ArticleLiterature Review

Effects of COVID-19 on the nervous system

August 2020
Cell 183(1)

DOI:10.1016/j.cell.2020.08.028

Authors:

Costantino Iadecola

Weill Cornell Medical College

Josef Anrather

Weill Cornell Medical College

Neurological complications have emerged as a significant cause of morbidity and mortality in the ongoing COVID-19 pandemic. Beside respiratory insufficiency, many hospitalized patients exhibit neurological manifestations, ranging from headache and loss of smell, to confusion and disabling strokes. COVID-19 is also anticipated to take a toll on the nervous system in the long term. Here we will provide a critical appraisal of the potential for neurotropism and mechanisms of neuropathogenesis of SARS-CoV-2, as they relate to the acute and chronic neurological consequences of the infection. Finally, we will examine potential avenues for future research and therapeutic development.

Sequelae of long COVID, known and unknown: A review of updated information

Article

Mar 2023

Over three years have passed since the COVID-19 pandemic started. The dangerousness and impact of COVID-19 should definitely not be ignored or underestimated. Other than the symptoms of acute infection, the long-term symptoms associated with SARS-CoV-2 infection, which are referred to here as "sequelae of long COVID (LC)", are also a conspicuous global public health concern. Although such sequelae were well-documented, the understanding of and insights regarding LC-related sequelae remain inadequate due to the limitations of previous studies (the follow-up, methodological flaws, heterogeneity among studies, etc.). Notably, robust evidence regarding diagnosis and treatment of certain LC sequelae remain insufficient and has been a stumbling block to better management of these patients. This awkward situation motivated us to conduct this review. Here, we comprehensively reviewed the updated information, particularly focusing on clinical issues. We attempt to provide the latest information regarding LC-related sequelae by systematically reviewing the involvement of main organ systems. We also propose paths for future exploration based on available knowledge and the authors' clinical experience. We believe that these take-home messages will be helpful to gain insights into LC and ultimately benefit clinical practice in treating LC-related sequelae.

COVID-19: infection and neurological complications

Article

Full-text available

Mar 2022

The issues of neurological complications after coronavirus disease 2019 (COVID-19) are highlighted, since coronaviruses affect not only the respiratory system but also other organs and systems of the body, notably they can cause neurological disorders and diseases. There is little evidence for a direct mechanism of SARS-CoV-2 virus neuroinvasiveness and neurotoxicity. Various mechanisms of coronavirus invasion into the brain are discussed - anterograde and retrograde, neuronal spread, transcriptional and hematogenous pathways. Retrograde / anterograde transport and transsynaptic transmission of the virus have been confirmed by in vitro studies, notably SARS-CoV-2 can enter the central nervous system through olfactory nerve receptor cells. Once in the olfactory bulb, the coronavirus can spread to the cortex and other brain structures, in particular the hippocampus and spinal cord. Invasion of the virus into the central nervous system is also possible by spreading along peripheral nerves, such as along the vagus nerve, which innervates the lungs and intestines. The virus invasion into the central nervous system through the blood-brain barrier is considered to be one of the most frequent routes. There are several possible mechanisms for the spread of SARS-CoV-2 across the blood-brain barrier (circulation of viral particles in the bloodstream, viral transcytosis through vascular and capillary endothelial cells, infection of leukocytes with viruses and their transmission of viruses across the blood-brain barrier ("Trojan horse")). However, there is no robust evidence of CNS infection with SARS-CoV-2. Hypoxia induced by the cytokine storm and respiratory distress lead to the impairment of brain metabolism and neurological complications development. There is an ongoing debate as to whether neurological disorders are primary neurological symptoms or secondary consequences of acute respiratory distress syndrome and inflammation. Among the large number of disorders of the nervous system, there are five main types with long-term neurological complications associated with COVID-19: 1) encephalopathy with delirium / psychosis, 2) inflammatory syndromes of the central nervous system, including encephalitis, myelitis, acute disseminated encephalomyelitis, 3) ischemic strokes (half of them with pulmonary embolism), 4) peripheral neuropathies, Guillain-Barré syndrome and brachial plexopathies, 5) other disorders of the central nervous system. Incompleteness or inconsistency of statistical data on neurological complications after infection was noted. Further study is required of all early and long-term manifestations of neurological disorders and diseases in mild and asymptomatic manifestations of infection, acute and long COVID-19 and after vaccination.

Spatial Mapping of Genes Implicated in SARS-CoV-2 Neuroinvasion to Dorsolateral Prefrontal Cortex Gray Matter

Article

Full-text available

Jan 2023

Introduction: SARS-CoV-2 is the newest beta coronavirus family member to demonstrate neuroinvasive capability in severe cases of infection. Despite much research activity in the SARS-CoV-2/COVID-19 space, the gene-level biology of this phenomenon remains poorly understood. In the present analysis, we leveraged spatial transcriptomics methodologies to examine relevant gene heterogeneity in tissue retrieved from the human prefrontal cortex. Methods: Expression profiles of genes with established relations to the SARS-CoV-2 neuroinvasion process were spatially resolved in dorsolateral prefrontal cortex tissue (N = 4). Spotplots were generated with mapping to six (6) previously defined gray matter layers. Results: Docking gene BSG, processing gene CTSB, and viral defense gene LY6E demonstrated similar spatial enrichment. Docking gene ACE2 and transmembrane series proteases involved in spike protein processing were lowly expressed across DLPFC samples. Numerous other findings were obtained. Conclusion: Efforts to spatially represent expression levels of key SARS-CoV-2 brain infiltration genes remain paltry to date. Understanding the sobering history of beta coronavirus neuroinvasion represents a weak point in viral research. Here we provide the first efforts to characterize a motley of such genes in the dorsolateral prefrontal cortex.

Neurological complications of COVID-19

Article

Dec 2022

COVID-19 has caused several pandemic peaks worldwide due to its high variability and infectiousness, and COVID-19 has become a long-standing global public health problem. There is growing evidence that SARS-CoV-2 frequently causes multi-organ injuries and more severe neurological manifestations. Therefore, increased awareness of possible neurological complications is beneficial in preventing and mitigating the impact of long-term sequelae and improving the prognostic outcome of critically ill patients with COVID-19. Here, we review the main pathways of SARS-CoV-2 neuroinvasion and the potential mechanisms causing neurological damage. We also discuss in detail neurological complications, aiming to provide cutting-edge basis for subsequent related basic research and clinical studies of diagnosis and treatment.

Neurological symptoms and comorbidity profile of hospitalized patients with COVID-19

Article

Full-text available

Mar 2023

Background The neurological manifestations in COVID-19 adversely impact acute illness and post-disease quality of life. Limited data exist regarding the association of neurological symptoms and comorbid individuals. Objective To assess neurological symptoms in hospitalized patients with acute COVID-19 and multicomorbidities. Methods Between June 2020 and July 2020, inpatients aged 18 or older, with laboratory-confirmed COVID-19, admitted to the Hospital São Paulo (Federal University of São Paulo), a tertiary referral center for high complexity cases, were questioned about neurological symptoms. The Composite Autonomic Symptom Score 31 (COMPASS-31) questionnaire was used. The data were analyzed as a whole and whether subjective olfactory dysfunction was present or not. Results The mean age of the sample was 55 ± 15.12 years, and 58 patients were male. The neurological symptoms were mostly xerostomia (71%), ageusia/hypogeusia (50%), orthostatic intolerance (49%), anosmia/hyposmia (44%), myalgia (31%), dizziness (24%), xerophthalmia (20%), impaired consciousness (18%), and headache (16%). Furthermore, 91% of the patients had a premorbidity. The 44 patients with subjective olfactory dysfunction were more likely to have hypertension, diabetes, weakness, shortness of breath, ageusia/hypogeusia, dizziness, orthostatic intolerance, and xerophthalmia. The COMPASS-31 score was higher than that of previously published controls (14.85 ± 12.06 vs. 8.9 ± 8.7). The frequency of orthostatic intolerance was 49% in sample and 63.6% in those with subjective olfactory dysfunction (2.9-fold higher risk compared to those without). Conclusion A total of 80% of inpatients with multimorbidity and acute COVID-19 had neurological symptoms. Chemical sense and autonomic symptoms stood out. Orthostatic intolerance occurred in around two-thirds of the patients with anosmia/hyposmia. Hypertension and diabetes were common, mainly in those with anosmia/hyposmia.

Severe pediatric acute encephalopathy syndromes related to SARS-CoV-2

Article

Full-text available

Feb 2023

Background and objectives To clarify whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection cause acute encephalopathy in children and which are the most common syndromes that cause them and what are the outcomes. Methods A nationwide web-based survey among all members of the Japanese Society of Child Neurology to identify pediatric patients aged < 18 years who developed acute encephalopathy in Japan between 1 January 2020 and 31 May 2022 associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection confirmed by polymerase chain reaction or antigen tests using pharyngeal swabs. Acute encephalopathy was defined as acute onset of impaired consciousness lasting > 24 h or an altered mental state; neurological symptoms arising within 2 weeks of onset of COVID-19 or multisystem inflammatory syndrome in children (MIS-C)/pediatric inflammatory multisystem syndrome (PIMS); evidence of SARS-CoV-2 infection; and reasonable exclusion of other diseases. Patients were divided into the known clinico-radiological acute encephalopathy syndrome group and unexplained or unclassifiable acute encephalopathy group. Outcomes were assessed by pediatric cerebral performance category (PCPC) score at hospital discharge. Results Of the 3,802 society members, 217 representing institutions responded, and 39 patients with suspected acute encephalopathy were reported, of which 31 met inclusion criteria. Of these patients, 14 were diagnosed with known clinico-radiological acute encephalopathy syndromes, with acute encephalopathy with biphasic seizures and late reduced diffusion (five patients) being the most common. Five developed acute encephalopathy associated with MIS-C/PIMS. Among 31 patients, 9 (29.0%) had severe sequelae or died (PCPC ≥ 4). Two of three patients with encephalopathy with acute fulminant cerebral edema and two with hemorrhagic shock and encephalopathy syndrome died. The PCPC scores were higher in the known clinico-radiological acute encephalopathy syndrome group than in the unexplained or unclassifiable acute encephalopathy group ( P < 0.01). Discussion Acute encephalopathy related to SARS-CoV-2 infection was demonstrated to be more severe than that caused by other viruses in Japan. Acute encephalopathy syndromes characterized by specific neuroradiological findings was associated with poor clinical outcomes.

Pain Management in the Post-COVID Era-An Update: A Narrative Review

Article

Full-text available

Feb 2023

An extensive computer search (from January 2020 to January 2023) was conducted including literature from the PubMed, Scopus, MEDLINE, Web of Science, and EMBASE databases. According to preset criteria, a total of 58 articles were included in this review article. Generally, any patient who becomes infected with COVID-19 can develop post-COVID-19 conditions. The course of COVID-19 is divided into three main stages: acute COVID-19 (up to 4 weeks), post-acute COVID-19 (from 4 to 12 weeks), and post-COVID (from 12 weeks to 6 months). If a more protracted course of COVID (over 6 months) is demonstrated, the term "long-COVID" is used. Although the acute stage of COVID-19 infection most commonly manifests with acute respiratory symptoms, one very common symptom of the disease is pain, while the most common symptoms of post-COVID syndrome are shortness of breath, dry cough, fatigue, loss of olfactory and gustatory function, tightness and chest pain, sleep and mood disturbances, body aches, muscle and joint pain, sore throat, fever, and persistent headaches. All observations demonstrated a high incidence of chronic pain syndromes of various localization in the post- and long-COVID period. Post-COVID chronic pain might include a newly developed chronic pain as a part of post-viral syndrome; worsening of preexisting chronic pain due to the associated changes in the medical services, or a de novo chronic pain in healthy individuals who are not infected with COVID. Chronic pain during and post-COVID-19 pandemic is an important health issue due to the significant impacts of pain on the patients, health care systems, and society as well. Therefore, it is important that patients with chronic pain receive effective treatment according to their specific needs. Accordingly, the main goal of this review article is to provide a broad description about the post-COVID pain and to explore the impact of long COVID-19 on chronic pain patients, and also to give brief reports about the prevalence, risk factors, possible mechanisms, different presentations, and the management tools through a systematic approach.

COVID-19, SARS-CoV-2 Vaccination, and Human Herpesviruses Infections

Article

Full-text available

Jan 2023

Peter A C Maple

There are several human herpesviruses. A common characteristic of infection by these viruses is latency, by which the virus assumes a non-replicative state, subverting the attentions of the host’s immune response. In immunocompetent hosts, herpesviruses are immunologically controlled, although periodic virus shedding can occur. In situations where immunological control is lost, herpesviruses can reactivate and produce clinically apparent disease. It is now becoming apparent that COVID-19 or exposure to COVID-19 vaccines can exert several effects on the immune system. The pandemic of COVID-19 shows no sign of abating, with new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants continuing to evolve. Several COVID-19 vaccines have been developed, and much of the world’s population has either experienced COVID-19 or been vaccinated against it. There are an increasing number of reports of associations between herpesvirus infections or reactivations and COVID-19 or COVID-19 vaccination. For instance, a positive cytomegalovirus serostatus may indicate a greater likelihood of severe COVID-19, and herpes simplex virus reactivation may be linked to increased mortality. Epstein–Barr virus reactivation appears to be associated with post-acute sequelae of COVID-19. Finally, herpes zoster has been reported to be associated with COVID-19 vaccination. This brief narrative review will provide several insights into associations between herpesvirus infections or reactivations and COVID-19 or SARS-CoV-2 vaccination.

COVID-19 Pandemic and Neurocognitive Process: New Scenarios for Understanding and Treatment

Chapter

Full-text available

Nov 2022

COVID-19 disease was defined as a disease of primary respiratory system. However, symptoms associated with central nervous system were detected in approximately 2/3 of the hospitalized patients. The rate of ischemic cerebrovascular diseases is higher in central nervous system. In addition, hemorrhagic cerebrovascular diseases, encephalitis and/or encephalopathy are the other diseases. Complex pathogenesis was demonstrated in the central nervous system diseases associated with SARS-CoV-2. It was reported that SARS-CoV-2 virus could directly invade the central nervous system, especially via the olfactory nerves or the haematological pathway. As a result, endothelial cells, pericytes and/or neurons can be infected (direct pathway). Another mechanism is central nervous system deficit resulting from peripheral immune reactivation (indirect pathway). All these etiopathogenetic results support that COVID-19 disease is associated with cognitive dysfunction. Cerebral hypoperfusion associated with vascular endothelial structures is the main factor in the etiopathogenesis. It was reported that COVID-19 disease induced amyloid-β (Aβ) and α-synuclein phosphorylation. Besides, it was detected that this process was associated with tau and TDP-43 pathology. “Cognitive COVID-19” is a term that describes acute and long-term cognitive changes in people infected with SARS-CoV-2. Encephalopathy, delirium and cognitive disorders are most frequently detected. In this chapter, the clinical and etiopathogenetic processes of cognitive dysfunction after COVID-19 disease were evaluated. In addition, the disease, disease process and treatment were evaluated in general.

COVID-19 and neurological complications: A review

Article

Full-text available

Nov 2022

Infections with viruses have detrimental effects on neurological functions, and even cause severe neurological damage. There is mounting evidence that coronaviruses (CoV) as well as SARS-CoV-2 exhibit neurotropic abilities and might cause neurological problems. Neuroinvasive viruses are not fully understood, which makes it important to investigate their impact on the nervous system. In this paper, we review research into neurological complications associated with CoV.

Hospitalisation for COVID-19 predicts long lasting cerebrovascular impairment: A prospective observational cohort study

Article

Full-text available

Nov 2022

Human coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has multiple neurological consequences, but its long-term effect on brain health is still uncertain. The cerebrovascular consequences of COVID-19 may also affect brain health. We studied the chronic effect of COVID-19 on cerebrovascular health, in relation to acute severity, adverse clinical outcomes and in contrast to control group data. Here we assess cerebrovascular health in 45 patients six months after hospitalisation for acute COVID-19 using the resting state fluctuation amplitudes (RSFA) from functional magnetic resonance imaging, in relation to disease severity and in contrast with 42 controls. Acute COVID-19 severity was indexed by COVID-19 WHO Progression Scale, inflammatory and coagulatory biomarkers. Chronic widespread changes in frontoparietal RSFA were related to the severity of the acute COVID-19 episode. This relationship was not explained by chronic cardiorespiratory dysfunction, age, or sex. The level of cerebrovascular dysfunction was associated with cognitive, mental, and physical health at follow-up. The principal findings were consistent across univariate and multivariate approaches. The results indicate chronic cerebrovascular impairment following severe acute COVID-19, with the potential for long-term consequences on cognitive function and mental wellbeing.

Identifying cerebral microstructural changes in patients with COVID-19 using MRI: A systematic review

Article

Full-text available

Mar 2023

COVID-19 and Its Impact on Onset and Progression of Parkinson’s and Cognitive Dysfunction

Chapter

Full-text available

Mar 2023

In the COVID-19 pandemic, neurological complications have emerged as a significant cause of morbidity and mortality. A wide range of neurological manifestations ranging from cognitive or memory disturbances, headache, loss of smell or taste, confusion, and disabling strokes have been reported during and post COVID conditions. The COVID-19 virus can utilize two possible pathways for invasion into the brain, either through retrograde axonal transport (olfactory route) or by crossing the blood-brain barrier (BBB). Furthermore, the production of SARS-CoV-2-associated cytokines, such as interleukin (IL)-6, IL-17, IL-1b, and tumor necrosis factor (TNF), is able to disrupt the BBB. The neuroinvasive nature of SARS-CoV-2 has a more severe impact on patients with preexisting neurological manifestations such as Parkinson’s disease (PD). Pathological features of PD include selective loss of dopaminergic neurons in the substantia nigra pars compacta and aggregation of α-syn proteins present in neurons. Interaction between SARS-COV-2 infection and α-synuclein might have long-term implications on the onset of Parkinsonism by the formation of toxic protein clumps called amyloid fibrils—a hallmark of Parkinson’s. Molecular modeling is an emerging tool to predict potential inhibitors against the enzyme α-synuclein in neurodegenerative diseases by using plant bioactive molecules.

Neurological Consequences of Pulmonary Emboli in COVID-19 Patients: A Study of Incidence and Outcomes in the Kingdom of Saudi Arabia

Article

Full-text available

Feb 2023
BSRCCS

Citation: Bakhsh, E.; Shaban, M.; Alzoum, M.A.; AlNassir, A.M.; Bin Hamad, A.A.; Alqahtani, M.S.; AlAyoubi, L.A.F.; Alamri, R.M.; Alamri, N.F. Neurological Consequences of Pulmonary Emboli in COVID-19 Patients: A Study of Incidence and Outcomes in the Kingdom of Saudi Arabia. Brain Sci. 2023, 13, 343. https://doi. Abstract: Pulmonary embolism (PE) is a significant consequence that is becoming more common in COVID-19 patients. The current study sought to determine the prevalence and risk factors for PE in a study population of COVID-19 patients, as well as the relationship between PE and neurological se-quelae. The research also sought to analyze the consistency of neurological examination and imaging techniques in detecting neurological problems. The research comprised a total of 63 individuals with COVID-19. The incidence of PE in the study group was 9.5% for smokers, 23.8% for obese patients, 33.3% for hypertensive patients, and 19% for diabetic patients, according to the findings. After adjusting for possible confounders such as age, gender, BMI, smoking, hypertension, and diabetes, a logistic regression analysis indicated that the probabilities of having neurological complications were 3.5 times greater in individuals who had PE. In conclusion, the present study highlights the high incidence of PE among patients with COVID-19 and the association between PE and neurological complications. The study also emphasizes the importance of a thorough neurological examination and imaging studies in the detection of neurological complications in patients with PE.

Enfermedad Vascular Cerebral en COVID-19, Revisión desus Mecanismos Patologicos, Diagnostico por Imagen e implicaciones Terapéuticas

Article

Full-text available

Feb 2023

La enfermedad cerebrovascular aguda, particularmente el accidente cerebrovascular isquémico, ha surgido como una complicación grave de la infección por el síndrome respiratorio agudo severo coronavirus 2 (SARS-CoV-2). La acumulación de datos sobre pacientes con accidente cerebrovascular asociado con COVID-19 ha arrojado luz sobre las especificidades relacionadas con la presentación clínica, los hallazgos de neuroimagen y sus resultados. Dichas especificidades incluyen una propensión a la oclusión de vasos grandes, accidente cerebrovascular multiterritorial y compromiso de vasos afectados de otra manera poco común. Por el contrario, la enfermedad cerebral de vasos pequeños, la trombosis venosa cerebral y la hemorragia intracerebral parecen ser menos frecuentes. Los casos que presen-taban encefalopatía o encefalitis con crisis epilépticas sintomáticas que presagiaban un accidente cerebrovascular fueron particularmente desafiantes. La patogénesis y el manejo óptimo del accidente cerebrovascular isquémico asociado con COVID-19 aún son inciertos, pero la evidencia emergente sugiere que la coagulopatía y la endoteliopatía desencadenadas por tormentas de citoquinas representan posibles mecanismos a los que se puede apuntar. Algunos problemas de manejo específicos en esta población incluyen la dificultad para identifi-car signos clínicos de accidente cerebrovascular en pacientes críticos en la unidad de cuidados intensivos, así como la necesidad de una vía protegida para imágenes cerebrales, trombólisis intravenosa y trombectomía mecánica, teniendo en cuenta que "el tiempo es cerebro" también para pacientes con COVID-19. ICTUS 2023;4(1):e31012304001 Palabras clave-SARS-CoV-2, Coronavirus, Enfermedad cerebrovascular, Coagulopatía, Evento cerebrovascular hemorrágico, Compli-caciones neurológicas Abstract-Cerebrovascular disease in COVID-19, Review of its Pathological Mechanisms, Diagnostic Imaging and Therapeutic Implications Acute cerebrovascular disease, particularly ischemic stroke, has emerged as a serious complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The accumulation of data on stroke patients associated with COVID-19 has shed light on speci-ficities related to clinical presentation, neuroimaging findings, and their outcomes. Such specificities include a propensity for large-vessel occlusion, multiterritorial stroke, and involvement of otherwise uncommonly affected vessels. In contrast, cerebral small vessel disease, cerebral venous thrombosis, and intracerebral hemorrhage appear to be less common. Cases presenting with encephalopathy or encephalitis with seizures presaging stroke were particularly challenging. The pathogenesis and optimal management of ischemic stroke associated with COVID-19 remain uncertain, but emerging evidence suggests that cytokine storm-triggered coagulopathy and endotheliopathy represent possible target mechanisms. Some specific management issues in this population include the difficulty in identifying clinical signs of stroke in critically ill patients in the intensive care unit, as well as the need for a protected pathway for brain imaging, intravenous thrombolysis, and mechanical thrombectomy, considering that "time is brain. a lso for patients with COVID-19. ICTUS 2023;4(1):e31012304001

The brain reacting to COVID-19: analysis of the cerebrospinal fluid proteome, RNA and inflammation

Article

Full-text available

Feb 2023
J NEUROINFLAMM

Abstract Patients with COVID-19 can have a variety of neurological symptoms, but the active involvement of central nervous system (CNS) in COVID-19 remains unclear. While routine cerebrospinal fluid (CSF) analyses in patients with neurological manifestations of COVID-19 generally show no or only mild inflammation, more detailed data on inflammatory mediators in the CSF of patients with COVID-19 are scarce. We studied the inflammatory response in paired CSF and serum samples of patients with COVID-19 (n = 38). Patients with herpes simplex virus encephalitis (HSVE, n = 10) and patients with non-inflammatory, non-neurodegenerative neurological diseases (n = 28) served as controls. We used proteomics, enzyme-linked immunoassays, and semiquantitative cytokine arrays to characterize inflammatory proteins. Autoantibody screening was performed with cell-based assays and native tissue staining. RNA sequencing of long-non-coding RNA and circular RNA was done to study the transcriptome. Proteomics on single protein level and subsequent pathway analysis showed similar yet strongly attenuated inflammatory changes in the CSF of COVID-19 patients compared to HSVE patients with, e.g., downregulation of the apolipoproteins and extracellular matrix proteins. Protein upregulation of the complement system, the serpin proteins pathways, and other proteins including glycoproteins alpha-2 and alpha-1 acid. Importantly, calculation of interleukin-6, interleukin-16, and CXCL10 CSF/serum indices suggest that these inflammatory mediators reach the CSF from the systemic circulation, rather than being produced within the CNS. Antibody screening revealed no pathological levels of known neuronal autoantibodies. When stratifying COVID-19 patients into those with and without bacterial superinfection as indicated by elevated procalcitonin levels, inflammatory markers were significantly (p

Neurological infection and complications of SARS-CoV-2: A review

Article

Feb 2023
MEDICINE

The primary target of severe acute respiratory syndrome coronavirus 2 is the respiratory system including the nose and lungs, however, it can also damage the kidneys, cardiovascular system and gastrointestinal system. Many recent reports suggested that severe acute respiratory syndrome coronavirus 2 infections can also affect the central nervous system as well as peripheral nervous system that lead to the several neurological complications. The virus can break the blood brain barrier and enters the brain via haematological route or directly by the angiotensin-converting enzyme 2 receptors present on endothelial cells of many cerebral tissues. The neurological complications are manifested by headache, dizziness, encephalopathy, encephalitis, cerebrovascular disease, anosmia, hypogeusia, muscle damage, etc. This review article described the possible routes and mechanism of nervous system infection and the range of neurological complications of COVID-19 that may help the medical practitioners and researchers to improve the clinical treatment and reduce the mortality rate among patients with viral diseases.

SARS-CoV-2 Possible Etiology of Cerebral Venous Thrombosis in a Teenager: Case Report and Review of Literature

Article

Full-text available

Jan 2023

Cerebral venous thrombosis in pediatric patient has a varied etiology. The authors present the case of a teenager who, since the debut of SARS-CoV-2 infection, has accused intermittent right side hemicrania, which has become persistent in association with nausea and vomiting since the 5th day of quarantine. She was hospitalized in the 9th day since the debut. Neuroimaging revealed extended venous cerebral thrombosis affecting the right sigmoid sinus, the transverse sinus bilaterally, the confluence of the transverse sinuses and the right internal jugular vein. The evolution was favorable under anticoagulant and symptomatic treatment. Laboratory tests excluded other etiological causes for the cerebral venous thrombosis, thus the authors consider that cerebral thrombosis is a possible complication of SARS-CoV-2 infection in teenagers.

Study of neuroanatomical sequelae associated with post-COVID- 19 syndrome

Article

Full-text available

Feb 2022

Objective: To point out the neuroanatomic repercussions that the Post-COVID Syndrome triggers in individuals and address the pathophysiology of SARS-CoV-2 infection. Literature review: COVID-19 is an acute viral respiratory disease. Post-COVID-19 Syndrome gets its name because it is a set of clinical manifestations that persist for longer than two or three weeks after the onset of symptoms. Among the related disorders, neuroanatomical sequelae stand out, such as injuries with the ability to generate significant morbidity and mortality. Final considerations: It is concluded that this syndrome is associated with relevant sequelae, such as in the Central Nervous System. There were descriptions of different neurological manifestations such as stroke, ageusia, headache, Guillain-Barré syndrome, encephalopathy, anosmia, and dizziness. It is essential to further studies to support patient management with the best evidence to reduce morbidities.

Longitudinal changes in global structural brain connectivity and cognitive performance in former hospitalized COVID-19 survivors: an exploratory study

Article

Full-text available

Jan 2023
EXP BRAIN RES

Background Long-term sequelae of COVID-19 can result in reduced functionality of the central nervous system and substandard quality of life. Gaining insight into the recovery trajectory of admitted COVID-19 patients on their cognitive performance and global structural brain connectivity may allow a better understanding of the diseases' relevance. Objectives To assess whole-brain structural connectivity in former non-intensive-care unit (ICU)- and ICU-admitted COVID-19 survivors over 2 months following hospital discharge and correlate structural connectivity measures to cognitive performance. Methods Participants underwent Magnetic Resonance Imaging brain scans and a cognitive test battery after hospital discharge to evaluate structural connectivity and cognitive performance. Multilevel models were constructed for each graph measure and cognitive test, assessing the groups' influence, time since discharge, and interactions. Linear regression models estimated whether the graph measurements affected cognitive measures and whether they differed between ICU and non-ICU patients. Results Six former ICU and six non-ICU patients completed the study. Across the various graph measures, the characteristic path length decreased over time (β = 0.97, p = 0.006). We detected no group-level effects (β = 1.07, p = 0.442) nor interaction effects (β = 1.02, p = 0.220). Cognitive performance improved for both non-ICU and ICU COVID-19 survivors on four out of seven cognitive tests 2 months later (p < 0.05). Conclusion Adverse effects of COVID-19 on brain functioning and structure abate over time. These results should be supported by future research including larger sample sizes, matched control groups of healthy non-infected individuals, and more extended follow-up periods.

Blood-brain barrier disruption in Long COVID-associated cognitive impairment

Preprint

Full-text available

Sep 2022

Vascular disruption has been heavily implicated in COVID-19 pathogenesis and may predispose the neurological sequelae associated with the condition now known as long COVID. To date, no studies have objectively assessed blood-brain barrier (BBB) function in individuals with neurological complications stemming from prior SARS-CoV-2 infection. Here, we explored the neurobiological effects of SARS-CoV-2 infection in humans with acute infection (n = 76) and those with persistent long COVID with and without neurological impairment. Following acute infection, patients with neurological impairment had increased serum S100β, indicative of BBB disruption. Furthermore, using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in long COVID patients (n = 32), we observed elevated BBB permeability in distinct neuroanatomical regions including the frontal cortex, occipital lobe and temporal lobes which correlated with global brain volume and white matter volume deficits in patients with neurological impairment. Patients with neurological impairment had increased levels of blood-based biomarkers including GFAP, TGFβ and IL8 with levels of TGFβ that correlated with BBB permeability and structural brain changes. Peripheral blood mononuclear cells isolated from unaffected and long COVID patients had persistent upregulation of inflammatory markers including IFNA/G and showed increased adhesion to human brain endothelial cells in vitro . Finally, exposure of endothelial cells to serum from long COVID patients induced increases in ICAM-1, VCAM-1 and TNF irrespective of neurological sequelae. Together, these data suggest that sustained systemic inflammation and persistent localised BBB dysfunction is a feature of long COVID-associated neurological impairment. Importantly, this may also be therapeutically relevant in the treatment and clinical management of this patient group.

Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) following COVID-19 vaccines: A systematic review

Article

Jan 2023
REV NEUROL-FRANCE

Background: The global COVID-19 pandemic began in March 2019, and given the number of casualties and adverse effects on the economy, society, and all aspects of the health system, efforts have been made to develop vaccines from the beginning of the pandemic. Numerous vaccines against COVID-19 infection have been developed in several technologies and have spread rapidly. There have been reported multiple complications of the COVID-19 vaccines as with other vaccines. A number of studies have reported multiple sclerosis (MS ) and neuromyelitis optica spectrum disorder (NMOSD) as complications of COVID-19 vaccines. Methods: First, we found 954 studies from 4 databases (PubMed, Embase, Scopus, and Web of Science) from inception to March 1st, 2022. Next, duplicate articles were eliminated, and 476 studies remained. Then 412 studies were removed according to inclusion and exclusion criteria. After obtaining the full text of 64 articles, 12 studies were selected finally. Results: The data were extracted from included studies in a table. Our data includes demographic data, comorbidities, vaccines information and side effects, NMOSD and MS symptoms, laboratory and cerebrospinal fluid (CSF) findings, magnetic resonance imaging (MRI) results, treatment, and outcome of all cases. Conclusion: MS and NMOSD are two neuroinflammatory disorders that arise in the CNS. Cases of MS and NMOSD have been reported following COVID-19 vaccination. Nevertheless, more studies with more subjects are needed to assess any possible relationship between the COVID-19 vaccine and central nervous system demyelination.

Transient diabetes insipidus in critically ill COVID19 patients

Article

Jan 2023

Purpose: Vasopressin has become an important vasopressor drug while treating a critically ill patient to maintain adequate mean arterial pressure. Diabetes insipidus (DI) is a rare syndrome characterized by the excretion of a large volume of diluted urine, inappropriate for water homeostasis. We noticed that several COVID19 patients developed excessive polyuria suggestive of DI, with a concomitant plasma sodium-level increase and/or low urine osmolality. We noticed a temporal relationship between vasopressin treatment cessation and polyuria periods. We reviewed those cases to better describe this phenomenon. Methods: We retrospectively collected COVID19 ECMO patients' (from July 6, 2020, to November 30, 2021) data from the electronic medical records. By examining urine output, urine osmolality (if applicable), plasma sodium level, and plasma osmolality, we set DI diagnosis. We described the clinical course of DI episodes and compared baseline characteristics between patients who developed DI and those who did not. Results: Out of 37 patients, 12 had 18 episodes of DI. These patients were 7 years younger and had lower severity scores (APACHE-II and SOFA). Mortality difference was not seen between groups. 17 episodes occurred after vasopressin discontinuation; 14 episodes were treated with vasopressin reinstitution. DI lasted for a median of 21 h, with a median increase of 14 mEq/L of sodium. Conclusions: Temporary DI prevalence after vasopressin discontinuation in COVID19 ECMO patients might be higher than previously described for vasopressin-treated patients.

SELF-ASSESSMENT OF HEARING USING A MOBILE APP AMONG COVID-19 PATIENTS

Article

Full-text available

Dec 2022
J Hear Sci

Introduction The effect of SARS-CoV-2 on hearing has not been thoroughly examined. Factors limiting hearing tests in COVID-19 patients are hygiene requirements and the need to use specialized equipment. The objective of the study was to assess changes in hearing thresholds between diagnosis of COVID-19 and convalescence using a mobile app. Material and methods Patients with mild to moderate COVID-19 symptoms, who were isolating at home were enrolled in the study between 1 September 2020 and 31 January 2021. Subjects answered an online medical survey and self-assessed hearing thresholds using the Hearing Test<sup>TM</sup> mobile app (e-audiologia.pl). These procedures were done twice, once at the time of diagnosis and again 2 weeks after convalescence. Results A total of 67 subjects were found eligible for the study. At most frequencies the patients’ hearing did not differ between the first and second examinations; however, for 4 kHz, a statistically significant improvement in the hearing threshold was found ( p = 0.05). Survey review revealed noticeable improvement ( p = 0.001) over time in smell, taste, and nasal congestion. Conclusions It seems that SARS-CoV-2 infection caused a transient and selective (at 4 kHz) hearing impairment in patients who had had mild to moderate infection. The results suggest that as olfactory function returns after COVID-19, an improvement in hearing can be expected. Solutions based on mobile technology are useful for monitoring the hearing of patients in a pandemic.

Developmental pathways linked to the vulnerability of adult midbrain dopaminergic neurons to neurodegeneration

Article

Full-text available

Dec 2022

Nilima Prakash

The degeneration of dopaminergic and other neurons in the aging brain is considered a process starting well beyond the infantile and juvenile period. In contrast to other dopamine-associated neuropsychiatric disorders, such as schizophrenia and drug addiction, typically diagnosed during adolescence or young adulthood and, thus, thought to be rooted in the developing brain, Parkinson’s Disease (PD) is rarely viewed as such. However, evidences have accumulated suggesting that several factors might contribute to an increased vulnerability to death of the dopaminergic neurons at an already very early (developmental) phase in life. Despite the remarkable ability of the brain to compensate such dopamine deficits, the early loss or dysfunction of these neurons might predispose an individual to suffer from PD because the critical threshold of dopamine function will be reached much earlier in life, even if the time-course and strength of naturally occurring and age-dependent dopaminergic cell death is not markedly altered in this individual. Several signaling and transcriptional pathways required for the proper embryonic development of the midbrain dopaminergic neurons, which are the most affected in PD, either continue to be active in the adult mammalian midbrain or are reactivated at the transition to adulthood and under neurotoxic conditions. The persistent activity of these pathways often has neuroprotective functions in adult midbrain dopaminergic neurons, whereas the reactivation of silenced pathways under pathological conditions can promote the survival and even regeneration of these neurons in the lesioned or aging brain. This article summarizes our current knowledge about signaling and transcription factors involved in midbrain dopaminergic neuron development, whose reduced gene dosage or signaling activity are implicated in a lower survival rate of these neurons in the postnatal or aging brain. It also discusses the evidences supporting the neuroprotection of the midbrain dopaminergic system after the external supply or ectopic expression of some of these secreted and nuclear factors in the adult and aging brain. Altogether, the timely monitoring and/or correction of these signaling and transcriptional pathways might be a promising approach to a much earlier diagnosis and/or prevention of PD.

The contribution of gut-brain axis to development of neurological symptoms in COVID-19 recovered patients: A hypothesis and review of literature

Article

Full-text available

Dec 2022

The gut microbiota undergoes significant alterations in response to viral infections, particularly the novel SARS-CoV-2. As impaired gut microbiota can trigger numerous neurological disorders, we suggest that the long-term neurological symptoms of COVID-19 may be related to intestinal microbiota disorders in these patients. Thus, we have gathered available information on how the virus can affect the microbiota of gastrointestinal systems, both in the acute and the recovery phase of the disease, and described several mechanisms through which this gut dysbiosis can lead to long-term neurological disorders, such as Guillain-Barre syndrome, chronic fatigue, psychiatric disorders such as depression and anxiety, and even neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. These mechanisms may be mediated by inflammatory cytokines, as well as certain chemicals such as gastrointestinal hormones (e.g., CCK), neurotransmitters (e.g., 5-HT), etc. (e.g., short-chain fatty acids), and the autonomic nervous system. In addition to the direct influences of the virus, repurposed medications used for COVID-19 patients can also play a role in gut dysbiosis. In conclusion, although there are many dark spots in our current knowledge of the mechanism of COVID-19-related gut-brain axis disturbance, based on available evidence, we can hypothesize that these two phenomena are more than just a coincidence and highly recommend large-scale epidemiologic studies in the future.

SARS-CoV-2 (COVID-19) as a possible risk factor for neurodevelopmental disorders

Article

Full-text available

Dec 2022

Pregnant women constitute one of the most vulnerable populations to be affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the cause of coronavirus disease 2019. SARS-CoV-2 infection during pregnancy could negatively impact fetal brain development via multiple mechanisms. Accumulating evidence indicates that mother to fetus transmission of SARS-CoV-2 does occur, albeit rarely. When it does occur, there is a potential for neuroinvasion via immune cells, retrograde axonal transport, and olfactory bulb and lymphatic pathways. In the absence of maternal to fetal transmission, there is still the potential for negative neurodevelopmental outcomes as a consequence of disrupted placental development and function leading to preeclampsia, preterm birth, and intrauterine growth restriction. In addition, maternal immune activation may lead to hypomyelination, microglial activation, white matter damage, and reduced neurogenesis in the developing fetus. Moreover, maternal immune activation can disrupt the maternal or fetal hypothalamic-pituitary-adrenal (HPA) axis leading to altered neurodevelopment. Finally, pro-inflammatory cytokines can potentially alter epigenetic processes within the developing brain. In this review, we address each of these potential mechanisms. We propose that SARS-CoV-2 could lead to neurodevelopmental disorders in a subset of pregnant women and that long-term studies are warranted.

Opportunities and Challenges of Human IPSC Technology in Kidney Disease Research

Article

Full-text available

Dec 2022

Human induced pluripotent stem cells (iPSCs), since their discovery in 2007, open a broad array of opportunities for research and potential therapeutic uses. The substantial progress in iPSC reprogramming, maintenance, differentiation, and characterization technologies since then has supported their applications from disease modeling and preclinical experimental platforms to the initiation of cell therapies. In this review, we started with a background introduction about stem cells and the discovery of iPSCs, examined the developing technologies in reprogramming and characterization, and provided the updated list of stem cell biobanks. We highlighted several important iPSC-based research including that on autosomal dominant kidney disease and SARS-CoV-2 kidney involvement and discussed challenges and future perspectives.

Symptoms, challenges and consequences of COVID-19 sequelae and their suggestive Reforms: An overview

Article

Nov 2022

Kalpa Mandal

Post-COVID-19 human memory impairment: A PRISMA-based systematic review of evidence from brain imaging studies

Article

Full-text available

Dec 2022

Many people with coronavirus disease 2019 (COVID-19) report varying degrees of memory impairment. Neuroimaging techniques such as MRI and PET have been utilized to shed light on how COVID-19 affects brain function in humans, including memory dysfunction. In this PRISMA-based systematic review, we compared and summarized the current literature looking at the relationship between COVID-19-induced neuropathological changes by neuroimaging scans and memory symptoms experienced by patients who recovered from COVID-19. Overall, this review suggests a correlational trend between structural abnormalities (e.g., cortical atrophy and white matter hyperintensities) or functional abnormalities (e.g., hypometabolism) in a wide range of brain regions (particularly in the frontal, parietal and temporal regions) and memory impairments in COVID-19 survivors, although a causal relationship between them remains elusive in the absence of sufficient caution. Further longitudinal investigations, particularly controlled studies combined with correlational analyses, are needed to provide additional evidence.

Meet changes with constancy: Defence, antagonism, recovery, and immunity roles of extracellular vesicles in confronting SARS-CoV-2

Article

Full-text available

Dec 2022

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has wrought havoc on the world economy and people's daily lives. The inability to comprehensively control COVID-19 is due to the difficulty of early and timely diagnosis, the lack of effective therapeutic drugs, and the limited effectiveness of vaccines. The body contains billions of extracellular vesicles (EVs), which have shown remarkable potential in disease diagnosis, drug development, and vaccine carriers. Recently, increasing evidence has indicated that EVs may participate or assist the body in defence, antagonism, recovery and acquired immunity against SARS-CoV-2. On the one hand, intercepting and decrypting the general intelligence carried in circulating EVs from COVID-19 patients will provide an important hint for diagnosis and treatment; on the other hand, engineered EVs modified by gene editing in the laboratory will amplify the effectiveness of inhibiting infection, replication and destruction of ever-mutating SARS-CoV-2, facilitating tissue repair and making a better vaccine. To comprehensively understand the interaction between EVs and SARS-CoV-2, providing new insights to overcome some difficulties in the diagnosis, prevention and treatment of COVID-19, we conducted a rounded review in this area. We also explain numerous critical challenges that these tactics face before they enter the clinic, and this work will provide previous 'meet change with constancy' lessons for responding to future similar public health disasters. Extracellular vesicles (EVs) provide a 'meet changes with constancy' strategy to combat SARS-CoV-2 that spans defence, antagonism, recovery, and acquired immunity. Targets for COVID-19 diagnosis, therapy, and prevention of progression may be found by capture of the message decoding in circulating EVs. Engineered and biomimetic EVs can boost effects of the natural EVs, especially anti-SARS-CoV-2, targeted repair of damaged tissue, and improvement of vaccine efficacy.

Completed Suicide Linked to the COVID-19 Pandemic by Using the Psychological Autopsy Method in Sibiu County, Romania: Case Series and Literature Review

Article

Full-text available

Nov 2022

The COVID-19 pandemic is associated with suicide, as some data suggests. Our study aims to investigate the emergence of eleven completed suicide cases suspected to be linked to the COVID-19 pandemic during the restrictive measures imposed by the Romanian government, and to identify the consequences of mental health, suicidal motivation, and behavioral changes. To this end, we analyzed the deceased’s medical records and applied the psychological autopsy method to the relatives/caregivers of the deceased for a suicidal investigation history, within conducted free-flow discussions. To highlight behavioral changes that occurred in the distant antecedents as well as immediately before the suicidal act, we used two sets of closed questions comprised of fifteen alarm signs, including depressive and/or anxiety symptoms. Our results showed that a deterioration of the mental status, especially concerning depressive and anxiety symptoms, was evident in people without or with pre-existing psychiatric pathology. The suicidal motivation proved to be complex including, in addition to the SARS-CoV-2 infection, social and economic consequences of the COVID-19 pandemic. We noted an intensification of the investigated alarm signs and even the emergence of new warning signs in the recent antecedents. Based on our findings, we reaffirmed the important role of the psychological autopsy method in suicide investigation, proving that it can detect the specific impact of the COVID-19 pandemic on people prone to suicide. This impact can be psycho-emotional, social, and/or economical, and thus we can state that the COVID-19 pandemic and its consequences can be, at least, a triggering factor that enhances completed suicide risk. Further studies are needed in this particular area because correlations between the COVID-19 pandemic and completed suicide do not appear to be accidental.

Bilateral Carotid Artery Dissections and Ischemic Stroke in a Patient With COVID-19: A Case Report

Article

Nov 2022

An unresponsive patient with COVID-19 infection should prompt immediate evaluation with consideration of a vast differential diagnosis entailing a multitude of diagnostic and therapeutic interventions in the emergency department. We report a case of an unresponsive 41-year-old female with COVID-19 infection and a history of rheumatoid arthritis who presented to the emergency department with bilateral carotid artery dissections and left internal carotid artery thrombus that extended into the middle cerebral artery. This case calls into question if COVID-19 is coincidentally or causally associated with acute vascular and thromboembolic disease.

Acute and long‑term psychiatric symptoms associated with COVID‑19 (Review)

Article

Nov 2022

Coronavirus disease 2019 (COVID-19) started spreading at the end of 2019 and despite the immediate actions of various governments with strict control, more and more individuals became infected daily. Due to the uncertainty and insecurity that still exists around this pandemic, there is an acute need for information and knowledge of what severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection entails. Respiratory and other physical symptoms received most of the medical attention, however, infected patients were also at risk for developing psychiatric and mental health disorders, such as depression, anxiety, and sleep disturbances. Available research reports a so-called 'post-COVID-19 syndrome', which refers to new and/or persistent signs and symptoms for over 12 weeks, following SARS. The aim of the present review was to provide a general overview of the psychiatric symptoms developed during SARS-CoV-2 infection and their long-term outcome, highlighting that, through follow-up with surviving patients it was revealed that some of the psychiatric symptoms of COVID-19 persisted for a long time after discharge and were also associated with negative effects on global functioning and lower quality of life.

Molecular and cellular mechanisms involved in tissue-specific metabolic modulation by SARS-CoV-2

Article

Full-text available

Nov 2022

Coronavirus disease 2019 (COVID-19) is triggered by the SARS-CoV-2, which is able to infect and cause dysfunction not only in lungs, but also in multiple organs, including central nervous system, skeletal muscle, kidneys, heart, liver, and intestine. Several metabolic disturbances are associated with cell damage or tissue injury, but the mechanisms involved are not yet fully elucidated. Some potential mechanisms involved in the COVID-19- induced tissue dysfunction are proposed, such as: (a) High expression and levels of proinflammatory cytokines, including TNF-α IL-6, IL-1β, INF-α and INF-β, increasing the systemic and tissue inflammatory state; (b) Induction of oxidative stress due to redox imbalance, resulting in cell injury or death induced by elevated production of reactive oxygen species; and (c) Deregulation of the renin-angiotensin-aldosterone system, exacerbating the inflammatory and oxidative stress responses. In this review, we discuss the main metabolic disturbances observed in different target tissues of SARS-CoV-2 and the potential mechanisms involved in these changes associated with the tissue dysfunction.

Efectos antiinflamatorio y neurotrófico de los neurolépticos atípicos en el manejo del COVID-19 en pacientes con esquizofrenia

Chapter

Feb 2023

La enfermedad por Coronavirus 2019 (Covid-19) causada por la infección del Coronavirus del Síndrome Agudo Respiratorio 2 (SARS-CoV-2) es capaz de afectar las células neuronales generando neuroinflamación. La neuroinflamación también es una característica fisiopatológica de diversas enfermedades mentales graves como la esquizofrenia, en la cual incluso se ha relacionado con las alteraciones de neuroplasticidad descritas en la enfermedad. Los neurolépticos atípicos, que son los fármacos de elec- ción para el tratamiento de la esquizofrenia, además de sus mecanismos monoaminérgicos mediante los cuales atenúan la sintomatología positiva principalmente, poseen propiedades anti-inflamatorias, antioxidantes y neurotróficas que podrían estar contribuyendo a su efecto terapéutico. Por lo tanto, se sugiere que los neurolépticos atípicos podrían estar contribuyendo a un mejor pronóstico del Covid-19 en pacientes con esquizofrenia mediante la modulación de la neuroinflamación.

Lipopolysaccharide-binding protein expression is increased by stress and inhibits monoamine synthesis to promote depressive symptoms

Article

Feb 2023
IMMUNITY

Monoamine insufficiency is suggested to be associated with depressive features such as sadness, anhedonia, insomnia, and cognitive dysfunction, but the mechanisms that cause it are unclear. We found that the acute-phase protein lipopolysaccharide-binding protein (LBP) inhibits monoamine biosynthesis by acting as an endogenous inhibitor of dopamine-β-hydroxylase (DBH) and aromatic-L-amino-acid-decarboxylase (DDC). LBP expression was increased in individuals with depression and by diverse stress challenges in mice. LBP antibodies and LBP knockdown inhibited monoamine insufficiency and depression-like features in mice, which worsened with LBP overexpression or administration. Monoamine insufficiency and depression-like symptoms were not induced by stressful stimuli in LBP-deficient mice, further highlighting a role for LBP in stress-induced depression, and a peptide we designed that blocks LBP-DBH and LBP-DDC interactions showed anti-depression effects in mice. This study reveals an important role for LBP in regulating monoamine biosynthesis and suggests that targeting LBP may have potential as a treatment for some individuals with depression.

Detection of SARS-CoV-2 viral proteins and genomic sequences in human brainstem nuclei

Article

Full-text available

Feb 2023

Neurological manifestations are common in COVID-19, the disease caused by SARS-CoV-2. Despite reports of SARS-CoV-2 detection in the brain and cerebrospinal fluid of COVID-19 patients, it is still unclear whether the virus can infect the central nervous system, and which neuropathological alterations can be ascribed to viral tropism, rather than immune-mediated mechanisms. Here, we assess neuropathological alterations in 24 COVID-19 patients and 18 matched controls who died due to pneumonia/respiratory failure. Aside from a wide spectrum of neuropathological alterations, SARS-CoV-2-immunoreactive neurons were detected in the dorsal medulla and in the substantia nigra of five COVID-19 subjects. Viral RNA was also detected by real-time RT-PCR. Quantification of reactive microglia revealed an anatomically segregated pattern of inflammation within affected brainstem regions, and was higher when compared to controls. While the results of this study support the neuroinvasive potential of SARS-CoV-2 and characterize the role of brainstem inflammation in COVID-19, its potential implications for neurodegeneration, especially in Parkinson’s disease, require further investigations.

Role of the MicroRNAs in the Pathogenic Mechanism of Painful Symptoms in Long COVID: Systematic Review

Article

Full-text available

Feb 2023
INT J MOL SCI

The ongoing pandemic of COVID-19 has caused more than 6.7 million tragic deaths, plus, a large percentage of people who survived it present a myriad of chronic symptoms that last for at least 6 months; this has been named as long COVID. Some of the most prevalent are painful symptoms like headache, joint pain, migraine, neuropathic-like pain, fatigue and myalgia. MicroRNAs are small non-coding RNAs that regulate genes, and their involvement in several pathologies has been extensively shown. A deregulation of miRNAs has been observed in patients with COVID-19. The objective of the present systematic review was to show the prevalence of chronic pain-like symptoms of patients with long COVID and based on the expression of miRNAs in patients with COVID-19, and to present a proposal on how they may be involved in the pathogenic mechanisms of chronic pain-like symptoms. A systematic review was carried out in online databases for original articles published between March 2020 to April 2022; the systematic review followed the PRISMA guidelines, and it was registered in PROSPERO with registration number CRD42022318992. A total of 22 articles were included for the evaluation of miRNAs and 20 regarding long COVID; the overall prevalence of pain-like symptoms was around 10 to 87%, plus, the miRNAs that were commonly up and downregulated were miR-21-5p, miR-29a,b,c-3p miR-92a,b-3p, miR-92b-5p, miR-126-3p, miR-150-5p, miR-155-5p, miR-200a, c-3p, miR-320a,b,c,d,e-3p, and miR-451a. The molecular pathways that we hypothesized to be modulated by these miRNAs are the IL-6/STAT3 proinflammatory axis and the compromise of the blood–nerve barrier; these two mechanisms could be associated with the prevalence of fatigue and chronic pain in the long COVID population, plus they could be novel pharmacological targets in order to reduce and prevent these symptoms.

The SARS-CoV-2 spike S1 protein induces global proteomic changes in ATII-like rat L2 cells that are attenuated by hyaluronan

Article

Jan 2023

The COVID-19 pandemic continues to impose a major impact on global health and economy since its identification in early 2020, causing significant morbidity and mortality worldwide. Caused by the SARS-CoV-2 virus, along with a growing number of variants, COVID-19 has led to 651,918,402 confirmed cases, and 6,656,601 deaths worldwide (as of December 27, 2022; https://covid19.who.int/). Despite advances in our understanding of COVID19 pathogenesis, the precise mechanism by which SARS-CoV2 causes epithelial injury is incompletely understood. In this current study, robust application of global-discovery proteomics identified highly significant induced changes by the Spike S1 protein of SARS-CoV-2 in the proteome of alveolar type II (ATII)-like Rat L2 cells that lack ACE2 receptors. Systems biology analysis revealed that the S1 induced proteomics changes were associated with three significant network hubs: E2F1, CREB1/ RelA, and ROCK2/ RhoA. We also found that pre-treatment of L2 cells with High Molecular Weight Hyaluronan (HMW-HA), greatly attenuated the S1 effects on the proteome. Western blotting analysis and cell cycle measurements confirmed the S1-upregulation of E2F1 and ROCK2/RhoA in L2 cells and the protective effects of HMW-HA. Taken as a whole, our studies revealed profound and novel biological changes that contribute to our current understanding of both S1 and Hyaluronan biology. This data shows that the S1 protein may contribute to epithelial injury induced by SARS-CoV-2. In addition, our work supports the potential benefit of HMW-HA in ameliorating SARS CoV2 induced cell injury (236 words).

Epidemiological Effects of the COVID‐19 Pandemic on Modifiable Risk Factors for Dementia

Article

Jan 2023

Interfacial shear stress transfer between elastoplastic fiber and elastic matrix

Article

Apr 2023
J MECH PHYS SOLIDS

Acute Necrotizing Encephalopathy Following Presumed COVID-19 Infection: The First Iranian Report in Children

Article

Full-text available

Jan 2023

In the fifth’s SARS-CoV-2 infection peak, although extended vaccination, still there is some reports of neurologic complications of covid-19 in children like adult. Though often we expose to benign neurologic features but sometimes there is unusual clinicoradiologic presentation. Thus, report of uncommon neurologic manifestations can help us to better understand of main pathophysiology in pediatric brain involvement. In this report, we present a five-year- old previously healthy girl that arrive to our hospital with fever, vomiting and loss of consciousness, on lumbar puncture there was mild protein elevation without poleocytosis and nasopharyngeal swap PCR for COVID-19 was positive. Brain imaging 10 hours after admission, revealed findings suggestive of acute necrotizing encephalopa thy (ANE). In spite of extensive brain involvement, after prompt initiation of high dose methylprednisolone and IV immunoglobulin, there was dramatic improvement after 3 months’ follow-up. To our knowledge, this is the first Iranian report and the second report on the world.

The role of calcium and calcium regulating hormonal system in the mechanisms of COVID-19 contagiousness and severity

Article

Jan 2022

Calcium is involved in all vital processes of the body: synaptic transmission, memory development, immunity, blood clotting, heart contractions, etc. In this regard, it is important to understand the involvement of calcium in the development of SARS-CoV-2 virus infection and COVID-19 disease. We have studied the existing scientific literature, looking for the involvement of both calcium and calcium-regulating hormones (parathyroid hormone, calcitonin, vitamin D) in COVID contagiousness and severity of disease. Separately, both hypocalcemia and vitamin D deficiency have been identified in a number of large clinical trials as a predictor of mortality in patients hospitalized with COVID-19. Angiotensin-converting enzyme-2 plays a key role in contagiousness with the SARS-CoV-2 virus, and its formation is a calcium-calmodulin-dependent process. In our opinion, in order to prevent the penetration and spreading of the virus in the body, this link should be targeted with the usage of drugs that activate the calcium calmodulin system. Calcium blockers used parallel with hypocalcemia, to some extent, reduce the spreading of the virus in the body in the acute phase of the disease, but it is possible that in the future they lead to deeper and long-term complications - cognitive dysfunction. However, we did not find any study in the literature that aimed to identify calcium-dependent mechanisms in a complex, dynamic study of the same patients. Therefore, this question is still open in science, because without understanding how the amount of calcium-regulating hormones changes during the disease, without understanding how much phosphorus changes in parallel with calcium, it is impossible to get a complete picture of the disease on the role of calcium-dependent mechanisms in development. Only a summary of such combined data will allow us to reach a scientifically based conclusion, to explain the mechanisms by which hypocalcemia occurs, and by what possible mechanisms it can be prevented.

The interplay between severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) and the hypothalamic and endocrinal disorders: A Mini-review

Article

Full-text available

Jan 2023

The worldwide medical systems are still being severely impacted by the coronavirus disease-2019 (COVID-19) pandemic, which is responsible for catastrophic mortality and morbidity. It becomes more and more obvious that this unique respiratory virus's impacts go beyond the respiratory system as time goes on and our comprehension of it deepens. The transmembrane serine protease 2 (TMPRSS2) protein is necessary for the severe acute respiratory syndrome coronavirus 2, which is the cause of COVID-19, to gain cellular entry through the angiotensin-converting enzyme 2 (ACE2) receptor. Most endocrine glands exhibit high levels of expression for ACE2 and TMPRSS2. This pays the attention to the effect of COVID-19 on the endocrine system. Besides its capability to pass to the central nervous system especially the hypothalamus inducing a lot of functional disorders in COVID-19 individuals. Although effective vaccines became widely available, and mortality declined but attention is shifting more and more to the lengthy health impacts on COVID-19 survivors. To inform suitable research and effective management, this review provides an overview of the data examining the impacts of COVID-19 on the endocrine glands besides the hypothalamus. In addition, we reported if the endocrinal and thalamic disorders could affect the incidence and progress of COVID-19.

Long COVID and Aviation Safety

Article

Full-text available

Dec 2022

Young Hwan Kwon

COVID‐19: Neurology Perspective

Chapter

Dec 2022

COVID‐19 is known to involve the nervous system, for which three pathways have been suggested: (i) retrograde through neurons, (ii) angiotensin‐converting enzyme 2 (ACE‐2) expression in neurons, and (iii) hematogenous dissemination. In addition, damage to the central nervous system is mediated by an indirect effect of the virus causing a cytokine storm. In this chapter, the pathophysiologic mechanism of the involvement of nervous system in COVID‐19 and also its clinical manifestations and the diagnostic and therapeutic approach to the neurologic complications is reviewed.

perlas en neurologia clinica

Book

Full-text available

Dec 2022

La Neurología es una especialidad medica encargada del estudio de la estructura, desarrollo y función del sistema nervioso. Las enfermedades neurológicas afectan a personas de todos los grupos etarios, desde jóvenes y de forma predominante a aquellos de edad avanzada, puede afectar las capacidades y la funcionalidad de los afectados hasta llegar a limitar la realización de actividades básicas de la vida diaria y con frecuencia ocasionar discapacidad y dependencia; por lo tanto, es esencial para los médicos estar capacitados y actualizados en esta área, para abordar de forma integral las patología neurológica. El presente trabajo analiza siete temas selectos en neurología, inicialmente desde un enfoque sindromático que incluye el temblor como manifestación motora de múltiples enfermedades, enfermedades degenerativas y neuromusculares, el enfoque de anticoagulación posterior a eventos neurológicos (cardioembólico y hemorrágico), enfermedad cerebrovascular en COVID-19 y criptogenica hasta la temida epilepsia en el embarazo. El objetivo principal del presente texto es presentar una revisión de las controversias actuales y perspectivas futuras para cada uno de los temas seleccionados, de esta manera ofrecer un panorama y una guía en su abordaje. Se concluye que es fundamental el conocimiento del componente genético en algunas patologías, la comprensión de los mecanismos fisiopatológicos, la actualización en las herramientas de diagnóstico precoz y tratamiento oportuno, con el fin de brindar una mejor calidad de vida de cada uno de los pacientes con estas patologías.

Cavernous sinus thrombosis linked to COVID-19 infection: a case report.

Preprint

Full-text available

Nov 2022

Introduction The severity of SARS-CoV-2 virus infection is mainly related to its respiratory complications. However, it can also lead to numerous and varied thromboembolic events. Symptoms may include headache, fever, and neurological disorders. Since 2020, the clinical presentation of COVID-19 infection have become increasingly varied, leading in some cases to complex symptom associations, including numerous neurological symptoms. SARS-CoV-2 may lead to neurotropism which could reach the central nervous system and all cranial nerves. Cavernous sinus thrombosis is a rare condition, occurring as a complication of an ear, nose, and throat (ENT) or facial infection. Case presentation A 73-year-old man without personal or family history of thrombosis, was referred to the emergency room for a sudden appearance of diplopia and ptosis, 3 days after testing positive for COVID-19 infection. An initial head CT-scan found no signs of stroke. He underwent a cerebral MRI 7 days later, which revealed a thrombosis of his right cavernous sinus. A brain CT scan follow-up 7 days later showed regression of the thrombosis with complete recanalization of the cavernous sinus. This was accompanied by a complete regression of diplopia and fever. He was discharged from the hospital 10 days after hospital admission. Conclusions In this case report, we describe a rare event of cavernous thrombophlebitis following a COVID-19 infection.

Neurological Involvement in Children with COVID-19 and MIS-C: A Retrospective Study Conducted for More than Two Years in a Pediatric Hospital

Article

Full-text available

Nov 2022

This study aimed to evaluate the type and severity of neurological involvement in children with SARS-CoV-2 infection or multisystem inflammatory syndrome in children (MIS-C) and compare these findings between the two groups. Children hospitalized with the diagnosis of COVID-19 or MIS-C at Meyer Children’s Hospital between February 2020 and June 2022 were retrospectively studied. One hundred twenty-two patients were enrolled, 95 in the COVID-19 group and 27 in the MIS-C group. In the COVID-19 group, impairment of consciousness was found in 67.4% of patients, headache in 18.9% and about 16.8% of patients experienced seizures. In this group, three patients were diagnosed with arterial ischemic stroke and one patient was diagnosed with Guillain-Barré syndrome (GBS). In the MIS-C group, about 70% of patients experienced consciousness impairment, about 20% behavioral changes, and another 20% mood deflection. Neurological symptoms and signs were highly heterogeneous and could be differentiated in COVID-19 and MIS-C. Consciousness impairment remained the most frequent manifestation in both groups, potentially underlying an encephalopathy. We also highlight the importance of considering psychiatric symptoms in children with COVID-19 and/or MIS-C. Most neurological manifestations were mild in our series; however, severe complications such as ischemic stroke and GBS are worthy of note.

Neuropathologic features of four autopsied COVID‐19 patients

Article

Full-text available

Aug 2020

Published descriptions of the neuropathological features of COVID‐19 patients have been controversial, ranging from only modest or no pathology to severe hypoxic and hemorrhagic phenotypes, thrombotic complications, acute disseminated encephalomyelitis‐like changes, and encephalitis and meningitis. Here we describe the neuropathological findings of four COVID‐19‐positive patients autopsied at the Helsinki University Hospital during the spring of 2020. While three of the patients (age range 63–90) exhibited merely mild to moderate hypoxia‐associated changes, one 38‐year‐old subject with obesity, diabetes (type 2), Parkinson’s disease, and a very severe clinical course was found to have severe ischemic injury, abundant microhemorrhages and enlarged perivascular spaces most pronounced in the white matter and deep gray matter. The pattern of ischemic changes suggested a defect in microcirculation. In addition, a few small perivascular white matter lesions, with macrophages engulfing myelin, were found. No signs of encephalitis or meningitis were detected in any of the patients. When conducting RT‐PCR and immunohistochemical analyses of brain tissue we could not demonstrate in any of the patients marked injury or presence of SARS‐CoV2 in the olfactory epithelium, olfactory bulbs, or brain areas responsible for respiratory control. In conclusion, our small autopsy series demonstrates various hypoxia‐associated neuropathological features in COVID‐19 patients, but no evidence of neurotropism or meningitis/encephalitis.

Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection

Article

Full-text available

Oct 2020
NAT MED

Understanding the pathophysiology of SARS-CoV-2 infection is critical for therapeutic and public health strategies. Viral–host interactions can guide discovery of disease regulators, and protein structure function analysis points to several immune pathways, including complement and coagulation, as targets of coronaviruses. To determine whether conditions associated with dysregulated complement or coagulation systems impact disease, we performed a retrospective observational study and found that history of macular degeneration (a proxy for complement-activation disorders) and history of coagulation disorders (thrombocytopenia, thrombosis and hemorrhage) are risk factors for SARS-CoV-2-associated morbidity and mortality—effects that are independent of age, sex or history of smoking. Transcriptional profiling of nasopharyngeal swabs demonstrated that in addition to type-I interferon and interleukin-6-dependent inflammatory responses, infection results in robust engagement of the complement and coagulation pathways. Finally, in a candidate-driven genetic association study of severe SARS-CoV-2 disease, we identified putative complement and coagulation-associated loci including missense, eQTL and sQTL variants of critical complement and coagulation regulators. In addition to providing evidence that complement function modulates SARS-CoV-2 infection outcome, the data point to putative transcriptional genetic markers of susceptibility. The results highlight the value of using a multimodal analytical approach to reveal determinants and predictors of immunity, susceptibility and clinical outcome associated with infection.

Non-neuronal expression of SARS-CoV-2 entry genes in the olfaory system suggests mechanisms underlying COVID-19-associated anosmia

Article

Full-text available

Jul 2020

Altered olfactory function is a common symptom of COVID-19, but its etiology is unknown. A key question is whether SARS-CoV-2 (CoV-2) – the causal agent in COVID-19 – affects olfaction directly, by infecting olfactory sensory neurons or their targets in the olfactory bulb, or indirectly, through perturbation of supporting cells. Here we identify cell types in the olfactory epithelium and olfactory bulb that express SARS-CoV-2 cell entry molecules. Bulk sequencing demonstrated that mouse, non-human primate and human olfactory mucosa expresses two key genes involved in CoV-2 entry, ACE2 and TMPRSS2. However, single cell sequencing revealed that ACE2 is expressed in support cells, stem cells, and perivascular cells, rather than in neurons. Immunostaining confirmed these results and revealed pervasive expression of ACE2 protein in dorsally-located olfactory epithelial sustentacular cells and olfactory bulb pericytes in the mouse. These findings suggest that CoV-2 infection of non-neuronal cell types leads to anosmia and related disturbances in odor perception in COVID-19 patients.

LY6E impairs coronavirus fusion and confers immune control of viral disease

Article

Full-text available

Nov 2020

Zoonotic coronaviruses (CoVs) are substantial threats to global health, as exemplified by the emergence of two severe acute respiratory syndrome CoVs (SARS-CoV and SARS-CoV-2) and Middle East respiratory syndrome CoV (MERS-CoV) within two decades1–3. Host immune responses to CoVs are complex and regulated in part through antiviral interferons. However, interferon-stimulated gene products that inhibit CoVs are not well characterized4. Here, we show that lymphocyte antigen 6 complex, locus E (LY6E) potently restricts infection by multiple CoVs, including SARS-CoV, SARS-CoV-2 and MERS-CoV. Mechanistic studies revealed that LY6E inhibits CoV entry into cells by interfering with spike protein-mediated membrane fusion. Importantly, mice lacking Ly6e in immune cells were highly susceptible to a murine CoV—mouse hepatitis virus. Exacerbated viral pathogenesis in Ly6e knockout mice was accompanied by loss of hepatic immune cells, higher splenic viral burden and reduction in global antiviral gene pathways. Accordingly, we found that constitutive Ly6e directly protects primary B cells from murine CoV infection. Our results show that LY6E is a critical antiviral immune effector that controls CoV infection and pathogenesis. These findings advance our understanding of immune-mediated control of CoV in vitro and in vivo—knowledge that could help inform strategies to combat infection by emerging CoVs. Here, the authors identify lymphocyte antigen 6E (LY6E) as a coronavirus (CoV) restriction factor that prevents infection of B cells and dendritic cells. LY6E inhibits both human and mouse CoV entry into cells by interfering with viral spike protein-mediated membrane fusion. It facilitates an antiviral immune response that prevents liver disease and reduces death in the mouse model of MHV-A59 CoV infection.

LY6E Restricts the Entry of Human Coronaviruses, Including the Currently Pandemic SARS-CoV-2

Article

Full-text available

Jul 2020

Virus entry into host cells is one of the key determinants of host range and cell tropism and is subjected to the control of host innate and adaptive immune responses. In the last decade, several interferon-inducible cellular proteins, including IFITMs, GILT, ADAP2, 25CH, and LY6E, had been identified to modulate the infectious entry of a variety of viruses. Particularly, LY6E was recently identified as a host factor that facilitates the entry of several human-pathogenic viruses, including human immunodeficiency virus, influenza A virus, and yellow fever virus. Identification of LY6E as a potent restriction factor of coronaviruses expands the biological function of LY6E and sheds new light on the immunopathogenesis of human coronavirus infection.

SARS, MERS, COVID-19: Clinical Manifestations and Organ-System Complications: A Mini Review

Article

Full-text available

Jul 2020

Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS) and Coronavirus Disease 2019 (COVID-19) are caused by three distinct coronaviruses belonging to the same genus. COVID-19 and its two predecessors share many important features in their clinical presentations, and in their propensity for progression to severe disease which is marked by high rates of morbidity and mortality. However, comparison of the three viral illnesses also reveals a number of specific differences in clinical manifestations and complications, which suggest variability in the disease process. This narrative review delineates the pulmonary, cardiac, renal, gastrointestinal, hepatic, neurological, and hematologic complications associated with these three respiratory coronaviruses. It further describes the mechanisms of immune hyperactivation-particularly cytokine release syndrome-implicated in the multi-organ system injury seen in severe cases of MERS, SARS, and COVID-19.

Elevated serum levels of S100A8/A9 and HMGB1 at hospital admission are correlated with inferior clinical outcomes in COVID-19 patients

Article

Full-text available

Jul 2020

Neutrophil Extracellular Traps (NETs) Contribute to Immunothrombosis in COVID-19 Acute Respiratory Distress Syndrome

Article

Full-text available

Jun 2020

COVID-19 affects millions of patients worldwide with clinical presentation ranging from isolated thrombosis to acute respiratory distress syndrome (ARDS) requiring ventilator support. Neutrophil extracellular traps (NETs) originate from decondensed chromatin released to immobilize pathogens and can trigger immunothrombosis. We studied the connection between NETs and COVID-19 severity and progression. We conducted a prospective cohort study of COVID-19 patients (n=33) with age- and sex-matched controls (n=17). We measured plasma myeloperoxidase (MPO)-DNA complexes (NETs), Platelet Factor 4, RANTES, and selected cytokines. Three COVID-19 lung autopsies were examined for NETs and platelet involvement. We assessed NET formation ex vivo in COVID-19 neutrophils and in healthy neutrophils incubated with COVID-19 plasma. We also tested the ability of neonatal NET-Inhibitory Factor (nNIF) to block NET formation induced by COVID-19 plasma. Plasma MPO-DNA complexes increased in COVID-19 with intubation (P<0.0001) and death as outcome (P<0.0005). Illness severity correlated directly with plasma MPO-DNA complexes (P=0.0360), while PaO2/FiO2 correlated inversely(P=0.0340). Soluble and cellular factors triggering NETs were significantly increased in COVID-19 and pulmonary autopsies confirmed NET-containing microthrombi with neutrophil-platelet infiltration. Finally, COVID-19 neutrophils ex vivo displayed excessive NETs at baseline and COVID-19 plasma triggered NET formation which was blocked by nNIF. Thus, NETs triggering immunothrombosis may, in part, explain the prothrombotic clinical presentations in COVID-19 and NETs may represent targets for therapeutic intervention.

Neuroinvasive potential of SARS-CoV-2 revealed in a human brain organoid model

Preprint

Full-text available

Jun 2020

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Reports indicate that 30-60% of patients with COVID-19 suffer from CNS symptoms. Yet, there is no consensus whether the virus can infect the brain, or what the consequences of infection are. Following SARS-CoV-2 infection of human brain organoids, clear evidence of infection was observed, with accompanying metabolic changes in the infected and neighboring neurons. Further, no evidence for the type I interferon responses was detected. We demonstrate that neuronal infection can be prevented either by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Finally, using mice overexpressing human ACE2, we demonstrate in vivo that SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality. These results provide evidence for the neuroinvasive capacity of SARS-CoV2, and an unexpected consequence of direct infection of neurons by SARS-CoV2.

Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report

Preprint

Full-text available

Jun 2020

Background: Coronavirus disease 2019 (COVID-19) is associated with diffuse lung damage. Corticosteroids may modulate immune-mediated lung injury and reducing progression to respiratory failure and death. Methods: The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is a randomized, controlled, open-label, adaptive, platform trial comparing a range of possible treatments with usual care in patients hospitalized with COVID-19. We report the preliminary results for the comparison of dexamethasone 6 mg given once daily for up to ten days vs. usual care alone. The primary outcome was 28-day mortality. Results: 2104 patients randomly allocated to receive dexamethasone were compared with 4321 patients concurrently allocated to usual care. Overall, 454 (21.6%) patients allocated dexamethasone and 1065 (24.6%) patients allocated usual care died within 28 days (age-adjusted rate ratio [RR] 0.83; 95% confidence interval [CI] 0.74 to 0.92; P<0.001). The proportional and absolute mortality rate reductions varied significantly depending on level of respiratory support at randomization (test for trend p<0.001): Dexamethasone reduced deaths by one-third in patients receiving invasive mechanical ventilation (29.0% vs. 40.7%, RR 0.65 [95% CI 0.51 to 0.82]; p<0.001), by one-fifth in patients receiving oxygen without invasive mechanical ventilation (21.5% vs. 25.0%, RR 0.80 [95% CI 0.70 to 0.92]; p=0.002), but did not reduce mortality in patients not receiving respiratory support at randomization (17.0% vs. 13.2%, RR 1.22 [95% CI 0.93 to 1.61]; p=0.14). Conclusions: In patients hospitalized with COVID-19, dexamethasone reduced 28-day mortality among those receiving invasive mechanical ventilation or oxygen at randomization, but not among patients not receiving respiratory support.

Acute encephalopathy with elevated CSF inflammatory markers as the initial presentation of COVID-19

Article

Full-text available

Jun 2020
BMC NEUROL

Background: COVID-19 is caused by the severe acute respiratory syndrome virus SARS-CoV-2. It is widely recognized as a respiratory pathogen, but neurologic complications can be the presenting manifestation in a subset of infected patients. Case presentation: We describe a 78-year old immunocompromised woman who presented with altered mental status after witnessed seizure-like activity at home. She was found to have SARS-CoV-2 infection and associated neuroinflammation. In this case, we undertake the first detailed analysis of cerebrospinal fluid (CSF) cytokines during COVID-19 infection and find a unique pattern of inflammation in CSF, but no evidence of viral neuroinvasion. Conclusion: Our findings suggest that neurologic symptoms such as encephalopathy and seizures may be the initial presentation of COVID-19. Central nervous system inflammation may associate with neurologic manifestations of disease.

The hypothalamus as a hub for putative SARS-CoV-2 brain infection

Preprint

Full-text available

Jun 2020

Most patients with COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), display neurological symptoms, and respiratory failure in certain cases could be of extra-pulmonary origin. With reports detecting SARS-CoV-2 in some post-mortem patient brains, the routes, targets and consequences of brain infection merit investigation. Hypothalamic neural circuits play key roles in sex differences, diabetes, hypertension, obesity and aging, all risk factors for severe COVID-19, besides being connected to brainstem cardiorespiratory centers. Here, human brain gene-expression analyses reveal that the hypothalamus and associated regions express angiotensin-converting enzyme 2 and transmembrane proteinase, serine 2, which mediate SARS-CoV-2 cellular entry, in correlation with several genes or pathways involved in physiological functions or viral pathogenesis. Immunolabeling in human and animal brains suggests that the hypothalamus could be central to SARS-CoV-2 brain invasion through multiple routes, and that sex hormones and metabolic diseases influence brain susceptibility.

Interferon-Induced Transmembrane Protein (IFITM3) Is Upregulated Explicitly in SARS-CoV-2 Infected Lung Epithelial Cells

Article

Full-text available

Jun 2020

Current guidelines for COVID-19 management recommend the utilization of various repurposed drugs. Despite ongoing research toward the development of a vaccine against SARS-CoV-2, such a vaccine will not be available in time to contribute to the containment of the ongoing pandemic. Therefore, there is an urgent need to develop a framework for the rapid identification of novel targets for diagnostic and therapeutic interventions. We analyzed publicly available transcriptomic datasets of SARS-CoV infected humans and mammals to identify consistent differentially expressed genes then validated in SARS-CoV-2 infected epithelial cells transcriptomic datasets. Comprehensive toxicogenomic analysis of the identified genes to identify possible interactions with clinically proven drugs was carried out. We identified IFITM3 as an early upregulated gene, and valproic acid was found to enhance its mRNA expression as well as induce its antiviral action. These findings indicate that analysis of publicly available transcriptomic and toxicogenomic data represents a rapid approach for the identification of novel targets and molecules that can modify the action of such targets during the early phases of emerging infections like COVID-19.

Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study

Article

Full-text available

Jun 2020
LANCET INFECT DIS

Background COVID-19 is characterised by respiratory symptoms, which deteriorate into respiratory failure in a substantial proportion of cases, requiring intensive care in up to a third of patients admitted to hospital. Analysis of the pathological features in the lung tissues of patients who have died with COVID-19 could help us to understand the disease pathogenesis and clinical outcomes. Methods We systematically analysed lung tissue samples from 38 patients who died from COVID-19 in two hospitals in northern Italy between Feb 29 and March 24, 2020. The most representative areas identified at macroscopic examination were selected, and tissue blocks (median seven, range five to nine) were taken from each lung and fixed in 10% buffered formalin for at least 48 h. Tissues were assessed with use of haematoxylin and eosin staining, immunohistochemical staining for inflammatory infiltrate and cellular components (including staining with antibodies against CD68, CD3, CD45, CD61, TTF1, p40, and Ki-67), and electron microscopy to identify virion localisation. Findings All cases showed features of the exudative and proliferative phases of diffuse alveolar damage, which included capillary congestion (in all cases), necrosis of pneumocytes (in all cases), hyaline membranes (in 33 cases), interstitial and intra-alveolar oedema (in 37 cases), type 2 pneumocyte hyperplasia (in all cases), squamous metaplasia with atypia (in 21 cases), and platelet–fibrin thrombi (in 33 cases). The inflammatory infiltrate, observed in all cases, was largely composed of macrophages in the alveolar lumina (in 24 cases) and lymphocytes in the interstitium (in 31 cases). Electron microscopy revealed that viral particles were predominantly located in the pneumocytes. Interpretation The predominant pattern of lung lesions in patients with COVID-19 patients is diffuse alveolar damage, as described in patients infected with severe acute respiratory syndrome and Middle East respiratory syndrome coronaviruses. Hyaline membrane formation and pneumocyte atypical hyperplasia are frequent. Importantly, the presence of platelet–fibrin thrombi in small arterial vessels is consistent with coagulopathy, which appears to be common in patients with COVID-19 and should be one of the main targets of therapy. Funding None.

Neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway into the central nervous system

Preprint

Full-text available

Jun 2020

The causative agent of the current pandemic and coronavirus disease 2019 (COVID-19) is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Understanding how SARS-CoV-2 enters and spreads within human organs is crucial for developing strategies to prevent viral dissemination. For many viruses, tissue tropism is determined by the availability of virus receptors on the surface of host cells. Both SARS-CoV and SARS-CoV-2 use angiotensin-converting enzyme 2 (ACE2) as a host receptor, yet, their tropisms differ. Here, we found that the cellular receptor neuropilin-1 (NRP1), known to bind furin-cleaved substrates, significantly potentiates SARS-CoV-2 infectivity, which was inhibited by a monoclonal blocking antibody against the extracellular b1b2 domain of NRP1. NRP1 is abundantly expressed in the respiratory and olfactory epithelium, with highest expression in endothelial cells and in the epithelial cells facing the nasal cavity. Neuropathological analysis of human COVID-19 autopsies revealed SARS-CoV-2 infected NRP1-positive cells in the olfactory epithelium and bulb. In the olfactory bulb infection was detected particularly within NRP1-positive endothelial cells of small capillaries and medium-sized vessels. Studies in mice demonstrated, after intranasal application, NRP1-mediated transport of virus-sized particles into the central nervous system. Thus, NRP1 could explain the enhanced tropism and spreading of SARS-CoV-2.

Suppressive myeloid cells are a hallmark of severe COVID-19

Preprint

Full-text available

Jun 2020

'Severe Acute Respiratory Syndrome - Coronavirus-2' (SARS-CoV-2) infection causes Coronavirus Disease 2019 (COVID-19), a mild to moderate respiratory tract infection in the majority of patients. A subset of patients, however, progresses to severe disease and respiratory failure with acute respiratory distress syndrome (ARDS). Severe COVID-19 has been associated with increased neutrophil counts and dysregulated immune responses. The mechanisms of protective immunity in mild forms and the pathogenesis of dysregulated inflammation in severe courses of COVID-19 remain largely unclear. Here, we combined two single-cell RNA-sequencing technologies and single-cell proteomics in whole blood and peripheral blood mononuclear cells (PBMC) to determine changes in immune cell composition and activation in two independent dual-center patient cohorts (n=46 + n=54 COVID-19 samples), each with mild and severe cases of COVID-19. We observed a specific increase of HLA-DR high CD11c high inflammatory monocytes that displayed a strong interferon (IFN)-stimulated gene signature in patients with mild COVID-19, which was absent in severe disease. Instead, we found evidence of emergency myelopoiesis, marked by the occurrence of immunosuppressive pre-neutrophils and immature neutrophils and populations of dysfunctional and suppressive mature neutrophils, as well as suppressive HLA-DR low monocytes in severe COVID-19. Our study provides detailed insights into systemic immune response to SARS-CoV-2 infection and it reveals profound alterations in the peripheral myeloid cell compartment associated with severe courses of COVID-19.

Neuropathology of COVID-19: a spectrum of vascular and acute disseminated encephalomyelitis (ADEM)-like pathology

Article

Full-text available

Jul 2020
ACTA NEUROPATHOL

We report the neuropathological findings of a patient who died from complications of COVID-19. The decedent was initially hospitalized for surgical management of underlying coronary artery disease. He developed post-operative complications and was evaluated with chest imaging studies. The chest computed tomography (CT) imaging results were indicative of COVID-19 and he was subsequently tested for SARS-CoV-2, which was positive. His condition worsened and he died after more than 2 weeks of hospitalization and aggressive treatment. The autopsy revealed a range of neuropathological lesions, with features resembling both vascular and demyelinating etiologies. Hemorrhagic white matter lesions were present throughout the cerebral hemispheres with surrounding axonal injury and macrophages. The subcortical white matter had scattered clusters of macrophages, a range of associated axonal injury, and a perivascular acute disseminated encephalomyelitis (ADEM)-like appearance. Additional white matter lesions included focal microscopic areas of necrosis with central loss of white matter and marked axonal injury. Rare neocortical organizing microscopic infarcts were also identified. Imaging and clinical reports have demonstrated central nervous system complications in patients’ with COVID-19, but there is a gap in our understanding of the neuropathology. The lesions described in this case provide insight into the potential parainfectious processes affecting COVID-19 patients, which may direct clinical management and ongoing research into the disease. The clinical course of the patient also illustrates that during prolonged hospitalizations neurological complications of COVID may develop, which are particularly difficult to evaluate and appreciate in the critically ill.

Pathophysiology of SARS-CoV-2: Targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience

Preprint

Full-text available

May 2020

BACKGROUND Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and its associated clinical syndrome COVID-19 are causing overwhelming morbidity and mortality around the globe, disproportionately affecting New York City. A comprehensive, integrative autopsy series that advances the mechanistic discussion surrounding this disease process is still lacking. METHODS Autopsies were performed at the Mount Sinai Hospital on 67 COVID-19 positive patients and data from the clinical records were obtained from the Mount Sinai Data Warehouse. The experimental design included a comprehensive microscopic examination carried out by a team of expert pathologists, along with transmission electron microscopy, immunohistochemistry, RNA in situ hybridization, as well as immunology and serology assays. RESULTS Laboratory results of our COVID-19 cohort show elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8 and TNFα. Autopsies revealed large pulmonary emboli in four cases. We report microthrombi in multiple organ systems including the brain, as well as conspicuous hemophagocytosis and a secondary hemophagocytic lymphohistiocytosis-like syndrome in many of our patients. We provide electron microscopic, immunofluorescent and immunohistochemical evidence of the presence of the virus and the ACE2 receptor in our samples. CONCLUSIONS We report a comprehensive autopsy series of 67 COVID-19 positive patients revealing that this disease, so far conceptualized as a primarily respiratory viral illness, also causes endothelial dysfunction, a hypercoagulable state, and an imbalance of both the innate and adaptive immune responses. Novel findings reported here include an endothelial phenotype of ACE2 in selected organs, which correlates with clotting abnormalities and thrombotic microangiopathy, addressing the prominent coagulopathy and neuropsychiatric symptoms. Another original observation is that of macrophage activation syndrome, with hemophagocytosis and a hemophagocytic lymphohistiocytosis-like disorder, underlying the microangiopathy and excessive cytokine release. We discuss the involvement of critical regulatory pathways.

COVID-19: the vasculature unleashed

Article

Full-text available

May 2020
NAT REV IMMUNOL

On the basis of emerging evidence from patients with COVID-19, we postulate that endothelial cells are essential contributors to the initiation and propagation of severe COVID-19. Here, we discuss current insights into the link between endothelial cells, viral infection and inflammatory changes and propose novel therapeutic strategies. Here, Carmeliet and colleagues discuss the role of endothelial cells in inflammation and viral infection and propose novel therapeutic strategies for COVID-19.

SARS2-CoV-2 and Stroke in a New York Healthcare System

Article

Full-text available

May 2020

Background and purpose: With the spread of coronavirus disease 2019 (COVID-19) during the current worldwide pandemic, there is mounting evidence that patients affected by the illness may develop clinically significant coagulopathy with thromboembolic complications including ischemic stroke. However, there is limited data on the clinical characteristics, stroke mechanism, and outcomes of patients who have a stroke and COVID-19. Methods: We conducted a retrospective cohort study of consecutive patients with ischemic stroke who were hospitalized between March 15, 2020, and April 19, 2020, within a major health system in New York, the current global epicenter of the pandemic. We compared the clinical characteristics of stroke patients with a concurrent diagnosis of COVID-19 to stroke patients without COVID-19 (contemporary controls). In addition, we compared patients to a historical cohort of patients with ischemic stroke discharged from our hospital system between March 15, 2019, and April 15, 2019 (historical controls). Results: During the study period in 2020, out of 3556 hospitalized patients with diagnosis of COVID-19 infection, 32 patients (0.9%) had imaging proven ischemic stroke. Cryptogenic stroke was more common in patients with COVID-19 (65.6%) as compared to contemporary controls (30.4%, P=0.003) and historical controls (25.0%, P<0.001). When compared with contemporary controls, COVID-19 positive patients had higher admission National Institutes of Health Stroke Scale score and higher peak D-dimer levels. When compared with historical controls, COVID-19 positive patients were more likely to be younger men with elevated troponin, higher admission National Institutes of Health Stroke Scale score, and higher erythrocyte sedimentation rate. Patients with COVID-19 and stroke had significantly higher mortality than historical and contemporary controls. Conclusions: We observed a low rate of imaging-confirmed ischemic stroke in hospitalized patients with COVID-19. Most strokes were cryptogenic, possibly related to an acquired hypercoagulability, and mortality was increased. Studies are needed to determine the utility of therapeutic anticoagulation for stroke and other thrombotic event prevention in patients with COVID-19.

Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic

Article

Full-text available

May 2020

Background Before the COVID-19 pandemic, coronaviruses caused two noteworthy outbreaks: severe acute respiratory syndrome (SARS), starting in 2002, and Middle East respiratory syndrome (MERS), starting in 2012. We aimed to assess the psychiatric and neuropsychiatric presentations of SARS, MERS, and COVID-19. Methods In this systematic review and meta-analysis, MEDLINE, Embase, PsycINFO, and the Cumulative Index to Nursing and Allied Health Literature databases (from their inception until March 18, 2020), and medRxiv, bioRxiv, and PsyArXiv (between Jan 1, 2020, and April 10, 2020) were searched by two independent researchers for all English-language studies or preprints reporting data on the psychiatric and neuropsychiatric presentations of individuals with suspected or laboratory-confirmed coronavirus infection (SARS coronavirus, MERS coronavirus, or SARS coronavirus 2). We excluded studies limited to neurological complications without specified neuropsychiatric presentations and those investigating the indirect effects of coronavirus infections on the mental health of people who are not infected, such as those mediated through physical distancing measures such as self-isolation or quarantine. Outcomes were psychiatric signs or symptoms; symptom severity; diagnoses based on ICD-10, DSM-IV, or the Chinese Classification of Mental Disorders (third edition) or psychometric scales; quality of life; and employment. Both the systematic review and the meta-analysis stratified outcomes across illness stages (acute vs post-illness) for SARS and MERS. We used a random-effects model for the meta-analysis, and the meta-analytical effect size was prevalence for relevant outcomes, I² statistics, and assessment of study quality. Findings 1963 studies and 87 preprints were identified by the systematic search, of which 65 peer-reviewed studies and seven preprints met inclusion criteria. The number of coronavirus cases of the included studies was 3559, ranging from 1 to 997, and the mean age of participants in studies ranged from 12·2 years (SD 4·1) to 68·0 years (single case report). Studies were from China, Hong Kong, South Korea, Canada, Saudi Arabia, France, Japan, Singapore, the UK, and the USA. Follow-up time for the post-illness studies varied between 60 days and 12 years. The systematic review revealed that during the acute illness, common symptoms among patients admitted to hospital for SARS or MERS included confusion (36 [27·9%; 95% CI 20·5–36·0] of 129 patients), depressed mood (42 [32·6%; 24·7–40·9] of 129), anxiety (46 [35·7%; 27·6–44·2] of 129), impaired memory (44 [34·1%; 26·2–42·5] of 129), and insomnia (54 [41·9%; 22·5–50·5] of 129). Steroid-induced mania and psychosis were reported in 13 (0·7%) of 1744 patients with SARS in the acute stage in one study. In the post-illness stage, depressed mood (35 [10·5%; 95% CI 7·5–14·1] of 332 patients), insomnia (34 [12·1%; 8·6–16·3] of 280), anxiety (21 [12·3%; 7·7–17·7] of 171), irritability (28 [12·8%; 8·7–17·6] of 218), memory impairment (44 [18·9%; 14·1–24·2] of 233), fatigue (61 [19·3%; 15·1–23·9] of 316), and in one study traumatic memories (55 [30·4%; 23·9–37·3] of 181) and sleep disorder (14 [100·0%; 88·0–100·0] of 14) were frequently reported. The meta-analysis indicated that in the post-illness stage the point prevalence of post-traumatic stress disorder was 32·2% (95% CI 23·7–42·0; 121 of 402 cases from four studies), that of depression was 14·9% (12·1–18·2; 77 of 517 cases from five studies), and that of anxiety disorders was 14·8% (11·1–19·4; 42 of 284 cases from three studies). 446 (76·9%; 95% CI 68·1–84·6) of 580 patients from six studies had returned to work at a mean follow-up time of 35·3 months (SD 40·1). When data for patients with COVID-19 were examined (including preprint data), there was evidence for delirium (confusion in 26 [65%] of 40 intensive care unit patients and agitation in 40 [69%] of 58 intensive care unit patients in one study, and altered consciousness in 17 [21%] of 82 patients who subsequently died in another study). At discharge, 15 (33%) of 45 patients with COVID-19 who were assessed had a dysexecutive syndrome in one study. At the time of writing, there were two reports of hypoxic encephalopathy and one report of encephalitis. 68 (94%) of the 72 studies were of either low or medium quality. Interpretation If infection with SARS-CoV-2 follows a similar course to that with SARS-CoV or MERS-CoV, most patients should recover without experiencing mental illness. SARS-CoV-2 might cause delirium in a significant proportion of patients in the acute stage. Clinicians should be aware of the possibility of depression, anxiety, fatigue, post-traumatic stress disorder, and rarer neuropsychiatric syndromes in the longer term. Funding Wellcome Trust, UK National Institute for Health Research (NIHR), UK Medical Research Council, NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London.

Steroid‐responsive encephalitis in Covid‐19 disease

Article

Full-text available

May 2020

Covid‐19 infection has the potential for targeting the central nervous system and several neurological symptoms have been described in patients with severe respiratory distress. Here we described the case of a 60‐year old subject with SARS‐CoV‐2 infection but only mild respiratory abnormalities who developed an akinetic mutism due to encephalitis. MRI was negative whereas EEG showed generalized theta slowing. CSF analyses during the acute stage were negative for SARS‐CoV‐2, positive for pleocytosis and hyperproteinorrachia, and showed increased IL‐8 and TNF‐α concentrations while other infectious or autoimmune disorders were excluded. A progressive clinical improvement along with a reduction of CSF parameters was observed after high‐dose steroid treatment, thus arguing for an inflammatory‐mediated brain involvement related to Covid‐19. This article is protected by copyright. All rights reserved.

Pericyte-specific vascular expression of SARS-CoV-2 receptor ACE2 - implications for microvascular inflammation and hypercoagulopathy in COVID-19 patients

Preprint

Full-text available

May 2020

Accumulating clinical observations suggest pathogenesis beyond viral pneumonia and its secondary consequences in COVID-19 patients. In particular, many patients develop profound hyperinflammation and hypercoagulopathy with disseminated thrombogenesis and thromboembolism, which we observe also in a Swedish COVID-19 intensive care patient cohort. To understand these vascular manifestations, it is important to establish the potential vascular entry point(s) of the SARS-CoV-2 virus, i.e. which vascular cell types express the SARS-CoV-2 receptor ACE2. We present data that ACE2 is specifically and highly expressed in microvascular pericytes, but absent from endothelial cells, perivascular macrophages and fibroblasts. Mice with pericyte ablation show increased expression and release of Von Willebrand Factor from microvascular endothelial cells, suggesting that pericytes orchestrate thrombogenic responses in neighboring endothelial cells. Identifying pericytes rather than endothelial cells as the ACE2-expressing cells in the vasculature may explain why hypertension, diabetes and obesity are risk factors for severe COVID-19 patients, as these conditions are characterized by an impaired endothelial barrier function, allowing SARS-CoV-2 to reach and infect the pericytes that are normally shielded from the blood behind an intact endothelial barrier. This novel COVID-19-pericyte hypothesis is testable, offers explanations for some of the most enigmatic and lethal aspects of COVID-19 and calls for further investigations into the possible benefits of preventive anticoagulant therapy.

Brain MRI Findings in Patients in the Intensive Care Unit with COVID-19 Infection

Article

Full-text available

May 2020

Online supplemental material is available for this article.

Two patients with acute meningo‐encephalitis concomitant to SARS‐CoV‐2 infection

Article

Full-text available

May 2020

In December 2019, a cluster of patients with pneumonia of unknown cause led to the identification of a new strain of pandemic coronavirus called Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Since the first SARS‐CoV outbreak, human coronaviruses are known for their neurological tropism. If respiratory complications are at the forefront of clinical presentation of SARS‐CoV‐2, neurological involvement remains poorly described and understood. We report here two patients infected with SARS‐CoV‐2 who presented with neurological symptoms and signs.

Cell entry mechanisms of SARS-CoV-2

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Effects of COVID-19 on the nervous system

Abstract

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