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Reye syndrome - Wikipedia
Reye syndrome
Reye syndrome is a rapidly worsening brain disease.[2]
Symptoms may include vomiting, personality changes,
confusion, seizures, and loss of consciousness.[1] Even
though liver toxicity typically occurs, jaundice usually does
not.[2] Death occurs in 20–40% of those affected and
about a third of those who survive are left with a
significant degree of brain damage.[2][3]
The cause of Reye syndrome is unknown.[2] It usually
begins shortly after recovery from a viral infection, such as
influenza or chickenpox.[1] About 90% of cases in children
are associated with aspirin (salicylate) use.[2] Inborn
errors of metabolism are also a risk factor.[3] Changes on
blood tests may include a high blood ammonia level, low
blood sugar level, and prolonged prothrombin time.[2]
Often the liver is enlarged.[2]
Prevention is typically by avoiding the use of aspirin in
children.[1] When aspirin was withdrawn for use in
children a decrease of more than 90% in rates of Reye
syndrome was seen.[2] Early diagnosis improves
outcomes.[1] Treatment is supportive.[1] Mannitol may be
used to help with the brain swelling.[2]
The first detailed description of Reye syndrome was in
1963 by Douglas Reye, an Australian pathologist.[4]
Children are most commonly affected.[2] It affects fewer
than one in a million children a year.[2] The general
recommendation to use aspirin in children was withdrawn
because of Reye syndrome, with use of aspirin only
recommended in Kawasaki disease.[3]
Reye syndrome
Other names
Reye's syndrome
Appearance of a liver from a child who died of
Reye syndrome as seen with a microscope.
Hepatocytes are pale-staining due to
intracellular fat droplets.
Pronunciation /raɪ ˈsɪndroʊm/ rye SIN-drohm
Specialty
Pediatrics
Symptoms
Vomiting, personality changes,
confusion, seizures, loss of
consciousness[1]
Complications Persistent vegetative state,
coma
Causes
Unknown[2]
Risk factors
Aspirin use in children, viral
infection[1][2]
Treatment
Supportive care[1]
Medication
Mannitol[2]
Prognosis
1⁄
3rd
Signs and symptoms
Frequency
Causes
Aspirin
Less than one in a million
children a year[2]
Deaths
~30% chance of death[2][3]
Contents
long term disability[2][3]
Diagnosis
Differential diagnosis
Treatment
Prognosis
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Epidemiology
History
References
External links
Signs and symptoms
Reye syndrome progresses through five stages:[5][6][7]
Stage I
Rash on palms of hands and feet
Persistent, heavy vomiting that is not relieved by not eating
Generalized lethargy
Confusion
Nightmares
No fever usually present[8]
Headaches
Stage II
Stupor
Hyperventilation
Fatty liver (found on biopsy)
Hyperactive reflexes
Stage III
Continuation of Stage I and II symptoms
Possible coma
Possible cerebral edema
Rarely, respiratory arrest
Stage IV
Deepening coma
Dilated pupils with minimal response to light
Minimal but still present liver dysfunction
Stage V
Very rapid onset following stage IV
Deep coma
Seizures
Multiple organ failure[9]
Flaccidity
Hyperammonemia (above 300 mg/dL of blood)
Death
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Causes
The cause of Reye syndrome is unknown.[2] It usually begins shortly after recovery from a viral infection,
such as influenza or chickenpox.[1] About 90% of cases in children are associated with aspirin (salicylate)
use.[2] Inborn errors of metabolism are also a risk factor.[3]
The association with aspirin has been shown through epidemiological studies. The diagnosis of "Reye
Syndrome" greatly decreased in the 1980s, when genetic testing for inborn errors of metabolism was
becoming available in developed countries.[10] A retrospective study of 49 survivors of cases diagnosed
as "Reye's Syndrome" showed that the majority of the surviving patients had various metabolic
disorders, particularly a fatty-acid oxidation disorder medium-chain acyl-CoA dehydrogenase
deficiency.[11]
Aspirin
There is an association between taking aspirin for viral illnesses and the development of Reye
syndrome,[12] but no animal model of Reye syndrome has been developed in which aspirin causes the
condition.[10]
The serious symptoms of Reye syndrome appear to result from damage to cellular mitochondria,[13] at
least in the liver, and there is a number of ways that aspirin could cause or exacerbate mitochondrial
damage. A potential increased risk of developing Reye syndrome is one of the main reasons that aspirin
has not been recommended for use in children and teenagers, the age group for which the risk of lasting
serious effects is highest.
In some countries, oral mouthcare product Bonjela (not the form specifically designed for teething) has
labeling cautioning against its use in children, given its salicylate content. There have been no cases of
Reye syndrome following its use, and the measure is a precaution.[14] Other medications containing
salicylates are often similarly labeled as a precaution.
The Centers for Disease Control and Prevention (CDC), the U.S. Surgeon General, the American
Academy of Pediatrics (AAP) and the Food and Drug Administration (FDA) recommend that aspirin and
combination products containing aspirin not be given to children under 19 years of age during episodes
of fever-causing illnesses. Hence, in the United States, it is advised that the opinion of a doctor or
pharmacist should be obtained before anyone under 19 years of age is given any medication containing
aspirin (also known on some medicine labels as acetylsalicylate, salicylate, acetylsalicylic acid, ASA, or
salicylic acid).
Current advice in the United Kingdom by the Committee on Safety of Medicines is that aspirin should
not be given to those under the age of 16 years, unless specifically indicated in Kawasaki disease or in the
prevention of blood clot formation.[15]
Diagnosis
Differential diagnosis
Causes for similar symptoms include
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Various inborn metabolic disorders
Viral encephalitis
Drug overdose or poisoning
Head trauma
Liver failure due to other causes
Meningitis
Kidney failure
Shaken baby syndrome
Treatment
Treatment is supportive.[1] Mannitol may be used to help with the brain swelling.[2]
Prognosis
Documented cases of Reye syndrome in adults are rare. The recovery of adults with the syndrome is
generally complete, with liver and brain function returning to normal within two weeks of onset.
In children, mild to severe permanent brain damage is possible, especially in infants. Over thirty percent
of the cases reported in the United States from 1981 through 1997 resulted in fatality.
Epidemiology
Reye syndrome occurs almost exclusively in children. While a few adult cases have been reported over
the years, these cases do not typically show permanent neural or liver damage. Unlike in the United
Kingdom, the surveillance for Reye syndrome in the United States is focused on people under 18 years of
age.
In 1980, after the CDC began cautioning physicians and parents about the association between Reye
syndrome and the use of salicylates in children with chickenpox or virus-like illnesses, the incidence of
Reye syndrome in the United States began to decline, prior to the FDA's issue of warning labels on
aspirin in 1986.[10] In the United States between 1980 and 1997, the number of reported cases of Reye
syndrome decreased from 555 cases in 1980 to about two cases per year since 1994. During this time
period 93% of reported cases for which racial data were available occurred in whites and the median age
was six years. In 93% of cases a viral illness had occurred in the preceding three-week period. For the
period 1991–1994, the annual rate of hospitalizations due to Reye syndrome in the United States was
estimated to be between 0.2 and 1.1 per million population less than 18 years of age.
During the 1980s, a case-control study carried out in the United Kingdom also demonstrated an
association between Reye syndrome and aspirin exposure.[16] In June 1986, the United Kingdom
Committee on Safety of Medicines issued warnings against the use of aspirin in children under 12 years
of age and warning labels on aspirin-containing medications were introduced. United Kingdom
surveillance for Reye syndrome documented a decline in the incidence of the illness after 1986. The
reported incidence rate of Reye syndrome decreased from a high of 0.63 per 100,000 population less
than 12 years of age in 1983–1984 to 0.11 in 1990–1991.
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From November 1995 to November 1996 in France, a national survey of pediatric departments for
children under 15 years of age with unexplained encephalopathy and a threefold (or greater) increase in
serum aminotransferase and/or ammonia led to the identification of nine definite cases of Reye
syndrome (0.79 cases per million children). Eight of the nine children with Reye syndrome were found
to have been exposed to aspirin. In part because of this survey result, the French Medicines Agency
reinforced the international attention to the relationship between aspirin and Reye syndrome by issuing
its own public and professional warnings about this relationship.[17]
History
The syndrome is named after Douglas Reye, who, along with fellow physicians Graeme Morgan and Jim
Baral, published the first study of the syndrome in 1963 in The Lancet.[18] In retrospect, the occurrence
of the syndrome may have first been reported in 1929. Also in 1964, George Johnson and colleagues
published an investigation of an outbreak of influenza B that described 16 children who developed
neurological problems, four of whom had a profile remarkably similar to Reye syndrome. Some
investigators refer to this disorder as Reye-Johnson syndrome, although it is more commonly called
Reye syndrome. In 1979, Karen Starko and colleagues conducted a case-control study in Phoenix,
Arizona, and found the first statistically-significant link between aspirin use and Reye syndrome.[19]
Studies in Ohio and Michigan soon confirmed her findings[20] pointing to the use of aspirin during an
upper respiratory tract or chickenpox infection as a possible trigger of the syndrome. Beginning in 1980,
the CDC cautioned physicians and parents about the association between Reye syndrome and the use of
salicylates in children and teenagers with chickenpox or virus-like illnesses. In 1982 the U.S. Surgeon
General issued an advisory, and in 1986 the Food and Drug Administration required a Reye syndromerelated warning label for all aspirin-containing medications.[21]
References
1. "NINDS Reye's Syndrome Information Page" (https://web.archive.org/web/20160801041308/http://w
ww.ninds.nih.gov/disorders/reyes_syndrome/reyes_syndrome.htm). NINDS. September 25, 2009.
Archived from the original (http://www.ninds.nih.gov/disorders/reyes_syndrome/reyes_syndrome.ht
m) on August 1, 2016. Retrieved August 8, 2016.
2. Pugliese, A; Beltramo, T; Torre, D (October 2008). "Reye's and Reye's-like syndromes". Cell
Biochemistry and Function. 26 (7): 741–6. doi:10.1002/cbf.1465 (https://doi.org/10.1002%2Fcbf.146
5). PMID 18711704 (https://pubmed.ncbi.nlm.nih.gov/18711704). S2CID 22361194 (https://api.sema
nticscholar.org/CorpusID:22361194).
3. Schrör, K (2007). "Aspirin and Reye syndrome: a review of the evidence". Paediatric Drugs. 9 (3):
195–204. doi:10.2165/00148581-200709030-00008 (https://doi.org/10.2165%2F00148581-2007090
30-00008). PMID 17523700 (https://pubmed.ncbi.nlm.nih.gov/17523700). S2CID 58727745 (https://a
pi.semanticscholar.org/CorpusID:58727745).
4. McMillan, Julia A.; Feigin, Ralph D.; DeAngelis, Catherine; Jones, M. Douglas (2006). Oski's
Pediatrics: Principles & Practice (https://books.google.com/books?id=VbjFQiz8aR0C&pg=PA2306).
Philadelphia: Lippincott Williams & Wilkins. p. 2306. ISBN 9780781738941. Archived (https://web.arc
hive.org/web/20160815193822/https://books.google.ca/books?id=VbjFQiz8aR0C&pg=PA2306) from
the original on August 15, 2016.
5. Knight, J. (2009). "Reye's Syndrome" (https://web.archive.org/web/20130522211538/http://www.healt
hychild.net/TheMedicineChest.php?article_id=491). Healthy Child Care. 12 (4). Archived from the
original (http://www.healthychild.net/TheMedicineChest.php?article_id=491) on May 22, 2013.
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6. Boldt, D.W. (February 2003). "Reye Syndrome" (http://www.hawaii.edu/medicine/pediatrics/pedtext/s
18c17.html). University of Hawaii John A. Burns School of Medicine. Archived (https://web.archive.or
g/web/20130306163225/http://www.hawaii.edu/medicine/pediatrics/pedtext/s18c17.html) from the
original on March 6, 2013.
7. "What is Reye's Syndrome?" (http://www.reyessyndrome.org/facts.html). National Reye's Syndrome
Foundation. 1974. Archived (https://web.archive.org/web/20130511040842/http://www.reyessyndrom
e.org/facts.html) from the original on May 11, 2013.
8. "Reye's Syndrome" (http://kidshealth.org/parent/infections/bacterial_viral/reye.html). KidsHealth.org.
Nemour Foundation. Archived (https://web.archive.org/web/20150206230220/http://kidshealth.org/pa
rent/infections/bacterial_viral/reye.html) from the original on February 6, 2015. Retrieved February 6,
2015.
9. Ku AS, Chan LT (April 1999). "The first case of H5N1 avian influenza infection in a human with
complications of adult respiratory distress syndrome and Reye's syndrome". Journal of Paediatrics
and Child Health. 35 (2): 207–9. doi:10.1046/j.1440-1754.1999.t01-1-00329.x (https://doi.org/10.104
6%2Fj.1440-1754.1999.t01-1-00329.x). PMID 10365363 (https://pubmed.ncbi.nlm.nih.gov/1036536
3). S2CID 7985883 (https://api.semanticscholar.org/CorpusID:7985883).
10. Orlowski JP, Hanhan UA, Fiallos MR (2002). "Is aspirin a cause of Reye's syndrome? A case
against". Drug Safety. 25 (4): 225–31. doi:10.2165/00002018-200225040-00001 (https://doi.org/10.2
165%2F00002018-200225040-00001). PMID 11994026
(https://pubmed.ncbi.nlm.nih.gov/11994026). S2CID 20552758 (https://api.semanticscholar.org/Corp
usID:20552758).
11. Orlowski JP (August 1999). "Whatever happened to Reye's syndrome? Did it ever really exist?".
Critical Care Medicine. 27 (8): 1582–7. doi:10.1097/00003246-199908000-00032 (https://doi.org/10.
1097%2F00003246-199908000-00032). PMID 10470768 (https://pubmed.ncbi.nlm.nih.gov/1047076
8).
12. Hurwitz, E. S. (1989). "Reye's syndrome". Epidemiologic Reviews. 11: 249–253.
doi:10.1093/oxfordjournals.epirev.a036043 (https://doi.org/10.1093%2Foxfordjournals.epirev.a03604
3). PMID 2680560 (https://pubmed.ncbi.nlm.nih.gov/2680560).
13. Gosalakkal JA, Kamoji V (September 2008). "Reye syndrome and reye-like syndrome". Pediatric
Neurology. 39 (3): 198–200. doi:10.1016/j.pediatrneurol.2008.06.003 (https://doi.org/10.1016%2Fj.pe
diatrneurol.2008.06.003). PMID 18725066 (https://pubmed.ncbi.nlm.nih.gov/18725066).
14. "New advice on oral salicylate gels in under 16s" (https://web.archive.org/web/20090426205906/htt
p://www.mhra.gov.uk/NewsCentre/Pressreleases/CON044014) (Press release). Medicines and
Healthcare products Regulatory Agency. April 23, 2009. Archived from the original (http://www.mhra.
gov.uk/NewsCentre/Pressreleases/CON044014) on April 26, 2009. Retrieved May 1, 2009.
15. "2.9 Antiplatelet drugs". British National Formulary for Children. British Medical Association and
Royal Pharmaceutical Society of Great Britain. 2007. p. 151.
16. Hall SM, Plaster PA, Glasgow JF, Hancock P (1988). "Preadmission antipyretics in Reye's
syndrome" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1779086). Arch. Dis. Child. 63 (7): 857–
66. doi:10.1136/adc.63.7.857 (https://doi.org/10.1136%2Fadc.63.7.857). PMC 1779086 (https://www.
ncbi.nlm.nih.gov/pmc/articles/PMC1779086). PMID 3415311 (https://pubmed.ncbi.nlm.nih.gov/34153
11).
17. Autret-Leca E, Jonville-Béra AP, Llau ME, et al. (2001). "Incidence of Reye's syndrome in France: a
hospital-based survey". Journal of Clinical Epidemiology. 54 (8): 857–62. doi:10.1016/S08954356(00)00366-8 (https://doi.org/10.1016%2FS0895-4356%2800%2900366-8). PMID 11470397 (htt
ps://pubmed.ncbi.nlm.nih.gov/11470397).
18. Reye RD, Morgan G, Baral J (1963). "Encephalopathy and fatty degeneration of the viscera. A
Disease entity in childhood". Lancet. 2 (7311): 749–52. doi:10.1016/S0140-6736(63)90554-3 (https://
doi.org/10.1016%2FS0140-6736%2863%2990554-3). PMID 14055046 (https://pubmed.ncbi.nlm.nih.
gov/14055046).
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19. Starko KM, Ray CG, Dominguez LB, Stromberg WL, Woodall DF (December 1980). "Reye's
syndrome and salicylate use". Pediatrics. 66 (6): 859–864. PMID 7454476 (https://pubmed.ncbi.nlm.
nih.gov/7454476).
20. Mortimor, Edward A. Jr.; et al. (June 1, 1980). "Reye Syndrome-Ohio, Michigan" (http://pediatrics.aap
publications.org/cgi/content/abstract/69/6/810). Morbidity and Mortality Weekly Report. 69 (29): 532,
810–2. PMID 7079050 (https://pubmed.ncbi.nlm.nih.gov/7079050). Archived (https://web.archive.org/
web/20080611051716/http://pediatrics.aappublications.org/cgi/content/abstract/69/6/810) from the
original on June 11, 2008.
21. "Aspirin Labels to Warn About Reye Syndrome" (https://www.nytimes.com/1986/03/08/us/aspirin-lab
els-to-warn-about-reye-syndrome.html). The New York Times. Associated Press. March 8, 1986.
Archived (https://web.archive.org/web/20160305064153/http://www.nytimes.com/1986/03/08/us/aspir
in-labels-to-warn-about-reye-syndrome.html) from the original on March 5, 2016.
External links
NINDS Reye's Syndrome Information Page (http://www.ninds.nih.gov/disorders/reyes_syndrome/rey
es_syndrome.htm)
Classification ICD-10: G93.7 (htt D
ps://icd.who.int/bro
wse10/2019/en#/G
93.7) · ICD-9-CM:
331.81 (http://www.i
cd9data.com/getIC
D9Code.ashx?icd9
=331.81) · MeSH:
D012202 (https://w
ww.nlm.nih.gov/cgi/
mesh/2015/MB_cg
i?field=uid&term=D
012202) ·
DiseasesDB:
11463 (http://www.d
iseasesdatabase.co
m/ddb11463.htm) ·
SNOMED CT:
74351001 (http://sn
omed.info/id/74351
001)
External
resources
https://en.wikipedia.org/wiki/Reye_syndrome
MedlinePlus:
001565 (https://ww
w.nlm.nih.gov/medli
neplus/ency/article/
001565.htm) ·
eMedicine:
emerg/399 (https://
emedicine.medscap
e.com/emerg/399-o
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verview) · Patient
UK: Reye
syndrome (https://p
atient.info/doctor/re
yes-syndrome) ·
Orphanet: 3096 (htt
ps://www.orpha.net/
consor/cgi-bin/OC_
Exp.php?lng=en&E
xpert=3096)
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