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Reye's syndrome: down but not out. (Case Report).

Abstract: Reye's syndrome presents as acute central nervous system and liver dysfunction in children. Its incidence has seen a sharp decline in parallel with the decline in the use of aspirin in the pediatric age group. This report describes a patient with Reye's syndrome and serves as a reminder for health professionals to continue to discourage the use of aspirin for the treatment of viral infections.


Reye's syndrome was first described as a separate clinical entity by Reye et al (1) in 1963. It is characterized by acute encephalopathy and hepatopathy with characteristic anatomic and biochemical changes, (2) and predominantly affects children. After reaching an incidence of 400 to 600 cases per year in the United States in the 1970s and early 1980s, the incidence had decreased to approximately two cases per year by 1997. (3) This decline has been attributed to the sharp decrease in the use of aspirin for treating children. (3,4) Another reason for this decline may be improvement in the diagnosis of metabolic diseases, such as medium-chain acyl-coenzyme A dehydrogenase deficiency, that cause illnesses similar to Reye's syndrome. (5) A MEDLINE search revealed no new reported cases in the United States since 1997. This dramatic disappearance of a once-feared childhood illness is considered a public health triumph because of the concerted effort by health care professionals and government agencies to educate t he public about the probable role of aspirin in Reye's syndrome. (6) The almost complete disappearance of this disease, however, poses the danger that public awareness of its epidemiologic link with aspirin will decline and lead to reemergence of this problem. We report one such case.

Case Report

A 3-year-old boy was brought to a referring hospital in December 1999 with a 5-day history of fever and symptoms of an upper respiratory tract infection. His family had given him acetaminophen and aspirin for symptomatic relief. Two days before his admission, he developed profuse, nonbilious vomiting and was taken to a local emergency department, where he was diagnosed with pharyngitis and otitis media. He was prescribed amoxicillin/potassium clavulanate suspension and promethazine suppositories and sent home.

On presentation to the emergency department on the day of admission, the patient was noted to be combative, responding inappropriately to verbal commands. He had dystonia thought to be due to the promethazine therapy. He was treated with intravenous diphenhydramine, and he also received intravenous lorazepam for possible seizures. Noncontrast computed tomography (CT) of the head showed no abnormality.

Six hours after admission to the referring hospital, patient was noted to be tachycardiac and hypotensive (systolic blood pressure, 50-60 nun Hg), and he had poor peripheral perfusion with capillary refill rate of 5 to 6 seconds. Laboratory investigations revealed the following values: blood glucose, 40 mg/dl; total bilirubin, 1.1 mg/dl; alkaline phosphatase, 272 lU/L; aspartate aminotransferase (AST), 1,060 IU/L; and ammonia, 753 [micro]mol/L. Arterial blood gas analysis showed a pH of 7.2, [PCO.sub.2] of 34 mm Hg, [PO.sub.2] of 179 mm Hg, and base deficit of 14 mmol/L. Salicylate level was 3.9 mg/dl. He was administered a bolus of glucose and normal saline and treated with vancomycin and cefiriaxone. Dopamine was started at 10 [micro]g/kg/min. The transport team performed a rapid-sequence intubation, as his Glasgow Coma Score was 5, and he was noted to have decorticated posturing (Stage 3 of the neurologic stages of Reye's syndrome).

Upon arrival at our pediatric intensive care unit (PICU), the patient was unresponsive to all stimuli. His pupils were sluggishly reactive, he had occasional spontaneous breaths, and he was having decerebrate posturing (Stage 4). He was hyperventilated and was administered a dose of mannitol. Noncontrast head CT was repeated, which showed diffuse cerebral edema with impending uncal herniation. Treatment with sodium benzoate was started in an attempt to decrease the ammonia level. He was treated with the inotropic agents dopamine and milrinone, which resulted in improved perfusion.

The patient received approximately 30 ml/kg fresh frozen plasma to correct his coagulation parameters. An intraparenchymal monitor of intracranial pressure (ICP) was placed, and the opening pressure was noted to be 65 mm Hg. After cooling the patient's core temperature to 34[degrees]C and treatment with mannitol and pentobarbital, ICP normalized.

Laboratory investigations performed to determine the etiology of this acute hepatic failure showed a salicylate level of 1.7 mg/dl and acetaminophen level of 10 [micro]g/ml. Hepatitis B surface antigen, hepatitis core antibody, hepatitis C antibody, and Epstein-Barr virus titers were negative. Test for hepatitis A total antibody was positive, but there was insufficient quantity of serum to determine whether the antibodies to hepatitis A were immunoglobulin G (IgG) or immunoglobulin M (IgM). The serum amino acid and urine organic acid screening tests were negative. Cultures for bacteria and viruses from blood, urine, and respiratory tract remained negative. A percutaneous liver biopsy, performed at the bedside under ultrasonographic guidance, showed macrovesicular and microvesicular steatosis, with central hepatocellular nuclei and essentially no intralobular inflammation (Figs. 1 and 2). This histologic picture was consistent with the diagnosis of Reye's syndrome.

On Day 2 of his admission to the PICU, the patient' s liver function test results had stabilized, and the ammonia level had returned to normal. By Day 3, however, he exhibited no cranial nerve function. Computed tomography was repeated, which showed severe cerebral edema with persistent uncal herniation. The patient was declared brain dead on Day 4.

Autopsy confirmed the presence of severe steatosis in the absence of any other findings histologic examination of the liver, which is characteristic of Reye's syndrome. Autopsy also revealed severe cerebral edema with cerebellar tonsillar herniation, early acute renal tubular necrosis, pulmonary edema, and focal acute bronchitis and tracheitis.


Reye's syndrome is characterized by an acute noninflammatory encephalopathy and fatty degeneration in the liver, marked by microvesicular steatosis. The first clinical sign is usually vomiting starting 4 to 5 days after a viral illness, most commonly varicella or influenza. The encephalopathy progresses from mild confusion (Stage 1), through progressive loss of neurologic function, to loss of brainstem reflexes (Stage 5). (7) Mild hyperbilirubinemia and at least a threefold increase in AST, alanine aminotransferase (ALT), and ammonia levels mark the hepatic failure. Hypoglycemia may affect primarily infants and young children. Histologic examination of the liver in these patients shows microvesicular steatosis with no evidence of inflammation or necrosis (Figs. 1 and 2). At an ultrastructural level, the liver shows a decreased number of enlarged mitochondna, with loss of dense granules and an increase in the smooth endoplasmic reticulum. (8)

Although the exact etiology of this syndrome is unclear, strong evidence supports the hypothesis that it follows aspirin use after influenza A or B, varicella, or adenovirus infections. (9-11) The sharp decline in the incidence of this disease after the issuance of the Surgeon General's advisory in 1982 and the placement of mandatory waming labels on all aspirincontaining medicines in 1986 is further support for this link. Of interest in our patient was the positive hepatitis A total antibody test. We found an earlier case report in which hepatitis A was concomitantly present in an adult patient with Reye's syndrome. (12). In patients with hepatitis A or B, the liver histologically shows marked inflammation, necrosis, and cholestasis. These features were not present in our patient.

A number of inherited metabolic diseases may present similarly to Reye's syndrome. (13, 14) Some of these are listed in Table 1. These diseases need to be excluded as causes for the presenting illness before the diagnosis of Reye's syndrome may be made. No inbom error of metabolism was found in our patient.

Therapy consists of supportive measures aimed at decreasing intracerebral pressure, decreasing the ammonia level, and replacing proteins synthesized by the liver. Intracranial pressure monitoring has been used in this setting, (15, 16) although in the setting of cytotoxic edema (17) its utility is debatable. Ammonia reduction measures include use of ammonia-scavenging salts (eg, sodium benzoate), bowel cleansing to decrease ammonia production by lactulose and minocycline, or dialysis.

Patient outcome depends on the stage of neurologic symptoms. Patients presenting in Stage 1 or 2 have a mortality rate of 20 to 25%, Stage 3 or 4 patients have a mortality rate of approximately 50 to 60%, and Stage 5 patients have a 90% mortality rate. (3) A significant number of the survivors have mild to severe neurologic sequelae.


The incidence of Reye's syndrome has decreased markedly in the past 10 to 15 years, mostly due to the awareness by health professionals and the general public of its probable link with the use of aspirin in children. As this case illustrates, however, physicians and other health professionals involved in primary care must continue to remind their patients' caregivers to avoid using salicylates (both aspirin and bismuth salicylate) during febrile illnesses in children.
Table 1

Metabolic disorders that have presentations similar to Reye's syndrome

Disorders of ureagencsis
 Partial ornithine transcarbamoylasc deficiency
 Partial carbamoylphosphatc deficicncy
 Partial arginosuccinic acid synthase deficiency
Disorders of mitochondrial fatty acid oxidation and ketogenesis
 Medium-chain acyl-coenzyme A dehydrogenase deficiency
 Light-chain acyl-coenzyme A dehydrogenase deficiency
 Carnitine transport defect
Organic acidurias
 Glutaricaciduria, type 1
Carbohydrate metabolism
Respiratory-chain disorders

Accepted January 14, 2002.


(1.) Reye R, Morgan G, Baral J. Encephalopathy and fatty degeneration of the viscera: A disease entity in childhood. Lancet 1963;2:749-752.

(2.) Wharton M, Chorba TL, Vogt RL, Morse DL, Buehler JW. Case definitions for public health surveillance. MMWR Recomm Rep l990;39(RR13): 1-43.

(3.) Belay ED, Bresee JS, Holman RC, et al. Reye's syndrome in the United States from 1981 through 1997. N Engl J Med 1999;340:1377-1382.

(4.) Hardie RM, Newton LH, Bruce JC, et al. The changing clinical pattem of Reye's syndrome 1982-1990. Arch Dis Child 1996;74:400-405.

(5.) Orlowski JP. Whatever happened to Reye's syndrome? Did it ever really exist? Crit Care Med 1999;27:1582-1587.

(6.) Monto AS. The disappearance of Reye's syndrome: A public health triumph. N Engl J Med 1999;340: 1423-1424 (editorial).

(7.) Chesney P. Pediatric infectious disease-associated syndromes, in Fuhrman BP, Zimmerman JJ (eds): Pediatric Critical Care. St. Louis, Mosby, 1998, ed 2, pp 1107-1108.

(8.) Daugherty CC, Gartside PS, Heubi JE, Saalfeld K, Snyder J. A morphometric study of Reye's syndrome: Correlation of reduced mitochondrial numbers and increased mitochondrial size with clinical manifestations. Am J Pathol 1987;l29:313-326,

(9.) Cox NJ, Subbarao K. Influenza. Lancet 1999;354:1277-1282.

(10.) Preblud SR, Orenstein WA, Bart KJ. Varicella: Clinical manifestations, epidemiology and health impact in children. Pediatr Infect Dis 1984;3:505-509.

(11.) Edwards KM, Bennett SR, Gamer WL, et al. Reye's syndrome associated with adenovirus infections in infants. Am J Dis Child 1985:139:343-346.

(12.) Duerksen DR, Jewell LD, Mason AL, Bain VG. Co-existence of hepatitis A and adult Reye's syndrome. Gut 1997;41:121-124.

(13.) Greene CL, Blitzer MG, Shapira E. Inborn errors of metabolism and Reye syndrome: Differential diagnosis. J Pediatr 1988;113:156-159.

(14.) Saudubray J, Charpentier C. Clinical phenotypes: Diagnosis/algorithms, in Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease. New York, McGraw-Hill Health Professions Division, 1995, vol 1, ed 7, pp 348-349.

(15.) Chi CS, Law KL, Wong TT, Su GY, Lin N. Continuous monitoring of intracranial pressure in Reye's syndrome: 5 years experience. Acta Paediatr Jpn 1990;32:426-434.

(16.) Jenkins JG, Glasgow JE, Black GW, et al. Reye's syndrome: Assessment of intracranial monitoring. Br Med .1 (Clin Res Ed) 1987;294:337-338.

(17.) Blisard KS, Davis LE. Neuropathologic findings in Reye's syndrome. .1 Child Neurol 1991;6:41-44.


* Reye's syndrome is an acute encephalopathy and hepatopathy with characteristic biochemical and anatomic changes.

* Reye's syndrome is associated with the use of aspirin to treat viral illnesses in children.

* The incidence of Reye's syndrome decreased dramatically after the use of aspirin to treat children was curtailed.

* To make the diagnosis of Reye's syndrome, it is necessary to rule out metabolic diseases, including acidurias, respiratory chain disorders, and disorders of ureagenesis, mitochondrial fatty acid oxidation, and carbohydrate metabolism.

* This case illustrates the need for continued education of the public and health care professionals regarding the dangers of treating children with aspirin during a febrile illness.

From thc Departments of Pediatrics and Pathology, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, AR.

Reprint requests to Adnan T. Bhutta, MBBS, Fellow, Critical Care Medicine, Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, 800 Marshall Street, Slot 512-12, Little Rock, AR 72202-3591. Email:

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Author:Schexnayder, Stephen M.
Publication:Southern Medical Journal
Geographic Code:1USA
Date:Jan 1, 2003
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