Reye’s syndrome

Reye’s Syndrome

1. REYE AND REYE-LIKE SYNDROMES Dr / Reyad Alfaky

2. DEFINITION  is characterized by acute noninflammatory encephalopathy and fatty degenerative liver failure.

3. DEFINITION is a postinfectious triad consisting of Encephalopathy fatty liver degeneration transaminase elevation the most common secondary mitochondrial hepatopathy

4. INTRODUCTION    Affects all organs Primarily the brain and liver. Multi Stage Illness Stage 0-6

5. 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.

6. 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%

7. PATHOPHYSIOLOGY    Acute Encephalopathy Generalized brain dysfunction Fatty tissue infiltration Liver most prominent Other organs also effected

8. Pathology Hepatic changes Cerebral changes Renal changes

9. 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

10. Etiology Reye syndrome is precipitated in genetically susceptible individuals by the interaction of viral infection (influenza, varicella) salicylate use

11. Other agents Acetaminophen, outdated tetracycline valproic acid Warfarin zidovudine . didanosine , some neoplastic drugs have been associated with Reye syndrome or Reye-like syndrome. Nonsteroidal anti-inflammatory drugs, including sodium diclofenac and mefenamic acid association with antiemetics , such as phenothiazines association with acetaminophen was reported but has been refuted.

12. Other agents Reye syndrome or Reye-like syndrome may also be associated with insecticides; herbicides; aflatoxins; isopropyl alcohol; paint; paint thinner; margosa (neem) oil; hepatotoxic mushrooms; 

13. IEM is suggested by recurrence of symptoms precipitating factors, including prolonged fasting changes in diet decompensation out of proportion to intercurrent illnesses failure to thrive neurologic abnormalities neurologic dysfunction family members with similar symptoms and/or unexplained infant deaths.

14. Factors that increase concern for an IEM include the following: No viral prodrome No exposure to aspirin or toxin with association to Reye syndrome Patients younger than 3 years (in particular, those younger than 1 year) Patient or family history of Reye syndrome–like illness Preexisting failure to thrive Baseline neurologic abnormalities Liver dysfunction or elevated ammonia level, particularly if elevated for longer than 1 week with or without waxing and waning

15. 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.

16. Clinical features mild febrile viral illness recovered Profuse vomiting encephalopathy 3d 0d 2d

17. Signs/Symptoms Mimics viral illnesses Hard to diagnose Persistent/recurrent vomiting Listlessness Personality changes (Irritability or combative) Disorientation or confusion Delirium Convulsions Loss of consciousness

18. Clinical features Lethargy is typically the first neurologic manifestation. Irritability, restlessness, delirium, seizures, and coma occur.  

19. 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.

20. Clinical features Diarrhea and hyperventilation may be the first signs in children younger than 2 years.

21. Physical Examination protracted vomiting, with or without clinically significant dehydration hepatomegaly in 50% minimal or absent jaundice lethargy progressing to encephalopathy, obtundation , coma, seizures, and paralysis. 

22. 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

23. 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

24. 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

25. Diagnostic criteria The CDC developed the following diagnostic criteria for Reye syndrome [7, 8] : Acute noninflammatory encephalopathy with an altered level of consciousness 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 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 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 Brain biopsy with findings of cerebral edema without inflammation or necrosis

26. Complications Brain herniation, status epilepticus, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and diabetes insipidus Acute respiratory failure and aspiration pneumonia Cardiac arrhythmias Myocardial infarction Cardiovascular collapse Gastrointestinal bleeding and pancreatitis Acute renal failure Sepsis Death

27. DIFFERENTIAL DIAGNOSIS Metabolic disease Organic acidurias Disorders of oxidative phosphorylation Urea cycle defects ( carbamoyl phosphate synthetase , ornithine transcarbamylase ). Defects in fatty acid oxidation metabolism Acyl-CoA dehydrogenase deficiencies Systemic carnitine deficiency Hepatic carnitine palmitoyltransferase deficiency 3-OH, 3-methylglutaryl-CoA lyase deficiency Fructosemia

28. DIFFERENTIAL DIAGNOSIS Central nervous system infections or intoxications Meningitis Encephalitis toxic encephalopathy Hepatic encephalopathy of any cause Hemorrhagic shock with encephalopathy

29. DIFFERENTIAL DIAGNOSIS Drug and toxin ingestion Salicylate cyanide,amiodarone , chloramphenicol , iron, antimycin A, the emetic toxin of Bacillus cereus, and nucleoside analogs Valproate Nucleoside analogs directly inhibit mitochondrial respiratory chain complexes. Fialuridine 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 Jamaican vomiting sickness

30. 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

31. Diagnosis Of Reye Syndrome no test is specific for Reye syndrome, the diagnosis must be one of exclusion.

32. Diagnosis Of Reye Syndrome All children with manifestations suggestive of Reye syndrome should be tested for IEM

33. 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 Acute noninflammatory encephalopathy documented Hepatopathy documented No more reasonable explanation for the cerebral and hepatic abnormalities

34. Diagnosis Of Reye Syndrome Acute noninflammatory encephalopathy documented by: Alteration in the level of consciousness and, if available, a record of cerebrospinal fluid containing ≤ 8 leukocytes per mm 3 or Histologic specimen demonstrating cerebral edema without perivascular or meningeal inflammation

35. Diagnosis Of Reye Syndrome Hepatopathy documented either by Liver biopsy or autopsy considered to be diagnostic of Reye’s syndrome or by threefold or greater rise in the levels of serum aspartate aminotransferase , serum alanine aminotransferase , or serum ammonia and

36. 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

37. Diagnosis Of Reye Syndrome The diagnosis is probable if: Serum ammonia is elevated above 125-150 pg / dL . Serum transaminase values are 2- over 100 times normal. The prothrombin time is prolonged (unresponsive to vitamin K). The cerebrospinal fluid is normal. The diagnosis is confirmed by liver biopsy.

38. 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

39. 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

40. 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)

41. LABORATORY TESTS Workup to exclude  inborn errors of metabolism (IEMs) must be performed 

42. Treatment INITIAL STABILIZATION/THERAPY Addressing issues of airway, breathing, and circulation are paramount. Monitor and control for increased intracranial pressure

43. Treatment patient should be observed in the ICU with close monitoring of intracranial pressure and cerebral perfusion pressure.

44. Treatment Education: Inform parents about the risk. Pre Hospital Treatment: ABCs CBG Especially if pt <1y/o or has an AMS Manage Hypoglycemia Transport

45. 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

46. TREATMENT Supportive cerebral edema : Mannitol, glycerol, or hyperventilation Prevention Influenza vaccine Varicella vaccine Avoidance of aspirin in children, especially during influenza and varicella outbreaks

47. TREATMENT Monitoring Vital Sign : Pulse, respiration, blood pressure and coma stage hourly. Serum urea, electrolytes, osmolality , and glucose every 4 hr. Urine output and ECG continuously

48. TREATMENT Intravenous Fluid Therapy Unless dehydrated, restrict fluids . Use glucose 10-15% solution because glycogen depletion is common. Add sodium chloride and potassium when necessary

49. TREATMENT Coagulopathy Vitamin K fresh plasma platelet transfusion Hyperthermia should be avoided

50. TREATMENT 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)

51. TREATMENT ; Intensive care 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).

52. TREATMENT ; Intracranial pressure (ICP) 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.

53. TREATMENT Intracranial pressure (ICP) Abnormal levels can be managed by Controlled ventillation . Avoidance of painful stimuli, physiotherapy, and tracheal suction. 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. Pancuronium bromide 0.1 mg/ kg to decrease cerebral blood volume through muscular relaxation and increased peripheral blood pooling, Fluid restriction. , Cooling the body to 3 1°C by ice packs that may reduce cerebral O2 requirement

54. TREATMENT Intracranial pressure (ICP) If these measures fail to maintain normal ICP and CPP: Dexamethasone 0.2 mg/ kg/ 6 hr. Cerebral decompression by bifrontal craniotomy.

55. 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 .

56. 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

57. Mortality/Morbidity Death Usually caused by ICP Other Causes: Myocardial Dysfunction Cardiovascular collapse Respiratory failure Renal failure GI bleeding Status epilepticus Sepsis

58. Increased risk of mortality Age younger than 5 years, with a relative risk of 1.8 (95% CI, 1.5-2.1) 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 Central venous pressure (CVP) less than 6 mm H 20 Ammonia level greater than 45 µg/ dL (26 µ mol /L), with a relative risk of 3.4 (95% CI, 1.9-6.2) [4] Glucose value less than 60 mg/ dL Hypoproteinemia unresponsive to fresh frozen vitamin K and fresh frozen plasma (FFP) Muscle involvement

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