MECHANISMS OF CENTRAL NERVOUS SYSTEM DAMAGE IN COVID-19

The issues of diagnosis and treatment of nervous system damage in the new coronavirus infection (COVID-19) remain relevant, regardless of information and experience in treating such patients, accumulated nowadays. The review contains updated data on the ways of SARS-CoV-2 invasion, examines mechanisms of central nervous system damage: direct virus-induced damage, immune dysfunction, excessive thrombo-inflammation, coagulation disorder, cytokine and metabolic imbalance, hypoxia, etc.;it presents clinical examples with one variant of damage — the development of Guillain-Barre syndrome that, to some extent, allows to confirm the virus neurotropism. Doctors' knowledge about this infection is constantly expanding, new information appears on its various neuropsychiatric effects during an acute period and post-COVID syndrome, on symptoms, treatment and prevention strategy. These data enables to understand better the reasons for developing the main clinical manifestations, from a headache or myalgia to more severe symptoms, such as a stroke, psychosis and anosmia, severity and reversibility of their course. Although several hypothesis of CNS damage pathogenesis in COVID-19 are being discussed, the unified pathophysiological mechanism of many dysfunctions remains unclear, and, probably, additional factors, such as social isolation during a pandemic, presence and treatment in the intensive care unit, premorbid somatic status of a patient, contribute to the development of some registered nervous system disorders. © 2023, HIV Infection and Immunosuppressive Disorders.All Rights Reserved.

Immunogenetic landscape of COVID-19 infections related neurological complications

The human leukocyte antigen (HLA) is a critical component of antigen presentation and plays crucial role in conferring differential susceptibility and severity of diseases caused by viruses such as COVID-19. The immunogenetic profile of populations, BCG vaccination status, and a host of lifestyle factors might contribute to the observed variations in mortality rates due to COVID-19. These genetic, epigenetic, and environmental factors could widely influence infection dynamics and immune responses against COVID-19. The aim of this review is to provide an update on HLA association with SARS-CoV-2 infection in global populations and to highlight the possible neurological involvements. We also set out to explore the HLA immunogenetic markers related to COVID‐19 infections that can be used in screening high‐risk individuals for personalized therapies and in community-based vaccine development. © 2023 Elsevier Inc. All rights reserved.

Patient Centricity: Design and Conduct of Clinical Trials in Orphan Diseases: Third of Three Sets of Expanded Proceedings from the 2020 ISCTM Autumn Conference on Pediatric Drug Development

This article expands on a session, titled "Patient Centricity: Design and Conduct of Clinical Trials in Orphan Diseases," that was presented as part of a two-day meeting on Pediatric Drug Development at the International Society for Central Nervous System (CNS) Clinical Trials and Methodology (ISCTM) Autumn Conference in Boston, Massachusetts, in October 2020. Speakers from various areas of pediatric drug development addressed a variety of implications of including children in drug development programs, including implications for rare/orphan diseases. The speakers have written summaries of their talks. The session's lead Chair was Dr. Joan Busner, who wrote introductory and closing comments. Dr. Simon Day, regulatory consultant, outlined some of the past mistakes that have plagued trials that did not consult with patient groups in the early design phase. Dr. Atul Mahableshwarkar provided an industry perspective of a recent trial that benefited from the inclusion of patient input. Drs. Lucas Kempf and Maria Sheean provided regulatory input from the perspectives of the United States (US) Food and Drug Administration (FDA) and European Medicines Agency (EMA), respectively. Dr. Judith Dunn outlined a novel approach for assessing and rank ordering patient and clinician clinical meaningfulness and the disconnect that may occur. Dr. Busner provided closing comments, tied together the presented issues, and provided a synopsis of the lively discussion that followed the session. In addition to the speakers above, the discussion included two representatives from patient advocacy groups, as well as an additional speaker who described the challenges of conducting a pediatric trial in the US and European Union (EU), given the often competing regulatory requirements. This article should serve as an expert-informed reference to those interested and involved in CNS drug development programs that are aimed at children and rare diseases and seek to ensure a patient-centric approach.Copyright © 2023, Matrix Medical Communications. All rights reserved.

The influence of post-COVID syndrome on cognitive functions of students

A survey of senior students of the Faculty of General Medicine of the NAO MUK who had recovered from Covid-19 was conducted. The disease in all respondents proceeded in a mild form or moderate severity. Post-covid syndrome developed in students who had a coronavirus infection in the form of moderate severity. The most frequent complications were loss of smell and taste, cough and shortness of breath, as well as cognitive dysfunction in the form of impaired attention, memory and thinking. The decline in performance is associated with the above violations of the central nervous system.

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.

Therapeutic prospects of naturally occurring p38 MAPK inhibitors tanshinone IIA and pinocembrin for the treatment of SARS-CoV-2-induced CNS complications.

P38 mitogen-activated protein kinase (p38 MAPK) signaling pathway is closely related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) replication and hyperinflammatory responses in coronavirus disease 2019 (COVID-19). Therefore, blood-brain barrier-penetrating p38 MAPK inhibitors have good potential for the treatment of central nervous system (CNS) complications of COVID-19. The aim of the present study is the characterization of the therapeutic potential of tanshinone IIA and pinocembrin for the treatment of CNS complications of COVID-19. Studies published in high-quality journals indexed in databases Scopus, Web of Science, PubMed, and so forth were used to review the therapeutic capabilities of selected compounds. In continuation of our previous efforts to identify agents with favorable activity/toxicity profiles for the treatment of COVID-19, tanshinone IIA and pinocembrin were identified with a high ability to penetrate the CNS. Considering the nature of the study, no specific time frame was determined for the selection of studies, but the focus was strongly on studies published after the emergence of COVID-19. By describing the association of COVID-19-induced CNS disorders with p38 MAPK pathway disruption, this study concludes that tanshinone IIA and pinocembrin have great potential for better treatment of these complications. The inclusion of these compounds in the drug regimen of COVID-19 patients requires confirmation of their effectiveness through the conduction of high-quality clinical trials.

Essential Multiorgan Pathophysiology of COVID-19

Typical manifestations of coronavirus disease-2019 (COVID-19) include mild-to-moderate "flu-like” symptoms, although more severe manifestations have been reported. The pathophysiology of COVID-19 is complex, and its clinical spectrum might not be limited to local pneumonia, but rather may represent a multisystem illness with potential for severe acute respiratory distress syndrome (ARDS) and multiorgan impairment. In this context, the aim of the present handbook is to provide an overview of possible multisystemic manifestations and therapeutic strategies, in order to guide the clinician to deal with COVID-19 critical illness and to prevent potential systemic consequences. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

Special Isue: Virtual anatomy, histology and embryology in research and education. (Special Isue: Virtual anatomy, histology and embryology in research and education.)

This issue contains 13 articles on the use of virtual anatomy, histology and embryology in research and education;digital histological morphometry of the human pineal gland in a postmortem study, with endocrine and neurological clinical implications;an international collaborative approach to learning histology using a virtual microscope;delivery anatomy kits to help keep practical veterinary classes during the COVID-19 pandemic;how virtual animal anatomy facilitated a successful transition to online instruction and supported student learning during the coronavirus pandemic;using videos in active learning in veterinary anatomy;dissection videos as a virtual veterinary anatomy peer learning tool at the University of Tehran during the COVID-19 pandemic;a new virtual platform for teaching comparative animal neuroanatomy based on metameric slices of the central nervous system;application of student remote and distance research in neuroanatomy by mapping Dscaml1 expression with a LacZ gene trap in mouse brain;implementing a multi-colour genetic marker analysis technique for embryology education;impact of COVID-19 on student attainment and pedagogical needs when undertaking independent scientific research;extended reality veterinary medicine case studies for diagnostic veterinary imaging instruction and assessing student perceptions and examination performance and students' performance in teaching neuroanatomy using traditional and technology-based methods. 16 proceedings from the Trans-European Pedagogic Anatomy Research Group (TEPARG) Hybrid Meeting entitled "Hybrid Anatomy Education: Barriers and Enablers for Students and Educators" held in Barcelona, Spain, during 5 March 2022, are also included.

Towards Neuro-CoViD-19.

CoViD-19 is the current pandemic caused by the Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2). Infection by SARS-CoV-2 occurs via the binding of its S protein to the angiotensin-converting enzyme-2 receptor (ACE2-R). S binding to ACE2-R leads to a drop in ACE2, a homolog of angiotensin converting enzyme (ACE). In the central nervous system (CNS), ACE mediates neuroinflammation, neurodegeneration and neurotoxicity responsible for several CNS disorders. ACE2 counteracts the damaging effects of ACE on CNS neurons. SARS-CoV-2 can directly access the CNS via the circulation or via cranial nerve I and the olfactory bulb. Inactivation of ACE2 following binding of SARS-CoV-2 S protein to ACE2-R in situ might blunt ACE2-moderating effects upon ACE CNS neurotoxicity and neurodegeneration. Here, we propose a neurobiological mechanism directly involving SARS-CoV-2 binding to ACE2-R in the etiology of putative Neuro-CoViD-19.

COVID-19 and the brain.

Entering the third year into the pandemic, overwhelming evidence demonstrates that Coronavirus disease 2019 (COVID-19) infection is a systemic illness, often with involvement of the central nervous system. Multiple mechanisms may underlie the development of neurologic manifestations of illness, including hypoxia, systemic illness, hypercoagulability, endothelial dysfunction, general critical illness, inflammatory response, and neurotropism of the severe acute respiratory syndrome coronavirus 2 (SARS-Co-V2) virus. COVID-19 infection is associated with neurologic involvement in all stages; acute infection, subacute/post-infection, and growing evidence also suggests during a chronic phase, the post-acute sequalae of COVID-19 (PASC). With over 20,000 published articles on COVID and the brain at the time of writing, it is virtually impossible to present an unbiased comprehensive review of how SARS-Co-V2 impacts the nervous system. In this review, we will present an overview of common neurologic manifestations, in particular focusing on the cerebrovascular complications, and proposed pathophysiology.

Transcriptome Profiling in Autoimmune Diseases

Autoimmune diseases are a group of different inflammatory disorders characterized by systemic or localized inflammation, affecting approximately 0.1–1% of the general population. Several studies suggest that genetic risk loci are shared between different autoimmune diseases and pathogenic mechanisms may also be shared. The strategy of performing differential gene expression profiles in autoimmune disorders has unveiled new transcripts that may be shared among these disorders. Microarray technology and bioinformatics offer the most comprehensive molecular evaluations and it is widely used to understand the changes in gene expression in specific organs or in peripheral blood cells. The major goal of transcriptome studies is the identification of specific biomarkers for different diseases. It is believed that such knowledge will contribute to the development of new drugs, new strategies for early diagnosis, avoiding tissue autoimmune destruction, or even preventing the development of autoimmune disease. In this review, we primarily focused on the transcription profiles of three typical autoimmune disorders, including type 1 diabetes mellitus (destruction of pancreatic islet beta cells), systemic lupus erythematosus (immune complex systemic disorder affecting several organs and tissues), and multiple sclerosis (inflammatory and demyelinating disease of the nervous system). © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2014, 2022.

Neurological diseases caused by coronavirus infection of the respiratory airways

Infections of the central nervous system (CNS) infections are critical problems for public health. They are caused by several different organisms, including the respiratory coronaviruses (CoVs). CoVs usually infect the upper respiratory tract causing the common cold. However, in infants, and in elderly and immunocompromised persons, they can also affect the lower respiratory tract causing pneumonia and various syndromes of respiratory distress. CoVs also have neuroinvasive capabilities because they can spread from the respiratory tract to the CNS. Once infection begins in the CNS cells, it can cause various CNS problems such as status epilepticus, encephalitis, and long‐term neurological disease. This neuroinvasive properties of CoVs may damage the CNS as a result of misdirected host immune response, which could be associated with autoimmunity in susceptible individuals (virus‐induced neuro‐immunopathology) or associated with viral replication directly causing damage to the CNS cells (virus‐induced neuropathology). In December 2019, a new disease named COVID‐19 emerged which is caused by CoVs. The significant clinical symptoms of COVID‐19 are related to the respiratory system, but they can also affect the CNS, causing acute cerebrovascular and intracranial infections. We describe the possible invasion routes of coronavirus in this review article, and look for the most recent findings associated with the neurological complications in the recently published literature.

Assessment of SARS-CoV-2 infection in astrocytes

Discovered in late 2019 in a market in the city of Wuhan, Hubei Province, China, SARS-CoV-2 is an important member of the Coronaviridae family, responsible for bringing the whole world into a state of alert causing a global pandemic. The virus has been identified as causing a characteristic clinical condition known as "Corona-virus disease 2019" (COVID-19), causing an Acute Respiratory Syndrome. Being a respiratory virus, transmitted by direct contact with an infected person and by touching contaminated surfaces, SARS-CoV-2 quickly spread throughout the world, causing a pandemic, having today more than 535 million people infected and causing more than million deaths. In addition to the respiratory system, the virus is present in other cells in the body. Findings show the presence of SARS-CoV-2 in cerebrospinal fluid associated with changes in the expression of neuronal inflammation markers, as well as an increased expression of cytokines released by astrocytes, indicating an alteration in the Central Nervous System (CNS). In this project, we analyzed the effects of SARS-CoV-2 infection directly on astrocytes, glial cells that are extremely important for the maintenance of homeostasis and CNS defense. Therefore, we produced astrocytes from three human iPSC strains to verify aspects of cell morphology and physiology, as well as gene and protein expression, after infection with the virus. We found that SARS-CoV-2 is capable of infecting astrocytes, but some studies are still needed to better elucidate its role in the interaction with this cell type in the CNS.

Optic neuropathy after COVID-19 vaccination: Case report and systematic review

Purpose:: To report a case of anterior ischemic optic neuropathy (AION) following COVID-19 vaccination and provide a systematic review of all published cases of optic neuropathy following COVID-19 vaccination. Method(s):: A systematic literature search was performed using PubMed and Ovid MEDLINE for cases of optic neuropathy following COVID-19 vaccination. Terms used in the search included "COVID-19 vaccination", "optic neuropathy", "optic neuritis", and "ischemic optic neuropathy". Titles and s were initially screened then full texts of eligible studies were reviewed for data extraction. Only cases published in the English language, peer reviewed, and that included details on optic nerve involvement were included. All study types were eligible for inclusion. Result(s):: Including our patient, a total of 10 patients (8 females) were identified as developing optic neuropathy following COVID-19 vaccination. Five patients (50.0%) were diagnosed with AION, while 4 (40.0%) were diagnosed with optic neuritis. One patient was diagnosed with papillitis and neuroretinitis. Three patients (30.0%) had bilateral involvement. Mean age of patients was 48.5+/-19.7 years. Mean time from vaccination to onset of ophthalmic symptoms was 6.5+/-6.4 days. Median (IQR) presenting visual acuity was logMAR 0.3 (0-1). For the 8 eyes which had both presenting and final follow-up visual acuity, median (IQR) presenting vision was logMAR 0.2 (0-0.7) and at final follow-up was logMAR 0 (0-0.05) (P=0.184). Conclusion(s):: COVID-19 vaccination may result in optic neuropathy in the form of optic neuritis and ischemic optic neuropathy. Further studies are needed to determine the incidence, management, and prognosis of optic neuropathies associated with COVID-19 vaccination.Copyright © 2022

Impact of triple intrathecal prophylaxis in acute lymphoblastic leukemia adults receiving HyperCVAD: A COVID-19 practice change.

Treatment of acute lymphoblastic leukemia (ALL) requires both systemically and locally directed therapies to prevent central nervous system (CNS) recurrence. In response to restrictions brought on by the COVID-19 pandemic, our institution adopted triple intrathecal (IT) chemotherapy for CNS prophylaxis during HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine). We retrospectively reviewed records of newly diagnosed adult all patients who were consecutively treated with HyperCVAD between January 2011 and July 2022. Outcomes of patients who received triple IT chemotherapy and standard of care (SOC) CNS prophylaxis were compared. The primary endpoint was CNS relapse-free survival (RFS) while secondary endpoints included cumulative incidence of relapse, overall survival, number of outpatient, and total ITs per patient, and CNS treatment-related toxicities. A total of 37 patients including 21 in the triple IT and 16 in the SOC cohorts were evaluated. There were no differences between the triple IT and SOC cohorts with respect to CNS-RFS (89.6% vs. 80.4%; HR, 1.55; 95% CI, 0.45-5.39; p = .49), cumulative incidence of relapse (8.9% vs. 19.6%; HR, 1.14; 95% CI, 0.3-5.3; p = .87), and overall survival (89.6% vs. 85.7%; HR, 0.91; 95% CI, 0.20-4.21; p = .90) at 2-years. Significantly fewer IT doses were administered in the triple IT cohort (p = .011) and the number of additional outpatient appointments to administer IT chemotherapy were markedly reduced as 98.6% of IT doses were administered during scheduled admissions compared to 76.8% (p < .001). The adoption of triple IT chemotherapy did not increase CNS treatment-related toxicities but rather, the inverse was observed. Triple IT chemotherapy during HyperCVAD represents a feasible alternative to SOC CNS prophylaxis, especially during times of resource restriction and when minimization of patient exposures is desired.

Encephalitis associated with a monoclonal protein band present in blood, urine and cerebrospinal fluid.

Introduction: Monoclonal protein bands are present mainly in blood and secondary in urine representing specific antibody produced in excess by abnormal lymphocytes or plasma cells.We describe a case of a patient with acute encephalitis associated with an unexpected finding of a monoclonal protein band present in blood, urine and in cerebrospinal fluid (CSF). Case presentation: This 50-year-old woman with no significant past medical history, with the exception of unintentional weight loss exceeding 5 kg over the last 3 months, presented to the emergency department with seizures and altered mental status, after 3 days of vomiting and headaches. Magnetic Resonance Imaging showed lesions suspicious for infectious encephalitis/meningitis and for ischemia possibly related to central nervous system (CNS) autoimmune vasculopathy/vasculitis. The patient died the following day after losing brainstem reflexes. Testing for the previously mentioned etiologies returned negative with the exception of high protein concentration and increased immunoglobulin gamma (IgG) concentration in the CSF. Protein electrophoresis, ordered in error, showed a well-defined IgG with lambda light chain monoclonal protein band running in similar positions in serum, urine and in CSF. Due to SARS-CoV-2 PCR positivity no autopsy was performed. Conclusion: The presence of this monoclonal protein band produced in the CNS suggests the diagnosis of CNS myeloma. The accelerated course in this case could be the result of the CNS myeloma or lymphoma responding to SARS-CoV-2 infection. Testing for monoclonal protein bands in CSF, in patients with pertinent clinical presentation would boost the awareness of this these diseases improving patient care.

Measuring cognitive enhancement through pharmacology and sleep intervention

Cognitive enhancement (CE) is the pursuit of enhancing and increasing the core mental capacity above the normal level. With the advancement of science and technology, many different approaches to carry out enhancement are available. The use of psychostimulants as the choice of cognitive enhancer is rapidly growing. Although anecdotal and subjective evidences claim that these drugs work however, empirical evidences from studies in healthy adults show inconclusive evidences. One reason could be that these studies did not consider sleep as an important factor mediating the effect of stimulants on brain activities. My study 1 investigates the role of sleep in stimulant mediated CE. Along with sleep, there are other factors which are important when investigating the stimulants' effect of CE such as dosage, type of cognitive tasks, individual variability and bias of stimulant drugs toward certain cognitive domain. My study 2 investigates the evidences of bias by stimulants towards specific cognitive domain/s. Stimulants are addictive and comes with many side effects that may cause long term health issues. In my study 3, I investigated CE through targeted memory reactivation (TMR) which exploits the natural process of memory formation and strengthening during sleep with sensory stimulation to manipulate the memory strength. Specifically, in study 3 I developed a homebased- TMR protocol to selectively bias the weak and strong memories. This protocol was designed to carry out the study amidst the COVID pandemic lockdown. I developed a brand-new spatial memory cognitive task for remote online participation. The TMR intervention protocol is suitable for real world and naturalist setting without the participants having to come to the lab. This new homebased-TMR protocol shows some promising results. With future improvement and refinement, it could be turned into fully automated unsupervised TMR system. (PsycInfo Database Record (c) 2022 APA, all rights reserved)

Strategies for the Emergency Treatment of Pregnant Women with Neurological Symptoms during the COVID-19 Pandemic.

Coronavirus disease-19 (COVID-19) has been spreading all over the world for more than two years. Though several kinds of vaccines are currently available, emergence of new variants, spike mutations and immune escape have raised new challenges. Pregnant women are vulnerable to respiratory infections due to their altered immune defence and surveillance functions. Besides, whether pregnant persons should receive a COVID-19 vaccine is still under debate because limited data are available on the efficacy and safety of receiving a vaccine during pregnancy. Physiological features and lack of effective protection making pregnant women at high risk of getting infected. Another concern is that pregnancy may trigger the onset of underlying existing neurological disease, which is highly similar to those neurological symptoms of pregnant women caused by COVID-19. These similarities interfere with diagnosis and delay timely and effective management. Therefore, providing efficient emergency support for pregnant women suffering from neurological symptoms caused by COVID-19 remains a challenge among neurologists and obstetricians. To improve the diagnosis and treatment efficiency of pregnant women with neurological symptoms, we propose an emergency management framework based on the clinicians' experience and available resources. This emergency care system aimed at addressing the conundrums faced by the emergency guarantee system under COVID-19 pandemic and could serve as a potential multisystem project for clinical practice and medical education.