REYE’S SYNDROME

dr. Saptino Miro, SpPD-KGEH-FINASIM

 DEFINITIO
N
• is characterized by acute noninflammatory
encephalopathy and fatty degenerative
liver failure.
 DEFINITIO
• is a post infectiousN
triad consisting of
- Encephalopathy
- fatty liver degeneration
- transaminase elevation
• the most common secondary mitochondrial
hepatopathy
 Epidemiolog
• y
This disorder is rare.
• Age: Peak incidence is at about 6 year of age, with
most cases in the 4-12 year of age range
• Seasonal relation with influenza and varicella
outbreaks
• Case fatality rate: 25% to 50%
 PATHOPHYSIOLOG
A.
Y
Acute Encephalopathy

– Generalized brain
dysfunction

B. Fatty tissue infiltration

– Liver most prominent

– Other organs also effected

 Patholog
A. Hepatic changes
y
B. Cerebral
changes

C. Renal changes
 E tiology
• Reye syndrome is precipitated
in
–genetically susceptible individuals
–by the interaction of
• viral infection (influenza, varicella)
• salicylate use
 Other
1. Acetaminophen, agents
2. outdated tetracycline
3. valproic acid
4. Warfarin
5. zidovudine . didanosine,
6. some neoplastic drugs have been associated with Reye syndrome or Reye-like
syndrome.
7. Nonsteroidal anti-inflammatory drugs, including sodium diclofenac and mefenamic acid
8. association with antiemetics, such as phenothiazines
9. association with acetaminophen was reported but has been refuted.
 Other
• agents
Reye syndrome or Reye-like syndrome may also be associated
with
1. insecticides;
2. herbicides;
3. aflatoxins;
4. isopropyl alcohol;
5. paint; paint thinner; margosa (neem) oil;
6. hepatotoxic mushrooms;
 Signs/Symptom
• Biphasic course: s
– Prodromal febrile illness with resolution of symptoms
• Within 5–7 days, there is development of abrupt onset of protracted
vomiting and neurologic impairment.
– Marked behavioral changes including delirium,combativeness, disorientation,
and hallucination may occur.
• These typically develop in a child who was otherwise healthy prior to the
viral illness.
 Clinical
features

0d 3d 2d

Profuse vomiting encephalopathy

mild febrile
recovered
viral illness
 Signs/Symptom
• s
Mimics viral illnesses
– Hard to diagnose
1. Persistent/recurrent vomiting
2. Listlessness
3. Personality changes (Irritability or
combative)
4. Disorientation or confusion
5. Delirium
6. Convulsions
7. Loss of consciousness
 Clinical
features
• Lethargy is typically the first
neurologic manifestation.
• Irritability, restlessness, delirium, seizures,
and coma occur.
 Clinical
features
• Neurologic symptoms:
• They can rapidly progress to seizures (30%), coma, and death.

• There are no focal neurological signs

or features indicating meningeal
irritation.
 Clinical
features
• Diarrhea and hyperventilation may be the
first signs in children younger than 2 years.
 Physical
Examination
1. protracted vomiting, with or without clinically
significant dehydration
2. hepatomegaly in 50%
3. minimal or absent jaundice
4. lethargy progressing to encephalopathy, obtundation,
coma, seizures, and paralysis.
 Stag
• e and laboratory findings consistent
Stage 0 - Alert, abnormal history
with Reye syndrome, and no clinical manifestations
• Stage 1 - Vomiting, sleepiness, and lethargy

• Stage 2 - Restlessness, irritability, combativeness, disorientation,

delirium, tachycardia, hyperventilation, dilated pupils with sluggish

response, hyperreflexia, positive Babinski sign, and appropriate
response to noxious stimuli
 Stag
• e rigidity, and inappropriate response
Stage 3 - Obtunded, comatose, decorticate
to noxious stimuli
• Stage 4 - Deep coma, decerebrate rigidity, fixed and dilated pupils, loss
of oculovestibular reflexes, and dysconjugate gaze with caloric
stimulation
• Stage 5 - Seizures, flaccid paralysis, absent deep tendon reflexes (DTRs),
no pupillary response, and respiratory arrest
• Stage 6 - Patients who cannot be classified because they have been treated
 Clinical Staging of Reye’s
Grade Syndrome
Symptoms at Time of Admission
I Usually quiet, lethargicand sleepy, vomiting, laboratory evidence of liver dysfunction
II Deep lethargy, confusion,delirium, combative, hyperventilation, hyperreflexic
III Obtunded, light coma,seizures, decorticate rigidity, intact pupillary light reaction
IV
Seizures, deepening coma, decerebrate rigidity,loss of oculocephalic reflexes,
fixed pupils
V
Coma, loss of deep tendon reflexes, respiratory arrest, fixed dilated
pupils, flaccidity/decerebrate intermittent isoelectric
electroencephalogram
 Diagnostic
• The CDC developed the criteria
following diagnostic criteria for Reye syndrome :

I. Acute noninflammatory encephalopathy with an altered level of

consciousness
Hepatic dysfunction with a liver biopsy showing fatty metamorphosis without inflammation or
II. necrosis or a greater than 3-fold increase in alanine aminotransferase (ALT), aspartate
aminotransferase (AST), or ammonia levels

III.No other explanation for cerebral edema or hepatic

abnormality
Cerebrospinal fluid (CSF) with a white blood cell (WBC) count of 8 cells/µL or fewer (usually
IV. lymphocytes); note that lumbar puncture should not be performed in patients who are
hemodynamically unstable and/or those in whom increased intracranial pressure (ICP) is a

V. concern
Brain biopsy with findings of cerebral edema without inflammation or
necrosis
 Complication
s
1. Brain herniation, status epilepticus, syndrome of inappropriate secretion of antidiuretic hormone
(SIADH), and diabetes insipidus
2. Acute respiratory failure and aspiration pneumonia
3. Cardiac arrhythmias
4. Myocardial infarction
5. Cardiovascular collapse
6. Gastrointestinal bleeding and pancreatitis
7. Acute renal failure
8. Sepsis
9. Death
 DIFFERENTIAL
A. Metabolic DIAGNOSIS
disease
I. Organic
acidurias
II. Disorders of oxidative
phosphorylation
Urea cycle defects (carbamoyl phosphate synthetase, ornithine
III. transcarbamylase).
Defects in fatty acid oxidation
IV. metabolism
Acyl-CoA dehydrogenase deficiencies
V.
Systemic carnitine deficiency
VI.
Hepatic carnitine palmitoyltransferase deficiency
VII
3-OH, 3-methylglutaryl-CoA lyase deficiency
.
Fructosemi
VIII a
.
 DIFFERENTIAL
DIAGNOSIS
B. Central nervous system infections or
intoxications
I.
Meningitis
Encephalitis
II.
III. toxic encephalopathy
IV. Hepatic encephalopathy of any cause

C. Hemorrhagic shock with

encephalopathy
 DIFFERENTIAL
DIAGNOSIS
D. Drug and toxin
ingestion
I. Salicylate
cyanide,amiodarone, chloramphenicol, iron, antimycin A, the emetic toxin of Bacillus cereus, and
nucleoside analogs
III.
Valproate
Nucleoside analogs directly inhibit mitochondrial respiratory chain complexes.
IV. Fialuridine
reverse transcriptase inhibitors zidovudine, didanosine, stavudine, and zalcitabine used to treat HIV-
V. infected patients inhibit DNA polymerase-γ of mitochondria and can block elongation of mtDNA, leading to
mtDNA depletion

E. Jamaican vomiting
 Diagnosis Of Reye
Syndrome
• With the recognition that Reye syndrome is
rare,
• should be considered in the differential
diagnosis in any child with vomiting and altered
mental status and classic laboratory findings.
• A high index of suspicion is essential
 Diagnosis Of Reye
Syndrome
• no test is specific for Reye syndrome,
the
diagnosis must be one of exclusion.
 Diagnosis Of Reye
Syndrome
• All children with manifestations suggestive
of
Reye syndrome should be tested for IEM
 Diagnosis Of Reye
Syndrome
• According to the Centers for Disease Control
case
definition, the following conditions must be
met for consideration as
A. Acute noninflammatory encephalopathy a Reye’s syndrome
documented
case
B.
Hepatopathy documented

No more reasonable explanation for the cerebral and hepatic

C. abnormalities
 Diagnosis Of Reye
Syndrome
A. Acute noninflammatory
encephalopathy

I.documented by:
Alteration in the level of consciousness and, if available, a record
of

II. cerebrospinal fluid containing ≤ 8 leukocytes per mm 3 or

III Histologic specimen demonstrating cerebral edema without perivascular
. or
meningeal
inflammation
 Diagnosis Of Reye
Syndrome
B. Hepatopathydocumented either
by I. Liver biopsy
or
autopsy considered to be diagnostic of Reye’s syndrome or
II. by
III. threefold or greater rise in the levels of serum aspartate
aminotransferase,serum alanine aminotransferase, or
serum
ammonia and
 Diagnosis Of Reye
Syndrome
• The most important aspect of management is
to suspect the diagnosis early,
• i.e. think Reye syndrome in any acute
encephalopathy or any child whose recovery from
varicella or a respiratory illness is interrupted by
vomiting
 Diagnosis Of Reye
• Syndrome
The diagnosis is probable
if:
A. Serum ammonia is elevated above 125-150 pg /
dL.
Serum transaminase values are 2- over 100 times
B. normal.
The prothrombin time is prolonged (unresponsive to vitamin
C. K).
D. The cerebrospinal fluid is normal.

• The diagnosis is confirmed by liver

biopsy.
 LABORATORY
• Ammonia: TESTS
– Elevated.
– Three fold or more increase may indicate progression to coma
• Enzymes:
– Elevated levels of ALT, AST, glutamate dehydrogenase, lactate dehydrogenase,and creatinine
phosphokinase,
– but with normal alkaline phosphatase enzyme activity
– The activity of the mitochondrial enzyme; serum glutamate dehydrogenase is greatly increased.
– prolongation of prothrombin time
 LABORATORY
• TESTS
Carbohydrates:
– Hypoglycemia (at presentation of about 80% of cases).(in patients <4
yr)
– Raised precursors of gluconeogenesis (pyruvate, lactate, and alanine)

• Lipids:
– Raised non-esterified fatty acids.
– Reduced cholesterol, high density, low density,and very low density lipoproteins
 LABORATORY TESTS
• Aminoacids:
– Raised alanine, glutamine, and lysine

• Serum bilirubin levels are normal (patients remain anicteric).

• Cerebrospinal fluid
– is normal or contains < 8 white blood cells per milliliter

• Rarely a liver biopsy is indicated (in infants or in recurrent

cases)
 LABORATORY
TESTS
• Workup to exclude inborn errors of
metabolism(IEMs) must be
performed
 Treatment
• INITIAL STABILIZATION/THERAPY
–Addressing issues of airway, breathing, and
circulation are paramount.

–Monitor and control for increased intracranial pressure

 Treatment
• patient should be observed in the ICU with
close monitoring of intracranial pressure and
cerebral perfusion pressure.
 Treatment
• Education: Inform parents about the
risk.
• Pre Hospital Treatment:
– ABCs
– CBG
• Especially if pt <1y/o or has an AMS
– Manage Hypoglycemia
– Transport
 Treatment
• No specific treatment exists
– Monitor patient
– Treat metabolic abnormalities
– Prevent/control cerebral edema
– Stage specific care
– Cure?
• No cure: Recovery is dependant on severity of brain
swelling
• Faster progression worse prognosis
 TREATMEN
A. T
Supportive
cerebral edema : Mannitol, glycerol, or
B. hyperventilation
Preventio
C. n I. Influenza
vaccine
Varicella
II. vaccine
Avoidance of aspirin in children, especially during influenza and
III. varicella
outbreaks
 TREATMEN
I. Monitoring T
A. Vital Sign : Pulse, respiration, blood pressure and coma
stage hourly.

B. Serum urea, electrolytes, osmolality, and glucose every 4

hr.
Urine output and ECG
C. continuously
 TREATMEN
T Therapy
II. Intravenous Fluid
– Unless dehydrated, restrict fluids .
– Use glucose 10-15% solution because
glycogen depletion is common.
– Add sodium chloride and potassium when
necessary
 TREATMEN
III. T
Coagulopathy
A. Vitamin
K
fresh
B. plasma
platelet
C. transfusion
IV. Hyperthermia
– should be
avoided
 TREATMEN
V. Intensive care T
– The above mentioned measures may suffice
in patients with stage 1 severity,

– but in more severely ill, the child must be

transferred to intensive care unit (ICU)
 TREATMENT ; Intensive
careand artificial ventilation
VI. Intubation
– It is indicated to
• permit adequate oxygenation.

• Avoid hyperventilation (because it leads to hypocarbia,

resulting in cerebral vasoconstriction, reducing the blood
flow).
 Prognosi
• s is rapid and complete.
Grade 1disease: Recovery
• More severe disease: Neuropsychologic defects may be noted
(in intelligence, school achievement, visual-motor integration,
and concept formation).
• Death: Death is usually secondary to increased
intracranial pressure and herniation.
 Mortality/Morbidity
• Mortality
• Death occurs in about 30% to 40% of cases, primarily from cerebral
edema

• Decreased from 80% in 1963 to 31% in 1983

• Increased in 1996 back up to 50% (Conflicting information)

» Due to misdiagnosis