MED-NERD

Reye Syndrome ( Fatty Liver With Encephalopathy)

Outline:

• Overview
• Incidence
• Pathophysiology
• Causes
• Symptoms
• Diagnosis
• Differential diagnosis
• Treatment and management
• Complications
• Outcomes
• Prevention
• References

Overview:

Reye’s Syndrome or “fatty liver with encephalopathy” is a rare and fatal condition affecting mainly children and adolescents from 4 to 12 years, but may affect any age and presents with fatty liver failure and acute non-inflammatory encephalopathy following viral infection such as influenza or chickenpox or gastroenteritis and is associated with Aspirin intake. It was first defined in 1963 by an Australian pathologist R.D.K. who described 21 cases, and later by GM Johnson in the United states which announced Reye syndrome as a reportable disease in 1973.

Incidence:

Age:

-The peak incidence occurs from 5 to 14 years old although some cases have been reported in young adult and others in children less than one year.

Sex:

Occurs equally in both males and females.

Seasonal:

Most cases occur from December to April which is related to the incidence of respiratory viral infections.

Socioeconomically:

Children from rural and sub-urban areas usually are affected more than children from urban areas.

Racial:

About 5% of African American, 93% of white American, and the rest are American Indian, Asian, Native Alaskan. Nearly 12% White American and 67% African American of children less than one yea.

Before 1970s in the United States, cases of Reye syndrome were reported as encephalitis or drug intoxication. The peak annual incidence of 555 cases reported to the Centers for Disease Control and Prevention (CDC) was from 1979-1980

From the late 1980s, the incidence in the United States has decreased massively due to increased public awareness about the disease and the potential risk of using aspirin in children and early diagnosis of condition.

Studies have shown that there is a strong relation between Reye Syndrome and Salicylate intake especially Aspirin. Reye syndrome developed in less than 0.1% of children taking aspirin, on the other hand, more then 80% of Reye Syndrome cases were associated with aspirin intake 3 weeks before the condition developed.

Cases with previous diagnosis of Reye syndrome represent about 0.4%, and patients having a sibling with the syndrome were almost 2.9% taking into consideration that Inborn Error Metabolism (IEM) is one of the differential diagnosis of Reye syndrome.

Nowadays, only few cases are reported annually and the disease is extremely rare.

Pathophysiology:

The exact mechanism is not known yet. It is suggested that viral infection is associated with mitochondrial injury. Salicylates or aspirin may induce cellular damage to mitochondria and reduction in the activity of mitochondrial enzymes(e.g., pyruvate dehydrogenase [PDH], ornithine transcarbamylase [OTC], carbamyl phosphate synthetase [CPS]) leading to disruption of metabolism including disruptive oxidative phosphorylation and fatty-acid beta-oxidation.

Hepatic mitochondrial damage >> elevated ammonia levels (Hyperammonemia) >> astrocyte oedema >> neurologic manifestations including: diffuse cerebral oedema, loss of neurons, and elevated intracranial tension(ICT).

Causes: 

Although the exact cause is still unknown, Reye syndrome is mostly caused by viral pathogens including influenza A and B and chickenpox (varicella) viruses. According to the Centers for Disease Control and Prevention (CDC), cases of Reye syndrome between 1980 and 1997 were recorded as the following : influenza virus 73%, varicella 21%, and gastroenteritis 14%.

Less common viruses caused Reye syndrome were as the following:

Cytomegalovirus (CMV), Epstein-Barr (EBV), measles, parainfluenza, coxsackie, retrovirus, hepatitis, and adenovirus. It can also occur after receiving viral vaccines.

Moreover, the syndrome may be associated with bacterial pathogens including:

Mycoplasma, Shigella, salmonella, Chlamydia, and Bordetella pertussis.

Children and young adults infected by one of the previous pathogens and received aspirin or salicylates 2 or 3 weeks before developing the syndrome .

Symptoms:

Symptoms develop from 12 hours to 3 weeks (average, 3 days) after viral illness (mainly upper respiratory tract infection) and vomiting starts from 3 to 6 days after recovery from infection. Neurologic symptoms appear 24-48 hours after vomiting and lethargy is the first neurologic symptom to appear. In children less than 2 years, diarrhoea and hyperventilation appear first.

According to CDC that uses Hurwitz and adds stage 6 , clinical presentation of Reye syndrome pass through these stages : 

-Stage 0 (non-clinical stage): alert, no clinical manifestations, abnormal history and laboratory findings.

-Stage 1: Persistent vomiting, Confusion, increased somnolence (sleepiness), nightmares, Lethargy.

-Stage 2: Tachycardia, Hyperventilation, disorientation, Stupor, delirium, combativeness, Hyperreflexia, dilated and sluggish pupils, positive Babinski sign, inappropriate response to noxious stimuli.

-Stage 3: decorticate rigidity, coma, inappropriate response to noxious stimuli.

-Stage 4: deconjugate gaze with caloric stimuli, Pupil dilation with minimal response to light or fixed and dilated pupils, loss of oculovestibular reflexes, decerebrate rigidity and deep coma .

-Stage 5: Respiratory arrest, Flaccid paralysis, no pupillary response, absent deep tendon reflexes, seizures, death.

-Stage 6: patients receive curare or other medications that affect the level of consciousness and cannot be classified.

Diagnosis: 

There is not a specific test for Reye syndrome; however, diagnosis can be made through patient history, clinical presentation, physical, and laboratory findings to rule out other disorders.

According to CDC: 

Clinically:

-Alteration in consciousness

-Hepatomegaly and jaundice that minimally occurs with the syndrome.

-Lumbar puncture to obtain cerebrospinal fluid (CSF) showing less than or equal to 8 leukocytes/cu.mm, and it should not be performed in hemodynamically unstable patients or patients prone to increased ICT.

Laboratory tests:

-Urine and blood tests showing:

-Threefold or greater increased in the levels of the serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT) or serum ammonia.

-Hyperammonemia appears within 1 or 2 days of mental changes.

-Elevated liver function tests (alanine transaminase (ALT), aspartate transaminase (AST), bilirubin), hyperammonemia, abnormal coagulation studies, decreased serum bicarbonate , elevated amylase, and lipase.

-Lab values consistent with dehydration.

-Hypoglycaemia

Histopathologic findings:

-Liver biopsy or an autopsy to show histopathologic changes, (abnormal accumulation of triglycerides), performed mainly in children less than 2 years to rule out metabolic of toxic liver disorder.

-Histologic specimen showing cerebral oedema without inflammation.

-Fatty degeneration of the proximal lobules in the kidneys. 

-Pleomorphic, swollen mitochondria that are reduced in number, in all cells in addition to glycogen depletion and minimal tissue inflammation.

Others:

-CT or MRI to exclude other causes of encephalopathy( MRI show symmetric thalamic, white matter and basal ganglia lesions)

-Skin biopsy may be used.

-Electroencephalography (EEG) may show slow-wave activity in the early stages and flattened waves in advanced stages.

Differential diagnosis: 

-Inborn errors of metabolism (IEM) induce Reye-like syndrome similar to Reye syndrome, these disorders include: abnormalities in fatty acid metabolism and disorders of oxidative phosphorylation , urea cycle disorders (UCDs), organic acidurias, disorders of carbohydrate metabolism, long-chain acyl dehydrogenase deficiency, and inherited metabolic disorders (e.g., medium-chain acyl-CoA dehydrogenase deficiency (MCADD)).

- Other drug toxicities: warfarin, valproic acid, Acetaminophen, zidovudine didanosine, outdated tetracycline, some neoplastic drugs, Nonsteroidal anti-inflammatory drugs (e.g., sodium diclofenac and mefenamic acid), antiemetics(e.g., phenothiazines), and acetaminophen may have synergistic effect with salicylates.

-Insecticides, paint thinner, margosa (neem) oil, aflatoxins, herbicides, alcohol, hepatotoxic mushrooms, hypoglycin in ackee fruit (Jamaican vomiting sickness), isopropyl, and herbal medications with atractyloside.

-Hypoglycemia

-Encephalitis, Meningitis

-Lead and other heavy metal toxicities

-Intracranial bleeding

-Hepatic illnesses, neuromuscular diseases, 

-Obtundation (reduced level of consciousness) due to intussusception.

Treatment and management:

Reye syndrome is an emergency due to rapid progression. In general, the treatment is supportive aims to reach hemodynamic stability. Grade I severity may be managed by close observation while advanced stages require immediate treatment. Treatment may include: 

-Ventilation and airway intubation.

-Placement of a Foley catheter to monitor urine output. 

-Phenylacetate-sodium benzoate to treat hyperammonemia.

-Intravenous fluids: dextrose-containing fluids (D50, D10, D5, etc) with a serum glucose goal of 100-120mg/dl to treat hypoglycaemia.

-Sodium bicarbonate to treat acidosis.

-Vitamin K, cryoprecipitate, or frozen plasma (FFP) to treat coagulopathy.

-Cooling blanket or other methods to manage abnormally elevated body temperature (hyperthermia) to prevent increased cerebral metabolism and rigors.

-Diuretics to reduce swelling in the brain

Management of increased ICT:

-ICP monitoring

-Elevating the head of the bed to 30 degrees

-Lasix administration

-Sedation and analgesia

-Mannitol or hypertonic saline and Careful fluid regulation to prevent overhydration

-Seizure treatment and subsequent prophylaxis

Complications:

-Cardiovascular collapse, Myocardial infarction, Cardiac arrhythmias, Sepsis

-Cerebral herniation, Seizures, Status epilepticus, intellectual disability, defect in vision, hearing, or motor functions, poor attention span and memory, difficulties in speech and language, difficulties with concept formation, problems with everyday tasks, and difficulty swallowing.

-Aspiration pneumonia, Respiratory failure

-Gastrointestinal bleeding, Pancreatitis

-Renal failure, Diabetes insipidus

-Death

Outcomes: 

Mortality rate has dropped from 50% to about 20% over the past 4 decades. About two-thirds of patients have fully recovered. Recovery depends on the severity of the condition and is usually noticed in mild cases (e.g., Grade I severity). Advanced stages are at risk of long-term effects especially neurological problems. Comatose patients are at high risk of brain damage. Death is expected when complications occur especially cerebral oedema and increased ICT.

Prevention:

-Careful prescription of pain killers in patients suspected of having Reye syndrome.

-Children under 16 should also not take any products containing: salicylate, salicylic acid, salicylate salts, acetylsalicylate, and acetylsalicylic acid.

-If Aspirin or salicylates are required as long-term therapy, it should be given only by physicians and should be discontinued immediately after appearance of the first symptoms of Reye syndrome.

-Proper diagnosis and exclusion of IEM .

-CDC has recommended Influenza vaccine for children older than 6 months.

References:

(1) Chapman J, Arnold JK. Reye Syndrome. [Updated 2022 Jul 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. 

https://www.ncbi.nlm.nih.gov/books/NBK526101/

(2) Reye syndrome, National Health Service(NHS) ,UK.

 https://www.nhs.uk/conditions/reyes-syndrome/

(3)Online article: What is Reye's syndrome, Medically Reviewed by Amita Shroff, MD on December 01, 2020, webmed.

https://www.webmd.com/children/what-is-reye-syndrome

(4) Online article: Reye syndrome, National Organization for Rare Disorders (NORDS). https://rarediseases.org/rare-diseases/reye-syndrome/

(5) Popa SL, Chiarioni G, David L, Golea GI, Dumitrascu DL. Rare causes of emesis. Med Pharm Rep. 2020 Apr;93(2):127-132. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243886/

(6) Debra L Weiner, MD, PhD, Reye Syndrome Medication, Medscape.

https://emedicine.medscape.com/article/803683-medication

(7)D.A. Trauner, Reye Syndrome, Encyclopedia of Neuroscience, Academic Press, 2009, Pages 353-356.

https://www.sciencedirect.com/science/article/pii/B9780080450469006094