REYE AND REYE-LIKE SYNDROMES

Dr / Reyad Alfaky
 DEFINITION
• is characterized by acute noninflammatory
encephalopathy and fatty degenerative liver
failure.
 DEFINITION
• is a postinfectious triad consisting of
A. Encephalopathy
B. fatty liver degeneration
C. transaminase elevation
• the most common secondary mitochondrial hepatopathy
 INTRODUCTION
• Affects all organs

– Primarily the brain and liver.

• Multi Stage Illness

– Stage 0-6
 Hx of Reye’s Syndrome
• 1963; R.D.K. Reye described syndrome in Australia.
– Few months later G.M. Johnson described it in the US.
– Similar cases described as early as 1929.
• Occurrences
– Peaked during 1980
• 500 Cases
• >100 deaths in children
– Now <0.03-1 case per 100,000
• Peds <18y/o
• May be higher in regional viral epidemics
• <0.1% in peds with viral illness treated with ASA.
 Epidemiology
• This disorder is rare.
• Age: Peak incidence is at about 6 yr of age, with most
cases in the 4-12 yr age range
• Seasonal relation with influenza and varicella outbreaks
• Case fatality rate: 25% to 50%
 PATHOPHYSIOLOGY
A. Acute Encephalopathy

– Generalized brain dysfunction

B. Fatty tissue infiltration

– Liver most prominent

– Other organs also effected

 Pathology
A. Hepatic changes

B. Cerebral changes

C. Renal changes
 Etiology
• What causes it?
– NO ONE KNOWS?!?!?
• So where does ASA come in?
– Increases risk by 35 fold!
– 90-95% of cases in US had taken ASA during a preceding viral infection.
• Other possible causes
– Toxins
– Inborn Error of Metabolisim
– Follows Viral Illness
• Usually Chicken Pox or Influenza
 Etiology
• Reye syndrome is precipitated in
– genetically susceptible individuals
– by the interaction of
• viral infection (influenza, varicella)
• salicylate use
 Other agents
1. Acetaminophen,

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 outdated tetracycline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;
 IEM is suggested by
1. recurrence of symptoms

2. precipitating factors, including

I. prolonged fasting

II. changes in diet

3. decompensation out of proportion to intercurrent illnesses

4. failure to thrive

5. neurologic abnormalities

6. neurologic dysfunction

7. family members with similar symptoms and/or

8. unexplained infant deaths.

 Factors that increase concern for an IEM include the
following:
1. No viral prodrome

2. No exposure to aspirin or toxin with association to Reye syndrome

3. Patients younger than 3 years (in particular, those younger than 1 year)

4. Patient or family history of Reye syndrome–like illness

5. Preexisting failure to thrive

6. Baseline neurologic abnormalities

7. Liver dysfunction or elevated ammonia level, particularly if elevated for longer than 1
week with or without waxing and waning
 Signs/Symptoms
• Biphasic course:
– 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/Symptoms
• 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.
 Stage
• Stage 0 - Alert, abnormal history and laboratory findings consistent 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
 Stage
• Stage 3 - Obtunded, comatose, decorticate rigidity, and inappropriate response 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 with
curare or another medication that alters the level of consciousness
 Clinical Staging of Reye’s Syndrome
Grade 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 criteria
• The CDC developed the following diagnostic criteria for Reye syndrome [7, 8] :

I. Acute noninflammatory encephalopathy with an altered level of consciousness

II. Hepatic dysfunction with a liver biopsy showing fatty metamorphosis without inflammation or
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

IV. Cerebrospinal fluid (CSF) with a white blood cell (WBC) count of 8 cells/µL or fewer (usually
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 concern

V. Brain biopsy with findings of cerebral edema without inflammation or necrosis

 Complications
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 DIAGNOSIS
A. Metabolic disease
I. Organic acidurias
II. Disorders of oxidative phosphorylation
III. Urea cycle defects (carbamoyl phosphate synthetase, ornithine transcarbamylase).
IV. Defects in fatty acid oxidation metabolism
V. Acyl-CoA dehydrogenase deficiencies
VI. Systemic carnitine deficiency
VII. Hepatic carnitine palmitoyltransferase deficiency
VIII. 3-OH, 3-methylglutaryl-CoA lyase deficiency
IX. Fructosemia
 DIFFERENTIAL DIAGNOSIS
B. Central nervous system infections or intoxications
I. Meningitis
II. Encephalitis
III. toxic encephalopathy
IV. Hepatic encephalopathy of any cause

C. Hemorrhagic shock with encephalopathy

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

E. Jamaican vomiting sickness

 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 Reye’s syndrome case
A. Acute noninflammatory encephalopathy documented

B. Hepatopathy documented

C. No more reasonable explanation for the cerebral and hepatic abnormalities

 Diagnosis Of Reye Syndrome
A. Acute noninflammatory encephalopathy
documented by:
I. 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. Hepatopathy documented either by
I. Liver biopsy or
II. autopsy considered to be diagnostic of Reye’s syndrome or 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.
B. Serum transaminase values are 2- over 100 times normal.
C. The prothrombin time is prolonged (unresponsive to vitamin K).
D. The cerebrospinal fluid is normal.

• The diagnosis is confirmed by liver biopsy.

 LABORATORY TESTS
• Ammonia:
– 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
 TREATMENT
A. Supportive
B. cerebral edema : Mannitol, glycerol, or hyperventilation
C. Prevention
I. Influenza vaccine

II. Varicella vaccine

III. Avoidance of aspirin in children, especially during influenza and varicella

outbreaks
 TREATMENT
I. Monitoring
A. Vital Sign : Pulse, respiration, blood pressure and coma stage
hourly.

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

C. Urine output and ECG continuously
 TREATMENT
II. Intravenous Fluid Therapy
– Unless dehydrated, restrict fluids .
– Use glucose 10-15% solution because glycogen
depletion is common.

– Add sodium chloride and potassium when necessary

 TREATMENT
III. Coagulopathy

A. Vitamin K
B. fresh plasma
C. platelet transfusion
IV. Hyperthermia
– should be avoided
 TREATMENT
V. Intensive care

– 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 care
VI. Intubation and artificial ventilation
– It is indicated to
• permit adequate oxygenation.

• Avoid hyperventilation (because it leads to hypocarbia, resulting

in cerebral vasoconstriction, reducing the blood flow).
 TREATMENT ; Intracranial pressure (ICP)
VII.Intracranial pressure (ICP) monitoring
– It is performed by either a subdural transducer or through a cannula
inserted percutaneously in the presence of an open anterior fontanelle.

– Cerebral perfusion pressure (CPP) should be maintained between 50-

90 mmHg
• CPP = mean arterial pressure – ICP

• ICP should be held to less than 20 mmHg.

 TREATMENT Intracranial pressure (ICP)
• Abnormal levels can be managed by
I. Controlled ventillation.

II. Avoidance of painful stimuli, physiotherapy, and tracheal suction.

III. Pentobarbital (2.5 mg/ kg) to maintain a serum level of 20-30 |dg/ mL, decreasing cerebral blood
flow and the cerebral metabolic demands, and causing cerebral vasoconstriction.

IV. Pancuronium bromide 0.1 mg/ kg to decrease cerebral blood volume through muscular relaxation
and increased peripheral blood pooling,

V. Fluid restriction. ,

VI. Cooling the body to 3 1°C by ice packs that may reduce cerebral O2 requirement
 TREATMENT Intracranial pressure (ICP)
• If these measures fail to maintain normal ICP and

CPP:
I. Dexamethasone 0.2 mg/ kg/ 6 hr.

II. Cerebral decompression by bifrontal craniotomy.

 Prognosis
• Grade 1disease: Recovery is rapid and complete.

• 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
 Mortality/Morbidity
• Death
1. Usually caused by ICP
– Other Causes:
1. Myocardial Dysfunction
2. Cardiovascular collapse
3. Respiratory failure
4. Renal failure
5. GI bleeding
6. Status epilepticus
7. Sepsis
 Increased risk of mortality
1. Age younger than 5 years, with a relative risk of 1.8 (95% CI, 1.5-2.1)
2. Rapid progression from stage 1 to stage 3 and/or presentation with stage 4 or 5 (See Physical
Examination) - The death rate by stage at the time of admission is 18% for patients in stage 0 and
90% for those in stage 5; meaningful survival beyond stage 3 is unlikely; full recovery is possible for
patients in stages 0-2
3. Central venous pressure (CVP) less than 6 mm H 20
4. Ammonia level greater than 45 µg/dL (26 µmol/L), with a relative risk of 3.4 (95% CI, 1.9-6.2) [4]
5. Glucose value less than 60 mg/dL
6. Hypoproteinemia unresponsive to fresh frozen vitamin K and fresh frozen plasma (FFP)
7. Muscle involvement