COVID-19 related acute necrotizing encephalopathy and acute myocarditis in an adult female: a novel case report of brain injury and myocarditis.

BACKGROUND: Acute necrotizing encephalopathy (ANE) and myocarditis are both acute, life-threatening conditions that can be triggered by COVID-19. We report a case of sequential ANE and myocarditis following a COVID-19 infection. CASE PRESENTATION: A 27-year-old female patient was brought to the emergency department due to episodes of fever for two days and a 9-h altered state of consciousness. Her condition rapidly developed into stuporous and hemodynamic instability within serval hours. Veno-arterial extracorporeal membrane oxygenation (ECMO) was rapidly initiated with other supportive treatments. The following-up MRI showed bilateral, symmetrically distributed lesions in the brainstem, bilateral hippocampal regions, and bilateral basal ganglia, consistent with ANE. The diagnosis was confirmed through the detection of SARS-CoV-2 and the exclusion of other potential causes. After weeks of medical treatment, her condition stabilized, and she was transferred for further rehabilitation treatment. CONCLUSIONS: This case study indicates that COVID-19 may simultaneously and rapidly affect the central nervous system and cardiovascular system, leading to poor outcomes. Accurate diagnosis and timely invasive bridging therapy, when necessary, can be lifesaving. Further exploration of potential mechanisms underlying COVID-19 central nervous system (CNS) and cardiovascular system manifestations will be important.

Acute necrotizing encephalopathy in adult patients with influenza: a case report and review of the literature.

The neurological complications of influenza affect mainly the pediatric Asian population. In the category of influenza-associated encephalopathy, acute necrotizing encephalopathy (ANE) is a rapidly progressive and fulminant brain disorder associated with significant neurological sequelae and mortality. To date, only a few adult cases of influenza-associated ANE have been reported. We describe a 44-year-old woman who presented with rapid progression of consciousness impairment and recurrent generalized convulsions. Influenza was diagnosed three days prior to presentation, and infection with influenza A (H3N2) pdm09 was subsequently confirmed. A diagnosis of ANE was made based on the presence of characteristic brain MRI findings, the exclusion of central nervous system infection, and an elevated serum interleukin-6 level. Pulse steroid therapy followed by tocilizumab was initiated, which led to clinical stabilization and improvement. Genetic testing revealed that the patient carried heterozygous human leukocyte antigen DQB1 03:03 and DRB1 09:01 genotypes. An analysis of the adult cases of influenza-associated ANE in the literature and the present case revealed a wide range of ages (22-71 years), a short interval (median 3 days) between the clinical onset of influenza and ANE, and a high overall mortality rate (32%). The thalamus was the most frequent (91%) location of the lesions. Our report highlights the importance of identifying this devastating but treatable neurological complication of influenza in adults, especially those of Asian descent. As a cytokine storm is the most accepted pathogenic mechanism for ANE, cytokine-directed therapies may be promising treatments for which further investigation is warranted.

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.

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.

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.

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.

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.

COVID-19 related acute necrotizing encephalopathy with extremely high interleukin-6 and RANBP2 mutation in a patient with recently immunized inactivated virus vaccine and no pulmonary involvement.

BACKGROUND: We report the first case of COVID-19 associated acute necrotizing encephalopathy (ANE) without pulmonary disease in a patient with an extremely high interleukin-6 (IL-6) level and Ran Binding Protein 2 (RANBP2) mutation. CASE PRESENTATION: A 29-year-old woman recently immunized with inactivated viral vaccine-BBIBP32-CorV (Sinopharm) presented with alteration of consciousness. Her body temperature was 37° Celsius, blood pressure 42/31 mmHg, heart rate 130 bpm, respiratory rate 20 per minute, and oxygen saturation 98%. Respiratory examination was unremarkable. Neurological examination revealed stupor but preserved brainstem reflexes. Non-contrast computerized tomography of the brain showed symmetrical hypodense lesions involving bilateral thalami and cerebellar hemispheres characteristic of ANE. No pulmonary infiltration was found on chest radiograph. SARS-CoV-2 was detected by PCR; whole genome sequencing later confirmed the Delta variant. RANBP2 gene analysis revealed heterozygous Thr585Met mutation. Serum IL-6 was 7390 pg/mL. Urine examination showed pyelonephritis. Her clinical course was complicated by seizure, septic shock, acute kidney injury, and acute hepatic failure. She later developed coma and passed away in 6 days. CONCLUSIONS: ANE is caused by cytokine storm leading to necrosis and hemorrhage of the brain. IL-6 was deemed as a prognostic factor and a potential treatment target of ANE in previous studies. RANBP2 missense mutation strongly predisposes this condition by affecting mitochondrial function, viral entry, cytokine signaling, immune response, and blood-brain barrier maintenance. Also, inactivated vaccine has been reported to precipitate massive production of cytokines by antibody dependent enhancement (ADE). The true incidence of COVID-19 associated ANE is not known as were the predictors of its development. We proposed these potential two factors (RANBP2 mutation and ADE) that could participate in the pathogenesis of ANE in COVID-19 apart from SARS-CoV2 infection by itself. Further study is needed to confirm this hypothesis, specifically in the post-vaccination period. Role of RANBP2 mutation and its application in COVID-19 and ANE should be further elaborated.

Outcomes in influenza and RANBP2 mutation-associated acute necrotizing encephalopathy of childhood.

AIM: To evaluate clinical and imaging features in patients with acute necrotizing encephalopathy of childhood (ANEC) to identify predictors of RANBP2 mutations, influenza association, and long-term outcomes. METHOD: A retrospective chart review in patients with ANEC (2012-2020) seen at a tertiary pediatric center was performed. Children were included if they had acute inflammatory lesions in the basal ganglia and pons. Variables included presenting features, imaging characteristics, RANBP2 gene testing, nasopharyngeal swab findings, therapies, and long-term outcomes. RESULTS: Twenty patients were included (average age at presentation 3y 6mo, interquartile range  3y 7mo, SD  2y 8mo; 14 females, six males). Three of the 20 experienced recurrences; one of the 20 died. Ten patients were influenza positive. Seven patients were RANBP2 mutation positive. A higher likelihood of hemorrhage was observed in patients who were influenza positive compared to influenza negative (p=0.048). Patients with influenza had a higher degree of thalamic hemorrhage (2, p=0.035) and greater extent of diffusion restriction (3, p=0.035) in semiquantitive analysis. INTERPRETATION: Children with ANEC who are positive for influenza are more likely to have hemorrhage and greater thalamic swelling. RANBP2 status was predictive of relapse but not predictive of overall outcome.

A novel variation in RANBP2 associated with infection-triggered familial acute necrotizing encephalopathy.

Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy occurring in otherwise healthy children after common viral infections. The condition presents as a spectrum of symptoms ranging from infections to seizures and coma, with the potential to cause long-term neurocognitive impairment or death. Familial and recurrent ANE is referred to as ANE1. A four-generation Chinese family with ANE1 was recruited for genetic analysis. A novel missense variation, c.9041A > G, p.(Glu3014Gly) in RANBP2 was identified in this family. This study is the first to identify a novel variation in RANBP2 in a Chinese family with ANE1.

Roles of Nucleoporin RanBP2/Nup358 in Acute Necrotizing Encephalopathy Type 1 (ANE1) and Viral Infection.

Ran Binding Protein 2 (RanBP2 or Nucleoporin358) is one of the main components of the cytoplasmic filaments of the nuclear pore complex. Mutations in the RANBP2 gene are associated with acute necrotizing encephalopathy type 1 (ANE1), a rare condition where patients experience a sharp rise in cytokine production in response to viral infection and undergo hyperinflammation, seizures, coma, and a high rate of mortality. Despite this, it remains unclear howRanBP2 and its ANE1-associated mutations contribute to pathology. Mounting evidence has shown that RanBP2 interacts with distinct viruses to regulate viral infection. In addition, RanBP2 may regulate innate immune response pathways. This review summarizes recent advances in our understanding of how mutations in RANBP2 contribute to ANE1 and discusses how RanBP2 interacts with distinct viruses and affects viral infection. Recent findings indicate that RanBP2 might be an important therapeutic target, not only in the suppression of ANE1-driven cytokine storms, but also to combat hyperinflammation in response to viral infections.

COVID-19: A Global Threat to the Nervous System.

In less than 6 months, the severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) has spread worldwide infecting nearly 6 million people and killing over 350,000. Initially thought to be restricted to the respiratory system, we now understand that coronavirus disease 2019 (COVID-19) also involves multiple other organs, including the central and peripheral nervous system. The number of recognized neurologic manifestations of SARS-CoV-2 infection is rapidly accumulating. These may result from a variety of mechanisms, including virus-induced hyperinflammatory and hypercoagulable states, direct virus infection of the central nervous system (CNS), and postinfectious immune mediated processes. Example of COVID-19 CNS disease include encephalopathy, encephalitis, acute disseminated encephalomyelitis, meningitis, ischemic and hemorrhagic stroke, venous sinus thrombosis, and endothelialitis. In the peripheral nervous system, COVID-19 is associated with dysfunction of smell and taste, muscle injury, the Guillain-Barre syndrome, and its variants. Due to its worldwide distribution and multifactorial pathogenic mechanisms, COVID-19 poses a global threat to the entire nervous system. Although our understanding of SARS-CoV-2 neuropathogenesis is still incomplete and our knowledge is evolving rapidly, we hope that this review will provide a useful framework and help neurologists in understanding the many neurologic facets of COVID-19. ANN NEUROL 2020;88:1-11 ANN NEUROL 2020;88:1-11.

Acute hemorrhagic leukoencephalitis in a COVID-19 patient-a case report with literature review.

PURPOSE: Acute hemorrhagic leukoencephalitis (AHLE) is a rare and severe form of acute disseminated encephalomyelitis (ADEM). Only a few reports of AHLE in coronavirus disease 2019 (COVID-19) patients have been described to date. We report a case of COVID-19-related AHLE along with a literature review describing salient clinical and imaging characteristics. METHODS: A literature search was performed on Medline (2020-present), PubMed, Cochrane Library, CINAHL, and Google scholar on 28 January 2021 for all articles published using MeSH terms "COVID-19" or "SARS-CoV-2" with "Acute hemorrhagic leukoencephalitis" or "Acute hemorrhagic encephalitis." Relevant case reports and case series describing clinical and imaging features of AHLE associated with SARS-CoV-2 infection were included, data compiled, and critically reviewed. RESULTS: Acute onset encephalopathy and rapidly deteriorating neurological status is the common clinical presentation in AHLE. CSF analysis reveals elevated proteins and lymphocytic pleocytosis. Typical neuroimaging features include multifocal, variable-sized, poorly defined cerebral white matter lesions with cortical sparing. Involvement of the brainstem, cerebellar peduncles, and deep grey matter can also occur, although rarely. Lesions are hyperintense on T2-weighted (T2W) and fluid-attenuated inversion recovery (FLAIR) images, hypointense on T1W images, and show microhemorrhages, variable diffusion restriction, and post-contrast enhancement. Extensive microhemorrhages, brainstem involvement, and gross hemorrhage often portend a poor prognosis. CONCLUSION: Heightened awareness about the clinical and imaging presentation of COVID-19-related AHLE can positively alter the outcome in a select few by enabling early diagnosis and aggressive management.

Acute necrotizing encephalopathy: A case report.

Acute necrotizing encephalopathy (ANE) is a recently identified, uncommon encephalopathy affecting children. ANE is characterized by a preceding viral illness followed by seizures and rapid progressive neurologic deterioration. The diagnosis of ANE is made based on clinical presentation and characteristic multifocal brain lesions seen on computed tomography (CT). We report a previously healthy two-year-old boy who presented to our emergency department (ED) after a seizure in the setting of fever and diarrhea. He was ultimately diagnosed with ANE and treated with steroids and IVIG. Early identification of this high morbidity condition by its typical clinical picture and characteristic radiologic findings is key to allow for optimal treatment.

A Case Series of Acute Hemorrhagic Leukoencephalitis.

ABSTRACT: Acute hemorrhagic leukoencephalitis (AHL) is an acute, hemorrhagic demyelinating disease thought to be caused by an immune-mediated process. Acute hemorrhagic leukoencephalitis is both diagnostically challenging and fatal in the majority of cases. We present two cases of AHL unexpectedly diagnosed at autopsy. These cases demonstrate the often nonspecific and challenging nature of AHL clinical presentation, review neuropathological mimics, and emphasize the importance of considering this diagnosis in the forensic setting.

Acute necrotizing encephalopathy of childhood: a single-center experience

Background/aim: Acute necrotizing encephalopathy is a rare type of acute encephalopathy characterized by multi-ocal brain lesions and associated severe neurological findings and various organ dysfunctions may accompany it. Materials and Methods: Patients with acute necrotizing encephalopathy of childhood diagnosed by pediatric neurology and pediatric intensive care at Sami Ulus Maternity, Child Health and Diseases Training and Research Hospital between 2007 and 2020 were included in this study. Results: Nine patients (six females, three males) with a mean age of 4.05 ± 1.94 years (age range 1­6.5) were included in this study. The interval range between fever and encephalopathy in patients was 1­4 days. Influenza A (3H1N1, one untyped) was detected in four patients, influenza B in three patients, and no cause was found in two patients. Major clinical findings other than febrile encephalopathy in all patients were a hemodynamic shock in seven patients, seizures in six patients, vomiting in five patients, dystonia in three patients, and flaccid paralysis in the upper extremity in one patient. Despite all our treatment approaches, including plasmapheresis, moderate to severe neurological sequelae was observed in all of our patients, who survived even with significant radiological improvement. Three patients for whom we could not perform plasmapheresis died. Conclusion: Our study revealed that thalamic involvement increased as the interval shortened, and brainstem involvement increased in patients over four years of age. The presence of persistent vomiting accompanying encephalopathy during the parainfectious period and plasmapheresis treatment being a treatment option that could prevent mortality were cautionary for our study.

COVID-19 and Headache: A Primer for Trainees.

OBJECTIVE: To summarize for the trainee audience the possible mechanisms of headache in patients with COVID-19 as well as to outline the impact of the pandemic on patients with headache disorders and headache medicine in clinical practice. BACKGROUND: COVID-19 is a global pandemic caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2, of which a large subset of patients features neurological symptoms, commonly headache. The virus is highly contagious and is, therefore, changing clinical practice by forcing limitations on in-person visits and procedural treatments, more quickly shifting toward the widespread adaptation of telemedicine services. DESIGN/RESULTS: We review what is currently known about the pathophysiology of COVID-19 and how it relates to possible mechanisms of headache, including indirect, potential direct, and secondary causes. Alternative options for the treatment of patients with headache disorders and the use of telemedicine are also explored. CONCLUSIONS: Limited information exists regarding the mechanisms and timing of headache in patients with COVID-19, though causes relate to plausible direct viral invasion of the nervous system as well as the cytokine release syndrome. Though headache care in the COVID-19 era requires alterations, the improved preventive treatment options now available and evidence for feasibility and safety of telemedicine well positions clinicians to take care of such patients, especially in the COVID-19 epicenter of New York City.

[Influenza A-associated acute necrotizing encephalopathy]. / Encefalopatía necrotizante aguda asociada a influenza A.

INTRODUCTION: Acute necrotizing encephalopathy of childhood (ANEC) is a rare disease characterized by alteration of consciousness and multiple symmetric brain lesions mainly involving the thalamus. It presents a high mortality rate and severe sequelae. OBJECTIVE: To describe a school-age patient with influenza A-related ANEC with favorable evolution. CLINICAL CASE: Six-year-old boy with 3 days history of upper respiratory symptoms and fever (39 °C). One day previous to admission, he presented altered state of consciousness. A lumbar puncture was performed, showing a mild increase of protein level in CSF. MRI showed bilateral foci of symmetric restricted signal in the thalamus, mammillary bodies, periaqueductal gray, ventral tegmentum, hippocampus, and in both external capsules, which was compatible with ANEC. The patient received empirical treatment with methylprednisolone and oseltamivir. Subsequently, a positive result was received for influenza. Considering diagnosis and severity of illness, it was decided to administer immunoglobulin. The patient got better slowly but favorably. At discharge, he still was mildly bradypsychic with decreased visual acuity, spontaneous speech and walking with assistance. At 6 months of follow-up, the patient presented normal speech and gait, with persistent visual impairment in the right eye. CONCLUSIONS: Our patient presented ANEC, whose timely diagnosis and management were associated with a favorable neurological evolution in the long term. Although ANEC is an infrequent pathology, it has very high morbidity and mortality rates, so it is very important to have a high degree of suspicion in order to request a targeted imaging study, search for related infectious causes, and start proper treatment.