2 to 1.1 case per million reported in the United States between 1991 and 1994.

Widespread warnings again the use of aspirin in children were issued in the United States in 1980. A sharp decline in the number of reported cases of Reye syndrome followed this issuance. Similar patterns of incidence were observed in the United Kingdom. In 1986, the United Kingdon warned against the use of aspirin in children under the age of 12. Following that warning, the incidence fell from 0.63 cases per 100,000 in 1983-1984 to 0.11 cases per 100,000 in 1990 through 1991. Similar declines were also observed in France.

It should be noted that aspirin remains a mainstay of treatment for children diagnosed with Kawasaki disease. In children who require long-term salicylate therapy, clinicians and caregivers should remain vigilant in monitoring for signs and symptoms of Reye syndrome.[5][6]

Pathophysiology

The exact pathophysiology of Reye syndrome is not precisely known; however, it appears to involve mitochondrial injury in the setting of a viral illness. Aspirin may cause or perpetuate damage to cellular mitochondria resulting in inhibition of fatty-acid metabolism. The neurologic features of Reye syndrome likely result from hepatic mitochondrial dysfunction causing elevated ammonia levels. Hyperammonemia may induce astrocyte edema resulting in diffuse cerebral edema and subsequent elevated intracranial pressure. Pathology studies have revealed astrocyte edema, loss of neurons, fatty degeneration of kidneys, and a swollen and a reduced number of mitochondria.[7]

History and Physical

A high level of suspicion based on the history of presenting illness, clinical signs and symptoms and laboratory findings are required to make this rare diagnosis. Signs and symptoms of Reye syndrome typically develop between 12 hours and 3 weeks after recovery from a viral illness such as upper respiratory tract infection or gastroenteritis. The most common onset of vomiting occurs between 3 and 6 days after a viral illness. The CDC has described clinical progression as 5 distinct stages:

Stage 1

• Persistent, copious vomiting
• Lethargy, nightmares, increased somnolence
• Confusion

Stage 2

• Stupor, disorientation, combativeness, delirium
• Hyperreflexia, positive Babinski sign, lack of appropriate response to noxious stimuli, dilated and sluggish pupils
• Hyperventilation, tachycardia 

Stage 3

• Obtunded, comatose, decorticate rigidity

Stage 4

• Pupil dilation with minimal response to light or fixed and dilated pupils, deconjugate gaze with caloric stimuli
• Deep coma with decerebrate rigidity

Stage 5

• Seizures
• Flaccid paralysis, absent deep tendon reflexes, no pupillary response
• Respiratory arrest
• Death

Evaluation

The CDC has defined Reye syndrome using the following criteria:

"Acute noninflammatory encephalopathy that is documented clinically by a) an alteration in consciousness and, if available b) a record of cerebrospinal fluid (CSF) containing less than or equal to 8 leukocytes/cu.mm or a histologic specimen demonstrating cerebral edema without perivascular or meningeal inflammation.

Hepatopathy documented by either a) a liver biopsy or an autopsy considered to be diagnostic of Reye syndrome or b) a threefold or greater increased in the levels fo the serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT) or serum ammonia.

No more reasonable explanation for the cerebral and hepatic abnormalities."

Lab abnormalities associated with Reye syndrome include elevated liver function tests (ALT, AST, bilirubin), hyperammonemia, abnormal coagulation studies, elevated amylase, and lipase, decreased serum bicarbonate and lab values consistent with dehydration. The most common lab finding is an early rise in ammonia occurring within 1 to 2 days of mental status changes. If lumbar puncture is performed to obtain CSF, the leukocyte count must be below 8 to meet diagnostic criteria. Opening pressure may be elevated in later clinical stages of disease but may remain normal early on. [8][9][10] 

Treatment / Management

Reye syndrome is a rapidly progressing disease that may require invasive procedures early on to maintain hemodynamically stability and adequate respiratory function.  These may include placement of central venous access, airway intubation, and placement of a Foley catheter to monitor urine output. Additional specialized procedures such as liver biopsy and intracranial pressure monitoring may also be indicated.[11][2][12]

Treatment of Reye syndrome is mainly supportive and requires close monitoring of multiple clinical parameters best accomplished in an intensive care unit setting. Aggressive treatment may be required to correct the following serum abnormalities: 

• Hypoglycemia may be treated with dextrose-containing fluids (D50, D10, D5, etc) with a serum glucose goal of 100-120mg/dl.
• Acidosis may be treated with sodium bicarbonate (attention not to over correct or correct too rapidly) and ventilation management.
• Hyperammonemia may be treated with phenylacetate-sodium benzoate (Immunol) or sodium polystyrene sulfate (Kayexalate) but may require hemodialysis if level greater than 500mcg/dl.
• Coaguloathy may be treated (especially before invasive procedures or with clinically significant bleeding) using cryoprecipitate, fresh frozen plasma (FFP), or Vitamin K.

Measures to target treatment of increased ICP may include:

• Elevating the head of the bed to 30 degrees
• Control of fever to prevent increased cerebral metabolism and rigors
• ICP monitoring
• Lasix administration
• Careful fluid regulation to prevent overhydration
• Sedation and analgesia
• Mannitol or hypertonic saline
• Seizure treatment and subsequent prophylaxis

Differential Diagnosis

• Drug toxicity
• Hypoglycemia
• Encephalitis
• Meningitis
• Lead and other heavy metal toxicities
• Intracranial bleeding
• Mushroom toxicity

Complications

• Seizures
• Cerebral herniation
• Aspiration pneumonia
• Cardiac arrhythmias
• Cardiovascular collapse
• Pancreatitis
• Gastrointestinal bleeding
• Respiratory failure
• Renal failure
• Sepsis
• Death

Consultations

• Pediatrician
• Neurologist
• Hepatologist

Pearls and Other Issues

Signs and symptoms of Reye syndrome should prompt strong suspicion and investigation for undiagnosed inborn errors of metabolism (IEM). Features such as lack of viral prodrome, family history of IEM, a family history of unexplained encephalopathy, pre-existing neurologic symptoms, and patient age less than one year make the diagnosis of Reye syndrome less likely.

Enhancing Healthcare Team Outcomes

Given the high mortality of Reye syndrome despite treatment, the focus today is on prevention. Besides physicians, the nurse and the pharmacist are in a prime position to educate the parents about risk factors for the disorder. The family should be told to avoid the use of salicylates in children. Further, the parents should be educated about the symptoms and signs of Reyes syndrome and when to seek immediate help. Finally, the CDC recommends that all children over the age of 6 months should receive the influenza vaccine. The pharmacist should always speak to the family about the safe use of medications in children and alternative options for the management of fever and pain.[13][14][15]

Outcomes

Over the past 4 decades, the mortality rate of Reye syndrome has dropped from 60% to about 20%, chiefly due to early recognition and aggressive management. By preventing increased intracranial pressure and edema, death can be avoided in many children. For those who survive, full recovery has been noted in about two-thirds of patients. However, those children with elevated levels of ammonia usually have residual neurological deficits.[16][17] (Level III)