Reye’s syndrome is a rapidly progressive, life—threatening acute encephalopathy, combined with liver damage and, in the classical version, caused by taking acetylsalicylic acid against the background of a viral infectious disease. Manifests with sudden vomiting, then psychomotor agitation occurs, followed by apathy, lethargy, disorientation with the transition to a coma. It is diagnosed according to clinical data, taking into account anamnesis, results of biochemical and clinical blood tests, cerebrospinal fluid examination, ultrasound of the abdominal cavity, coagulogram, puncture liver biopsy. The basis of treatment is intensive therapy of hemodynamic, coagulation, respiratory disorders and cerebral edema. The earlier treatment is started, the more hopes for a favorable outcome.
General information
Reye’s syndrome (white liver disease) is an acute rapidly progressive encephalopathy that occurs in children under the age of 16. Isolated cases are described in adults. For the first time, a full description of the syndrome clinic was given in 1963 by the Australian pathologist Reye, after which the disease began to bear his name and was recognized as an independent nosology. Initially, specialists in the field of neurology and pediatrics associated Reye’s syndrome only with cases of acute encephalopathy that occurs after taking aspirin on the background of a viral infection. Later, so-called Rhea-like diseases were described. In this regard, aspirin-associated or classic Reye’s syndrome and atypical syndrome, including Reye-like syndromes, are currently classified.
The most common syndrome occurs among children aged 5 to 14 years, regardless of the sex of the child. The incidence varies: in the UK, in children under 18, it is 0.1 cases per 100 thousand, in the USA — 1 case per 100 thousand. In the 80s, there was a significant decrease in morbidity after the introduction of restrictions on the use of aspirin in children.
Causes
The etiopathogenesis of the syndrome has not been fully investigated. The classic syndrome develops as a result of taking salicylic acid preparations as antipyretics by children who have fallen ill with acute respiratory infections and other viral infections (more often flu, chickenpox, herpes, parainfluenza). It should be emphasized that we are not talking about an overdose of salicylates, but about taking them within the recommended age dosages. Other medications, hypoglycin, valproate, bacterial endotoxins, insecticides and other substances acting as mitochondrial poisons can act as etiofactors of Reye’s-like syndromes. According to studies conducted in the UK, in 10% of cases, Reye’s syndrome was accompanied by congenital metabolic disorders (fatty acid dysmetabolism, carnitine transferase deficiency, urea cycle disorders, glycerine kinase deficiency, etc.).
The main pathogenetic substrate of Reye’s syndrome is a disorder of the functioning of mitochondria, leading to cellular apoptosis (death). Triggers of mitochondrial disorders can be various exogenous (medications and other substances) and endogenous (dysmetabolic disorders) factors. It is suggested that Reye’s syndrome occurs in children with congenital subclinical insufficiency of mitochondrial enzymes. It is known that after absorption of salicylates and other substances, their metabolites enter the liver, where they have a toxic effect on mitochondria. The result is apoptosis of hepatocytes, fatty infiltration of the liver and a violation of its detoxification function. This is accompanied by a sharp increase in the concentration of hepatic transaminases and ammonia in the blood, several times higher than normal. These metabolites have a toxic effect on cerebral tissues, leading to the development of rapidly progressive toxic encephalopathy and cerebral edema.
Morphologically, Reye’s syndrome is characterized by small-drop fatty hepatosis, which is widespread and especially manifested along the periphery of the hepatic lobules. Expressed to a milder degree, fatty dystrophy is observed in other somatic organs: the pancreas, heart muscle, epithelium of the renal tubules. Degenerative changes of neurons and astrocyte edema are noted in cerebral tissues.
Reye’s syndrome symptoms
The classic Reye’s syndrome manifests on average 3 days after a viral infection, although this period can range from 12 hours to 21 days. With chickenpox, the onset of the syndrome occurs on the 4th-5th day of the rash. A mandatory symptom is vomiting. As a rule, it is of a multiple nature. 24-48 hours after the onset of vomiting, changes in the child’s behavior are noted, ranging from irritability and unusual excitement to lethargy and drowsiness. The child stops talking, does not want to eat and drink, contact with him is difficult. Quickly enough, the patient ceases to orient himself in the environment and in time, delirium occurs. These conditions are accompanied by hyperventilation. Then the child falls into a coma, which initially has an intermittent type and lasts no more than 3 hours, and then can last from 1-4 days to several weeks. In the last stage of the syndrome, respiratory arrest occurs.
Atypical Ray syndrome has a similar clinic, but usually debuts in the first 5 years of life. It is often formed against the background of congenital metabolic disorders. Basically, Reye’s syndrome of any type is characterized by rapid progression and leads to death without intensive treatment. In some cases, there may be a mild course and spontaneous stopping of the progression of symptoms.
Diagnostics
A pediatrician or neurologist can suspect Reye’s syndrome by identifying a history of a connection with a viral infection, taking aspirin and other sources of mitochondrial toxins, a typical clinic of the disease (vomiting with subsequent psycho-neurological disorders), an enlarged liver. A biochemical blood test with determination of the level of liver enzymes, ultrasound of the abdominal cavity, liver biopsy, and a study of the cerebrospinal fluid helps to verify Reye’s syndrome.
Blood biochemistry states an increase in AST and ALT by 3 or more times (in some cases by 20 times) with normal bilirubin content. A pathognomonic sign is a sharp increase in the level of ammonia. Hypoglycemia is observed in 40% of patients, as a rule, these are children under 5 years of age. The concentration of blood electrolytes may vary according to the degree of dehydration that develops due to vomiting and refusal to drink. In most cases, Reye’s syndrome is accompanied by a violation of the coagulation system, which is reflected in the coagulogram data. The clinical blood test remains within the normal range, sometimes there is a slight increase in white blood cells.
In order to exclude infectious pathology of the central nervous system, a lumbar puncture is performed. Examination of the cerebrospinal fluid indicates its sterility and does not reveal significant deviations in its composition, which makes it possible to exclude the infectious and inflammatory nature of encephalopathy. Ultrasound of the abdominal cavity organs determines an increase in the liver — hepatomegaly, its diffusely increased echogenicity and structural densification; similar changes in the pancreas are possible. If Reye’s syndrome cannot be established according to the above diagnostic methods, a liver biopsy is performed. Morphological examination of biopsies reveals a typical picture for the syndrome: the absence of inflammatory changes and the presence of signs of pronounced fatty degeneration.
Reye’s syndrome is a diagnosis of exclusion. Differential diagnosis is carried out with viral infections, encephalitis, meningitis, various intoxication syndromes, subarachnoid hemorrhage, etc. After recovery, children who have had the syndrome are referred to a geneticist’s consultation to exclude the presence of congenital metabolic diseases in them.
Treatment and prognosis
Suspicion of Reye’s syndrome is an indication for urgent hospitalization in the intensive care unit. Treatment is rather symptomatic and is aimed at relieving pathological processes occurring in the body and maintaining vital organs. Corticosteroids (mainly prednisone), infusions of electrolytes and vitamin K, mannitol are used to relieve brain edema. Intravenous fluid administration on the one hand is necessary for the speedy removal of ammonia and other toxic substances from the body, and on the other hand is limited due to the danger of progression of cerebral edema. Correction of circulatory disorders and hemostasis disorders is carried out. In case of respiratory disorders, tracheal intubation with hyperventilation is performed. Treatment is carried out with constant monitoring of blood pressure, blood gas composition, intracranial pressure.
Mortality at the initial stage of the syndrome is 5%, at the stage of intermittent coma — 50-60%, at the last stage — 95%. The cause of death is usually cerebral edema, less often respiratory failure, gastric bleeding due to coagulopathy, heart failure, sepsis or acute respiratory failure. If Reye’s syndrome is recognized at an early stage and appropriate therapy is immediately initiated, then we can hope for a successful outcome. Thanks to the improvement of diagnostic and treatment methods, the mortality rate was reduced from 40% recorded in the 1970s to 20% in the 1990s. The surviving children, as a rule, have a complete neuro-mental recovery.
To prevent the occurrence of the syndrome allows the refusal of the use of salicylates in children. Currently, many countries have a policy of replacing salicylates with paracetamol or ibuprofen if antipyretic therapy is necessary.