C H A P T E R 5 0

Reye Syndrome
Eugene S. Hurwitz

A syndrome involving the acute onset of encephalopathy

associated with fatty metamorphosis of the liver and
occurring primarily in children was described first by
Reye and colleagues10,12 in Australia and by Johnson and
associates9 in the United States. The similarities of these
two descriptions in separate countries led to the common
designation of this clinicopathologic entity as ReyeJohnson or Reye syndrome. Reye syndrome occurs most
frequently after a viral illness and is characterized by the
onset of severe vomiting followed by the development of
encephalopathy and hepatic dysfunction. The recognition in the early 1980s that the syndrome is associated
with the ingestion of aspirin during the antecedent viral
illness led to public awareness of this association, a decline
in aspirin use for such illnesses in children, and a dramatic
decline in the occurrence of this disease in the United
States.1

EPIDEMIOLOGY
In the United States, national surveillance for Reye syndrome was conducted first during the 1973 to 1974
nationwide outbreak of influenza B and influenza A
(H1N1). Such surveillance led to the recognition of outbreaks of Reye syndrome regionally and nationally that
were associated with outbreaks of influenza in these and
subsequent years.3 During the first 5 years of surveillance,
250 to 550 cases were reported nationallyan underestimate because it was based on voluntary reporting.11
Population-based studies conducted in several geographic
locations showed that the average annual incidence of the
syndrome was one or two cases per 100,000 children
younger than 18 years old. Adults rarely were affected.
Case-fatality rates reported through national surveillance, initially 40 percent, declined to 20 to 30 percent
in later years when the syndrome was prevalent, although
this rate undoubtedly was an overestimate because of the
tendency to report more severe and fatal cases through
this system.
Between 1980 and 1982, four case-control studies
reported an association between Reye syndrome and the
ingestion of aspirin during an antecedent respiratory or
chickenpox illness.4,13,14 The results of these studies subsequently were confirmed in the Public Health Service
Pilot and Main Studies of Reye Syndrome and
Medications.5-7 In these studies, more than 90 percent of
patients with Reye syndrome compared with 40 to 70
percent of controls had received aspirin for the antecedent respiratory or chickenpox illness; reported odds ratios
were 11.5 to 40. After these studies were reported,
676

publicity and recommendations from various expert

panels, including recommendations issued by the U.S.
Food and Drug Administration in 1985, led to a decline
in the use of aspirin and a decline in the incidence of Reye
syndrome, particularly in the age group that had been
affected mostchildren 5 to 15 years old.1

CLINICAL MANIFESTATIONS AND

LABORATORY FINDINGS
Reye syndrome is described classically as an illness characterized by the abrupt onset of severe vomiting and
progressive encephalopathy in a child who is just recovering from a viral illness, the most common of which are
influenza and chickenpox. The onset of these symptoms
typically occurs within several days after the onset of the
viral illness and commonly during a period when the
child seems to be recovering from this illness. In association with severeoften projectilevomiting, which
occurs for a transient period, are progressive encephalopathic changes that may follow stages from delirium
through confusion, agitation, and lethargy to coma if
untreated.
The definition used by the Centers for Disease Control
and Prevention (CDC) and widely adopted for clinical
purposes includes (1) evidence of acute encephalopathy
manifested by alterations in consciousness and documented, when available, by cerebrospinal fluid with less
than 9 106/L leukocytes or by biopsy or autopsy evidence of cerebral edema without perivascular or meningeal inflammation in histologic sections of the brain; (2)
evidence of liver involvement, including either biopsy or
autopsy findings of fatty metamorphosis of the liver if
available or, in the absence of such specimens, elevations
in liver enzymes (alanine aminotransaminase, aspartate
aminotransaminase, or serum ammonia) that typically are
more than three times normal levels; and (3) no other
more reasonable explanation for the cerebral or hepatic
abnormalities. The last requirement emphasizes that
Reye syndrome is a diagnosis of exclusion and that every
effort should be undertaken to identify other possible
causes for the clinical and laboratory abnormalities.
Liver biopsy or autopsy findings are considered characteristic and include panlobular microvesicular fat and
mitochondrial abnormalities on electron microscopic
examination showing peroxisome swelling and enlarged
pleomorphic mitochondria with loss of dense granules.
Additional findings include normal bilirubin levels and
absence of jaundice. Most patients also have hypoglycemia and a prolonged prothrombin time. The typically

elevated cerebrospinal fluid pressure in patients leads to

progressive stages of coma.
Staging criteria for Reye syndrome have been used to
define the level of encephalopathy. Patients have been
reported with liver involvement, but without evidence of
encephalopathy. These patients have been described as
having stage 0 encephalopathy and, although they do not
meet the CDC criteria for Reye syndrome, are considered to have mild disease. Patients with stage I encephalopathy are difficult to arouse and lethargic, whereas
patients with stage II are delirious and combative with
some movement. Patients with higher stages of encephalopathy (III to V) cannot be aroused and have progressively deeper stages of coma. These patients have a poor
prognosis, with a mortality rate approaching 50 percent
for patients admitted with stage III or greater and 90
percent for patients admitted with stage V.
Exclusion of other diseases that may resemble Reye
syndrome, such as salicylate toxicity, is essential in patients
with symptoms resembling this entity. Intensive laboratory investigations should be undertaken to exclude
such disorders. In young children, particularly children
younger than 3 years of age, inherited metabolic disorders frequently may mimic Reye syndrome and must be
excluded. Such metabolic disorders include disorders of
fatty acid oxidation, urea cycle disorders, carnitine transport defects, and organic acidemias. Laboratory studies
must be performed for the younger age group to exclude
these disorders before a diagnosis of Reye syndrome is
made, particularly because some of these disorders can
be treated effectively. With the declining incidence of
Reye syndrome in the typical age group (5 to 15 years)
after virtual elimination of the use of aspirin in children,
an increasing number of patients with features of Reye
syndrome are in this younger age group and ultimately
are found, after careful evaluation, to have one of the
many metabolic disorders that mimic this syndrome.
An acute encephalopathy mimicking Reye syndrome
was recently noted.8 This 11-year-old boys illness was
due to Bacillus cereus emetic toxin cereulide.

TREATMENT AND PREVENTION

The mainstay of treatment of Reye syndrome is early
recognition of disease and supportive care focusing on
various measures to control intracranial pressure and

50 Reye Syndrome

677

electrolyte and other abnormalities. Patients should have

glucose levels monitored, and early infusion of glucose is
considered by many physicians to improve outcome.
Comatose patients should be transferred to tertiary care
centers that have experience in caring for such patients
and can monitor and treat elevated intracranial pressure.
When such measures were undertaken before the decline
in incidence of this disease, they were associated with
improved outcome and decreased mortality. Other therapeutic measures that have been used include efforts to
reduce ammonia levels, such as exchange transfusions,
peritoneal dialysis, and total-body washout via cardiopulmonary bypass. With advances in supportive care, the
mortality rate declined to 10 to 20 percent in later years
before Reye syndrome became extremely rare.
Since the association between Reye syndrome and
aspirin has been recognized, aspirin no longer is recommended or used for the treatment of febrile illnesses in
children. Alternative antipyretics, including nonsteroidal
anti-inflammatory drugs and acetaminophen (Tylenol),
have replaced aspirin as the primary therapy for such illnesses. These medications have not been associated with
an increased risk for development of Reye syndrome.
Children with some disorders, including juvenile rheumatoid arthritis and Kawasaki disease, continue to be
given aspirin to treat these disorders. Efforts to reduce
the risk for development of Reye syndrome in these children have included influenza vaccination annually and
vaccination against chickenpox. Careful monitoring of
these children also is necessary to ensure early recognition and treatment of Reye syndrome should it occur.
A large number of over-the-counter aspirin-containing
products are available in the United States as well as in
other countries.2 It is often not recognized by parents
that these alternative medicine products contain aspirin
so that children with respiratory illness may on occasion
receive aspirin. Therefore, Reye syndrome may still occasionally occur.
NEW REFERENCE SINCE THE SIXTH EDITION
8. Ichikawa K, Gakumazawa M, Inaba A, et al. Acute encephalopathy
of Bacillus cereus mimicking Reye syndrome. Brain Dev 2010;
32:68890.
The full reference list for this chapter is available at
expertconsult.com.

50 Reye Syndrome 677.e1

REFERENCES
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8. Ichikawa K, Gakumazawa M, Inaba A, et al. Acute encephalopathy

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68890.
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