Viral entry and translation in brain endothelia provoke influenza-associated encephalopathy.

Influenza-associated encephalopathy (IAE) is extremely acute in onset, with high lethality and morbidity within a few days, while the direct pathogenesis by influenza virus in this acute phase in the brain is largely unknown. Here we show that influenza virus enters into the cerebral endothelium and thereby induces IAE. Three-weeks-old young mice were inoculated with influenza A virus (IAV). Physical and neurological scores were recorded and temporal-spatial analyses of histopathology and viral studies were performed up to 72 h post inoculation. Histopathological examinations were also performed using IAE human autopsy brains. Viral infection, proliferation and pathogenesis were analyzed in cell lines of endothelium and astrocyte. The effects of anti-influenza viral drugs were tested in the cell lines and animal models. Upon intravenous inoculation of IAV in mice, the mice developed encephalopathy with brain edema and pathological lesions represented by micro bleeding and injured astrocytic process (clasmatodendrosis) within 72 h. Histologically, massive deposits of viral nucleoprotein were observed as early as 24 h post infection in the brain endothelial cells of mouse models and the IAE patients. IAV inoculated endothelial cell lines showed deposition of viral proteins and provoked cell death, while IAV scarcely amplified. Inhibition of viral transcription and translation suppressed the endothelial cell death and the lethality of mouse models. These data suggest that the onset of encephalopathy should be induced by cerebral endothelial infection with IAV. Thus, IAV entry into the endothelium, and transcription and/or translation of viral RNA, but not viral proliferation, should be the key pathogenesis of IAE.

[A case of COVID-associated encephalopathy in a patient with multiple sclerosis]. / Klinicheskii sluchai COVID-assotsiirovannoi entsefalopatii u patsienta s rasseyannym sklerozom.

A case of acute encephalopathy manifested with impaired consciousness, hemichorrhea, speech and cognitive impairment in a female patient with COVID-19 and multiple sclerosis is presented. In the literature, there are isolated reports of such a combination of diseases, and therefore difficulties arise in carrying out differential diagnosis and prescribing therapy. Given the limited knowledge about the long-term consequences of COVID-19, systematic analysis of such cases and follow-up of such patients is necessary.

Severe A(H1N1)pdm09 influenza acute encephalopathy outbreak in children in Tuscany, Italy, December 2023 to January 2024.

A severe outbreak of influenza A(H1N1pdm09) infection in seven children (median age: 52 months) occurred between December 2023 and January 2024 in Tuscany, Italy. Clinical presentation ranged from milder encephalopathy to acute necrotizing encephalopathy (ANE) with coma and multiorgan failure; one child died. This report raises awareness for clinicians to identify and treat early acute encephalopathy caused by H1N1 influenza and serves as a reminder of severe presentations of influenza in young children and the importance of vaccination.

Genetic Comparison of Human Parainfluenza Virus Type 3 Detected in Respiratory Samples from Patients with Encephalopathy and Airway Inflammation in Aichi Prefecture, Japan.

Human parainfluenza virus type 3 (HPIV-3, human respirovirus 3) is the second most frequently detected virus in lower respiratory tract infections in children after human respiratory syncytial virus (HRSV). HPIV-3, similar to related respiratory viruses such as HRSV and influenza virus, may cause encephalopathy; however, the relevance of HPIV-3 as a pathogenic factor in encephalopathy is unknown. We attempted to detect HPIV-1, HPIV-2, HPIV-3, HPIV-4, HRSV, and human metapneumovirus (HMPV) in 136 patients with encephalitis/encephalopathy or suspected encephalitis/encephalopathy during a 6-year period from 2014 to 2019. HPIV-3 was detected in 6 patients, followed by HRSV in 3 patients. The HPIV-3 strains detected were closely related to those detected in a patient with respiratory disease during the same period. Although HPIV-3 is less widely recognized than HRSV as a triggering virus of encephalopathy, our results suggest that HPIV-3 is as important as HRSV. Surveillance of the causative viruses of encephalopathy, including HPIV-3, would help clarify the causes of encephalopathy in Japan, as the cause is currently reported in less than half of cases in Japan.

Myeloencephalitis as the only presentation of Omicron SARS-CoV-2 infection.

SARS-CoV-2 is now a major global health issue and manifests mainly as a respiratory disorder. Several other complications involving hypercoagulability, cardiovascular system and central nervous system have been described in the literature. Among these atypical presentations, encephalopathy associated with SARS-CoV-2 is a rare entity with heterogenous clinical and radiological findings. The direct presence of SARS-CoV-2 in cerebrospinal fluid (CSF) was rarely found in encephalopathy patients with acute SARS-Cov-2 infection.Here, we report a case of myeloencephalitis with positive real-time PCR for SARS-CoV-2 in CSF in a young woman presenting exclusively with neurological symptoms. Other differential diagnosis were extensively pursued by a comprehensive aetiological workup. To our knowledge, this is the first case report in the Omicron era. In the context of recent global explosion of SARS-Cov-2 infections, clinicians should consider this pathogen among other possible neurotropic agents and be familiar with its radiological and clinical presentations.

Delayed encephalopathy after COVID-19: A case series of six patients.

RATIONALE: Acute encephalopathy is a severe neurological complication of coronavirus disease 2019 (COVID-19). Most cases of acute encephalopathy associated with COVID-19 occur within several weeks of COVID-19 onset. We describe a case series of 6 patients who developed delayed encephalopathy (DE) after COVID-19. PATIENT CONCERNS AND DIAGNOSES: We evaluated patients who recovered from COVID-19 and showed acute disturbance of consciousness or focal neurological deficits without recurrence of pneumonitis. Six patients, 2 females and 4 males, with ages ranging from 65 to 83 years were included. Durations of hospitalization due to COVID-19 were between 25 and 44 days. The severity of COVID-19 was moderate in 5 and severe in 1 patient. Patients were rehospitalized for acute disturbance of consciousness concomitant with postural tremor and, abnormal behavior, hemiplegia, aphasia, or apraxia between 34 and 67 days after the onset of COVID-19. Chest computed tomography showed no exacerbation of pneumonitis. Brain magnetic resonance imaging showed no specific findings except in 1 patient with an acute lacunar infarction. Electroencephalogram demonstrated diffuse slowing in all patients. Repeat electroencephalogram after recovery from encephalopathy demonstrated normal in all patients. One of the 6 patients had cerebrospinal fluid (CSF) pleocytosis. CSF protein levels were elevated in all patients, ranging from 51 to 115 mg/dL. CSF interleukin-6 levels ranged from 2.9 to 10.9 pg/mL. The immunoglobulin index was 0.39 to 0.44. Qlim(alb) < QAlb indicating dysfunction of the blood-brain barrier was observed in all patients. Severe acute respiratory syndrome coronavirus 2 reverse transcription polymerase chain reaction of CSF was negative in all patients. Neuronal autoantibodies were absent in serum and CSF. INTERVENTIONS AND OUTCOMES: Immunotherapy including steroid pulses was administered to 3 patients; however, symptoms of encephalopathy resolved within several days in all patients, regardless of treatment with immunotherapy, and their consciousness levels were recovered fully. Notably, postural tremor remained for 2 weeks to 7 months. LESSONS: In our patients, DE after COVID-19 was characterized by symptoms of acute encephalopathy accompanied with tremor in the absence of worsening pneumonitis after the fourth week of COVID-19 onset. Our findings indicate blood-brain barrier dysfunction may contribute to the pathogenesis of DE after COVID-19.

Mechanisms of coronavirus infectious disease 2019-related neurologic diseases.

PURPOSE OF REVIEW: As of January 8, 2022, a global pandemic caused by infection with severe acute respiratory syndrome coronavirus (SARS-CoV)-2, a new RNA virus, has resulted in 304,896,785 cases in over 222 countries and regions, with over 5,500,683 deaths (www.worldometers.info/coronavirus/). Reports of neurological and psychiatric symptoms in the context of coronavirus infectious disease 2019 (COVID-19) range from headache, anosmia, and dysgeusia, to depression, fatigue, psychosis, seizures, delirium, suicide, meningitis, encephalitis, inflammatory demyelination, infarction, and acute hemorrhagic necrotizing encephalopathy. Moreover, 30-50% of COVID-19 survivors develop long-lasting neurologic symptoms, including a dysexecutive syndrome, with inattention and disorientation, and/or poor movement coordination. Detection of SARS-CoV-2 RNA within the central nervous system (CNS) of patients is rare, and mechanisms of neurological damage and ongoing neurologic diseases in COVID-19 patients are unknown. However, studies demonstrating viral glycoprotein effects on coagulation and cerebral vasculature, and hypoxia- and cytokine-mediated coagulopathy and CNS immunopathology suggest both virus-specific and neuroimmune responses may be involved. This review explores potential mechanistic insights that could contribute to COVID-19-related neurologic disease. RECENT FINDINGS: While the development of neurologic diseases during acute COVID-19 is rarely associated with evidence of viral neuroinvasion, new evidence suggests SARS-CoV-2 Spike (S) protein exhibits direct inflammatory and pro-coagulation effects. This, in conjunction with immune dysregulation resulting in cytokine release syndrome (CRS) may result in acute cerebrovascular or neuroinflammatory diseases. Additionally, CRS-mediated loss of blood-brain barrier integrity in specific brain regions may contribute to the expression of proinflammatory mediators by neural cells that may impact brain function long after resolution of acute infection. Importantly, host co-morbid diseases that affect vascular, pulmonary, or CNS function may contribute to the type of neurologic disease triggered by SARS-COV-2 infection. SUMMARY: Distinct effects of SARS-CoV-2 S protein and CNS compartment- and region-specific responses to CRS may underlie acute and chronic neuroinflammatory diseases associated with COVID-19.

Multimodal Investigation of Neuroinflammation in Aviremic Patients With HIV on Antiretroviral Therapy and HIV Elite Controllers.

BACKGROUND AND OBJECTIVES: The presence of HIV in the CNS has been related to chronic immune activation and cognitive dysfunction. The aim of this work was to investigate (1) the presence of neuroinflammation in aviremic people with HIV (PWH) on therapy and in nontreated aviremic PWH (elite controllers [ECs]) using a translocator protein 18 kDa radioligand; (2) the relationship between neuroinflammation and cognitive function in aviremic PWH; and (3) the relationship between [11C]-PBR28 signal and quantitative MRI (qMRI) measures of brain tissue integrity such as T1 and T2 relaxation times (rts). METHODS: [11C]-PBR28 (standard uptake value ratio, SUVR) images were generated in 36 participants (14 PWH, 6 ECs, and 16 healthy controls) using a statistically defined pseudoreference region. Group comparisons of [11C]-PBR28 SUVR were performed using region of interest-based and voxelwise analyses. The relationship between inflammation, qMRI measures, and cognitive function was studied. RESULTS: In region of interest analyses, ECs exhibited significantly lower [11C]-PBR28 signal in the thalamus, putamen, superior temporal gyrus, prefrontal cortex, and cerebellum compared with the PWH. In voxelwise analyses, differences were observed in the thalamus, precuneus cortex, inferior temporal gyrus, occipital cortex, cerebellum, and white matter (WM). [11C]-PBR28 signal in the WM and superior temporal gyrus was related to processing speed and selective attention in PWH. In a subset of PWH (n = 12), [11C]-PBR28 signal in the thalamus and WM regions was related to a decrease in T2 rt and to an increase in T1 rt suggesting a colocalization of increased glial metabolism, decrease in microstructural integrity, and iron accumulation. DISCUSSION: This study casts a new light onto the role of neuroinflammation and related microstructural alterations of HIV infection in the CNS and shows that ECs suppress neuroinflammation more effectively than PWH on therapy.

Neuroimaging Findings of Hospitalized Covid-19 Patients: A Canadian Retrospective Observational Study.

PURPOSE: Coronavirus disease (COVID-19) has been associated with neurologic sequelae and neuroimaging abnormalities in several case series previously. In this study, the neuroimaging findings and clinical course of adult patients admitted with COVID-19 to a tertiary care hospital network in Canada were characterized. METHODS: This is a retrospective observational study conducted at a tertiary hospital network in Ontario, Canada. All adult patients with PCR-confirmed COVID-19 admitted from February 1, 2020 to July 22, 2020 who received neuroimaging related to their COVID-19 admission were included. CT and MR images were reviewed and categorized by fellowship-trained neuroradiologists. Demographic and clinical data were collected and correlated with imaging findings. RESULTS: We identified 422 patients admitted with COVID-19 during the study period. 103 (24.4%) met the inclusion criteria and were included: 30 ICU patients (29.1%) and 73 non-ICU patients (70.9%). A total of 198 neuroimaging studies were performed: 177 CTs and 21 MRIs. 17 out of 103 imaged patients (16.8%) had acute abnormalities on neuroimaging: 10 had macrohemorrhages (58.8%), 9 had acute ischemia (52.9%), 4 had SWI abnormalities (23.5%), and 1 had asymmetric sulcal effacement suggesting possible focal encephalitis (5.8%). ICU patients were more likely to have positive neuroimaging findings, more specifically acute ischemia and macrohemorrhages (P < 0.05). Macrohemorrhages were associated with increased mortality (P < 0.05). CONCLUSION: Macrohemorrhages, acute ischemia and SWI abnormalities were the main neuroimaging abnormalities in our cohort of hospitalized COVID-19 patients. Acute ischemia and hemorrhage were associated with worse clinical status.

Influenza-associated Neurologic Complications in Hospitalized Pediatric Patients: A Multicenter Retrospective Study in Republic of Korea.

BACKGROUND: The rates of influenza-associated neurologic complications are variable among studies, and a difference has been observed between the Western and Asian countries. The study aims to evaluate the frequency and characteristics of influenza-associated neurologic complications. METHODS: We performed a retrospective review of hospitalized cases of influenza infection from October 2010 to April 2017 from 3 referral hospitals. RESULTS: A total of 1988 influenza cases were identified. Influenza-associated neurologic complications were 161 cases (8.1%); influenza virus A was detected in 113 (70.2%) cases, B in 47 (29.2%) cases and both A and B in 1 case (0.6%). Twenty-four patients (15%) had underlying neurologic diseases. The most common diagnosis was a simple febrile convulsion (44%), followed by complex febrile convulsion (29%), fever-provoked seizure under pre-existing neurologic disease or afebrile seizure (14%), encephalopathy/encephalitis (8%) and meningitis (5%). Most of the patients fully recovered (96%). Three patients (1.9%) died of myocarditis (n = 1), encephalopathy (n = 1), and simultaneous encephalitis and myocarditis (n = 1). Pre-existing neurologic disease, age groups of 6 months to 6 years and 6-12 years were a risk factor of influenza-associated neurologic complications with an adjusted odds ratio of 5.41 (95% confidence interval [CI] 3.23-9.06, P < 0.001), 12.99 (95% CI 1.77-95.19, P = 0.01) and 8.54 (95% CI 1.14-64.79, P = 0.04), respectively. There was no association between neuropsychiatric adverse events and oseltamivir prescription (P = 0.17). CONCLUSIONS: Influenza-associated neurologic complications are not uncommon, and most patients fully recovered. The frequency of influenza-associated neurologic complications in Korean children was not significantly different from that of children in Western countries.

Neuropathology and Inflammatory Cell Characterization in 10 Autoptic COVID-19 Brains.

COVID-19 presents with a wide range of clinical neurological manifestations. It has been recognized that SARS-CoV-2 infection affects both the central and peripheral nervous system, leading to smell and taste disturbances; acute ischemic and hemorrhagic cerebrovascular disease; encephalopathies and seizures; and causes most surviving patients to have long lasting neurological symptoms. Despite this, typical neuropathological features associated with the infection have still not been identified. Studies of post-mortem examinations of the cerebral cortex are obtained with difficulty due to laboratory safety concerns. In addition, they represent cases with different neurological symptoms, age or comorbidities, thus a larger number of brain autoptic data from multiple institutions would be crucial. Histopathological findings described here are aimed to increase the current knowledge on neuropathology of COVID-19 patients. We report post-mortem neuropathological findings of ten COVID-19 patients. A wide range of neuropathological lesions were seen. The cerebral cortex of all patients showed vascular changes, hyperemia of the meninges and perivascular inflammation in the cerebral parenchyma with hypoxic neuronal injury. Perivascular lymphocytic inflammation of predominantly CD8-positive T cells mixed with CD68-positive macrophages, targeting the disrupted vascular wall in the cerebral cortex, cerebellum and pons were seen. Our findings support recent reports highlighting a role of microvascular injury in COVID-19 neurological manifestations.

Microglia and Perivascular Macrophages Act as Antigen Presenting Cells to Promote CD8 T Cell Infiltration of the Brain.

CD8 T cell infiltration of the central nervous system (CNS) is necessary for host protection but contributes to neuropathology. Antigen presenting cells (APCs) situated at CNS borders are thought to mediate T cell entry into the parenchyma during neuroinflammation. The identity of the CNS-resident APC that presents antigen via major histocompatibility complex (MHC) class I to CD8 T cells is unknown. Herein, we characterize MHC class I expression in the naïve and virally infected brain and identify microglia and macrophages (CNS-myeloid cells) as APCs that upregulate H-2Kb and H-2Db upon infection. Conditional ablation of H-2Kb and H-2Db from CNS-myeloid cells allowed us to determine that antigen presentation via H-2Db, but not H-2Kb, was required for CNS immune infiltration during Theiler's murine encephalomyelitis virus (TMEV) infection and drives brain atrophy as a consequence of infection. These results demonstrate that CNS-myeloid cells are key APCs mediating CD8 T cell brain infiltration.

Clinical Characteristics of H1N1 Influenza A-Associated Mild Encephalopathy with Reversible Splenial Lesion: 4 Pediatric Cases.

OBJECTIVE: Mild encephalopathy with reversible splenial lesion (MERS) is associated with a variety of infections and anti-epileptic drug withdrawal. Here we report the clinical characteristics of H1N1 influenza A-associated MERS based on our experience of four pediatric cases. METHODS: A detailed retrospective analysis of four patients with H1N1 influenza A-associated MERS was performed at Guangzhou Women and Children's Medical Center. RESULTS: All patients exhibited mild influenza-like illness and seizures. Three patients presented with a new-onset seizure with fever after 5 years of age. 75% patients had altered mental status. For all four patients, influenza A (H1N1) viral RNA was detected in throat swab specimens at least twice. Brain magnetic resonance images revealed similar ovoid lesions in the corpus callosum, mainly in the splenium and for one patient in the splenium and genu of the corpus callosum. Only one patient had an abnormal electroencephalogram tracing. Cells and protein in the cerebrospinal fluid were normal in all patients. All patients received oseltamivir and one patient received intravenous immunoglobulin. As a result, all patients fully recovered after 2 months and showed no neurologic sequelae at discharge. CONCLUSION: This case series provides insight towards clinical features of H1N1 influenza A-associated MERS.

Mild encephalitis/encephalopathy with a reversible splenial lesion associated with respiratory syncytial virus infection in infants.

Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) is a clinicoradiologic syndrome typically characterized by transient mild encephalitis or encephalopathy with reversible lesions being found in the splenium of corpus callosum (SCC) by magnetic resonance imaging (MRI). A variety of pathogens including influenza virus, rotavirus, and adenovirus associated with MERS have been reported. However, respiratory syncytial virus (RSV)-related MERS is relatively rare in infants. In this study, we report two Chinese infants who suffered from RSV-related MERS. Both infants manifested as fever, seizure, and altered states of consciousness with confirmed detections of RSV-RNA in the specimens from throat swab. Clinical symptoms/signs such as apnea and shallow breathing were also noted in these two infants. Furthermore, brain MRI images indicated reversible isolated lesions with transiently reduced diffusion in the SCC. Fortunately, both of these two infants recovered completely following treatment within a month. Our study suggests that RSV may serve as a novel causative agent for MERS in infants. Clinicians should focus more attention on RSV-related MERS in infants in order to improve early accurate diagnosis and therapeutic decision making.

Acute cerebellitis following SARS-CoV-2 infection: A case report and review of the literature.

Novel coronavirus disease (COVID-19) first described in Wuhan, China in December 2019, has rapidly spread across the world and become a global public health emergency. Literature on the neurological manifestations of COVID-19 is limited. We report a 24-year-old male, who presented with vertigo, dysarthria, and bradyphrenia 3 weeks after being diagnosed with COVID-19 on nasopharyngeal reverse transcription polymerase chain reaction. The patient was diagnosed with acute cerebellitis based on magnetic resonance imaging features and showed improvement posttreatment with intravenous methylprednisone for 5 days. The scope of this article is to highlight the importance of early identification of neurological symptoms and timely management as the outcomes may be catastrophic.

POTENTIAL RISK OF BRAIN DAMAGE AND POOR DEVELOPMENTAL OUTCOMES IN CHILDREN PRENATALLY EXPOSED TO SARS-COV-2: A SYSTEMATIC REVIEW.

OBJECTIVE: To perform a systematic literature review to analyze existing data on the neurological effects of coronavirus on newborns. DATA: sources: We followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P), and searched the PubMed and Embase platforms for the keywords [brain damage OR pregnancy OR developmental outcomes] and [coronavirus OR SARS-CoV-2 OR SARS-CoV OR MERS-CoV] between January 1, 2000 and June 1, 2020. DATA: synthesis: Twenty-three reports described the course of pregnant women exposed to SARS-CoV-2, SARS-CoV, or MERS-CoV during the gestational period, eight to SARS-CoV-2, eight to SARS-CoV, and seven to MERS-CoV. No data were found on abnormalities in brain development or on a direct link between the virus and neurological abnormalities in the human embryo, fetus, or children. Spontaneous miscarriage, stillbirth, and termination of pregnancy were some complications connected with SARS/MERS-CoV infection. SARS-CoV-2 is not currently associated with complications in the gestational period. CONCLUSIONS: The literature has no data associating exposure to coronavirus during pregnancy with brain malformations and neurodevelopmental disorders. However, despite the lack of reports, monitoring the development of children exposed to SARS-CoV-2 is essential given the risk of complications in pregnant women and the potential neuroinvasive and neurotropic properties found in previous strains.

NK-lysin peptides ameliorate viral encephalopathy and retinopathy disease signs and provide partial protection against nodavirus infection in European sea bass.

Antimicrobial peptides (AMP) comprise a wide range of small molecules with direct antibacterial activity and immunostimulatory role and are proposed as promising substitutes of the antibiotics. Additionally, they also exert a role against other pathogens such as viruses and fungi less evaluated. NK-lysin, a human granulysin orthologue, possess a double function, taking part in the innate immunity as AMP and also as direct effector in the cell-mediated cytotoxic (CMC) response. This molecule is suggested as a pivotal molecule involved in the defence upon nervous necrosis virus (NNV), an epizootic virus provoking serious problems in welfare and health status in Asian and Mediterranean fish destined to human consumption. Having proved that NK-lysin derived peptides (NKLPs) have a direct antiviral activity against NNV in vitro, we aimed to evaluate their potential use as a prophylactic treatment for European sea bass (Dicentrarchus labrax), one of the most susceptible cultured-fish species. Thus, intramuscular injection of synthetic NKLPs resulted in a very low transcriptional response of some innate and adaptive immune markers. However, the injection of NKLPs ameliorated disease signs and increased fish survival upon challenge with pathogenic NNV. Although NKLPs showed promising results in treatments against NNV, more efforts are needed to understand their mechanisms of action and their applicability to the aquaculture industry.

The olfactory route is a potential way for SARS-CoV-2 to invade the central nervous system of rhesus monkeys.

Neurological manifestations are frequently reported in the COVID-19 patients. Neuromechanism of SARS-CoV-2 remains to be elucidated. In this study, we explored the mechanisms of SARS-CoV-2 neurotropism via our established non-human primate model of COVID-19. In rhesus monkey, SARS-CoV-2 invades the CNS primarily via the olfactory bulb. Thereafter, viruses rapidly spread to functional areas of the central nervous system, such as hippocampus, thalamus, and medulla oblongata. The infection of SARS-CoV-2 induces the inflammation possibly by targeting neurons, microglia, and astrocytes in the CNS. Consistently, SARS-CoV-2 infects neuro-derived SK-N-SH, glial-derived U251, and brain microvascular endothelial cells in vitro. To our knowledge, this is the first experimental evidence of SARS-CoV-2 neuroinvasion in the NHP model, which provides important insights into the CNS-related pathogenesis of SARS-CoV-2.