Acute Encephalopathy

Diagnosis and reasoning
This 4 year old girl has presented with an acute encephalopathy - a medical
emergency with potentially life threatening consequences.
She needs immediate resuscitation and stabilization, followed by close monitoring,

ideally in an intensive care setting; diagnostic evaluation can proceed in parallel
with this process.
The differential diagnosis here is wide; important etiologies to consider include

central nervous system (CNS) infections; cerebral tumors; intracranial hemorrhages
(which may be secondary to child abuse); metabolic derangements such as
hypoglycemia; electrolyte disturbances; liver or renal failure; endocrine disorders
such as diabetic ketoacidosis; sepsis; drug overdosage; and Reye or Reye-like
syndromes.
Note the history of a flu-like illness prior to the onset of symptoms; this raises
suspicion of an infectious etiology. Unfortunately though, most of the other causes
listed above can be precipitated or unmasked by an infection as well.
Note also the presence of mild hepatomegaly. This is a much more useful clue, as it
occurs in only a few of the conditions listed above: sepsis, liver failure and Reye
syndrome / Reye-like syndromes.
Her full blood count is unremarkable; while this does not completely exclude
sepsis, one would usually expect to see some form of derangement in sepsis severe
enough to cause encephalopathy.
Her liver profile brings to light some very interesting findings: marked elevation
of serum transaminases; a deranged prothrombin time; and hyperammonemia.
Very few conditions cause elevation of transaminases into the thousands - these
include acute viral hepatitis; ischemic hepatitis (shock liver); and hepatotoxicity
(including Reye's syndrome / Reye-like syndromes).
When considered alongside the clinical findings, this suggests that Reye syndrome
or a Reye-like syndrome is the most likely etiology; the hyperammonemia which is
over 1.5 times normal is supportive of this, as is the mild hypoglycemia.
One point against Reye syndrome is the presence of fever (as these individuals are
usually afebrile); however, this may be due to a coexisting infection.
Note also that while Reye syndrome is classically associated with salicylate
ingestion, it can also be precipitated by numerous other drugs - including
acetaminophen (paracetamol).
While definitive diagnosis of Reye syndrome requires a liver biopsy demonstrating

fatty changes, this should not be conducted in the acute stage, but following
stabilization; note also that the procedure is contraindicated in patients with a
coagulopathy.
Reye syndrome (and Reye like syndromes) is managed supportively. IV glucose should
be administered to correct her hypoglycemia, while fresh frozen plasma or
cryoprecipitate should be considered to correct the coagulopathy.
Cerebral edema resulting in raised intracranial pressure (ICP) is a very real

danger in these patients; it is essential to monitor the ICP and respond to any
deleterious changes.
Antibiotics are probably not required right now (as there is no evidence of a
bacterial infection); note also that drugs should be used with caution, given her
hepatic impairment.
Discussion Reye Syndrome is a rare condition characterized by an acute non-

inflammatory encephalopathy and fatty degenerative liver failure.
The condition typically occurs following a viral illness (particularly upper

respiratory tract infections, influenza, varicella, or gastroenteritis), and is
classically associated with the use of Aspirin. Note that paracetamol can also
precipitate this disease rarely.
The incidence peaks between the ages of 4 to 12 years (with a median of 6 years);
it is rare in newborns or individuals above 18 years of age. Both genders are
equally affected; curiously, rural and suburban populations appear to be more
frequently affected than urban dwellers.
The racial distribution is 93% white and 5% African American, with the remainder
mainly being Asian, American Indian, and Native Alaskan.
The pathophysiology involves generalized loss of mitochondrial function leading to

disturbances in fatty acid and carnitine metabolism. Hence, this entity is also
described as a mitochondrial hepatopathy.
'Classical' Reye syndrome has a biphasic course; a prodromal viral illness is

succeeded by pernicious vomiting of abrupt onset, after a symptom free interval of
1 to 7 days.
Subsequently, the vomiting is followed by delirium, stupor and an altered sensorium

(which may be as severe as a coma with generalised convulsions).
The clinical spectrum of the syndrome ranges from mild to fatal, lethargy to coma,
and hyperventilation to respiratory arrest.
Certain inherited errors of metabolism (IEM) may present with a clinical picture
very similar to Reye syndrome; these are called Reye-like diseases. These include
fatty acid oxidation disorders, organic acidurias, disorders of oxidative
phosphorylation, urea cycle disease, disorders of carbohydrate metabolism etc. The
distinction between true Reye Syndrome and IEM is often unclear.
The most common classification for the disease was devised by Lovejoy and is based
on clinical symptoms; the condition is categorized into 5 grades, ranging from
grade I to grade V.
Note that the centers for disease control (CDC) has an alternative classification
with 7 stages, from stage 0 to stage 6.
On examination, the liver may be enlarged but jaundice is characteristically

absent. Focal neurologic signs are usually not seen.
The diagnosis is usually based on clinical suspicion aided by lab findings. However
it is of utmost importance to exclude Reye-like conditions by performing specific
investigations.
A liver profile classically shows elevations of AST/ ALT greater than 3-fold,
prolonged PT and aPTT times, and elevation of serum ammonia over 1.5 times normal.
Elevation of lipase and amylase levels, blood urea nitrogen (BUN) and creatinine
levels, and free fatty acid and amino acid (eg, glutamine, alanine, and lysine)
levels may be seen.
Lactic dehydrogenase (LDH), serum bilirubin and alkaline phosphatase levels may be
high, normal or low.
Hypoglycemia is usually present, although blood glucose levels can be normal.
CSF analysis typically shows an elevated CSF pressure with low glucose and a WBC
count which does not exceed 8 cells/mm3.
Liver biopsy helps in the diagnosis and in ruling out metabolic or toxic liver
disease, but should only be performed when the patient is stable.
There is no specific treatment for Reye Syndrome; the management revolves around
supportive care, with special attention towards early detection and treatment of
complications.
In patients with relatively mild disease with no significant abnormalities (i.e.

grade 1 disease), close observation alone may be sufficient.
Where derangements are present, correction of fluid and electrolyte abnormalities,

correction of hypoglycemia, maintenance of serum albumin, pH and urine output in
normal ranges, and close monitoring of vital signs and laboratory values should be
performed.
Ondansetron may be administered to relieve the vomiting (which is central in

origin); antacids may be considered for gastrointestinal (GI) protection.
While the food and drug administration (FDA) has not approved a specific medication
for treatment of hyperammonemia in Reye Syndrome, note that sodium phenylacetate–
sodium benzoate is FDA-approved for treatment of acute hyperammonemia and
associated encephalopathy in patients with deficiencies in enzymes of the urea
cycle.
If a coagulopathy is present, it should be treated with fresh frozen plasma (FFP),

cryoprecipitate, platelets, vitamin K, and where necessary, exchange transfusion.
In severe disease, endotracheal intubation may be required to maintain the airway,

control ventilation, and prevent increased ICP.
The most lethal complication of Reye Syndrome is elevated ICP secondary to cerebral
edema; continuous monitoring of ICP, central venous pressure, arterial pressure, or
end-tidal carbon dioxide is essential. The ICP should be maintained to less than 20
mmHg and cerebral perfusion pressure to greater than 50 mmHg.
In patients with cerebral edema, the head should be elevated to 30 degrees and
fluid administration should be restricted to approximately 1500 mL/m2 per day to
avoid overhydration. Furosemide should be used where fluid overload is present.
If the above measures fail, mannitol should be administered. Seizures can be

treated with phenytoin.
The other main complications include; brain herniation, status epilepticus, acute
respiratory failure, acute renal failure and cardiovascular collapse.
The duration of disordered cerebral function during the acute stage of the illness
is the best predictor of eventual outcome. Mild cases may recover rapidly and
completely whereas more severe cases may result in permanent neuropsychological
defects.
Over time, the mortality rate of Reye Syndrome has decreased from 50% to less than
20% as a result of early diagnosis, recognition of mild cases, and aggressive
therapy.
Take home messages 1. Reye syndrome is characterized by acute encephalopathy and

fatty degenerative liver failure. 2. Early diagnosis is aided by a high level of
clinical suspicion and by assessment of hepatic functions. 3. There is no specific
treatment for Reye Syndrome; supportive care is based on the clinical stage of the
syndrome. 4. It is prudent to avoid the use of Aspirin as an antipyretic in
children with influenza or varicella.
References 1. P. Singh, JS Goraya, K Gupta, K Saggar, A Ahluwalia: Magnetic

resonance imaging findings in Reye syndrome: case report and review of the
literature.: J Child Neurol. 2011 Aug;26(8):1009-14. 2. J.A. Gosalakkal, V. Kamoji.
Reye syndrome and reye-like syndrome. Pediatr Neurol. Sep 2008;39(3):198-200. 3. A.
Pugliese, T Beltramo, D Torre: Reye's and Reye's-like syndromes: Cell Biochem
Funct. 2008 Oct;26(7):741-6. 4. E.D. Belay, J.S. Bresee, R.C. Holman, A.S. Khan, A.
Shahriari, L.B. Schonberger: Reye's syndrome in the United States from 1981 through
1997: N Engl J Med, 1999;340(18):1377-1382. 5. K. Schrör. Aspirin and Reye
syndrome: a review of the evidence. Paediatr Drugs. 2007;9(3):195-204. 6. M.
C.Kamienski: Reye syndrome: Am J Nurs. 2003 Jul;103(7):54-7. 7. Review of Aspirin /
Reye’s syndrome warning statement: Medicines Evaluation Committee: Department Of
Health and Aging, Therapeutic Goods Administration: 2004. 8. W. F. Balistreri: Reye
Syndrome and “Reye-like” Diseases: Nelson Textbook of Paediatrics: 16th edition.

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Diagnosis and reasoning

She needs immediate resuscitation and stabilization, followed by close monitoring,

The differential diagnosis here is wide; important etiologies to consider include

While definitive diagnosis of Reye syndrome requires a liver biopsy demonstrating

Cerebral edema resulting in raised intracranial pressure (ICP) is a very real

Discussion Reye Syndrome is a rare condition characterized by an acute non-

The condition typically occurs following a viral illness (particularly upper

The pathophysiology involves generalized loss of mitochondrial function leading to

'Classical' Reye syndrome has a biphasic course; a prodromal viral illness is

Subsequently, the vomiting is followed by delirium, stupor and an altered sensorium

On examination, the liver may be enlarged but jaundice is characteristically

Hypoglycemia is usually present, although blood glucose levels can be normal.

In patients with relatively mild disease with no significant abnormalities (i.e.

Where derangements are present, correction of fluid and electrolyte abnormalities,

Ondansetron may be administered to relieve the vomiting (which is central in

If a coagulopathy is present, it should be treated with fresh frozen plasma (FFP),

In severe disease, endotracheal intubation may be required to maintain the airway,

If the above measures fail, mannitol should be administered. Seizures can be

Take home messages 1. Reye syndrome is characterized by acute encephalopathy and

References 1. P. Singh, JS Goraya, K Gupta, K Saggar, A Ahluwalia: Magnetic

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