What are the clues for an inherited metabolic disorder in Reye syndrome? A single Centre study of 58 children.

OBJECTIVES: Reye Syndrome is an acute encephalopathy with increased liver enzymes and blood ammonia, without jaundice. The prevalence of an underlying inherited metabolic disorder (IMD) is unclear, nor the clinical or biological factors directing toward this diagnosis. Our aims were to define these clues in a large series of patients. PATIENTS AND METHODS: We retrospectively studied all patients with Reye admitted in our institution from 1995. We defined 3 groups: Group 1 with a confirmed IMD, Group 2 considered as free of IMD, Group 3 unclassified. Statistical analysis compared patients in Groups 1 and 2, to find criteria for a diagnosis of IMD. RESULTS: Fifty-eight children were included; 41 (71%) had a confirmed IMD, 12 (20%) were free of IMD, and 5 remained unclassified. IMDs included Urea Cycle Disorders (51%), Fatty-Acid Oxidation Disorders (24%), ketogenesis defects (5%), other mitochondrial energy metabolism defects (10%), NBAS mutation (7%), Glycosylation Disorders (2%). In Group 2, the trigger was a viral infection, or a drug, deferasirox in three children. Univariate analysis showed that onset before 2 years-old, recurrent Reye and the association with rhabdomyolysis were significantly associated with IMD. Blood ammonia was a poor discriminating marker. All children were admitted into the intensive care unit, 23% needed continuous venovenous hemodialysis and one died from brain oedema. CONCLUSION: Metabolic tests should be performed early in all cases of Reye, regardless of triggers. As they can be inconclusive, we suggest to systematically go to Next-Generation Sequencing study. These children should be transferred early to a specialized unit.

Histopathology of acute colchicine intoxication: novel findings and their association with clinical manifestations.

A 32-year-old woman attempted suicide by ingesting Gloriosa bulbs and died approximately 2 days later. Toxicological examination revealed a potentially fatal blood concentration of colchicine (0.096 mg/L). In addition to the increased mitotic figures in the gastrointestinal mucosa, a unique finding for acute colchicine intoxication, pathological examination showed microvesicular lipid droplets in the liver, kidney, heart, and conduction system. Furthermore, central chromatolysis of neurons was observed in the pontine nucleus, medial accessory olivary nucleus, nucleus of the solitary tract, and nucleus ambiguus. Grumose degeneration of the cerebellar dentate nucleus was also evident. These pathological findings may help identify colchicine intoxication, even in the absence of evidence suggesting ingestion during autopsy. Moreover, pathological changes in the heart and central nervous system may be associated with the development of serious complications of acute colchicine intoxication.

NBAS deficiency due to biallelic c.2809C > G variant presenting with recurrent acute liver failure with severe hyperammonemia, acquired microcephaly and progressive brain atrophy.

Biallelic pathogenic variants in the neuroblastoma amplified sequence (NBAS) gene were firstly (2015) identified as a cause of fever-triggered recurrent acute liver failure (RALF). Since then, some patients with NBAS deficiency presenting with neurologic features, including a motor delay, intellectual disability, muscular hypotonia and a mild brain atrophy, have been reported. Here, we describe a case of pediatric patient diagnosed with NBAS deficiency due to a homozygous c.2809C > G, p.(Pro937Ala) variant presenting with RALF with severe hyperammonemia, acquired microcephaly and progressive brain atrophy. Not reported in the literature findings include severe hyperammonemia during ALF episode, and neurologic features in the form of acquired progressive microcephaly with brain atrophy. The latter raises the hypothesis about a primary neurologic phenotype in NBAS deficiency.

A Severe Case of Reye's Syndrome with Multiorgan Dysfunction after Epstein-Barr Virus Infection.

A 20-month-old male infant with multiorgan dysfunction after Epstein-Barr virus (EBV) infection developed Reye's syndrome. He also suffered from acute liver failure, life-threatening cerebral edema, severe disseminated intravascular coagulation (DIC), and myocardial involvement. EBV infection aggravated the progress of Reye's syndrome, leading to death despite full supportive and symptomatic therapy. This critical case suggested that pediatricians should pay attention to multiorgan involvement of severe EBV infection.

Co-ingestion of aspirin and acetaminophen promoting fulminant liver failure: A critical review of Reye syndrome in the current perspective at the dawn of the 21st century.

In the paediatric population, there is some evidence of possible interaction, synergism, and co-toxicity of aspirin and acetaminophen. The toxicity of salicylates such as aspirin in this population is well known and documented, specifically in the form of Reye syndrome. The possible toxic synergism with aspirin and acetaminophen, however, is not previously described; though case reports suggest such co-toxicities with low levels of aspirin and other compounds can exist. In vitro studies into mechanistic processes of salicylate toxicity propose that there is a bi-directional link and potentiation with glutathione (GSH) depletion and salicylate toxicity. Data may suggest a plausible explanation for salicylate and acetaminophen toxic synergism. Further studies investigating this potential toxic synergism are warranted. Given the lack of awareness in the clinical community about potential toxic synergism between these relatively common medications, caution is advised in the co-administration of these drugs, particularly in communities using natural or alternative therapy.

Resveratrol protects against experimental induced Reye's syndrome by prohibition of oxidative stress and restoration of complex I activity.

This study was designed to investigate whether resveratrol could provide protection against Reye's syndrome induced by 4-pentenoic acid in Wistar albino rats. Compared with rats with untreated Reye's syndrome, 1 h pretreatment by low dose resveratrol (10 mg/kg by oral gavage) resulted in marked amelioration in liver functions in the form of significant decrease in serum transaminases (AST, ALT) and plasma ammonia levels, shortening of prothrombin time, and increase in serum albumin levels. In addition, resveratrol prohibited oxidative stress markers, as indicated by a significant increase in GSH and decrease in MDA, with restoration of complex I activity in liver tissues. The classical histopathological presentation in Reye's syndrome of microvesicular steatosis by light microscope and mitochondria distortion by electron microscope has been improved by resveratrol pretreatment. The efficient protection by resveratrol was determined by normalization in serum levels of AST and albumin, as well as complex I activity, GSH, and MDA. In conclusion, pretreatment by resveratrol in low doses could protect against Reye's syndrome partially via prohibition of oxidative stress and restoration of complex I activity. This may provide the opportunity to reconsider aspirin therapy for infants and young children. However, the verification of such results in clinical practice remains a challenge.

A Case Report on Acute Fatty Liver of Pregnancy: A Difficult Differential Diagnosis of Liver Disorder.

Acute fatty liver of pregnancy is a rare but potentially dangerous pregnancy condition with significant maternal and fetal fatality rates. The disorder is driven by a complex pathophysiology and clinically manifests as a rapid worsening in health conditions, increasing the rate of mortality and necessitating expert diagnosis and management. The condition progresses from spontaneous resolution to post-operative complications, resulting in negative consequences. We offer a case report of a young primigravida patient diagnosed with acute fatty liver of pregnancy at term. The report describes the clinical course and its effect. The perinatal result, however, could not be improved due to the late diagnosis. Over the last 40 years, death rates have been dramatically lowered because of competence and a multidisciplinary approach, increasing maternal-fetal outcomes. In this scenario, time management is crucial to success.

Pathological findings of liver steatosis that is difficult to evaluate with ultrasound.

Although new ultrasound (US) methods able to quantitatively assess liver fat content have been recently developed, B-mode US is still the major method for detecting liver steatosis during medical checkups. However, some pathological cases yield false-positive or false-negative liver steatosis results using B-mode US. In addition, histologically, the degree of fat deposits and the size of fat droplets in the liver can affect the sensitivity and specificity of the diagnosis of liver steatosis using B-mode US. As B-mode US evaluation of fatty liver relies on operator expertise, the operator should be aware that there are some cases of liver steatosis that are difficult to evaluate with B-mode US. Here, we describe the pathological findings of liver steatosis that is difficult to evaluate with US.

Case Report: MIS-C Temporarily Associated With COVID-19 Complicated by Reye's Syndrome.

We describe a 7-year-old child with multisystemic inflammatory syndrome that was temporarily associated with the novel coronavirus disease which evolved into serious illness, with coronary aneurysm, using human immunoglobulin and acetylsalicylic acid, in which clinical manifestations including hepatitis, convulsions, and coma were aggravated with Reye's syndrome. To date, there has been no report of the association of multisystemic inflammatory syndrome that is temporarily associated with the novel coronavirus disease and Reye's syndrome.

A rare case of Reye's syndrome induced by influenza A virus with use of ibuprofen in an adult.

BACKGROUND: Reye's syndrome (RS) is a rare but severe acute life-threating disease characterized by encephalopathy and fatty liver damage. Reye's syndrome is most common in children and rarely occurs in adults. CASE PRESENTATION: A 56-year-old woman was admitted to the emergency department with disturbance of consciousness and respiratory failure. She had taken ibuprofen for headache. Her Glasgow Coma Scale score was E3V3M5 on admission. The laboratory findings revealed acute liver failure with prothrombin time - international normalized ratio of 3.16, aspartate aminotransferase 12,548 IU/L, alanine aminotransferase 5,725 IU/L, and blood ammonia 102 µg/dL. Head magnetic resonance imaging showed hyperintense signals on diffusion-weighed images of globus pallidus.We diagnosed the patient with RS induced by influenza A and use of ibuprofen. The patient received supportive care in the intensive care unit and her clinical outcome was favorable. CONCLUSION: Ibuprofen might be a risk factor for RS.

Rare causes of emesis.

Prompt diagnosis in the emergency department in the case of a patient with emesis may be difficult due to the increasing prevalence of diseases which manifest with emesis. Furthermore, in the case of chronic symptomatology, management and therapy are even more complicated. One episode of emesis rarely causes complications, but severe or repetitive episodes of emesis can cause life-threatening complications. For this reason, the diagnosis of the underlying disease which manifests with emesis is mandatory to be established in a short time in order to choose the correct therapeutic option. In order to systemize the process of diagnosis, this clinical narrative review will discuss only rare causes of emesis.

Assessment of Reye's syndrome profile with data from the US Food and Drug Administration Adverse Event Reporting System and the Japanese Adverse Drug Event Report databases using the disproportionality analysis.

OBJECTIVES: Reye's syndrome is a rare and potentially fatal illness that is defined as encephalopathy accompanied by liver failure. The aim of this study was to assess Reye's syndrome profiles by analyzing data from the spontaneous reporting system database. METHODS: We analyzed reports of Reye's syndrome using the US Food and Drug Administration Adverse Event Reporting System and the Japanese Adverse Drug Event Report databases. The reporting odds ratio and proportional reporting rate were used to detect the pharmacovigilance signal. RESULTS: The US Food and Drug Administration Adverse Event Reporting System contains 12,201,620 reports from January 2004 to June 2020, of which 186 are on Reye's syndrome. The Japanese Adverse Drug Event Report contains 646,779 reports from April 2004 to September 2020, of which 30 are on Reye's syndrome. In the US Food and Drug Administration Adverse Event Reporting System database, the reporting odds ratios (95% confidence interval, number of cases) of aspirin, diclofenac, ibuprofen, acetaminophen, and valproate sodium were 404.6 (302.6-541.0, n = 80), 15.1 (6.7-34.1, n = 6), 26.2 (16.1-42.6, n = 18), 10.7 (5.5-20.9, n = 9), and 47.1 (26.2-84.6, n = 12), respectively. In the Japanese Adverse Drug Event Report database, the reporting odds ratios (95% confidence interval, number of cases) of aspirin, diclofenac, ibuprofen, loxoprofen, acetaminophen, and valproate sodium were 14.1 (5.4-36.8, n = 5), 51.7 (22.2-120.5, n = 7), 135.0 (40.8-446.2, n = 3), 17.6 (6.7-46.0, n = 5), 24.0 (9.2-62.6, n = 5), and 13.8 (3.3-57.9, n = 2), respectively. The reported number of female patients aged 30-39 years was the highest in the Japanese Adverse Drug Event Report. CONCLUSION: Although the frequency of the occurrence of Reye's syndrome is low, the possible risk of the disease occurring in adult females should be considered.

Adjuvant herbal therapy for targeting susceptibility genes to Kawasaki disease: An overview of epidemiology, pathogenesis, diagnosis and pharmacological treatment of Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is a self-limiting acute systemic vasculitis occur mainly in infants and young children under 5 years old. Although the use of acetylsalicylic acid (AAS) in combination with intravenous immunoglobulin (IVIG) remains the standard therapy to KD, the etiology, genetic susceptibility genes and pathogenic factors of KD are still un-elucidated. PURPOSE: Current obstacles in the treatment of KD include the lack of standard clinical and genetic markers for early diagnosis, possible severe side effect of AAS (Reye's syndrome), and the refractory KD cases with resistance to IVIG therapy, therefore, this review has focused on introducing the current advances in the identification of genetic susceptibility genes, environmental factors, diagnostic markers and adjuvant pharmacological intervention for KD. RESULTS: With an overall update in the development of KD from different aspects, our current bioinformatics data has suggested CASP3, CD40 and TLR4 as the possible pathogenic factors or diagnostic markers of KD. Besides, a list of herbal medicines which may work as the adjunct therapy for KD via targeting different proposed molecular targets of KD have also been summarized. CONCLUSION: With the aid of modern pharmacological research and technology, it is anticipated that novel therapeutic remedies, especially active herbal chemicals targeting precise clinical markers of KD could be developed for accurate diagnosis and treatment of the disease.

A Case of Reye Syndrome Caused by Influenza A Virus.

BACKGROUND: Reye syndrome is a rare and potentially life-threatening disease characterized by liver failure and hepatic encephalopathy. Multiple possible etiologies have been suggested, but only aspirin (acetylsalicylic acid) has been statistically proven to be a causative factor. We describe a case of Reye syndrome secondary to influenza A virus. CASE REPORT: A 2-year-old male with a recent history of influenza-like symptoms presented with neurologic deterioration. He had elevated liver enzymes, hyperammonemia, elevated creatinine, and hypoglycemia. Liver biopsy showed microvesicular steatosis consistent with Reye syndrome. He was given supportive care and recovered after 17 days with normalization of metabolic derangements. At 4-month follow-up, the patient had reached age-specific developmental milestones. CONCLUSION: The incidence of Reye syndrome has decreased since 1980 when the Centers for Disease Control and Prevention issued a warning against aspirin use in children. Consequently, any new incidence of Reye syndrome warrants investigation of other etiologies. This case adds to the evidence that causes other than aspirin can result in Reye syndrome.

Nonsteroidal anti-inflammatory drugs exposure and the central nervous system.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used agents in clinical practice. They are employed as anti-inflammatory, analgesic, and antipyretic agents for a wide spectrum of clinical conditions. Their anti-inflammatory properties are primarily due to inhibition of prostaglandin synthesis. In this paper we review the neurological effects associated with the use of NSAIDs. Acute CNS toxicity related to NSAID use is pervasive and varied. A prospective study looking at ibuprofen overdose noted that 30% of patients experience CNS effects ranging from drowsiness to coma. Case reports have identified numerous neurologic sequelae including ataxia, vertigo, dizziness, recurrent falls, nystagmus, headache, encephalopathy, and disorientation. Seizures have also been reported, mostly after overdose ingestions, but even therapeutic doses have occasionally been associated with seizures. One of the important neurologic side-effects attributed to the use of NSAIDs is aseptic meningitis. The clinical signs of drug-induced meningitis are similar to those of infectious meningitis and include fever, headache, photophobia, and stiff neck. The laboratory findings are also similar, including cerebrospinal fluid (CSF) pleocytosis of several hundred or thousand cells, mainly neutrophils, elevated levels of protein, normal or low glucose levels and negative cultures. Drug-induced meningitis is a transient disorder with an excellent prognosis. Most or all drugs used for the treatment of headache, including NSAIDs, may cause a condition known as medication overuse headache - a refractory chronic daily headache that tends to resolve following discontinuation of the analgesics. Reye's syndrome is a rare severe illness occurring mainly in children and adolescents and characterized by abnormal liver function, vomiting, and encephalopathy, with a mortality rate approaching 40%. The pathogenesis is currently unknown, but commonly the syndrome is preceded by a viral episode, with an intermediate latent period of 3-5 days. An association with aspirin use is strongly suggested. Aspirin, the classic and most commonly used NSAID, has a well-documented effect in inhibiting intravascular clotting, thus reducing the occurrence of ischemic strokes and other vascular events. NSAIDs, however, have a double impact on coagulation. On the one hand, most agents inhibit the synthesis of thromboxane in the platelets, thereby inhibiting coagulation. On the other hand, they also inhibit the production of prostacyclin by endothelial cells, resulting in a prothrombotic state. Selective inhibition of COX-2 by drugs such as rofecoxib (Vioxx) and valdecoxib (Bextra) results in specific inhibition of synthesis of prostaglandins participating in inflammation and was found to lead to vascular complications including an increased risk for stroke. The connection between inflammation and neuronal degeneration is well established. Most studies, including the prospective Rotterdam study, have found an inverse correlation between the use of NSAIDs and the risk for dementia. Two meta-analyses have found 40% and 25% reduction, respectively, in the risk of Alzheimer's disease among NSAID users. However, some large, well designed studies failed to confirm these results, and some even found that NSAID use is associated with cognitive decline. The clinical impact of NSAIDs on Parkinson's disease (PD) remains unclear. While some studies showed that chronic NSAID use is protective against PD, other studies could not confirm the existence of a significant relationship. A recent meta-analysis indicated that the use of non-aspirin NSAID, particularly ibuprofen, reduces the risk of PD by 15% while the use of aspirin did not show any effect.

Influenza a infection unmasking an underlying mitral valve stenosis in a 19-year-old boy.

Infection with Influenza virus is uncommon in the present times, though a number of cases were reported during pandemics in 1918 in various regions of America. We report a case where a young male patient presented to the hospital with a clinical picture of acute respiratory distress syndrome that turned out to be a viral pneumonia caused by Influenza A virus and it aggravated an underlying yet undiagnosed mitral valve stenosis.

[Aspirin and its danger: Reye syndrome in young adult]. / L'aspirine et ses dangers: syndrome de Reye chez un adulte jeune.

We describe the case of a 19-year-old male diagnosed with Reye syndrome within the context of viral pericarditis and salicylate ingestion. He presented a fatal brain oedema without liver failure. Brain biopsies obtained during a decompressive craniectomy led to the diagnosis.

Síndrome de Reye congénito asociado a varicela materna / Congenital Reye syndrome associated to varicella infection in pregnancy

Introducción: el síndrome de Reye es una encefalopatía aguda asociada a una degeneración grasa del hígado que usualmente es precedida de una infección respiratoria o varicela y tiene una alta prevalencia en niños menores de seis años. Objetivo: reportar un caso clínico de síndrome de Reye congénito asociado a la infección por varicela adquirida de la madre. Presentación de caso: se describen los hallazgos de la autopsia, la respectiva correlación clinicopatológica de un recién nacido de sexo masculino de 37 semanas de gestación, hijo de madre con varicela activa desde cuatro días antes del parto, quien presentó súbitamente palidez generalizada, bradicardia y apnea. Resultados: el examen histopatológico encontró en el citoplasma de los hepatocitos y túbulos renales un compromiso vacuolar que correspondía a grasa. En el cerebro se evidenció severo edema, sin inflamación perivascular o meníngea. Conclusión: corresponde a un caso de síndrome de Reye congénito asociado a varicela materna, que terminó manifestándose clínicamente como muerte súbita. Podría ser la primera publicación de un caso de síndrome de Reye congénito asociado a varicela materna. MÉD.UIS. 2014;27(3):113-121.

Introduction: Reye's syndrome is an acute encephalopathy associated with fatty degeneration of the liver that usually is preceded by a respiratory infection or chickenpox and is highly prevalent in children under 6 years old. Objective: to report a clinical case of congenital Reye's syndrome associated with varicella infection acquired from the mother. Case report: we describe the autopsy findings with the respective clinicopathological correlation of a male newborn of 37 weeks of gestation, son of mother with active varicella from 4 days before birth, who presented sudden paleness, bradycardia and apnea. Results: histopathologic examination found in the cytoplasm of hepatocytes and renal tubules a vacuolar commitment that corresponds to fat. The brain showed severe edema without perivascular or meningeal inflammation. Discussion and conclusion: it corresponds a case of congenital Reye's syndrome associated with varicella infection in pregnancy, who finished clinically as sudden death. This could be the first published case of congenital Reye's syndrome associated with varicella infection in pregnancy. MÉD.UIS. 2014;27(3):113-121.