The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition, David W. Boldt. This current second edition chapter is a revision and update of the original author’s work.
This is a 6 year old child who appears to be recovering from an upper respiratory infection when he develops vomiting. He may have taken aspirin (given by his grandmother), but he was supposed to have taken acetaminophen for symptomatic relief. He initially presents to the emergency department with agitation and restlessness. He subsequently develops convulsions which are treated with anticonvulsants, and he is admitted to the ICU.
Exam: VS T 37.8, P 100, RR 35, BP 115/75, oxygen saturation 99% in room air. Height, weight, and head circumference are at the 50th percentile. He is agitated and not cooperative. Head shows no signs of external trauma. Pupils are equal and reactive to light. Conjunctiva are clear, sclera nonicteric. EOMs cannot be fully tested, but they are conjugate. TMs are normal. Mouth is not easily examined. Neck reveals no adenopathy. Uncertain that neck is supple due to agitation. Heart sounds are regular rate and rhythm without murmurs. Lungs are clear. Abdomen is flat with normal bowel sounds. It is difficult to tell if he has any hepatosplenomegaly. No evidence of jaundice. No definite tenderness. No inguinal hernias are present. Testes are normal. He moves all extremities. Reflexes are not testable because of his agitation.
Labs: Serum bilirubin: Normal. Serum AST and ALT: increased. Serum ammonia: increased. Prothrombin time: prolonged. A CT scan of the brain is obtained which shows diffuse cerebral edema.
His neurologic symptoms rapidly worsen, and he becomes unresponsive. He is intubated and put on mechanical ventilation. Reye syndrome is suspected. A confirmatory liver biopsy reveals diffuse, small lipid deposits in the hepatocytes (microvesicular steatosis) without significant necrosis or inflammation. These findings are consistent with the diagnosis of Reye syndrome.
Reye syndrome (also called Reye's syndrome) is a rare but severe illness seen primarily in children between 4 months and 14 years of age with an average age of 6 years (1,2). No gender difference exists (1,3). The etiology of Reye syndrome is unknown. It is characterized by fatty degeneration in the liver and acute, noninflammatory encephalopathy that often progresses to coma (3).
Epidemics of Reye syndrome seem to occur during epidemics of influenza (1). Reye syndrome is typically associated with a viral infection that has been treated with salicylates (aspirin) for antipyretic therapy (3,4). Therefore, the use of aspirin is avoided in children (acetaminophen or ibuprofen is usually recommended instead, except in children with Kawasaki disease and juvenile idiopathic arthritis). The incidence of Reye syndrome has decreased since 1985 due to increased awareness concerning the use of aspirin (salicylates) in children especially with acute viral infections (1,5).
The pathogenesis of Reye syndrome is still unknown. However, the proposed pathological mechanism is mitochondrial dysfunction caused by salicylate metabolites (or some other toxin) during a viral infection (1,3,5). Aspirin metabolites decrease fatty acid beta-oxidation by reversible inhibition of mitochondrial enzymes. Mitochondrial damage leads to elevated short chain fatty acids, hyperammonemia, and cerebral edema (5).
Common signs and symptoms include vomiting, agitation, and irrational behavior, progressing to lethargy, stupor, restlessness, and convulsions. The usual progression of Reye Syndrome proceeds in the following biphasic clinical course. A febrile illness (e.g., chickenpox, influenza B, or an upper respiratory infection) occurs in a previously healthy child who then receives aspirin. This acute febrile phase is then followed by a period in which the child seems to have recovered (2). Subsequently, prolonged vomiting ensues 5 to 7 days after the onset of the initial illness. Simultaneously or within a few hours of this onset of vomiting, tachypnea, tachycardia, delirium, combativeness, disorientation, restlessness, and stupor usually occur (3). In severe cases, the neurologic symptoms rapidly progress to seizures, coma, and eventually death. Infants may present atypically with tachypnea, apnea, irritability, seizures, and hypoglycemia (1,2).
Reye Syndrome can be broken down into five stages (2,3,4). This may be preceded by a stage of agitation sometimes called Stage 0.
. . . . . Stage I: Patient is quiet, lethargic, sleepy, and is vomiting. Lab values indicate liver dysfunction.
. . . . . Stage II: Behavior undergoes changes characterized by deep lethargy, confusion, delirium, combative behavior, hyperventilation, and hyperreflexia.
. . . . . Stage III: The patient is obtunded. Seizures may be present at this stage. There is decorticate (flexor) posturing with intact pupillary light reflexes.
. . . . . Stage IV: Seizures are present and are accompanied by a deepening coma, decerebrate (extensor) posturing, loss of oculocephalic reflexes, and nonreactive pupils.
. . . . . Stage V: Neurologic status is characterized by coma, areflexia, respiratory arrest, and dilated and nonreactive pupils. The EEG at this point is isoelectric.
There is almost always a history of a preceding viral illness, especially influenza A or B virus or varicella virus infections (1,2). Examination may reveal a positive Babinski sign and hyperreflexia, as well as signs consistent with cerebral edema: dilated, sluggish pupils, and hyperpnea with irregular respirations (5). Hepatomegaly is sometimes present, but splenomegaly is absent. Jaundice and scleral icterus are typically absent; their presence makes the diagnosis of Reye syndrome doubtful (3).
Lab findings include hyperammonemia, normal bilirubin (though sometimes slightly elevated), normal alkaline phosphatase, elevated lactate dehydrogenase, prolonged prothrombin time (due to decreased liver-dependent clotting factors), variable hypoglycemia, and a threefold or greater elevation in serum transaminases (AST, ALT) (1,2,3). The level of transaminase elevation does not correlate well with the severity of the disease (3). An initial metabolic acidosis is associated with a compensatory respiratory alkalosis (1,3). The EEG shows diffuse arrhythmic delta activity (1). Hyperaminoacidemia (glutamine, alanine, and lysine) and hypercitrullinemia can be found, but these require specialized testing methods (5). Tissue histopathology demonstrates microvesicular steatosis of the liver (and to a lesser extent, the kidneys, heart, skeletal muscles, pancreas, and spleen) without inflammatory lesions (1,5). Electron microscopy shows large, pleomorphic mitochondria and swelling in the liver, brain, and other tissues (5). The cerebrospinal fluid analysis is acellular and normal, but the CSF pressure is elevated (1,5).
The Centers for Disease Control and Prevention’s (CDC) clinical definition of Reye syndrome is: 1) an acute, noninflammatory encephalopathy documented clinically by a) an alteration in consciousness and, if available, b) a record of the CSF containing less than or equal to 8 leukocytes/microliter or a histologic specimen demonstrating cerebral edema without perivascular or meningeal inflammation; 2) hepatopathy documented by either a) a liver biopsy or an autopsy considered to be diagnostic of Reye syndrome or b) a 3-fold or greater increased in the levels of AST, ALT, or serum ammonia; 3) lack of a more reasonable explanation for the cerebral and hepatic abnormalities (6).
Thus, the diagnosis of Reye syndrome is based largely on clinical findings, after the exclusion of other causes of encephalopathy (encephalitis, meningitis, toxins, neoplasms, hepatic failure, fulminant hepatitis, fatty acid oxidation defects and other metabolic disorders, intracranial hemorrhage, etc.) (3,5). Histopathology and electron microscopy of a liver biopsy can be used to confirm the diagnosis, but this is usually not done clinically (2). Inborn errors of metabolism present with Reye-like syndrome manifestations and must be distinguished from classic Reye syndrome. Urine gas chromatographic analysis and serum acyl-carnitine levels will help to differentiate Reye Syndrome from metabolic disorders (5). For example, medium-chain acyl CoA dehydrogenase (MCAD) deficiency is the most commonly diagnosed metabolic disorder associated with Reye-like syndrome. MCAD deficiency (an autosomal recessive disorder of fatty acid oxidation) results in hypoglycemia, hyperammonemia, elevated transaminases, and acute episodes of encephalopathy. In these patients, plasma acyl-carnitine levels would be elevated, whereas they would be normal in patients with Reye syndrome. All patients suspected of Reye syndrome should be screened extensively to exclude treatable inborn metabolic disorders (4,5).
Brain imaging studies (CT and MRI) are useful to rule out other causes of CNS pathology. Patients with Reye syndrome will generally exhibit findings of cerebral edema and increased intracranial pressure.
Treatment for Reye syndrome is supportive and corresponds to the stage of the syndrome (5,7). Hospitalization in the ICU is required to control intracranial pressure. Treatment measures include: tight regulation of fluid balance including use of a nasogastric tube, urinary catheter, pulse oximetry, continuous ECG, arterial and central venous pressure monitoring, intracranial pressure monitoring with or without a ventriculostomy drain, and therapies to reduce ammonia levels (1,2,7). Hypoglycemia is corrected if present, and serum glucose levels should be maintained between 150 and 200 mg/dl with intravenous glucose (2). If the patient is in grade 3 coma (see below), mechanical ventilation may be necessary.
Coma can be scored using the Glasgow Coma Scale. A simpler method is the AVPU scale (A=Alert, V=responds to Verbal stimuli, P=responds to Painful stimuli, U=Unresponsive). Similarly, grades can be used as follows: Grade 1=Subject is able to obey simple commands. Grade 2=No response to commands, but purposeful responses to pain are elicited. Grade 3=Nonpurposeful or nonfocal responses to pain (e.g., generalized withdrawal with sternal rub). Grade 4=No response to painful stimuli. Grade 5=Autonomic dysfunction with hypothermia, cardiovascular instability and apnea.
Intracranial pressure should be continuously monitored directly, and kept below 15 to 20 mmHg through the use of periodic mannitol infusions (0.5 to 1 g/kg every 4 hours), barbiturates, hyperventilation, neuromuscularblocking drugs, or ventricular CSF drainage (2,3,5). Induced hypothermia (30 to 33 degrees C) and barbitruate coma (pentobarbital 10 to 50 mg/kg/day) can be used to reduce the brain's metabolic needs during periods of elevated intracranial pressure (2,5). However, none of these therapies have been clearly demonstrated to protect the brain from progressive ischemic insult (3).
Systemic blood pressure should be monitored and kept high enough to maintain adequate cerebral perfusion pressure (the difference between mean arterial pressure and intracranial pressure) above 45 to 50 mmHg (5).
Maintenance fluids using intravenous 10% dextrose (to reverse hypoglycemia and to some degree as an osmotic agent) should be given at a rate sufficient to produce a urine flow of 1.0 to 1.5 ml/kg/h (2,3,5). Vitamin K 3 to 5 mg parenterally should be given to reduce the likelihood of coagulopathy due to vitamin K dependent factor depletion (5).
Reye syndrome is a serious neurologic condition, but an early diagnosis and the initiation of treatment before the onset of coma have reduced mortality rates to approximately 5% to 20% (5). The major factor contributing to morbidity and mortality is increased intracranial pressure secondary to cerebral edema (3). Survival is related to the degree of cerebral edema and the peak ammonia level on admission (5). Complications due to coma such as aspiration pneumonitis and respiratory failure also affect the prognosis. If death results, it is usually from refractory cerebral edema. Severe neurologic dysfunction may be present in children who recover from prolonged grade 3 or 4 coma (7).
1. True/False: Reye syndrome is most often preceded by a history of viral illness.
2. The cause of Reye syndrome is:
. . . . . a. liver failure
. . . . . b. brain abscess
. . . . . c. unknown
. . . . . d. inflammation
3. Which drug is associated with the development of Reye syndrome?
. . . . . a. antidepressants
. . . . . b. salicylates
. . . . . c. cancer chemotherapy
. . . . . d. barbiturates
4. Reye syndrome is primarily a disease of:
. . . . . a. adults
. . . . . b. the elderly
. . . . . c. children and adolescents
. . . . . d. infants
5. What is/are the most common feature(s) of Reye syndrome?
. . . . . a. liver infection
. . . . . b. rapid accumulation of fat in the liver
. . . . . c. noninflammatory neurologic dysfunction with brain swelling
. . . . . d. b and c
6. True/False: Because Reye syndrome is very rare, any child suspected of Reye syndrome should be tested for inborn errors of metabolism.
7. Treatment of Reye syndrome focuses on:
. . . . . a. monitoring and controlling intracranial pressure.
. . . . . b. ammonia reduction or detoxification.
. . . . . c. treating hypoglycemia.
. . . . . d. all of the above.
1. Ropper AH, Samuels MA. Chapter 40. The Acquired Metabolic Disorders of the Nervous System. In: Ropper AH, Samuels MA (eds). Adams and Victor's Principles of Neurology. 10th ed. New York: McGraw-Hill; 2014.
2. Pina-Garza JE. Chapter 2: Altered States of Consciousness. Fenichel's Clinical Pediatric Neurology. 7th ed. Philadelphia: Elsevier; 2013.
3. Durbin DR, Liacouras CA, Seiden JA. Chapter 89: Gastrointestinal Emergencies. In: Fleisher G, Ludwig S, Henretig F (eds). Textbook of Pediatric Emergency Medicine. 6th ed. Philadelphia: Lippincott; 2010.
4. Ibrahim SH, Balistreri WF. Ch. 361 -- Mitochondrial Hepatopathies. In: Behrman RE, et al (eds). Nelson Textbook of Pediatrics, 20th ed. Philadelphia: Elsevier; 2016.
5. Hurwitz ES. Chapter 50: Reye Syndrome. In: Feigin and Cherry's Textbook of Pediatric Infectious Diseases. 7th ed. Philadelphia: Elsevier; 2014. pg 676-677.
6. “Reye Syndrome 1990 Case Definition.” National Notifiable Diseases Surveillance System. Centers for Disease Control and Prevention. Last reviewed July 30, 2015.
7. Kamienski MC. Reye Syndrome: Patients Don't Always Have a History of Taking Aspirin or Display Obvious Symptoms. Am J Nursing 2003;103(7):54-57.
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