Case Based Pediatrics For Medical Students and Residents
Department of Pediatrics, University of Hawaii John A. Burns School of Medicine
Chapter XVIII.17. Reye Syndrome
David W. Boldt
February 2003

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This is a 2 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. He initially presents to the emergency department with irritability 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 50, BP 110/70, oxygen saturation 99% in room air. Height, weight, 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 non-icteric. EOMs cannot be fully tested, but they are conjugate. TMs are normal. Mouth is not easily examined. Neck reveals no adenopathy. He is agitated so it is not possible to be certain that his neck is supple. Heart regular without murmurs. Lungs are clear. Abdomen is flat with normal bowel sounds. It is difficult to tell if he has any hepatosplenomegaly. 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 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 illness seen exclusively in children less than 15 years of age. It is characterized by fatty changes in the liver and encephalopathy that often leads to coma. The number of cases of Reye syndrome has decreased in the last decade due to increased awareness concerning the use of aspirin (salicylates) in children.

Common signs and symptoms include vomiting, agitation, irrational behavior, progressing to lethargy, progressive stupor, restlessness, and convulsions. The usual progression of Reye Syndrome follows the following course: A febrile illness, chickenpox, or upper respiratory infection, occurs in a previously healthy child, followed by a period in which the child seems to have recovered. Subsequently, vomiting ensues 5-7 days after the onset of the initial illness. Simultaneously or within a few hours of this onset of vomiting, delirium, restlessness, and stupor usually occur. In severe cases, the neurologic symptoms rapidly progress to seizures, coma, and eventually death.

Reye Syndrome can be broken down into five stages. 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: 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 rigidity with intact pupillary light reflexes. Stage IV: Seizures are present and are accompanied by a deepening coma, decerebrate rigidity, loss of oculocephalic reflexes, and fixed pupils. Stage V: Characterized by coma, areflexia, respiratory arrest, fixed and dilated pupils, and intermittent flaccidity and decerebrate posturing. The EEG at this point is isoelectric.

There is almost always a history of a preceding viral illness, especially influenza A or B, or varicella. Examination may reveal a positive Babinski sign and hyperreflexia, consistent with cerebral edema; dilated, sluggish pupils, and hyperpnea with irregular respirations. Hepatomegaly is sometimes present, but splenomegaly is absent.

Lab findings include hyperammonemia, normal or slightly elevated bilirubin and alkaline phosphatase, prolonged prothrombin time, hypoglycemia (variable), and moderate to severe elevations in AST, ALT, and lactate dehydrogenase. Hyperaminoacidemia (glutamine, alanine, and lysine) and hypercitrullinemia can be found but these require special tests. Tissue histopathology demonstrates microvesicular steatosis of the liver, kidneys, and brain. The CSF analysis is normal, but the CSF pressure (i.e., ICP) is elevated.

Epidemics of Reye syndrome seem to occur during epidemics of influenza B virus. The use of salicylates (aspirin) is associated with Reye Syndrome, and therefore its use is contraindicated in children (acetaminophen or ibuprofen is usually recommended instead).

The proposed pathological mechanism in Reye is mitochondrial damage caused by salicylate metabolites or some other toxin during a viral infection. Mitochondrial damage leads to elevated short chain fatty acids, hyperammonemia, and directly to cerebral edema. In very young children, metabolic defects in fatty acid oxidation may contribute to the pathogenesis.

The diagnosis of Reye syndrome is based largely on clinical findings, after ruling out other causes of neurologic deterioration such as other encephalopathies, encephalitis, toxins, neoplasms, hepatic failure, fulminant hepatitis, fatty acid oxidation defects, other metabolic disorders, hemorrhage, etc. Histopathology and electron microscopy of a liver biopsy can be used to confirm the diagnosis, but this is usually not done clinically. Urine gas chromatographic analysis and serum acyl-carnitine levels will help to differentiate Reye Syndrome from metabolic disorders. Systemic carnitine deficiency (SCD) (which is an inherited defect of fatty acid oxidation), results in hypoglycemia, hyperammonemia, hypoprothrombinemia, and acute episodes of encephalopathy. SCD mimics the clinical picture seen in Reye Syndrome. In these patients, acyl-carnitine levels would be elevated, whereas they would be normal in patients with Reye syndrome.

Brain imaging studies (CT, MRI) are useful to rule out other causes of CNS dysfunction. Patients with Reye syndrome will generally exhibit findings of cerebral edema and increased intracranial pressure.

Treatment for Reye syndrome is supportive. Hypoglycemia is corrected if present. Measures to lower intracranial pressure (ICP) are initiated. Intensive care measures to monitor fluid status and physiologic function should be initiated (NG tube, Foley catheter, oximetry, ECG, arterial and central venous pressure lines). 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=Non-purposeful responses to pain (e.g., sternal rub). Grade 4=No response to painful stimuli. Grade 5=Autonomic dysfunction with hypothermia, cardiovascular instability and absent spontaneous respiration.

Intracranial pressure should be monitored directly which is best done with a ventricular catheter and kept below 15-20 mmHg through the use of periodic mannitol infusions (0.5-1g/kg every 4 hours), barbiturates, or ventricular CSF drainage. Systemic blood pressure should be monitored and kept high enough to maintain cerebral perfusion pressure (the difference between mean arterial pressure and intracranial pressure) above 45-50 mmHg.

Maintenance fluids using 10% glucose (to reverse hypoglycemia and to some degree as an osmotic agent) should be given at a rate sufficient to produce a urine flow of 1.0-1.5 ml/kg/h. Vitamin K, 3-5 mg intramuscularly, should be given to reduce the likelihood of coagulopathy due to vitamin K dependent factor depletion. Induced hypothermia (30-33 degrees C) and pentobarbital (10-50/mg/kg/day) can be used to decrease the brain's metabolic needs during periods of elevated intracranial pressure.

Reye syndrome is a serious neurologic condition, but roughly 70% of patients with Reye syndrome survive. Survival is related to the depth of the coma and the peak ammonia level on admission. 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. All patients should be screened for fatty acid oxidation defects and other metabolic defects.


Questions

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. too much fat in the diet

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. inflammation of the brain
. . . . . d. b and c

6. Treatment of Reye syndrome focuses on:
. . . . . a. Maintaining cerebral perfusion.
. . . . . b. Ammonia removal or detoxification.
. . . . . c. Treating hypoglycemia.
. . . . . d. Preventing urinary tract infection.


References

1. Sokol RJ, Narkewicz MR. Ch.20 - Liver and Pancreas. In: Hay WW, et al (eds). Current Pediatric Diagnosis and Treatment, 15th edition. 2001. Appleton and Lange, pp. 600-601.

2. Balistreri WF. Ch. 360 - Reye Syndrome and "Reye-like" Diseases. In: Behrman RE, et al (eds). Nelson Textbook of Pediatrics, 16th edition. 2000, Philadelphia: W.B. Saunders Company, pp. 1214-1216.


Answers to questions

1.True, 2.c, 3.b, 4.c, 5.d, 6.a


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