Research progress of respiratory virus infection associated acute necrotizing encephalopathy / 中华实用儿科临床杂志

Acute necrotizing encephalopathy (ANE) is a subtype of acute encephalopathy presented with disturbance of consciousness and symmetric bilateral thalamic necrosis in neuroradiology.Patients with ANE had a high mortality or severe neurological sequela.ANE usually secondary to virus infectious disease, in which influenza is a common etiology.During the 3 years of the worldwide pandemic of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection, ANE has become a severe complication and cause of death in children, which has aroused much concern.Here is a review of the research progress of epidemiology, pathogenesis, diagnosis, treatments and prognosis of ANE, in order to improve the knowledge of clinicians on this disease.

Clinical characteristics and prognosis of 13 cases of acute necrotizing encephalopathy of childhood / 中华实用儿科临床杂志

Objective:To analyze and summarize the clinical characteristics, diagnosis and treatment, head imaging changes and prognosis of acute necrotizing encephalopathy of childhood (ANEC), aiming to improve the understanding of this disease.Methods:Clinical data of 13 ANEC patients (there were 7 males and 6 females, the median age was 30 months) admitted to the Pediatric Intensive Care Unit (PICU) of Shengjing Hospital, China Medical University from January 2014 to December 2020 were retrospectively analyzed, including clinical manifestations, laboratory examinations, diagnosis and treatment procedures, and head imaging data.Survivors were followed up through telephone.Results:All patients had fever and convulsions before admission, and the median time between fever and consciousness disturbance was 48 hours.The magnetic resonance imaging scans showed symmetrical multifocal brain damages.All 13 patients used glucocorticoid treatment, 10 cases used human immunoglobulin treatment, 8 cases used plasma exchange treatment.A total of 7/13 patients died.Five children were regularly followed up, who presented normal height and weight development and normal immunity.One child had normal motor intelligence with the acceptable Pediatric Overall Performance Category Score, and the remaining 4 children had certain sequelae, mainly manifesting as slow speech speed and limited movement.Conclusions:ANEC mainly occurs in winter and young children with a high mortality.It progresses rapidly, and consciousness disturbance appears soon after fever and convulsion.Survivors usually have sequelae, mostly manifesting as slow speech speed and limited movement, which can be significantly improved after systematic rehabilitation treatment.

Analysis of prognosis and influencing factors of childhood acute necrotizing encephalopathy / 中华实用儿科临床杂志

Objective:To analyze the prognosis and influencing factors of acute necrotizing encephalopathy (ANE) in children.Methods:Clinical data of ANE patients admitted to Pediatric Intensive Care Unit, Beijing Children′s Hospital, Capital Medical University from March 2012 to February 2019 were retrospectively analyzed.Survivors were followed up by telephone or outpatient department, and the quality of life was evaluated by pediatric overall performance category scale.The t-test or rank sum test was used for comparison between groups, and the COX risk regression was used to analyze the influencing factors of prognosis. Results:A total of 38 patients were enrolled in this study with the male-to-female ratio of 1.24∶1.00, and median age of 29.5(10.0-130.0) months.They were followed up for the median of 27(15-96) months.The overall survival rate at 7 days, 14 days and 2 months after disease onset were 57.9%, 42.1%, and 34.2%, respectively.The mortality rate at discharge was 34.2%(13/38 cases), and the cumulative mortality rate at the 1 st, 3 rd and 12 th months after discharge was all 68.4%(26/38 cases). The complete reco-very rate was 10.5%(4/38 cases) after one-year follow-up.The univariate analysis indicated that cardiopulmonary resuscitation before admission, Glasgow coma score < 5 at admission, complication with shock/cerebral hernia/multiple organ dysfunction syndrome, creatine kinase isoenzyme> 100 U/L, lactate dehydrogenase>1 000 U/L, hypoalbuminemia, hyperglycemia, hyperurea, prolonged prothrombin time and elevated international standardized ratio were risk factors for the prognosis of ANE in children ( β=3.519, 6.967, 6.803, 3.000, 6.389, 3.471, 2.252, 1.616, 2.377, 3.092, 2.713, and 4.510, respectively, all P<0.05). Meanwhile, high-dose Methylprednisolone[20-30 mg/(kg·d)] and immunoglobulin (2 g/kg, divided into 2-5 days intravenous drip) treatment were protective factors ( β=0.625, 0.405, respectively, all P<0.05). The COX multivariate analysis showed that high-dose Methylprednisolone treatment [20-30 mg/(kg·d)] was an independent protective factor for the prognosis of children with ANE [95% CI: 0.449(0.213-0.944), P=0.035]. Conclusions:Early application of high-dose Methylprednisolone and immunoglobulin may contribute to the good clinical outcome.Children with neurological sequelae should be actively treated with rehabilitation, and the quality of life may be gradually improved.

Clinical study of 41 children with acute necrotizing encephalopathy / 中华实用儿科临床杂志

Objective:To investigate the clinical features and prognosis of acute necrotizing encephalopathy (ANE) in children.Methods:The clinical data and follow-up information of 41 pediatric patients with ANE treated in Wuhan Children′s Hospital, Tongji Medical College, Huazhong University of Science & Technology from January 2014 to September 2019 were retrospectively reviewed.Results:The 41 patients included 23 males and 18 females with the onset age of (4.4±3.2) years.The main prodromal symptoms were gastrointestinal (20/41 cases, 48.8%) and respiratory infections (19/41 cases, 46.3%). Acute encephalopathy progressed rapidly following the prodromal infection [29 cases (70.7%) ≤2 days], and patients had clinical manifestations of coma (32/41 cases, 78.0%), convulsion (32/41 cases, 78.0%), multiple organ dysfunction (27/41 cases, 65.9%), shock and disseminated intravascular coagulation were rarely occured, and 28 cases (68.3%) were admitted to intensive care unit for treatment.Brain magnetic resonance imaging (MRI) showed lesion involving thalamus (41/41 cases, 100.0%), periventricular white matter (34/41 cases, 82.9%), brainstem (31/41 cases, 75.6%), basal ganglia (26/41 cases, 63.4%), cerebral cortex and subcortex (20/41 cases, 48.8%) and cerebellum (18/41 cases, 43.9%). The common presentations on the apparent diffusion coefficient mapping of brain MRI were " tricolor pattern" or " bicolor pattern" of the thalamus.During follow-up (≥ 6 months), MRI showed that hemorrhage, cystic degeneration and atrophy changed dynamically with the progression of ANE.All cases were treated with glucocorticoids, 38 cases(92.7%) with intravenous immune globulin.Seven cases (17.1%) were died and the 34 survivors had different degrees of neurological dysfunction.Conclusions:ANE in children is a distinctive type of clinicoradiologic syndrome with rapid progression and various presentations.Brain MRI has typical imaging characteristics and dynamically indicates the progression of this disease.The treatment options are still limited, the prognosis is poor and the survivors are often with neurological dysfunction.

Clinical imaging features and prognosis of 40 children with influenza associated encephalopathy / 中华实用儿科临床杂志

Objective:To analyze the clinical and imaging features of influenza associated encephalopathy(IAE) in children, thus contributing to enhance the efficacy of early identification, timely treatment and prognosis.Methods:Clinical data, laboratory examination, imaging data, treatment and outcomes of 40 children with IAE diagnosed and treated in the Beijing Children′s Hospital, Capital Medical University from December 2016 to January 2020 were retrospectively analyzed.Clinical features were summarized and they were further classified according to clinical imaging features.The prognosis was compared and analyzed.Results:A total of 20 boys and 20 girls were recruited, with the age of attending hospital at (4.0±2.3) years (median, 3.2 years). There were 28 children with influenza A and 12 with influenza B. All children initially had fever, and the interval between fever and symptoms of neurological onset was 24 hours (0-120 hours). The most-common symptom of neurological onset was seizures(32 cases), among which 17 patients showed continuous seizures.All children presented encephalopathy at varying degrees, including 33 cases in coma and 7 in drowsiness or cognitive decline.Thirty cases developed central respiratory failure and received mechanical ventilation.Examination results showed 30 cases had elevated aspartate transaminase (AST), 18 cases had elevated alanine transaminase (ALT), 14 cases had elevated creatinine, 31 cases had elevated lactate dehydrogenase, 16 cases had elevated blood glucose and 1 case had significantly lowered blood glucose.Blood ammonia testing was performed in 38 children and 9 cases had elevated level.The whole exon sequencing in 6 cases showed de novo heterozygous mutation of the SCN1A gene in 1 case, and heterozygous mutation of the ATP1A2 gene inherited from the mother in another case.Lumbar puncture was performed in 35 cases, and all of them had a normal range of cerebrospinal fluid leukocyte counts, while 12 cases had elevated cerebrospinal fluid proteins.Abnormal image findings were examined in 33 cases and the acute necrotizing encephalopathy was the most common one (14 cases). All children received Peramivir or Oseltamivir after admission.A total of 28 cases were treated with glucocorticoids, and 29 cases were treated with immunoglobulin.Seventeen cases died, 9 cases had disability at varying degrees, and 14 cases recovered to the baseline.Patients were divided into good prognosis group and poor prognosis group.(1) Patients in good prognosis group presented significantly shorter interval between fever and first neurological symptoms[(22.7±12.2) h vs.(38.6± 30.9) h], higher Glasgow score on admission[(7.6±2.5) points vs.(4.5 ± 1.6) points], lower ALT [15.6 (9.0-1 631.5) U/L vs.140.2 (12.3-3 232.4) U/L] and lower AST [47.6 (25.4-1 721.3) U/L vs.251.8 (21.7-4 991.6) U/L] than those in poor prognosis group (all P<0.05). (2) Glucocorticoids were applied to 17 and 11 cases in good prognosis group and poor prognosis group, while immunoglobulins were applied to 17 and 12 cases, respectively ( P>0.05). (3) Patients were further classified into cytokine storm group, excitotoxicity group and unclassifiable group according to clinical imaging findings.The Glasgow score [ (4.6±1.7) points vs.(7.6±2.2) point vs.(7.3±2.8) points] and median modified Rankin Scale score (6.0 points vs.1.5 points vs.0) were significantly different among 3 groups (all P<0.01). Conclusions:Influenza associated encephalopathy is common in infants and young children.Fever, convulsions and rapidly progressing disturbance of consciousness are the most common clinical manifestations.Acute necrotizing encephalopathy is the most common subtype of clinical imaging syndrome.Acute onset and rapid progression predict the poor prognosis of influenza associated encephalopathy.

Acute Necrotizing Encephalopathy of Childhood: A Severe Case with Fatal Outcome

@#Acute necrotizing encephalopathy of childhood (ANEC) is a rare condition which is important for clinicians to recognize as it has a high mortality rate and can result in significant neurological morbidities. It presents as acute encephalopathy with radiological findings of symmetrical brain lesions in bilateral thalami, putamen, brain stem tegmentum, internal capsule, periventricular white matter and cerebellar medulla. Intravenous methylprednisolone is the mainstay of treatment. Immunoglobulin therapy and therapeutic hypothermia may be used as adjunctive therapy in cases with severe clinical and neuroradiological presentation. We present a case of severe ANEC and discuss the clinical manifestations, neuroimaging and management options.

Acute necrotizing encephalopathy with onset of youth: a case report / 中华神经科杂志

A young female patient with acute necrotizing encephalopathy (ANE) is reported,who aged 15 years,with a history of upper respiratory tract infection,main clinical manifestations of seizures and consciousness disorders,and brain MRI examination showing characteristic symmetrical bilateral abnormal signals at both thalamic area,pons,and cerebellar hemisphere.Imaging changes corresponded to pathophysiological changes.The initial manifestations were found to be brain swelling and edema.In the acute phase,hemorrhage and necrosis of the affected brain tissues were observed.The recovery period was characterized by hemosiderin deposition and cystic space formation,which was consistent with ANE diagnosis.By early use of high-dose gammaglobulin and methylprednisolone,the prognosis of the patient was good,proving that immunosuppressive therapy by corticosteroids and gammaglobulin is effective for ANE.

Arterial Spin Labelling Perfusion, Proton MR Spectroscopy and Susceptibility-Weighted MR Findings of Acute Necrotizing Encephalopathy: a Case Report

In this study, we report arterial spin labelling perfusion, proton MR spectroscopy and susceptibility-weighted MR findings of acute necrotizing encephalopathy in a child with rotavirus infection.

Clinical characteristics of acute necrotizing encephalopathy in childhood / 中国小儿急救医学

Objective To summary the clinical characteristics of acute necrotizing encephalopathy in childhood so as to estimate the prognosis and guide the therapy. Methods We collected and analyzed retro-spectively the data of 10 acute necrotizing encephalopathy cases hospitalized in the pediatric department of our hospital from January 2014 to April 2018. The clinical manifestations,laboratory examinations and imaging features were retrospectively analyzed. Results A total of 10 cases all had fever and convulsions (100％). There was no specific clinical manifestation in the early stage,always showing the symptoms of acute respira-tory infection or acute gastroenteritis. Mental malaise,lethargy,restlessness and frequent convulsions occured when the conditions aggravated. Nine patients had different degrees of consciousness disorder. It could be complicated by multiple organ dysfunction syndrome,hemophagocytic syndrome and so on. Eight patients un-derwent MRI. In acute phase, homogeneously prolonged T1 and T2 relaxation time of the brain lesions on MRI were found in most patients,and diffusion-weighted imaging ( DWI) and FLAIR showed high signal in-tensity. Six cases underwent head CT examination, hypodensities were seen on 4 cases. Cerebrospinal fluid (CSF) was detected in all patients,and the protein levels in CSF increased to varying degrees,while white blood cells did not increase. Of the 10 patients,3 died,1 was discharged normally,1 had hemophagocytic syn-drome,transferred to pediatric hematology department,and 5 patients were transferred to rehabilitation depart-ment. Conclusion Acute necrotizing encephalopathy in children always make progress rapidly, has high mortality,many survivors have severe neurological sequelae,which is worthy of being attention.

Acute necrotizing encephalopathy / 中华实用儿科临床杂志

Acute necrotizing encephalopathy (ANE)is a rare type of acute encephalopathy which occurs secondary to virus infection. Individuals who suffer from ANE usually have an exaggerated immune response to various viral infections. The pathologic change is focal vascular injury which leads to destruction of the blood - brain barrier and vascular permeability that cause brain edema,petechial hemorrhage,and necrosis. The imageological changes of ANE have diagnostic significance which show multifocal,symmetric brain lesions including bilateral thalamus 100％ invol-ving. Intravenous glucocorticoids,immunoglobulin,and plasmapheresis should be effective for treatment.

Clinical and genetic analysis of a family with familiar acute necrotizing encephalopathy due to mutation in the RANBP2 gene / 中华实用儿科临床杂志

Objective To analyze the clinical manifestations of familial acute necrotizing encephalopathy (ANE)and to improve the recognition of this disease. Methods The clinical data of a 25 - month - old girl with fa-milial and recurrent ANE with evidence of mutation in the RANBP2 gene were collected and analyzed,and the gene examination of their family members was performed. Results A previously healthy girl experienced recurrent ANE epi-sodes at the ages of 8 months,18 months and 25 months,respectively. At each beginning of each episodes the patient presented with lethargy and tremor of limbs following febrile illness of 3 - 4 days,even developed coma and convulsions in the last time. Brain magnetic resonance imaging showed bilateral and high T2 signal changes in thalamus,cerebellum and hippocampus. Abnormal signals also appeared in the brainstem,claustrum,corpus scallosum and cortex(temporal, parietal and cingulate)also appeared abnormal signals. Spinal MRI showed spinal cord involvement. The girl recovered after her first episode;she could speak but could not walk steadily after the second time;after the third episode,al-though she regained consciousness from coma,she could no longer speak or walk. The patient's sister died of encephali-tis at the age of 18 months. Her paternal uncle had suffered from dysnoesia from meningitis at his 17 months of age. The patient and her grandmother,father,uncle and one of her aunts harbored a mutation(c. 1754C ﹥ T)in RANBP2 gene. Conclusions Familial ANE has typical clinical manifestations and characteristic MRI findings. The patient with recur-rent history,especially with positive family history,should have the mutation in RANBP2 gene detected earlier in order to clarify the diagnosis of ANE.

Clinical outcome of acute necrotizing encephalopathy in related to involving the brain stem of single institution in Korea / 소아과

PURPOSE: Acute necrotizing encephalopathy (ANE) is a fulminant disease of the brain characterized by bilateral thalamic lesions, and is prevalent among children in East Asia. The prognosis of ANE is usually poor with a high mortality rate and neurological sequelae. This study aimed to delineate the clinical characteristics and prognostic factors of ANE. METHODS: We retrospectively analyzed clinical data of 399 pediatric patients with encephalitis who were admitted to Samsung Medical Center from December 1998 to March 2011. We enrolled ten patients (11 cases) with ANE and analyzed their demographic, clinical, and neuroimaging data. The location and extent of the brain regions were checked based on fluid-attenuated inversion recovery, T1-, and T2-weighted imaging findings; the presence of contrast enhancement, restricted diffusion, and hemorrhage. RESULTS: Ten patients were identified, including one patient with two episodes. The median age of onset was 1.5 years (0.4-8.4 years). The mortality rate was 40%, and only 30% of patients survived without neurological sequelae. The definite involvement of the brainstem on brain magnetic resonance imaging was significantly correlated with mortality (P=0.04). CONCLUSION: Broad and extensive brainstem involvement suggested the fulminant course of ANE. Early diagnosis of ANE before brainstem involvement, through careful identification of symptoms of brain dysfunction, may be the best way to achieve better neurological outcomes.

A case of acute necrotizing encephalopathy associated with parainfluenza virus infection / 소아과

Acute necrotizing encephalopathy (ANE) may be suspected when a young child presents with abrupt onset of altered mental status, seizures, or both. Definitive clinical diagnosis is based on magnetic resonance imaging (MRI) results. ANE is associated with influenza virus infections. Preliminary data suggests that up to 25% of ANE patients die, and up to 25% of ANE survivors develop substantial neurologic sequelae. Here, we describe a case of a comatose 22-month-old girl who was admitted to our hospital because of febrile illness and seizures. On day 13 of her illness, she died from ANE associated with infection from parainfluenza virus. Brain MRI results indicated diffuse bilateral symmetric signal changes in both basal ganglia, thalami, periventricular white matter, pons, and cerebral white matter, as well as generalized swelling of the brain.

Acute necrotizing encephalopathy.

Acute necrotizing encephalopathy (ANEC) is a rare disease well recognized in Japan but has not yet been reported from Indian subcontinent. We describe here a case of ANEC with the neuroimaging findings. P. vivax infection was detected as an associated finding and the treatment given.

Clinical Spectrum and Prognostic Factors of Acute Necrotizing Encephalopathy in Children

This study was conducted to investigate the etiology, the clinical characteristics and prognosis of acute necrotizing encephalopathy (ANE) in Korean children. Six children (1 yr to 7 yr) patients with ANE were enrolled. They were diagnosed by clinical and radiological characteristics and their clinical data were retrospectively analyzed. In a search of clinically plausible causes, brain MRI in all patients, mitochondrial DNA studies for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) and myoclonus epilepsy and ragged red fibers (MERRF) in four patients, and genomic typing on HLA DRB/HLA DQB genes in three patients were performed. All had precedent illnesses and the main initial symptoms included mental change (83%), seizures (50%), and focal deficits (50%). MRI revealed increased T2 signal density in the bilateral thalami and/or the brainstem in all patients. Mitochodrial DNA studies for MELAS and MERRF were negative in those children and HLA-DRB1*1401, HLA-DRB3*0202, and HLA-DQB1*0502 seemed to be significant. A high dose steroid was given to all patients, which seemed to be partly effective except for 2 patients. In conclusion, ANE is relatively rare, but can result in serious neurological complication in children. Early detection and appropriate treatment may lead to a better neurological outcome.

Two Cases of Influenza-associated Encephalopathy

Influenza-associated encephalopathy is typically associated with a sudden onset of high fever, severe convulsions, rapidly progressive coma and death within 2 or 3 days. It has been actively researched in Japan as it caused a tremendous increase in the number of deaths from 1997 to 2002. But there has been reported only one case in Korea, who was diagnosed on the basis of serologic testing by hemagglutinin inhibition. We report here a 14-month-old boy who was taken supportive care and a 3-year-old girl who was taken amantadine and methyprednisolone pulse therapy. Both of them were admitted under the diagnosis of influenza-associated encephalopathy on the basis of reverse transcription-polymerase chain reaction of nasopharyngeal fluid and cerebrospinal fluidm, brain magnetic resonance imagings. The first case was confirmed by the identification of influenza A/H3N2 in the cerebrospinal fluid culture by RT-PCR for the first time in Korea.

Genetic Propensity to Neuroinflammatory CNS Diseases in Korean Children: Molecular Typing of HLA Class II

PURPOSE: The study was aimed to investigate immunogenetic peculiarities of neuroinflammatory CNS diseases in Korean children. METHODS: A total of 16 children with neuroinflammatory CNS diseases(9 males and 7 females; mean age 7.5+/-4.2 years) were consecutively recruited. Genomic typings were performed on their HLA DRB/HLA DQB genes using PCR-SSOP/SSP techniques with Gel immunoelectrophoresis. RESULTS: The frequencies of HLA-DRB1*14(38%), HLA-DRB1*15(25%), HLA-DRB3* 02(50%), HLA-DQB1*05(56%) and DQB1*06(44%) were significantly increased compared with a control group. The frequencies of HLA-DRB1*15(50%) and HLA-DQB1*06(63%) were significantly increased in children with ADEM and HLA-DRB3*0202(100%), HLA- DRB1*1302(67%), HLA-DRB3*0301(67%), and HLA-DQB1*0301(67%) in children with multiple sclerosis. HLA-DRB1*1401, HLA-DRB3*0202, and HLA-DQB1*0502 were found in children with acute necrotizing encephalopathy. CONCLUSION:HLA-DRB1*14, HLA-DRB1*15, HLA-DRB3*02, HLA-DQB1*05 and DQB1*06 may be associated with the susceptibility to neuroinflammatory CNS diseases in Korean children. The frequencies of HLA-DRB1*1501, HLA-DRB5*0101, HLA-DRB3* 0301, and HLA-DQB1*0602 in Korean children with multiple sclerosis were not as high as those in western children. However, HLA-DRB3*0202 was seen in all the children with multiple sclerosis. Our data may provide further evidence that the immunogenetic backgrounds of neuroinflammatory CNS diseases in Korean children are distinctly different from those in Westerns. However, further studies are needed.

A Case of Relapsing Acute Necrotizing Encephalopathy

A 4-year-old boy showed two episodes of encephalitis/encephalopathy involving disturbed consciousness, convulsion, and paresis associated with the elevated levels of protein and no pleocytosis of the cerebrospinal fluid. MRI studies of the brain revealed symmetrical lesions in the brain stem and thalamus at the first episode, and their sizes were regressed. The lesions were enlarged to the previous size in the second episode. These episodes were not followed by an elevation of the anti-viral antibody titer. In the second episode, intravenous methylprednisolone therapy and intravenous immunoglobulin therapy were introduced.