|Year : 2021 | Volume
| Issue : 2 | Page : 146-148
Reye's syndrome, still an enigma after 50 years: Have the curtains finally been drawn?
Department of Pediatrics, Division of Pediatric Neurology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
|Date of Submission||24-Feb-2021|
|Date of Decision||28-Feb-2021|
|Date of Acceptance||11-Mar-2021|
|Date of Web Publication||31-May-2021|
Dr. Aman Elwadhi
Department of Pediatrics, Division of Pediatric Neurology, All India Institute of Medical Sciences, Rishikesh - 249 203, Uttarakhand
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Elwadhi A. Reye's syndrome, still an enigma after 50 years: Have the curtains finally been drawn?. Indian Pediatr Case Rep 2021;1:146-8
|How to cite this URL:|
Elwadhi A. Reye's syndrome, still an enigma after 50 years: Have the curtains finally been drawn?. Indian Pediatr Case Rep [serial online] 2021 [cited 2021 Jun 19];1:146-8. Available from: http://www.ipcares.org/text.asp?2021/1/2/146/317358
Despite tremendous advances in the understanding of the pathophysiology of diseases that plague humankind, a few diseases still remain poorly understood. Reye's syndrome (RS) is an exemplar of such entities. It is a rare and potentially fatal pediatric illness characterized by acute noninflammatory encephalopathy and fatty liver failure. Our quest for reviewing this condition was inspired by a case report published in Indian Pediatrics in April 1971 by Joseph and John that described three affected children from the same family. We present a brief review of RS, beginning from its discovery, to the present understanding and future prospects.
| Clinical Case Description|| |
The case report revolves around three siblings living in Nagari, Andhra Pradesh, who were sequentially admitted with acute febrile illnesses in a local hospital of repute. The first, the eldest sibling, a 10-year-old girl developed fever, headache, and seizures. On the 2nd day of illness, she was brought to the hospital in an unconscious state. Examination revealed hypertonia, a distended bladder, and dilated, nonreacting pupils. She succumbed within 2 h of admission. The very same day, the youngest sibling, a 6-year-old boy, also developed features of febrile encephalopathy but without any seizures. At admission, he had irregular breathing and was comatose and hypotonic, with dilated, nonreacting pupils. Despite supportive management, he deteriorated rapidly and expired within 30 min of hospitalization.
Both the children had similar investigation results. These included slightly elevated total leukocyte counts with a neutrophilic differential count, slightly elevated cerebrospinal fluid (CSF) cell count (7 and 13 cell/mm3 respectively), and postmortem liver histopathological findings of microvesicular fatty degeneration within preserved hepatic architecture. The same day the second issue, an 8-year-old boy also developed a fever and was immediately hospitalized. The child did not develop any neurological symptoms and had normal leukocyte counts. He remained febrile for 4 days and was discharged uneventfully on the 5th day. None of the children had any history of exposure to drugs, poisons, or chemicals. Other children, including their cousins who resided nearby and with whom they played, remained healthy.
In their discussion, the authors cite three reports of siblings with similar presentations reported from across the globe, including one from Vellore. The first article described nonlethal encephalopathy occurring 2 weeks after smallpox vaccination in a child, with severe and fatal encephalopathy developing in the elder sibling, who did not got vaccinated. The second described three siblings who developed varicella infection. Out of them, two developed encephalopathy and one expired. The third report was about two siblings who developed febrile encephalopathy without any identifiable preceding events and died within a week of each other. Joseph and John opined that the sequential and temporally close involvement observed in their case report indicated a common source epidemic that was more likely an infection than poisoning, given the varying incubation period. This was supported by the intrafamilial involvement and lack of similar presentation in the extended family and community.
| Brief Review|| |
Historical background and past knowledge
In 1954, an epidemic of febrile encephalopathy affected children of Uttar Pradesh, Bihar, and erstwhile Bengal. Common clinical features were hypoglycemia; fatty changes in the liver (found on post mortem analysis); inability to isolate any bacterial, protozoal, viral agent, or chemical poison; and high mortality. This mystery illness was named “Jamshedpur Fever” by Khan in 1954 and was probably the first report of the yet to be recognized RS.
RS was named after the Australian pathologist Ralph Douglas Kenneth Reye, who described 21 Australian children presenting with encephalopathy and fatty degeneration of viscera between 1951 and 1962. All of them exhibited anicteric firm hepatomegaly, neutrophilic leukocytosis, hypoglycemia, elevated hepatic transaminases, elevated prothrombin time, negative blood cultures, and low CSF sugar levels. The pathological hallmark was fatty degeneration of the liver and kidneys accompanied by cerebral edema without inflammatory changes. Mortality was high; out of 21 patients, 17 died.
What was known in the 70s
The national surveillance for RS was started by the Centers for Disease Control and Prevention (CDC), Atlanta, in 1973 to monitor RS during an epidemic of influenza B in America. Closer home, cases of acute encephalopathy with fatty visceral infiltration were also reported from Vellore and Chandigarh in the 1970s. In those days, RS was considered a biphasic illness that started with premonitory viral symptoms like upper respiratory tract infection, diarrhea, or the development of chickenpox, followed by encephalopathy, seizures, posturing, and irregular respiratory pattern. An infectious cause was suggested when it was noted that a few cases were occurring in siblings. The proposed etiology was an overwhelming viral infection, with superadded exposure to an unidentified toxin. Limited diagnostic modalities were available to determine underlying causes. Management was largely supportive and the outcome poor, largely due to late hospitalization.
Advances in the last 50 years
Various diagnostic criteria have been formulated for RS over the years. The most commonly used one is the CDC case definition. This requires fulfillment of the following criteria: (1) acute noninflammatory encephalopathy demonstrated clinically by an alteration of consciousness, CSF containing <8 leukocytes per mm3, or brain histology demonstrating cerebral edema without perivascular or meningeal inflammation; (2) hepatopathy demonstrated by either a liver biopsy/autopsy considered diagnostic of RS, or ≥ threefold rise in levels of Aspartate aminotransferase and Alanine aminotransferase, or serum ammonia; and (3) no other explanation for the cerebral and/or hepatic abnormalities.
It is now recognized that RS is not a single illness but a syndrome that has a seasonal variation and is due to multiple causes. Antecedent viral infection is a sine qua non. Implicated infections include influenza, varicella, measles, and that caused by coxsackie B or respiratory syncytial viruses. The postulated mechanism is that viral RNA diverts the host endoplasmic reticulum to synthesize viral proteins. This disturbs Kupffer cell function, triggering a cytokine cascade, especially tumor necrosis factor (TNF), which inhibits fatty acid oxidation. The increased levels of plasma ammonia and free fatty acids result in mitochondrial damage and fatty infiltration.
Toxins and drugs such as salicylates, paint thinner, aflatoxin, valproic acid, paracetamol, antiemetics, and insecticides can also induce RS. The association with aspirin and other salicylates has been extensively studied since the 1980s. These drugs enhance the in vitro release of TNF by macrophages and inhibit the release of the antiapoptotic nuclear factor, kappa B, causing rapid death of target cells. Aspirin metabolites inhibit the long-chain 3-hydroxyacyl-CoA dehydrogenase component of the mitochondrial trifunctional enzyme involved in β-oxidation. The characteristic neurologic features are probably due to hyperammonemia resulting from the hepatic mitochondrial dysfunction. This induces astrocyte edema, diffuse cerebral edema, and elevated intracranial pressure.
The growing body of evidence of an association between aspirin and RS led government and health agencies to issue various advisories: placement of warning labels on drug containers, avoiding aspirin in febrile children, and promotion of acetaminophen as a safer antipyretic. Following these steps, the incidence of RS fell so significantly that it was declared a “public health triumph.” However, there were arguments that favored a more complex etiology. For instance, countries such as Australia where aspirin was infrequently used continued to report cases, while countries such as France and Belgium which continued using aspirin did not.
As knowledge and diagnostic modalities have advanced over the years, many cases of RS have been reclassified and are referred to as “Reye's like syndrome.” A large proportion (148/598) of the RS surveillance data generated in the United Kingdom (1981–1996) underwent revision. Almost half of these included metabolic disorders such as medium chain acyl coenzyme A dehydrogenase deficiency, fatty acid oxidation defects, urea cycle disorders, organic aciduria, and carnitine deficiency. This led to another hypothesis emerging that of an underlying metabolic disease being triggered by unknown insults.
Timely hospitalization and intensive monitoring in RS are essential. Neurological assessment should be frequent as deterioration can be rapid. Investigations include hemogram, coagulogram, blood sugar, ammonia, hepatic enzymes, electrolytes, CSF analysis, antibodies against varicella and measles (when suspected), and a toxin screen (for salicylate, paracetamol, valproate, and organophosphate if indicated by history). A metabolic workup should include tandem mass spectrometry and gas chromatography/mass spectroscopy for amino acid and urinary organic acids, respectively. Management is supportive; consisting of maintenance of euglycemia (10% dextrose containing intravenous fluids), temperature and perfusion, correction of coagulopathy, initiation of measures to reduce cerebral edema, acidosis and hyperammonemia, and anticonvulsants where necessary. The prognosis improves with appropriate management; complete recovery, lesser probability of permanent hepatic damage, and fewer recurrence.
Incidence of RS has decreased over the last three decades, and cases are now scarce. The United States Food and Drug Administration Drug Event Reporting System and Japanese Adverse Drug Event Report databases have reported only 186 and 30 cases of RS, respectively, from 2004 to 2020. Most of these were due to the use of aspirin, 80 and 5 in America and Japan, respectively. Caregivers of children who require long-term salicylate therapy (i.e., Kawasaki disease, juvenile idiopathic arthritis, rheumatic arthritis, and thrombotic ischemic stroke) should receive customized counseling: information about the risks of influenza and varicella, and vaccination offered accordingly; recognition of symptoms of RS so that aspirin can be promptly stopped and the child hospitalized without delay.
To reiterate, the prevalence of RS varies geographically. It results from a complex interaction between a wide repertoire of known and unknown factors. Sporadic and epidemic cases should be investigated thoroughly. RS should be considered as a diagnosis of exclusion in children with acute febrile encephalopathy, or acute toxic-metabolic encephalopathy.
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Conflicts of interest
There are no conflicts of interest.
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