COVID-19-Related Encephalitis in a Child with PIK3CD Defect

Introduction: COVID-19 related encephalitis has been reported in pediatric patients;however, there are no reports in patients with inborn errors of immunity (IEI). Activated PI3K Delta Syndrome (APDS) is a disease of immune dysregulation with immunodeficiency, autoimmunity, and abnormal lymphoproliferation resulting from autosomal dominant gain-offunction variants in PIK3CD or PIK3R1 genes. We investigate a family with APDS, one mother and three children, one of whom developed COVID-19 related encephalitis. Method(s): Patients were consented to an IRB-approved protocol at our institution. Medical records and detailed immunophenotyping were reviewed. Family members were sequenced for IEI with a targeted gene panel. Result(s): The index case is a 10-year-old female with a known pathogenic variant in PIK3CD (c.3061 G > A, p.Glu1021Lys), who contracted SARS-COV-2 despite one COVID-19 vaccination in the series. Her disease course included COVID-related encephalitis with cerebellitis and compression of the pons, resulting in lasting truncal ataxia and cerebellar mutism. At that time, the patient was not on immunoglobulin replacement therapy (IgRT), but was receiving Sirolimus. Besides the index case, 3 family members (2 brothers, 1 mother) also share the same PIK3CD variant with variable clinical and immunological phenotypes. All children exhibited high transitional B-cells, consistent with developmental block to follicular B cell stage. Increased non-class switched IgM+ memory B cells and skewing towards CD21lo B cell subset, which is considered autoreactive-like, was observed in all patients. Of note, the patient had low plasmablasts, but normal immunoglobulins. Of her family members, only one was receiving both sirolimus and IgRT. Conclusion(s): We describe a rare case of COVID-19-related encephalitis in a patient with inborn error of immunity while not on IgRT. This may indicate infection susceptibility because of a lack of sufficient immunity to SARS-CoV-2, unlike the rest of her family with the same PIK3CD variant.Copyright © 2023 Elsevier Inc.

Major neurological syndromes with COVID-19: lessons to learn

Objective: Covid-19 is a highly infectious viral disease, and our understanding of the impact of this virus on the nervous system is limited. Therefore, we aimed to do a systematic analysis of the neurological manifestations. Methods: We retrospectively studied the clinical, laboratory, and radiological findings of patients with major neurological syndromes (MNS) in Covid-19 over 6 months. Results: We had 39 patients with major neurological syndromes (MNS). The most common MNS was cerebrovascular disease (CVD) (61.53%), in which ischemic stroke (83.33%), cortical sinus thrombosis (12.50%), and haemorrhagic stroke (4.16%) were seen. Among ischemic stroke patients, 50% had a large vessel occlusion, and 66.66% of patients with CVD had a significant residual disability. Cranial neuropathy (15.38%), GBS (10.26%), encephalitis (7.26%), and myelitis (5.12%) were the other MNS. Among the three encephalitis cases, two had CSF-Covid-19 PCR positivity and had severe manifestations and a poor outcome. Associated comorbidities included hypertension (30.76%), diabetes mellitus (12.82%), chronic kidney diseases (7.69%), and polycythaemia vera (2.56%). Lung involvement was seen in 64.1% of patients. Mortality was 17.94% in MNS with Covid-19. Conclusions: The most common major neurological syndrome associated with Covid-19 is CVD with increased frequency of large vessel occlusion causing significant morbidity and mortality. Simultaneous lung and other systemic involvement in MNS results in a deleterious outcome.

The Analysis of Oral and Fecal Virome Detects Multiple Novel Emerging Viruses in Snakes

Wild animals are considered reservoirs for emerging and reemerging viruses, such as the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Previous studies have reported that bats and ticks harbored variable important pathogenic viruses, some of which could cause potential diseases in humans and livestock, while viruses carried by reptiles were rarely reported. Our study first conducted snakes' virome analysis to establish effective surveillance of potential transboundary emerging diseases. Consequently, Adenoviridae, Circoviridae, Retroviridae, and Parvoviridae were identified in oral samples from Protobothrops mucrosquamatus, Elaphe dione, and Gloydius angusticeps based on sequence similarity to existing viruses. Picornaviridae and Adenoviridae were also identified in fecal samples of Protobothrops mucrosquamatus. Notably, the iflavirus and foamy virus were first reported in Protobothrops mucrosquamatus, enriching the transboundary viral diversity in snakes. Furthermore, phylogenetic analysis revealed that both the novel-identified viruses showed low genetic similarity with previously reported viruses. This study provided a basis for our understanding of microbiome diversity and the surveillance and prevention of emerging and unknown viruses in snakes.

Mania: An Atypical Presentation of probable Streptococcus Agalactiae Meningoencephalitis

Streptococcus agalactiae, also known as Group B Streptococcus (GBS), is a common pathogen in the neonatal period, causing meningitis and sepsis. In non-pregnant adults it is an unusual cause of meningitis. We report about an elderly female with several risk factors for invasive GBS infection who developed GBS meningoencephalitis one month after treatment for COVID-19 upper respiratory tract infection. The patient presented with mania, and the classic triad of headache, neck stiffness, and fever was absent which contributed to the delay in diagnosis. Following initiation of treatment with intravenous ceftriaxone she attained full recovery, and her behavior returned to baseline. This case illustrates an unusual presentation of an emerging infection and should alert clinicians about this presentation. By reporting this case we want to raise awareness about mania as a presenting feature of meningoencephalitis. This should lead to more timely diagnosis and better outcomes for future patients.

Lymphoproliferation- a clue towards an underlying monogenic disorder of immune dysregulation- a retrospective analysis from a single center in India

Background: Lymphoproliferation is the persistent proliferation of lymphoid cells and it's incidence in inborn errors of immunity varies from 0.7 to 18%. Material(s) and Method(s): This is a retrospective analysis of patients referred to the department of Immunology, B. J. Wadia Hospital for Children, Mumbai between March 2017 to December 2022. Inclusion criteria consisted of 3 months duration of significant lymphadenopathy and/or splenomegaly or history of lymphoma. The clinical characteristics, laboratory and molecular findings of the included patients were analyzed. Result(s): A total of 66 patients were included. There was a male preponderance with male:female ratio of 25:8. Median age of onset of lymphoproliferation was 4.75 years(Range 1 year to 60 years). Splenomegaly was seen in 75%. Infections included recurrent pneumonia (14/66), recurrent ear infections(5/66), COVID(4/66), one episode of pneumonia(6/66), herpes zoster(3/66), recurrent subcutaneous abscess (3/66), abdominal koch(3/66), chronic sinusitis(2/66), dermatophytosis(2/66), esophageal candidiasis(2/66), recurrent malaria(1/66), recurrent varicella(1/66), cryptococcal meningitis(1/66), gram negative sepsis(1/66), BCG adenitis(1/66), pseudomonas osteomyelitis(1/66), impetigo (1/66), pseudomonas urinary tract infection (1/66), chicken pox(1/66), herpes keratitis(1/66), dengue(1/66), Other manifestations included Evans plus phenotype(10/66), Evans phenotype(8/66), Autoimmune hemolytic anemia(5/66), bronchiectasis(5/66), Type 1 diabetes(3/66), hyper reactive airway disease(2/66), inflammatory bowel disease(4/66), autoimmune thrombocytopenia(2/66), stroke(3/66), hemophagocytic lymphohistiocytosis(2/66), hypertriglyceridemia(2/66), hypothyroidism(2/66), celiac disease(1/66), Type 2 diabetes(1/66), autoimmune encephalitis(1/66), autoimmune hepatitis(2/66), anti-parietal cell antibody(1/66), arthritis(1/66), autoimmune enteropathy(1/66), systemic lupus erythromatosus(1/66), primary biliary cirrhosis requiring liver transplant(1/66), nephrotic syndrome(1/66), lymphoedema(1/66), hypersplenism(1/66), recurrent oral ulcers(1/66), gout(1/66), dermatitis(1/66), ovarian teratoma(1/66), alopecia areata(1/66). Hodgkin's lymphoma(HL) was the most common malignancy(9/66), followed by non Hodgkin lymphoma(NHL)(6/66), transformation from NHL to HL(1/66), Burkitt to T-cell lymphoma(1/66), HL to DLBCL(1/66), HL to anaplastic T-cell lymphoma(1/66). EBV driven lymphoproliferation was seen in biopsy of21/66. Genetic testing showed mutations in LRBA(11/66), PIK3CD(5/66), CTLA4(3/66), TET2(2/66), IL2RA (1/66), IL12RB1(1/66), BACH2(1/66), PRKCD(1/66), TNFSFR13B(1/66), TNFAIP3(1/66), FAS(2/66), FASL(1/66), Caspase8(1/66), CARD11(1/66), RTEL1(1/66), AICD(1/66), PIK3R1(1/66), IKBKB(1/66). Treatment included IVIG, chemotherapy, rituximab, sirolimus, abatacept, HSCT. Conclusion(s): All children with persistent lymphoproliferation, with or without autoimmunity and/or infections should be worked up for an underlying monogenic disorder of immune dysregulation. Lymphomas presenting at abnormal site and/or age, relapse and EBV driven lymphomas require further evaluation. Presence of monogenic cause helps in providing targeted therapy.Copyright © 2023 Elsevier Inc.

Type 1 diabetes and environment . . . and other stories

A linked ecological analysis of environmental and demographic variables identified several factors, including poor air quality, outdoor light at night, and higher population density that were negatively associated with the incidence of diabetes (Diabetologia doi:10.1007/s00125-020-05087-7). A case-control study using a database of people known to have autoimmune disease raises anxiety about central nervous system inflammatory events (JAMA Neurol doi:10.1001/jamaneurol.2020.1162). A history of exposure to TNF inhibitors carried a threefold increase in risk both of demyelinating diseases, such as multiple sclerosis and optic neuritis, and of non-demyelinating conditions, such as encephalitis, neurosarcoidosis, and vasculitis.

Update on Viral Infections Involving the Central Nervous System in Pediatric Patients.

Infections of the central nervous system (CNS) are mainly caused by viruses, and these infections can be life-threatening in pediatric patients. Although the prognosis of CNS infections is often favorable, mortality and long-term sequelae can occur. The aims of this narrative review were to describe the specific microbiological and clinical features of the most frequent pathogens and to provide an update on the diagnostic approaches and treatment strategies for viral CNS infections in children. A literature analysis showed that the most common pathogens worldwide are enteroviruses, arboviruses, parechoviruses, and herpesviruses, with variable prevalence rates in different countries. Lumbar puncture (LP) should be performed as soon as possible when CNS infection is suspected, and cerebrospinal fluid (CSF) samples should always be sent for polymerase chain reaction (PCR) analysis. Due to the lack of specific therapies, the management of viral CNS infections is mainly based on supportive care, and empiric treatment against herpes simplex virus (HSV) infection should be started as soon as possible. Some researchers have questioned the role of acyclovir as an empiric antiviral in older children due to the low incidence of HSV infection in this population and observed that HSV encephalitis may be clinically recognizable beyond neonatal age. However, the real benefit-risk ratio of selective approaches is unclear, and further studies are needed to define appropriate indications for empiric acyclovir. Research is needed to find specific therapies for emerging pathogens. Moreover, the appropriate timing of monitoring neurological development, performing neuroimaging evaluations and investigating the effectiveness of rehabilitation during follow-up should be evaluated with long-term studies.

Mechanisms of SARS-CoV-2-induced Encephalopathy and Encephalitis in COVID-19 Cases.

The SARS-CoV-2 virus caused an unprecedented pandemic around the globe, infecting 36.5 million people and causing the death of over 1 million in the United States of America alone. COVID-19 patients demonstrated respiratory symptoms, cardiovascular complications, and neurologic symptoms, which in most severe cases included encephalopathy and encephalitis. Hypoxia and the uncontrolled proliferation of cytokines are commonly recognized to cause encephalopathy, while the retrograde trans-synaptic spread of the virus is thought to cause encephalitis in SARS-CoV-2-induced pathogenesis. Although recent research revealed some mechanisms explaining the development of neurologic symptoms, it still remains unclear whether interactions between these mechanisms exist. This review focuses on the discussion and analysis of previously reported hypotheses of SARS-CoV-2-induced encephalopathy and encephalitis and looks into possible overlaps between the pathogenesis of both neurological outcomes of the disease. Promising therapeutic approaches to prevent and treat SARS-CoV-2-induced neurological complications are also covered. More studies are needed to further investigate the dominant mechanism of pathogenesis for developing more effective preventative measures in COVID-19 cases with the neurologic presentation.

Seronegative acute encephalitis following COVID-19 vaccines: a case series of an overlooked diagnosis with literature review.

PURPOSE: Autoimmune encephalitis is a neurological emergency of new-onset altered mental status, caused by an exaggerated immune-mediated response that targets the central nervous system. Autoimmune encephalitis has become an emerging differential diagnosis, when a classical infection cannot explain neurological symptoms. Displaying overlapping clinical presentations, ranging from the insidious onset of cognitive deficiency to more severe forms of encephalopathy with refractory seizures, autoimmune encephalitis can be challenging for clinicians. When evidence of malignancy is absent and pathogenic autoantibodies are undetected, with typical clinical and imaging features of autoimmune encephalitis, seronegative autoimmune encephalitis may be considered. Recently, vaccination-related autoimmune encephalitis and acute encephalitis after COVID-19 vaccination have attracted attention. METHODS AND RESULTS: We report a case series consisting of three patients with autoimmune encephalitis occurring shortly after COVID-19 vaccination and a current review of all previous reported autoimmune encephalitis related to COVID-19 vaccines. CONCLUSION: We emphasise on the prompt diagnosis of autoimmune encephalitis induced by Covid-19 vaccines and its timely treatment to improve the clinical outcome of this severe neurological condition. Post-licencing vaccine safety surveillance for potential adverse events is essential for vaccine safety and public confidence.

Early autoimmunity and outcome in virus encephalitis: a retrospective study based on tissue-based assay.

To explore the autoimmune response and outcome in the central nervous system (CNS) at the onset of viral infection and correlation between autoantibodies and viruses. METHODS: A retrospective observational study was conducted in 121 patients (2016-2021) with a CNS viral infection confirmed via cerebrospinal fluid (CSF) next-generation sequencing (cohort A). Their clinical information was analysed and CSF samples were screened for autoantibodies against monkey cerebellum by tissue-based assay. In situ hybridisation was used to detect Epstein-Barr virus (EBV) in brain tissue of 8 patients with glial fibrillar acidic protein (GFAP)-IgG and nasopharyngeal carcinoma tissue of 2 patients with GFAP-IgG as control (cohort B). RESULTS: Among cohort A (male:female=79:42; median age: 42 (14-78) years old), 61 (50.4%) participants had detectable autoantibodies in CSF. Compared with other viruses, EBV increased the odds of having GFAP-IgG (OR 18.22, 95% CI 6.54 to 50.77, p<0.001). In cohort B, EBV was found in the brain tissue from two of eight (25.0%) patients with GFAP-IgG. Autoantibody-positive patients had a higher CSF protein level (median: 1126.00 (281.00-5352.00) vs 700.00 (76.70-2899.00), p<0.001), lower CSF chloride level (mean: 119.80±6.24 vs 122.84±5.26, p=0.005), lower ratios of CSF-glucose/serum-glucose (median: 0.50[0.13-0.94] vs 0.60[0.26-1.23], p=0.003), more meningitis (26/61 (42.6%) vs 12/60 (20.0%), p=0.007) and higher follow-up modified Rankin Scale scores (1 (0-6) vs 0 (0-3), p=0.037) compared with antibody-negative patients. A Kaplan-Meier analysis revealed that autoantibody-positive patients experienced significantly worse outcomes (p=0.031). CONCLUSIONS: Autoimmune responses are found at the onset of viral encephalitis. EBV in the CNS increases the risk for autoimmunity to GFAP.

A Young Female with SARS-CoV-2 Infection Presenting with Concurrent Neurological and Pulmonary Manifestations: A Case Report

Coronavirus disease 2019 (COVID-19), besides its well-known deleterious effects on the respiratory system, is also reported to affect the central nervous system (CNS), presenting with neurological manifestations, that are commoner among older patients with associated co-morbidities and in the critically ill with COVID pneumonia. Infective, cerebrovascular, and hypoxic-toxic-metabolic etiology have been implicated. Reported outcomes have been poor with persistent neurological deficits among the majority who have survived. We report a young lady who presented with neurological manifestations alongside moderately severe COVID-19 pneumonia. Diagnosed early and managed as severe encephalopathy after excluding infective and cerebrovascular aetiology. Responded well to conservative measures and made a complete recovery. Early recognition of neurological manifestations of COVID-19 disease followed by the institution of appropriate therapies improved the outcomes.

Neuroimaging Spectrum in COVID-19 Infection: A Single-Center Experience.

Background and Purpose The ongoing coronavirus disease 2019 (COVID-19) pandemic is a multisystemic disease and involvement of the nervous system is well established. The neurological and neuroimaging features of the disease have been extensively evaluated. Our study aimed to elucidate the neuroradiological findings in COVID-19 infected patients admitted to our institute during the first and second waves of the pandemic in India. Methods This was a single-center retrospective study of all COVID-19 positive patients who underwent neuroimaging between March 2020 and May 2021. The presenting neurological complaints, the imaging findings in computed tomography (CT) imaging, and/or magnetic resonance imaging (MRI) were recorded. They recorded the findings in the subheadings of ischemic stroke, hemorrhagic stroke, parainfectious demyelination, acute encephalitis syndrome, and changes of global hypoxic changes. Patients with age-related, chronic, and incidental findings were excluded. Results The study comprised of 180 COVID-19 positive patients who underwent neuroimaging. CT scan was performed for 169 patients, MRI for 28, and a combination of both CT and MRI was performed for 17 patients. Seventy percent of patients were males, and median age was 61.5 years (interquartile range: 48.25-70.75). Out of the 180 patients, 66 patients had nonspecific findings that could not be attributed to COVID-19 infection. In the remaining 114 patients, 77 (42.7%) had ischemic findings, while 22 (12.2%) had hemorrhagic stroke. Hypoxic ischemic changes were noted in five patients. The rest of the patients had a spectrum of changes including, cerebellitis (3), tumefactive demyelination (1), COVID-19-associated encephalitis (1), hemorrhagic acute demyelinating encephalomyelitis (1), transverse myelitis (1), cytotoxic lesions of corpus callosum (1), Guillain-Barre syndrome (1), and COVID-19-associated microhemorrhages (1). Conclusion Neurological manifestations of COVID-19 infection are not uncommon, and our understanding of this topic is expanding. A complex interplay of neurotropism and direct central nervous system invasion, immune activation and cytokine storm, vasculitis, and parainfectious processes are implicated in the pathophysiology. While the most common imaging finding was ischemic stroke, followed by hemorrhagic stroke, a diverse range of parainfectious findings was also noted in our study.

A Possible Case of Autoimmune Encephalitis After mRNA COVID-19 Booster Vaccine: A Case Report.

As the use of COVID-19 vaccines gains more prevalence, rare and uncommon side effects are reported in the medical literature. This is a case report of a 75-year-old male patient who presented on the second day after receiving the Moderna Bivalent mRNA COVID-19 booster vaccine with abrupt onset behavioral changes and global aphasia with no focal deficits. Stroke and infectious meningitis/encephalitis were ruled out. Signs of aseptic inflammation were seen on cerebrospinal fluid (CSF) analysis. Workup for autoimmune and paraneoplastic encephalitis was unyielding. The observation of rapid clinical improvement prompted watchful waiting that concluded in the resolution of clinical manifestations within less than a week of onset. This case is reported to support the currently limited knowledge of rare neurological sequelae of mRNA vaccine and is in line with recently published few cases that suggest vaccine-related encephalitis.

SARS-CoV-2 Infection Increases the Gene Expression Profile for Alzheimer's Disease Risk

The COVID-19 pandemic is a global outbreak of coronavirus, an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). One in five adults who have had COVID-19 in the past was still experiencing any one of the symptoms of long COVID like headache, brain fog, fatigue, and shortness of breath. Up to 30% of individuals with mild to severe infection show diverse neurological symptoms, including dementias. Hence, it is very much important to characterize the neurotropism and neurovirulence of the SARS-CoV-2 virus. This helps us understand the mechanisms involved in initiating inflammation in the brain, further leading to the development of earlyonset Alzheimer's disease and related dementias (ADRDs). In our brain gene expression analysis, we found that severe COVID-19 patients showed increased expression of innate immune response genes and genes that are implicated in AD pathogenesis. To study the infection-induced ADRDs, we used a mouse-adapted strain of the SARS-CoV-2 (MA10) virus to infect mice of different age groups (3, 6, and 20 Months). In this study, we found that aged mice showed evidence of viral neurotropism, prolonged viral infection, increased expression of tau aggregator FKBP51, interferoninducible gene Ifi204, and complement genes like C4 and C5AR1. Brain histopathology also showed the AD signature including tau-phosphorylation, tau-oligomerization, and alpha-synuclein expression in aged MA10-infected mice. The results from gene expression profiling of SARS-CoV-2 infected and AD brains and studies with MA10 aged mice show that COVID-19 infection increases the risk of AD in the aged population. Furthermore, this study helps us to understand the crucial molecular markers that are regulated during COVID infection that could act as major players in developing ADRDs. Future studies will be involved in understanding the molecular mechanisms of ADRD in response to COVID infection and developing novel therapies targeting AD.

Viral Myopericarditis and Viral Encephalitis as Manifestations of Covid-19 Infection: A Case Report

Intro: Coronavirus disease (COVID-19) is currently a global health crisis and is caused by a new strain of coronavirus. However, emerging literature of case reports noted possible extrapulmonary manifestations of the disease. Because COVID 19 is a relatively new disease, at present, little existing literature tackles the diagnosis and therapeutic management of COVID-19-related conditions outside the pulmonary system. Method(s): This is a case of a 24-year-old male presented with the chief complaint of sudden stiffening of all extremities. Non-contrast computed tomography (CT) scan was unremarkable. Chest X-ray revealed interstitial pneumonia and SARS-CoV-2 RT-PCR (OPS/NPS) was positive. Electrocardiogram (ECG) findings showed supraventricular tachycardia and had elevated Troponin I levels. Pertinent physical findings noted were slurring of speech, dysmetria, and vertical nystagmus. Finding(s): The patient was initially treated as a case of Bacterial Abscess versus Viral encephalitis. Pericardial ultrasound revealed small pericardial effusion and was started on Colchicine. Repeat cranial CT scan noted unremarkable results but due to persistence of symptoms, the patient was started with Dexamethasone. On Day 16 of illness, the patient was noted to have full resolution of symptoms. Rapid antibody testing was done which revealed positive for both IgG and IgM hence the patient was discharged with the final diagnosis of Viral Myopericarditis resolved, Viral encephalitis resolved, COVID-19 pneumonia recovered. Conclusion(s): Extrapulmonary manifestations have been reported increasingly as an atypical presentation of COVID 19 infection. Early recognition of viral myopericarditis and viral encephalitis as a manifestation of COVID 19 can lead to the initiation of proper treatment and management. More reports on these cases can aid future studies on diagnostics and therapeutic approaches during the COVID-19 pandemic.Copyright © 2023

Coexistence of Ophthalmic Shingles and COVID-19 in a Patient Who Applied with Encephalitis Clinic

Varicella zoster virus (VZV) is a member of the herpes virus family and is the causative agent of chickenpox and shingles. While chickenpox, which is the primary infection, is mostly seen in childhood, shingles is located latently in the dorsal root sensory ganglia and cranial nerve ganglia, causing recurrent attacks in adulthood. Shingles may rarely present with neurological complications such as encephalitis. Many diseases are seen in the coexistence of Coronavirus disease-2019 (COVID-19) due to the pandemic. In this case report, it was aimed to draw attention to the ophthalmic varicella zoster virus infection with a different clinical onset accompanied by COVID-19 who presented with the clinic of encephalitis.

A Case Report of an Atypical Neurological Presentation of COVID-19 in Pregnancy

Symptomatic patients with coronavirus disease 2019 (COVID-19) mostly have flu-like symptoms. However, neurologic manifestations are common and may be the early findings of COVID-19. Data for COVID-19 do not indicate an increased risk of infection in pregnant individuals, but the risk of disease severity and mortality is high in this patient population. We report a case of a pregnant woman in the 10th gestational week, who presented with neurological symptoms of sudden impairment in walking, balance, speech, and consciousness, started the night before, and a seven-day history of fever, chills, myalgia, and general weakness before admission. The polymerase chain reaction (PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was positive for the cerebrospinal fluid sample a day before the positive nasopharyngeal sample. Axial brain magnetic resonance imaging revealed the involvement of the spinothalamic tract. Following treatment with intravenous immunoglobulin, the patient's neurological condition gradually recovered, except for lower limb muscle strength, and she was discharged from the hospital on the 10th day of admission. This case is unique as it emphasizes the importance of considering COVID-19 when uncommon neurologic manifestations with negative nasopharyngeal PCR are present.Copyright © 2023, Author(s).

Infectious Lesions of the Central Nervous System

This book discusses all aspects infectious CNS pathology, including different bacterial, viral, fungal, mycoplasma and protozoan pathogens, accompanied by illustrations that show macro-and histopathological changes. It also presents microbiological, epidemiological and clinical data, with a particular focus on meningitis and encephalitis of different bacterial and viral aetiologies, influenza, COVID-19 and other viral and bacterial generalized infections. Further, the book explores the importance of mixed infections, including those in the late stages of HIV infection, as well as pathological changes in different age groups including newborns. A special chapter is devoted to the probable role of biological pathogens in noninfectious brain pathology. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

SARS-CoV-2 BA.5 CAUSES HIGHER REPLICATION AND LETHAL INFECTION IN K18-hACE2 MICE

Background: The continuous evolution of SARS-CoV-2 in the diverse immune landscape (natural, vaccine, hybrid) is giving rise to novel immune escape mutations. So far, the resulting new variants (BA.1, BA.2, BA.2.12.1) were observed to cause mild infections, however, BA.5 infections are associated with an increased risk of hospitalization.1 Therefore it is essential to investigate the pathogenesis of BA.5. Method(s): Here we compared the pathogenicity of Pre-Omicron (B.1.351) and Omicron (BA.1, BA.2.12.1, and BA.5) variants in wild-type C57BL/6J mice and K18-hACE2 mice. The virus replication kinetics was also studied in human Calu3, pulmonary alveolar type 2 (AT2) cells, and airway organoids (HAO). Cell-to-cell spread of virus was measured by syncytia formation assay and immunohistochemistry (IHC) of infected lungs. Result(s): In the results, infection in C57BL/6J mice showed severe weight loss ( >15%) for B.1.351 infected mice and moderate ( >5%) for BA.5 infected. C57BL/6J mice showed higher virus replication of B.1.351 followed by BA.5, BA.1, and BA.2.12.1. At the peak of virus replication (2 days) plaque-forming units from lung extract of BA.5 infected mice were two, and three logs higher compared to BA.1 and BA.2.12.1 respectively. BA.5 infection was lethal to 80% of infected K18-hACE2 mice, whereas the mice looked normal after infection with BA.1 and BA.2.12.1. BA.5 infected mice showed high virus replication in brain tissue. Surprisingly the syncytia formation assay and IHC for BA.5 was comparable to that of B.1.351, indicating the higher cell-to-cell spread of BA.5 and B.1.351 compared to BA.1 and BA.2.12.1, which is one of the measures of pathogenicity. Calu3 and HAO showed the same trend of virus replication as was observed in-vivo experiments however AT2 cells were found to be resistant to BA.5 replication. Conclusion(s): These results suggest that the BA.5 variant (lineage) of Omicron has the potential to regain the pathogenicity as it shows increased virulence compared to other Omicron sub-variants. Lethal infection of BA.5 in K18-hACE2 mice may be attributed to catastrophic encephalitis and increased cell-to-cell spread.