Topic Editor: Grant E. Fraser, M.D., FRACGP, FACRRM, ASTEM
Review Date: 1/20/2013
Definition
Reye's syndrome is a rare disorder predominantly affecting young children and is characterized by acute, non-inflammatory encephalopathy and fatty hepatic degeneration. The underlying cause is mitochondrial dysfunction; most commonly post viral illness in which the child has taken salicylates.
Most cases occurred between the 1950's to the late 1980's. Fatality rates, generally from cerebral edema, have at times been as high as 50%.
Description
- Reye's syndrome is a potentially life-threatening condition in which vomiting occurs after a viral illness (starting at an average of 3 days after). Following this onset of vomiting, neurologic deterioration begins, generally in the ensuing 1-2 days
- Viral infections most commonly implicated are influenza B, influenza A, and varicella. Virtually any virus that can cause respiratory or gastroenteritis symptoms has been documented to lead to this syndrome. Live vaccines, measles, rubella, herpes simplex, Epstein Barr Virus and Cytomegalovirus have also less commonly preceded this syndrome
- Most affected individuals will be children (average age 7 years old) or adolescents. Reye's syndrome can rarely affect adults
- The majority of cases (>80%) will have recently consumed salicylates (aspirin), generally as symptomatic treatment for the preceding viral illness. It is a matter of debate whether unclear if salicylates are cause this syndrome
- Pathogenesis: This condition is an acquired mitochondrial disease resulting in significant hepatic, renal, skeletal muscle, and cerebral mitochondrial dysfunction. Hepatic mitochondrial injury results in decreased gluconeogenesis with resulting disruption of the urea cycle, thus leading to hyperammonemia, hypoglycemia, and elevated short-chain fatty acids. These changes are felt to lead to cerebral edema and the encephalopathy seen in this syndrome
Epidemiology
Incidence/Prevalence
- A total of 1,207 cases of Reye's syndrome in children were reported to Centers for Disease Control and Prevention (CDC) between 1981 and 1997
- The peak incidence of Reye's syndrome was observed in 1980 with 555 cases
- Incidence has sharply declined since CDC warnings were issued in 1980 regarding a link between Reye's Syndrome and aspirin products, particularly following influenza or varicella infection
- Some authors point out that Reye's syndrome appeared suddenly in the early 1950s and was already on the decline before warnings about aspirin use in children with viral syndromes were made in the 1980s
- Presently Reye's syndrome is very rare with just a handful of cases occurring annually in the U.S.
Age
- Reye's syndrome is primarily a pediatric condition, with the majority of cases occurring in children aged 5–14 years. Peak incidence occurs in those aged 6 years
- The condition is rare in newborn and adults
- It is felt that many cases classified as Reye's syndrome in infants and younger children during the time this condition was prevalent, were likely due to inborn errors of metabolism, which were yet to be classified at the time
Gender
- The condition affects both genders equally
Race
- Between 1980 and 1997, CDC data indicated the incidence of Reye's syndrome was significantly higher among Caucasians (93%) as compared to African Americans (5%) and Asians (2%)
Risk factors
- Children aged 5–14 years
- Caucasian race
- Exposure to salicylates (aspirin)
- Recent viral infection
- Spring or winter season
- Toxin exposure
Etiology
- Viral infections most commonly implicated are influenza B, influenza A, and varicella. Virtually any virus that can cause respiratory or gastroenteritis symptoms has been documented to lead to this syndrome. Live vaccines, measles, rubella, herpes simplex, Epstein Barr Virus and Cytomegalovirus have also less commonly preceded this syndrome
- Occurrence rates increase during influenza outbreaks
- Epidemiologic studies have shown a link between use of salicylates, particularly aspirin, and Reye's syndrome
- The US Food and Drug Administration (FDA) requires warning labels regarding the use of salicylates in children
- The National Reye's Syndrome Foundations, the American Academy of Pediatrics, and the CDC recommend that aspirin containing products not be used by anyone <19 years of age during fever-causing illnesses
- Some authors point out that Reye's syndrome appeared suddenly in the early 1950s and was already on the decline before warnings about aspirin use in children with viral syndromes were made in the 1980s
History
- Patients should be asked about risk factors, such as preceding viral illness and salicylate use
- When reviewing the clinical course, it is expected that the patient's history will be of some, albeit a brief period of recovery following their viral infection, with onset of prolonged vomiting a few days to weeks following the initial viral illness
- Following onset of vomiting, neurologic symptoms generally start to become evident in the next 1-2 days. The most commonly noted symptoms are usually lethargy and impaired mental status
- There may be additional history of symptoms such as agitation, irritability, confusion, seizures, and delirium
- Infants may have diarrhea and rapid breathing
Physical findings on examination
- Physical Findings may include:
- Noteworthy negative findings in Reye's syndrome:
- Agitation
- Altered level of consciousness/delirium
- Babinski's sign positive
- Findings of dehydration (dry mucous membranes, tachycardia, delayed capillary refill)
- Hepatomegally (present in 50% of patients)
- Hyperreflexia or areflexia
- Hypertension
- Hyperventilation (especially infants)
- Hypoventilation – Respiratory failure in stage 5 disease
- Irritability
- Pain response – generally diminished
- Posturing (decorticate/decerebrate) in stage 3-4 disease
- Pupillary response sluggish or unresponsive
- Tachycardia
- Vomiting
- The progression of Reye's syndrome can be classified into 6 clinical stages according to the National Reye Syndrome Surveillance System (1980 through 1997)
- Stage 0 (Non-clinical): Patient remains alert and wakeful; clinical manifestations may be absent, but has a history and laboratory findings consistent with Reye's syndrome
Stage 1: Vomiting, somnolence, lethargy, difficult to arouse - Stage 2: Restlessness, irritability, combativeness, delirium, tachycardia, hyperventilation, sluggish pupillary response, hyperreflexia, and positive Babinski sign
- Stage 3: Decorticate posturing, unarousable, obtunded, hyperventilating, and absence of pain response
- Stage 4: Unarousable, deep coma, decerebrate posturing, fixed and dilated pupils, absence of corneal and oculocephalic reflexes
- Stage 5: Characterized by unarousability, seizures, flaccid paralysis, loss of deep tendon reflexes, absence of pupillary response, and respiratory arrest
- Stage 6: Patient cannot be classified due to treatment with medications that alter consciousness such as curare (e.g. neuromuscular blockers/paralytics) or similar drugs
General treatment items
- There is no specific treatment for Reye's syndrome. Supportive treatment is aimed at managing metabolic and physiologic abnormalities, and control of intracranial hypertension
- Stage 1
- Stage 1 patients require close neurological evaluation and monitoring for complications
- Availability of a pediatric intensive care unit (PICU) is needed if not already admitted to this setting
- The focus on supportive care, management of hypoglycemia, correction of metabolic disturbances, especially hyperammonemia, and control of cerebral edema
- Vital signs and level of consciousness should be monitored continuously
- Elevated intracranial pressure (ICP) should be controlled by administering intravenous (IV) fluids at 2/3 maintenance rate. Care should be taken to avoid over-hydration as it could worsen cerebral edema
- Hypoglycemia should be promptly corrected with IV administration of dextrose solution along with serial serum glucose monitoring
- Serum ammonia levels and liver function should be assessed every 4 to 8 hours
- Coagulopathy, typically hypo-prothrombinemia (e.g. prolonged INR) can be treated with vitamin K. Fresh frozen plasma may be needed in vitamin K is ineffective
- Stage 2
- Patients in this stage generally require PICU admission
- Patients should be monitored for signs of coma that necessitate use of endotracheal intubation and mechanical ventilation to maintain the airway and ventilation
- It is critical to prevent elevation of ICP. The head of the bed may be raised to a 30-degree angle to allow for effective venous drainage. Other interventions may include controlled hyperventilation and use of furosemide or osmotic diuretics (mannitol)
- Correction of hyperammonemia is extremely important as it significantly contributes to cerebral edema. Sodium benzoate/sodium phenylacetate infusion is indicated to correct hyperammonemia. Ondansetron should be administered prior to starting the infusion to prevent vomiting
- Stages 3–5
- Patients in stages 3–5 require aggressive treatment in a PICU setting
- Patients undergoing elective endotracheal intubation should have this performed by rapid sequence induction, and will usually require ongoing sedation until extubated
- IV Mannitol or hypertonic saline should be administered if ICP is not controlled by conservative methods
Sedation and analgesia are essential, since anxiety and pain may result in increased ICP - Seizures should be controlled with anticonvulsant drugs. Phenytoin or fosphenytoin are drugs of choice; acutely benzodiazepines such as midazolam, lorazepam or diazepam may be used
- Hemodialysis may be valuable in reduction of hyperammonemia
- Pulmonary complications may be effectively prevented through pulmonary hygiene
- An ICP monitoring device such as a subarachnoid screw may be required for ICP monitoring, with a goal of pressure <20 mmHg
- Goal cerebral perfusion pressure of 50-70 mmHg (CPP=MAP-ICP)
- CPP = Cerebral perfusion pressure
- MAP = Mean arterial pressure
- ICP = Intracranial pressure
Medications indicated with specific doses
Antihyperammonemic agents
- Sodium benzoate/sodium phenylacetate [IV]
AntiemeticsDiuretics- Furosemide [IM/IV]
- Mannitol [IV]
Anticonvulsants- Phenytoin [IM/IV]
- Fosphenytoin [IM/IV]
- Midazolam [IM/IV]
- Lorazepam [IM/IV]
- Diazepam [IM/IV]
Disposition
Admission criteria
- All patients with suspected or confirmed Reye's syndrome require hospital admission, generally to a pediatric intensive care unit (PICU). If in stage 0 or 1, close monitoring in a step-down unit from PICU may be acceptable, so long as PICU is readily available
- Tertiary care is generally required, as ICP monitoring facilities, access to neurosurgery and neurology is often needed
Discharge criteria
- Criteria for discharge vary by patient, however, resolution of encephalopathy and abnormal laboratory values, clinically well, eating and mobilizing; is generally sufficient for safe discharge, with close follow-up
