Pathogenesis and Management of Acute Necrotizing Encephalopathy.

INTRODUCTION: During the COVID-19 pandemic, many cases of acute necrotizing encephalopathy (ANE) secondary to COVID-19 have been reported. ANE is characterized by a rapid onset, a fulminant course, and low morbidity and fatality rates. Therefore, clinicians need to be vigilant for such disorders, especially during the influenza virus and COVID-19 epidemics. AREAS COVERED: The authors summarize the most recent studies on the clinical spectrum and treatment essentials of ANE to provide references for prompt diagnosis and improved treatment of this rare but fatal disease. EXPERT OPINION: ANE is a type of necrotizing lesion of the brain parenchyma. There are two major types of reported cases. One is isolated and sporadic ANE, which is primarily caused by viral infections, particularly influenza and HHV-6 virus. The other type is familial recurrent ANE, which is caused by RANBP2 gene mutations. ANE patients have rapid progression and a very poor prognosis, with acute brain dysfunction occurring within days of viral infection and requiring admission to the intensive care unit. Clinicians still need to investigate and find solutions for the problems of early detection and treatment of ANE.

SARS-CoV-2-Related Acute Necrotizing Encephalopathy of Childhood With Good Response to Tocilizumab in an Adolescent.

BACKGROUND: Acute necrotizing encephalopathy of childhood (ANEC) is a rare parainfectious neurological disorder. ANEC is associated with a high mortality rate and poor neurological outcomes. ANEC is postulated to arise from immune-mediated or metabolic processes driven by viral infections. Although there have been some case reports of acute necrotizing encephalopathy with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coinfection in adults, paediatric cases are rare. METHODS: A single case report of SARS-CoV-2-related ANEC in an 11-year-old boy is presented through retrospective chart review. Literature search was performed using PubMed, Embase, Cochrane database, and Google Scholar to compare and analyze similar cases of parainfectious immune-mediated encephalopathies related to SARS-CoV-2 in children. RESULTS: An 11-year-old boy with acute SARS-CoV-2 infection presented with ophthalmoplegia, ataxia, and aphasia. Neuroimaging findings demonstrated significant swelling and signal changes in bilateral thalami, brainstem, and cerebellar hemispheres, consistent with ANEC. His high ANEC Severity Score indicated poor neurological prognosis. Treatment with a combination of early steroid therapy, intravenous immunoglobulin therapy, and targeted interleukin 6 (IL-6) blockade yielded good neurological improvements. Literature search identified 19 parainfectious immune-mediated neurological disorders related to SARS-CoV-2 in children. The only other pediatric ANEC case identified was postinfectious and thus not included. CONCLUSIONS: This is the first report of a pediatric case of SARS-CoV-2-related ANEC, which responded well to early immunotherapy, including IL-6 blockade. Early immunotherapy with IL-6 blockade can be considered as an adjunct in managing severe ANEC.

Pathogenesis and Preventive Tactics of Immune-Mediated Non-Pulmonary COVID-19 in Children and Beyond.

The COVID-19 pandemic has evolved to immune escape and threatened small children and the elderly with a higher severity and fatality of non-pulmonary diseases. These life-threatening non-pulmonary COVID-19 diseases such as acute necrotizing encephalopathies (ANE) and multisystem inflammatory syndrome in children (MIS-C) are more prevalent in children. However, the mortality of multisystem inflammatory syndrome in adults (MIS-A) is much higher than that of MIS-C although the incidence of MIS-A is lower. Clarification of immunopathogenesis and genetic susceptibility of inflammatory non-pulmonary COVID-19 diseases would provide an appropriate guide for the crisis management and prevention of morbidity and fatality in the ongoing pandemic. This review article described three inflammatory non-pulmonary COVID-19 diseases including (1) meningoencephalitis (ME), (2) acute necrotizing encephalopathies (ANE), and (3) post-infectious multisystem inflammatory syndrome in children (MIS-C) and in adults (MIS-A). To prevent these life-threatening non-pulmonary COVID-19 diseases, hosts carrying susceptible genetic variants should receive prophylactic vaccines, avoid febrile respiratory tract infection, and institute immunomodulators and mitochondrial cocktails as early as possible.

Acute necrotizing encephalopathy in association with COVID-19 Infection: A case report

This case report is to highlight a case of acute necrotizing encephalopathy in association with COVID-19 infection in a previously healthy male. A healthy 31-year old man presented with acute delirium at day 10 of fever. Clinical examination revealed the patient was confused and had jaw opening dystonia with myorhythmia orofacial movement. Polymerase chain reaction test for COVID-19 was positive, with a normal plain computed tomography brain finding on day 1 of admission. In the ward, patients had episodes of fall and a contrast CT brain revealed bilateral thalamic hypodensities. Patient's condition remained static despite regular Intravenous dexamethasone, Intravenous Thiamine and Tablet Haloperidol. Magnetic Resonance Imaging done on day 17 of illness demonstrated diffuse bilateral thalamic hyperintensities with subtle hyperintensities of bilateral dentate nuclei and pons on T2W/FLAIR. The bilateral thalamic lesions showed blooming on GRE. The findings were consistent with ANEC post COVID-19 infection. Patient improved after 3 days of IV Methylprednisolone 1g once daily combined with Trihexyphenidyl and benzodiazepine. He was discharged well on Day 22. Repeated MRI Brain 6 weeks post infection showed resolving bilateral thalamic lesions which correlated with improving clinical symptoms.COVID-19 viral infection which may be linked to an acute severe encephalopathy, was thought to represent an immune-mediated phenomena which responded to steroid treatment. We presented a type of COVID-19 related neurologic presentation that improved clinically, and radiologically with treatment.

From ran(bp2) dom to Recurrent: A Case of Familial Acute Necrotizing Encephalopathy

Introduction: Acute necrotizing encephalopathy (ANE) is a rare condition often triggered by infection and characterized by febrile prodromal illness, seizures, altered mental status and bilateral brain lesions. While many cases are isolated, a recurrent familial pattern has been linked to missense mutation of the gene encoding RAN binding protein 2 (RANBP2). Early administration of high dose steroids has been associated with improved outcomes, while IVIG and tocilizumab have also shown benefit. Case Description: A two-year-old male presented with vomiting, somnolence and seizure-like activity. Evaluation revealed positive SARS-CoV2, adenovirus and rhinovirus/enterovirus PCR by nasopharyngeal swab, and Mycoplasma pneumoniae IgM. MRI showed numerous foci of restricted diffusion and microhemorrhage as well as necrotic change in the internal capsules. He was diagnosed with ANE. He recovered to neurologic baseline following treatment with IVIG and corticosteroids. After six months, the patient presented with similar symptoms. SARS-CoV2 IgG was positive, but no new infectious pathogens were identified. Cerebrospinal fluid (CSF) analysis showed elevated IL-6 and IL-8 levels, suggestive of inflammatory breakdown of the blood-brain barrier. Brain MRI demonstrated worsened bilateral T2/fluid attenuated inversion reduction signal abnormalities and necrosis within the midbrain and pons bilaterally, concerning for recurrent ANE. Following multidisciplinary consultation, the patient was treated with corticosteroids and IVIG. Tocilizumab was later added due to elevated CSF IL-6. Worsening MRI findings (Figure 1) coupled with decrease in strength and spontaneous movement prompted plasma exchange (PLEX) therapy. While his exam improved after PLEX, treatment was discontinued due to development of a pericardial effusion. The patient steadily improved neurologically and was transitioned to inpatient rehabilitation with an ongoing steroid taper, monthly IVIG, and tocilizumab therapy. Given recurrence of ANE, an epilepsy genetic sequencing panel was ordered and revealed heterozygous mutation in RANBP2 (c.1966A>G p.Ile656Val). Discussion: During the patient's initial presentation, it was reasonable to conclude an infectious trigger for ANE given the presence of several potential inciting pathogens. Upon recurrence, investigation of underlying genetic predisposition was warranted. This patient exhibited the classic clinical and radiographic findings of recurrent ANE and was found to have RANBP2 mutation. Available literature suggests pathogenicity of the same mutation identified in this case due to its location in a highly conserved genetic region and its presence in affected members of a family with ANE. To our knowledge, this is the second report of this specific RANBP2 mutation in association with ANE. Conclusion: While ANE may present as a singular event following infection, recurrence is rare and should prompt evaluation of underlying genetic predisposition. Consideration of familial ANE with testing for RANBP2 mutation may lead to early genetic counseling. Our case also provides additional support for the pathogenicity of the RANBP2 (p.Ile656Val) mutation. (Figure Presented).

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.

Multi-detector computed tomography and 3Tesla magnetic resonance imaging in assessment of COVID-19 intracranial complications

Background: The novel worldwide coronavirus (COVID-19) pandemic, first appearing in Wuhan, China, has allured immense global attention. To our comprehension, this research work accommodates the largest isolation hospital-conducted cohort of coronavirus patients in which neuro-radiological complications were retrospectively assessed. To the present day, our full understanding of COVID-19 and its spectrum of diverse complications still remains insufficient. Moreover, the number of reported neurological complications albeit the global spread of the coronavirus pandemic is also widely lacking due to the constrained implementation of MR neuro-imaging in COVID-19 patients. Results: Forty-eight males and 26 females met the inclusion criteria, with a mean age 60.55 (ranged from 22 to 88 years old). The frequent clinical manifestation has impaired level of consciousness 55.4%. Most commonly recurring radiological findings were ischemic stroke 54.06% and parenchymal hematomas and hemorrhage 25.69%. Other less imaging brain findings were certain diagnostic entities, i.e., PRES, cerebral edema, leuko-encephalopathic WM abnormalities, microhemorrhages, vascular thrombosis and acute necrotizing encephalopathy. Soaring mortality rates correlated with serious neuro-radiological manifestations, being highest with infarction 57.5%, p = 0.908 and hemorrhage/hematomas 63.2%, p = 0.604. Conclusions: Intra-cranial complications were significantly detectable in COVID-19 infection and correlated with severity of illness. Outstanding higher mortality rates were associated with worsening neuro-radiological complications.

Case Report: Acute Necrotizing Encephalopathy Following COVID-19 Vaccine.

Objectives: Acute necrotizing encephalopathy (ANE) is a rare neurological disorder arising from a para- or post-infectious "cytokine storm. "It has recently been reported in association with coronavirus disease 2019 (COVID-19) infection. Methods: A 56-year-old male with a diagnosis of ANE 48 h following the first dose of ChAdOx1 nCoV-19 vaccination was investigated. Cytokine analyses on serum and cerebrospinal fluid (CSF) were performed. The patient was treated with high-dose corticosteroids and followed clinically and radiologically. Results: Favorable clinical and radiological outcomes were noted. There was an upregulation in serum levels of CXCL5, CXCL1, Il-8, IL-15, CCL2, TGF-B, and EGF, and up-regulation in CSF levels of CXCL5, IL-2, IL-3, and IL-8. Discussion: As COVID-19 infection has been previously reported as a possible rare cause of ANE, we speculate on an aberrant immune response mechanism that was brought about by the vaccine. To increase our understanding of the pathogenesis of ANE in the context of COVID-19 vaccination and to better define its clinical features and outcomes, clinicians and scientists should continue reporting convincing cases of such entities.

Association of acute disseminated encephalomyelitis (ADEM) and COVID-19 in a pediatric patient.

Cases of acute disseminated encephalomyelitis (ADEM) and its hyperacute form, acute hemorrhagic leukoencephalitis (AHLE), have been reported in coronavirus disease 2019 (COVID-19) patients as rare, but most severe neurological complications. However, histopathologic evaluations of ADEM/AHLE pathology in COVID patients are extremely limited, so far having only been reported in a few adult autopsy cases. Here we compare the findings with an ADEM-like pathology in a pediatric patient taken through a biopsy procedure. Understanding the neuropathology may shed informative light on the autoimmune process affecting COVID-19 patients and provide critical information to guide the clinical management.

COVID-19 Associated Encephalopathies and Cerebrovascular Disease: The New Orleans Experience

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic that is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has had a dramatic impact on healthcare systems and a variable disease course. Emerging evidence demonstrates that SARS-CoV-2 is associated with central nervous system (CNS) disease. In this series, we describe CNS manifestations in critical COVID-19 patients at our tertiary academic center. METHODS: A single center retrospective cross-sectional analysis of all patients admitted to our tertiary care academic center inNewOrleans, Louisiana on April 22, 2020, who were in critical condition due to COVID-19 and developed new onset of neurological disease. Patients were grouped into one of three categories according to imaging and clinical features: encephalopathy, acute necrotizing encephalopathy, and vasculopathy. RESULTS: A total of 27 of 76 (35.5%) critical COVID-19 patients met inclusion criteria. Mean age was 59.8 years (range 35-91 years) and most had an underlying medical condition, including hypertension (63%), diabetes mellitus type 2 (52%), obesity (26%), and/or chronic kidney disease (22%). Sixty three percent had evidence of neurological injury on CT, 30% on MRI, 15% on non-invasive vascular imaging, and 44% on EEG. CT findings most often included subacute ischemic strokes, diffuse hypoattenuation, subcortical parenchymal hemorrhages, and focal hypodensities within deep structures. MRI findings included diffuse involvement of deep white matter, the corpus callosum, and the basal ganglia. For patients with acute ischemic stroke, vascular findings consisted of irregular proximal focal stenosis of the supraclinoid internal carotid artery. Twenty patients (74%) were designated with COVID-19 associated encephalopathy, two (7%) with COVID-19 associated acute necrotizing encephalopathy, and five (19%) with COVID-19 associated vasculopathy. CONCLUSION: A one-day snapshot of COVID-19 admissions at a tertiary academic center in New Orleans, LA revealed a high percentage of patients with new neurological disease. Although clinical presentations varied, they were broadly categorized. A better understanding of the neurological sequalae and radiographic findings will help clinicians mitigate the impact of this disease.

COVID 19 RELATED ACUTE NECROTIZING ENCEPHALOPATHY COMPLICATED WITH PITUITARY APOPLEXY

Background: Severe Acute Respiratory Syndrome Corona Virus 2(SARS-Cov2) is well known to cause a multitude of neurologic conditions out of which remains the rather rare condition of Acute Necrotizing Encephalopathy. It's a devastating condition with early immunotherapy bringing a more favorable outcome. Pathophysiology suggests the dysregulation of the blood brain barrier secondary to the cytokine storm. Pituitary apoplexy is an unrelated acute condition in which there is either hemorrhagic or non- hemorrhagic necrosis of the pituitary gland. It again has multiple predisposing factors including changes in intracranial pressure and underlying coagulation disorders. Case Presentation: A thirty-five-year-old male patient with poorly controlled diabetes presented to our emergency department with fever, cough and progressive respiratory distress for three days. He was drowsy with clinical features of bronchopneumonia and his COVID PCR was positive (He had taken only the first dose of Sinopharm nearly a month before). Within twenty-four hours, he was sent to the ICU for ventilatory support mainly due to low GCS. His HRCT Chest revealed severe COVID pneumonia. MRI brain revealed high signal intensities involving cerebellum, brainstem, bilateral thalami and mesial temporal lobes compatible with acute necrotizing encephalopathy with a pituitary macroadenoma and bleeding into it. He received high dose steroids followed by plasma exchange leading to resolution of the above changes within a month but passed away at the end of six weeks due to secondary bacterial sepsis. Discussion: Here the pituitary macroadema was an incidental finding and the bleeding was postulated to be secondary to changes in intra cranial pressure. Both the Necrotizing encephalopathy and the pituitary apoplexy might have resulted in the reduced conscious level in the above patient in the background of severe COVID pneumonia. The immunotherapy was successful in resolution of the radiologic changes though the patient deteriorated clinically following a transient improvement due to bacterial sepsis.

Acute necrotizing encephalopathy secondary to COVID-19.

Coronavirus disease 2019 causes a range of presentations, including central nervous system involvement. Acute necrotizing encephalopathy (ANE), in particular, is a growing area of investigation. A high index of clinical suspicion is necessary for early diagnosis and appropriate management. Here, we describe two cases of suspected ANE secondary to the severe acute respiratory syndrome coronavirus-2 virus.

The Impact of COVID-19 On Comorbidities: A Review Of Recent Updates For Combating It.

Coronavirus disease is caused by the SARS-CoV-2 virus. The virus first appeared in Wuhan (China) in December 2019 and has spread globally. Till now, it affected 269 million people with 5.3 million deaths in 224 countries and territories. With the emergence of variants like Omicron, the COVID-19 cases grew exponentially, with thousands of deaths. The general symptoms of COVID-19 include fever, sore throat, cough, lung infections, and, in severe cases, acute respiratory distress syndrome, sepsis, and death. SARS-CoV-2 predominantly affects the lung, but it can also affect other organs such as the brain, heart, and gastrointestinal system. It is observed that 75 % of hospitalized COVID-19 patients have at least one COVID-19 associated comorbidity. The most common reported comorbidities are hypertension, NDs, diabetes, cancer, endothelial dysfunction, and CVDs. Moreover, older and pre-existing polypharmacy patients have worsened COVID-19 associated complications. SARS-CoV-2 also results in the hypercoagulability issues like gangrene, stroke, pulmonary embolism, and other associated complications. This review aims to provide the latest information on the impact of the COVID-19 on pre-existing comorbidities such as CVDs, NDs, COPD, and other complications. This review will help us to understand the current scenario of COVID-19 and comorbidities; thus, it will play an important role in the management and decision-making efforts to tackle such complications.

A case of successive development of possible acute necrotizing encephalopathy after COVID-19 pneumonia.

COVID-19 infection often results in an excessive inflammatory response with a spectrum of neurological manifestations. Here, we describe an 81-year-old female with severe COVID-19 pneumonia and subsequent alteration of consciousness after high-dose intravenous dexamethasone and remdesivir. A non-contrast head computed tomography (CT) demonstrated bilateral hypodensities involving bilateral cerebellar hemispheres, thalami, cerebral peduncles and medial parieto-occipital areas. There was no improvement and repeat CT showed progression with findings suggestive of acute necrotizing encephalopathy. Interleukin-6 levels were initially normal; however, subsequent levels were found to be markedly elevated. Acute necrotizing encephalopathy associated with COVID-19 may occur in the setting of severe pneumonia and may represent an immune-mediated process involving inflammatory cytokines such as interleukin-6.

The Novel Coronavirus Infection (COVID-19) and Nervous System Involvement: Mechanisms of Neurological Disorders, Clinical Manifestations, and the Organization of Neurological Care.

The new coronavirus SARS-CoV-2 and the disease it causes COVID-19 involves not only respiratory system damage, but can also lead to disorders of the central and peripheral nervous system, as well as the muscular system. This article presents published data and our own observations on the course of neurological disorders in COVID-19 patients. There is a relationship between the severity of COVID-19 and the severity and frequency of neurological manifestations. Severe neurological disorders are mostly seen in severe cases of COVID-19 and include acute cerebrovascular accidents (aCVA), acute necrotizing encephalopathy, and Guillain-Barré syndrome. Factors potentially complicating the course of COVID-19 and increasing the development of neurological complications include arterial hypertension, diabetes mellitus, and chronic cardiac and respiratory system diseases. Questions of the possible effects of human coronaviruses on the course of chronic progressive neurological diseases are addressed using multiple sclerosis (MS) as an example. We discuss the management of patients with aCVA and MS depending on the risk of developing coronavirus infection.

Extensive cerebellar involvement and cognitive impairment in COVID-19-associated acute necrotizing encephalopathy.

Neurological complications of the newly appeared severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are increasingly recognized. Here, we report a case of a young male presenting with a clinical and neuroimaging scenario of an acute necrotizing encephalopathy related to the coronavirus disease 2019 (COVID-19). This case is notable by its distinct pattern of magnetic resonance imaging findings of an extensive involvement of the cerebellum, and emergence of cognitive and behavioral impairment.

[Novel coronavirus infection (COVID-19) and nervous system involvement: pathogenesis, clinical manifestations, organization of neurological care]. / Novaya koronavirusnaya infektsiya (COVID-19) i porazhenie nervnoi sistemy: mekhanizmy nevrologicheskikh rasstroistv, klinicheskie proyavleniya, organizatsiya nevrologicheskoi pomoshchi.

Novel coronavirus SARS-CoV-2 and COVID-19, besides affecting the respiratory system, may lead to central and peripheral nervous system disorders and also cause muscular symptoms. The authors review the literature and own clinical case with respect to nervous system involvement in COVID-19 patients. There is a correlation between the severity of COVID-19 and the severity and frequency of neurologic complications. Severe neurologic symptoms are primarily observed in patients with severe COVID-19. Neurologic-associated symptoms may include stroke, acute necrotizing encephalopathy, and Guillen-Barre syndrome. Diseases that potentially aggravate COVID-19 and increase the risk of neurologic complications include arterial hypertension, diabetes, chronic diseases of the heart and respiratory system. The probable impact of human coronaviruses on chronic and progressive diseases of the nervous system with particular respect to multiple sclerosis is reviewed. A triage plan for stroke and MS patients during the COVID-19 pandemic, depending on the risk of coronavirus infection, is presented.

The neurological significance of COVID-19: Lesson learn from the pandemic.

Coronavirus Infectious Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; previously known as 2019 novel coronavirus) is an emerging and rapidly evolving health issue that has been widespread globally and become a pandemic. The typical symptoms of COVID-19 are: a cough, shortness of breath and a fever; from the initial estimates, about 15% of COVID-19 patients present with severe respiratory symptoms and requires hospitalization and intensive care. Recent accumulated evidences showed that the neurological insults also occurred in patients with COVID-19, ranging from mild headache to severe neurological symptoms. In this review, we summarize the COVID-19 and neurological significance of COVID-19.