Ferritin as an Effective Predictor of Neurological Outcomes in Children With Acute Necrotizing Encephalopathy.

BACKGROUND: Acute necrotizing encephalopathy (ANE) is a fulminant disease with poor prognosis. Cytokine storm is the important phenomenon of ANE that affects the brain and multiple organs. The study aimed to identify whether hyperferritinemia was associated with poor prognosis in patients with ANE. METHODS: All patients with ANE had multiple symmetric lesions located in the bilateral thalami and other regions such as brainstem tegmentum, cerebral white matter, and cerebellum. Neurological outcome at discharge was evaluated by pediatric neurologists using the Pediatric Cerebral Performance Category Scale. All risk factors associated with poor prognosis were further analyzed using receiver operating characteristic curve analysis. RESULTS: Twenty-nine patients with ANE were enrolled in the current study. Nine (31%) patients achieved a favorable neurological outcome, and 20 (69%) patients had poor neurological outcomes. results The group of poor neurological outcome had significantly higher proportion of shock on admission and brainstem involvement. Based on multivariate logistic regression analysis, ferritin, aspartate aminotransferase (AST), and ANE severity score (ANE-SS) were the predictors associated with outcomes. The appropriate cutoff value for predicting neurological outcomes in patients with ANE was 1823 ng/mL for ferritin, 78 U/L for AST, and 4.5 for ANE-SS. Besides, comparison analyses showed that higher level of ferritin and ANE-SS were significantly correlated with brainstem involvement (P < 0.05). CONCLUSIONS: Ferritin may potentially be a prognostic factor in patients with ANE. Hyperferritinemia is associated with poor neurological outcomes in patients with ANE and ferritin levels more than 1823 ng/mL have about eightfold increased risk of poor neurological outcome.

A Rare Case of COVID-19 Related Acute Necrotizing Encephalopathy With the RANBP2 Mutation in a Pediatric Patient.

Acute necrotizing encephalopathy (ANE) is a rare childhood neurological disorder. The familiar type of ANE (ANE1) is associated with a mutation in the RANBP2 gene. Both SARS-CoV-2 and RANBP2 mutations are responsible for the manifestation of a hyper-inflammatory response that invades the central nervous system and plays a key role in the rapid progression of encephalopathy.

[Weston-Hurst syndrome. A case report and literature review]. / Síndrome de Weston Hurst. Reporte de un caso y revisión de la literatura.

Background: Acute disseminated encephalomyelitis is an autoimmune and demyelinating disease. It is rare in adults. It has 3 main variants. One of them is Weston-Hurst syndrome, also called acute hemorrhagic leukoencephalitis. The objective was to share the experience in the diagnostic and therapeutic approach of this rare disease, as well as make a review of the current bibliography, in order to collaborate in the knowledge of this disease. Clinical case: 27-year-old woman, with a viral respiratory infection 2 weeks prior to the development of a neurological syndrome characterized by paresthesia, motor deficit, status epilepticus and acute encephalopathy, progressing rapidly to coma, with evidence in MRI of diffuse hemorrhagic lesions in cerebral white matter with demyelination and peripheral edema. It was administered steroid treatment for 5 days, with improvement of symptoms, but with motor and sensory deficits persisting. Conclusion: Acute disseminated encephalomyelitis and its variants are rare entities, with an important range of differential diagnosis, which must be identified and quickly treated to avoid their lethal or disabling outcome.

Introducción: la encefalomielitis aguda diseminada es una enfermedad autoinmune y desmielinizante. Es rara en el adulto. Cuenta con tres variantes principales. Una de ellas es el síndrome de Weston Hurst, también conocido como leucoencefalitis hemorrágica aguda. El objetivo fue compartir la experiencia en el abordaje diagnóstico y terapéutico de esta rara enfermedad, así como hacer una revisión de la bibliografía actual, a fin de colaborar con el conocimiento de esta. Caso clínico: mujer de 27 años con cuadro de infección respiratoria viral 2 semanas previas al desarrollo de síndrome neurológico caracterizado por parestesias, déficit motor, estatus epiléptico y encefalopatía aguda, el cual progresó a estado de coma y evidenció en resonancia magnética lesiones difusas hemorrágicas en sustancia blanca cerebral con desmielinización y edema periférico. Se inició tratamiento con esteroides por 5 días con mejora de síntomas, aunque persistió el déficit motor y sensitivo. Conclusión: la encefalomielitis aguda diseminada y la variante hemorrágica de esta son entidades raras, con una importante gama de diagnóstico diferencial, que deben ser identificadas y tratadas de forma rápida para evitar su letal o incapacitante desenlace.

[Acute hemorrhagic leukoencephalitis with a subacute onset]. / Ostryi gemorragicheskii leikoentsefalit Khersta, variant podostrogo techeniya.

Acute hemorrhagic leukoencephalitis (AHLE), also called Hurst's encephalitis, is a rare demyelinating disease of the central nervous system characterized by rapid progression and acute inflammation of the white matter of the brain and spinal cord. AHLE is currently considered as a rare, most severe variant of acute disseminated encephalomyelitis. Clinically AHLE is characterized by a fulminant course with a rapid development of encephalopathy and multifocal neurological symptoms. AHLE is associated with high mortality rate that requires immediate and aggressive treatment initiation. This article describes a case of AHLE with an atypical course, a subacute form, which is extremely rarely described in the literature, with the progressive symptoms' development over several months. Due to delayed treatment initiation, unfortunately, a fatal outcome has been observed. Subsequent histological examination of the autopsy material confirmed the presence of a subacute form of AHLE in the patient.

[Acute hemorrhagic leukoencephalopathy. Case report]. / Leucoencefalopatía hemorrágica aguda. Reporte de caso.

Background: Acute hemorrhagic leukoencephalitis (AHLE) is an inflammatory disease of the brain, with a fulminant course that leads to a hemorrhagic demyelination of the central nervous system, having a poor prognosis and high mortality. Most of the times associated to crossed reactivity and molecular mimicry. Clinical case: : We present a case report of a previously healthy young woman with an acute and multifocal clinical course, preceded by a viral respiratory tract infection, followed by a rapid disease progression and a delay in the diagnosis. The clinical, neuroimaging and cerebrospinal fluid featured suggested the diagnosis of AHLE, despite efforts and management with immunosuppression and intensive care, the response to treatment was poor leaving the patient with a severe neurological impairment. Conclusion: There is little evidence regarding the clinical course and treatment of this disease, and more studies are needed to better characterize it and to provide further information about its prognosis and management. This paper gives a systematic review of the literature.

Introducción: la leucoencefalitis hemorrágica aguda (AHLE, por sus siglas en inglés) es una enfermedad inflamatoria del cerebro que conduce a una desmielinización hemorrágica del sistema nervioso central (SNC), de mal pronóstico y alta mortalidad. Muchas veces se asocia a diferentes patógenos que provocan un mimetismo molecular. Caso clínico: presentamos un caso de origen mexicano, que presento una clínica de una evolución aguda de tipo multifocal. Inicialmente asociado a un cuadro de origen infeccioso, aparentemente viral. Posterior a ese cuadro el paciente presenta una evolución tórpida, con retraso del diagnóstico. Acude con las manifestaciones clínicas, radiológicas y en líquido cefalorraquídeo compatibles con la enfermedad, aunque se da tratamiento inmunosupresor de manera energética la paciente presenta poca respuesta al tratamiento, con muchas secuelas por la enfermedad. Conclusión: existen poca evidencia sobre la evolución clínica y el manejo médico de la enfermedad y se necesitan más estudios para caracterizarla mejor y brindar más información sobre su pronóstico y manejo. En este artículo se provee una revisión sistemática de la bibliografía.

Biallelic variants in ribonuclease inhibitor (RNH1), an inflammasome modulator, are associated with a distinctive subtype of acute, necrotizing encephalopathy.

PURPOSE: Mendelian etiologies for acute encephalopathies in previously healthy children are poorly understood, with the exception of RAN binding protein 2 (RANBP2)-associated acute necrotizing encephalopathy subtype 1 (ANE1). We provide clinical, genetic, and neuroradiological evidence that biallelic variants in ribonuclease inhibitor (RNH1) confer susceptibility to a distinctive ANE subtype. METHODS: This study aimed to evaluate clinical data, neuroradiological studies, genomic sequencing, and protein immunoblotting results in 8 children from 4 families who experienced acute febrile encephalopathy. RESULTS: All 8 healthy children became acutely encephalopathic during a viral/febrile illness and received a variety of immune modulation treatments. Long-term outcomes varied from death to severe neurologic deficits to normal outcomes. The neuroradiological findings overlapped with ANE but had distinguishing features. All affected children had biallelic predicted damaging variants in RNH1: a subset that was studied had undetectable RNH1 protein. Incomplete penetrance of the RNH1 variants was evident in 1 family. CONCLUSION: Biallelic variants in RNH1 confer susceptibility to a subtype of ANE (ANE2) in previously healthy children. Intensive immunological treatments may alter outcomes. Genomic sequencing in children with unexplained acute febrile encephalopathy can detect underlying genetic etiologies, such as RNH1, and improve outcomes in the probands and at-risk siblings.

MRI of fatal course of acute hemorrhagic leukoencephalitis in a child with SARS-CoV-2 omicron BA 2.0 infection.

We present a pediatric case of acute hemorrhagic leukoencephalitis associated with SARS-CoV-2 Omicron BA 2.0 infection. A previously healthy girl presented with ataxia and diplopia three weeks after the COVID-19 confirmation from a nasopharyngeal swab. Acute and symmetrical motor weakness and drowsiness ensued within the following 3 days. She then became spastic tetraplegic. MRI revealed multifocal lesions in the cerebral white matter, basal ganglia, and brainstem, with hemorrhagic changes confirmed with T1-hyperintensity and hypointensity on susceptibility-weighted images. Peripheral areas of decreased diffusion, increased blood flow, and rim contrast enhancement were noted in the majority of lesions. She was treated with a combination of intravenous immunoglobulin and methylprednisolone pulse therapy. Neurological deterioration ensued with coma, ataxic respiratory pattern and decerebrate posture. Repeated MRI performed on day 31 revealed progression of abnormalities, hemorrhages and brain herniation. Despite the administration of plasma exchange, she died two months after admission.

De novo RANBP2 variant in a fetal demise case with cerebral intraparenchymal hemorrhage.

Fetal intracranial hemorrhage (ICH) may result from a wide array of causes, either associated with maternal or fetal risk factors. In the last decade, monogenic causes of susceptibility to fetal ICH have been described, in particular in association with COL4A1 and COL4A2 genes. A peculiar form of ICH is acute necrotizing encephalitis (ANE), which is characterized by a rapid-onset severe encephalopathy following an abnormal inflammatory response to an otherwise banal infection. It usually affects healthy children and it is thought to be multifactorial, with a genetic predisposition. RANBP2 gene has been extensively associated with ANE susceptibility. We hereby present a unique case of a 42-year-old secundigravida with intrauterine fetal demise at 35 weeks of gestation. Trio-based whole-exome sequencing performed on both parents and fetal DNA showed a de novo likely pathogenic variant in the RANBP2 gene on 2q13. At the fetal autopsy, subtentorial hematoma and cerebral intraparenchymal hemorrhage were present. We speculate that this might be a new phenotypic presentation of RANBP2-associated disease. However, more similar fetal cases need to be reported in order to reinforce this hypothesis.

Neurological features related to influenza virus in the pediatric population: a 3-year monocentric retrospective study.

Influenza virus is generally characterized by fever, myalgia, and respiratory symptoms. Neurological entities have already been described, such as acute necrotizing encephalitis (ANE). We aimed to highlight the non-exceptional nature and explore the clinical spectrum and evolution of neurological features related to influenza virus in children. This monocentric observational study included patients under 18 years old, positive for influenza virus, between January 2017 and April 2019 in a pediatric university hospital. Patients were classified into two groups: those with or without a previous significant neurological or metabolic disorder. Two hundred eighty-nine children were identified with influenza infection. Thirty seven had a neurological manifestation: 14 patients who had previous significant neurological or metabolic disorder and 23 patients with no medical history. We identified several clinical patterns: 22 patients had seizures, 7 behavior disorders, 5 disturbances of consciousness, and 3 motor deficits. Four were diagnosed with a known influenza-associated neurological syndrome: 1 ANE, 1 cytotoxic lesion of the corpus callosum, 1 hemiconvulsion-hemiplegia-epilepsia syndrome, and 1 recurrent encephalitis in the context of a RANBP2 mutation. The neurological outcome was favorable in most cases. None of the patients with previous significant disorder retained sequalae or had a recurrence. Two patients had a fatal outcome, and both had a predisposing disorder. CONCLUSION: Various neurological manifestations can be associated with influenza virus. Certain entities led to a poor prognosis, but in most cases, symptoms improved within a few days. The severity of the neurological manifestations correlated with previous neurological or metabolic disorders. WHAT IS KNOWN: • Influenza viruses are well known pathogens with a seasonal epidemic evolution, particularly affecting children. These viruses cause acute fever with respiratory symptoms, associated with myalgia and headaches. Neurological presentation in influenza-virus infection is a well-established possibility as influenza virus is considered to be responsible for 27 to 36% of childhood encephalitis. Some specific and severe entity as acute necrotizing encephalitis, cytotoxic lesion of the corpus callosum, or Hemiconvulsion-hemiplegia-epilepsy syndrome are well described. WHAT IS NEW: • In a French monocentric cohort of 37 children with influenza-related neurologic manifestations, the majority of these manifestations, including seizure, drowsiness, motor deficiency, hallucination… are self limiting and do not lead to after-effects. In rare cases (4/37), they may reveal severe encephalitis requiring rapid and appropriate treatment. Otherwise, comparison of a group of 14 children with underlying neurological or metabolic disorder with a group of 23 children free of any significant disorder show that the severity of the neurological manifestations was largely related to previous neurological or metabolic disorders highlighting the importance of vaccination in this population.

Factors associated with outcomes of severe acute necrotizing encephalopathy: A multicentre experience in Malaysia.

This case series compared clinical variables and various combinations of immunotherapy received with outcomes of patients with severe acute necrotizing encephalopathy (ANE). We performed a retrospective review of clinical variables, immunotherapy received, and outcomes (based on the modified Rankin Scale) in Malaysia between February 2019 and January 2020. Twenty-seven children (12 male), aged 7 months to 14 years (mean 4 years) at diagnosis were included. Of these, 23 had an ANE severity score of 5 to 9 out of 9 (high risk). Eleven patients received tocilizumab (four in combination with methylprednisolone [MTP], seven with MTP + intravenous immunoglobulin [IVIG]) and 16 did not (two received MTP alone, 14 received MTP + IVIG). Nine died. Among the survivors, six had good outcomes (modified Rankin Score 0-2) at 6 months follow-up. All patients who received tocilizumab in combination with MTP + IVIG survived. Twenty children received first immunotherapy within 48 hours of admission. No significant association was found between the timing of first immunotherapy with outcomes. Those with brainstem dysfunction (p = 0.016) were observed to have poorer outcomes. This study showed a trend towards better survival when those with severe ANE were treated with tocilizumab in combination with MTP + IVIG. However, larger studies will be needed to determine the effect of this regime on the long-term outcomes.

Pediatric recurrent acute necrotizing encephalomyelitis, RANBP2 genotype and Sars-CoV-2 infection: Diagnosis, pathogenesis and targeted treatments from a case study.

Acute necrotizing encephalopathy (ANE) is a rare disease not yet described in children with Covid-19. RANBP2 gene variations are implicated in recurrences in the genetic form of ANE, the so called ANE1. We report the first case of pediatric ANE1 following Sars-CoV-2 infection. She had a first episode at 2 years of age following influenza type A with full recovery, many other respiratory and non-respiratory febrile viral infections without recurrences and a severe recurrence following Sars-CoV-2 infection, suggesting a potentiation effect on cytokine cascade. Her MRI showed the typical pattern of injury resembling that of mitochondrial disorders, and supported the role of RANBP2 in mitochondrial homeostasis. This case rises attention on diagnostic challenges and offers several interesting tips for discussion about new perspectives in pathogenesis and targeted treatments.