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Neurobiology of COVID-19
Abstract
Anosmia, stroke, paralysis, cranial nerve deficits, encephalopathy, delirium, meningitis, and seizures are some of the neurological complications in patients with coronavirus disease-19 (COVID-19) which is caused by acute respiratory syndrome coronavirus 2 (SARS-Cov2). There remains a challenge to determine the extent to which neurological abnormalities in COVID-19 are caused by SARS-Cov2 itself, the exaggerated cytokine response it triggers, and/or the resulting hypercoagulapathy and formation of blood clots in blood vessels throughout the body and the brain. In this article, we review the reports that address neurological manifestations in patients with COVID-19, who may present with acute neurological symptoms (e.g., stroke), even without typical respiratory symptoms such as fever, cough, or shortness of breath. Next, we discuss the different neurobiological processes and mechanisms that may underlie the link between SARS-Cov2 and COVID-19 in the brain, cranial nerves, peripheral nerves, and muscles. Finally, we propose a basic "NeuroCovid" classification scheme that integrates these concepts and highlights some of the short-term challenges for the practice of neurology today and the long-term sequalae of COVID-19 such as depression, OCD, insomnia, cognitive decline, accelerated aging, Parkinson's disease, or Alzheimer's disease in the future. In doing so, we intend to provide a basis from which to build on future hypotheses and investigations regarding SARS-Cov2 and the nervous system.
... Neurological complications of acute COVID-19 involve the brain, cranial nerves and peripheral nerves (41) with clinical manifestations that include thromboembolic strokes, intracranial hemorrhages as well as encephalitis, meningoencephalitis and neuropathy. It is not uncommon that acute neurological phenomenolgy may persist for weeks and also for a more prolonged period, which can last from months to years after recovery from the initial infection (42). ...
... It is not uncommon that acute neurological phenomenolgy may persist for weeks and also for a more prolonged period, which can last from months to years after recovery from the initial infection (42). Mechanistically, the neuropathogenesis of acute COVID-19 remains unclear (41,43), and the elucidation of whether the neurological effects in COVID-19 are a) mediated directly by SARS-CoV-2 virus or b) an indirect effect of the virus itself (namely, hypercoagulopathy) or an immunemediated/autoimmune-mediated (such as the cytokine storm) neuroinflammation (41) is a matter of great importance biologically and clinically. Neurohistopathological studies have demonstrated acute hypoxic ischemic injury in the cerebrum and cerebellum in brain tissue of patients who have undergone autopsy (e.g., [44][45][46]. ...
Current views on immunity support the idea that immunity extends beyond defense functions and is tightly intertwined with several other fields of biology such as virology, microbiology, physiology and ecology. It is also critical for our understanding of autoimmunity and cancer, two topics of great biological relevance and for critical public health considerations such as disease prevention and treatment. Central to this review, the immune system is known to interact intimately with the nervous system and has been recently hypothesized to be involved not only in autonomic and limbic bio-behaviors but also in cognitive function. Herein we review the structural architecture of the brain network involved in immune response. Furthermore, we elaborate upon the implications of inflammatory processes affecting brain-immune interactions as reported recently in pathological conditions due to SARS-Cov-2 virus infection, namely in acute and post-acute COVID-19. Moreover, we discuss how current neuroimaging techniques combined with ad hoc clinical autopsies and histopathological analyses could critically affect the validity of clinical translation in studies of human brain-immune interactions using neuroimaging. Advances in our understanding of brain-immune interactions are expected to translate into novel therapeutic avenues in a vast array of domains including cancer, autoimmune diseases or viral infections such as in acute and post-acute or Long COVID-19.
... Epileptic seizures, encephalitis, necrotizing hemorrhagic encephalopathy, strokes, and rhabdomyolysis have also been testified in association with COVID-19 infection. [15][16][17] In many patients, some long-term after-effects have also been identified and reported, namely, a significant musculoskeletal load, including ligament, tendon, bone, and joint abnormalities, which can be included under the bracket of musculoskeletal and neuromuscular dysfunction. 18 The outbreak of the novel coronavirus disease has reshaped our understanding of infectious diseases and their effects on human health. ...
... Encephalitis, necrotizing hemorrhagic encephalopathy, strokes, epileptic captures, and rhabdomyolysis have also been testified in SARS-CoV-2 infection. 15,17 Focussing on these effects (Table 2), the World Federation of Neurology has emphasized on reporting and registering the short-tenure and mild and long-tenure and critical results of COVID-19 on the neuromuscular system. 22 These disorders are a collection of extremely different ailments, most of which are hereditary or autoimmune in nature and can affect individuals of all age groups at varying rates. ...
The emergence of the novel coronavirus-based illness, COVID-19, in late 2019 marked a watershed moment in modern history. Initially identified in Wuhan, China, this viral epidemic swiftly transformed into a global pandemic, affecting worldwide. The World Health Organization (WHO) officially labeled the virus as “Severe Acute Respiratory Syndrome Coronavirus 2” (SARS-CoV-2) and the ensuing disease as Coronavirus Disease 2019 (COVID-19) on February 11, 2020. The spectrum of effects induced by COVID-19 encompasses a diverse array of conditions, ranging from sensory disturbances like anosmia and ageusia to more intricate manifestations, including headaches and, alarmingly, multiorgan failure and neuromuscular dysfunction, and even deaths were reported. COVID-19 triggers a vigorous inflammatory response characterized by the overproduction of pro-inflammatory cytokines. “Cytokine storm” significantly underwrites the worsening of the condition of patients, resulting in abnormalities such as ARDS. The major reason behind mortality from COVID-19 is respiratory failure instigated by ARDS. Throughout the early respiratory contamination, SARS-CoV-2 was hypothesized to target type-II pneumocytes lining the respiratory passage that specifically expressed TMPRSS2 and ACE2 receptors. The extra-pulmonary consequences of COVID-19 have been linked to the occurrence of these receptors in the skeletomuscular and brain tissues. As a result, it is condemning to comprehend the unique pathophysiological mechanisms behind the virus's manner of invasion in the tissues and also the disease's consequences. In this article, we focus on the complications caused by COVID-19 on musculoskeletal and neural tissues, the route of invasion, and the future perspective of dealing with the receptors whose expression leads to COVID-19 infection.
... So far, the most serious side effects have included olfactory disorders, gastrointestinal disorders, mental health problems, liver complications, etc. (5)(6)(7). One of the most common CNS comorbidities detected in COVID-19 patients in a considerable way is Alzheimer's disease (AD) (8). The most common neurodegenerative disease and the leading cause of dementia was considered by Alzheimer's disease. ...
... In Alzheimer's disease patients, the deposition of amyloid beta or neurofibrillary tangles damages key parts of the brain that is responsible for memory and learning (9). According to the WHO Trusted Source, approximately 55 million individuals worldwide suffer from dementia annually, and 60-70% of these cases account for Alzheimer's disease (8). The results of serum neurodegenerative biomarkers of patients of COVID-19 revealed symptoms related to encephalopathy. ...
Background
One of the negative effects of the COVID-19 illness, which has affected people all across the world, is Alzheimer’s disease. Oblivion after COVID-19 has created a variety of issues for many people. Predicting this issue in COVID-19 patients can considerably lessen the severity of the problem.
Methods
Alzheimer’s disease was predicted in Iranian persons with COVID-19 in using three algorithms: Nave Bayes, Random Forest, and KNN. Data collected by private questioner from hospitals of Tehran Province, Iran, during Oct 2020 to Sep 2021. For ML models, performance is quantified using measures such as Precision, Recall, Accuracy, and F1-score.
Results
The Nave Bayes, Random Forest algorithm has a prediction accuracy of higher than 80%. The predicted accuracy of the random forest algorithm was higher than the other two algorithms.
Conclusion
The Random Forest algorithm outperformed the other two algorithms in predicting Alzheimer’s disease in persons using COVID-19. The findings of this study could help persons with COVID-19 avoid Alzheimer’s problems.
... A study addressing neurocognitive deficits caused by COVID-19 infection divides neurological changes into three stages: the first occurring when the brain is unaffected by the cytokine storm, the second when the cytokine storm causes blood vessel inflammation, and the third when the cytokine storm damages the BBB [53,54] . ...
... Multiple cognitive complications have been found linked with the severity of SARS-CoV-2 infection, leading to COVID-19. Of recent, emergence of various evidence indicates SARS-CoV-2 as a cause of a plethora of neurological complications, including delirium among others [54] . In most cases, elderly patients with MCI or dementia have a higher tendency to possess neuropsychiatric symptoms including delirium [55] . ...
Introduction
SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has brought a conglomerate of novel chronic disabling conditions described as ‘Long COVID/Post-COVID-19 Syndrome’. Recent evidence suggests that the multifaceted nature of this syndrome results in both pulmonary and extrapulmonary sequelae,chronic dyspnoea, persistent fatigue, and cognitive dysfunction being the most common, debilitating symptoms. Several mechanisms engender or exacerbate cognitive impairment, including central nervous system (CNS) and extra-CNS causes, although the exact mechanism remains unclear. Both hospitalized and non-hospitalized patients may suffer varying degrees of cognitive impairment, ranging from fatigue and brain fog to prolonged deficits in memory and attention, detrimental to the quality-of-life years post-recovery. The aim of this review is to understand the underlying mechanisms, associations, and attempts for prevention with early intervention of long-term cognitive impairment post-COVID-19.
Methodology
A systematic search was conducted through multiple databases such as Medline, National Library of Medicine, Ovid, Scopus database to retrieve all the articles on the long term sequalae of cognitive dysfunction after Sars-Cov2 infection. The inclusion criteria included all articles pertinent to this specific topic and exclusion criteria subtracted studies pertaining to other aetiologies of cognitive dysfunction. This search was carefully screened for duplicates and the relevant information was extracted and analysed.
Results/discussion
To date, the exact pathogenesis, and underlying mechanisms behind cognitive dysfunction in COVID-19, remain unclear, hindering the development of adequate management strategies. However, the proposed mechanisms suggested by various studies include direct damage to the blood-brain barrier, systemic inflammation, prolonged hypoxia, and extended intensive care admissions. However, no clear-cut guidelines for management are apparent.
Conclusion
This review of the COVID-19 pandemic has elucidated a new global challenge which is affecting individuals’ quality of life by inducing long-term impaired cognitive function. We have found that comprehensive evaluations and interventions are crucial to address the cognitive sequelae in all COVID-19 patients, especially in patients with pre-existing cognitive impairment. Nevertheless, the authors recommend further research for the development of relevant, timely neurocognitive assessments and treatment plans.
... In 2019, the outbreak of the illness caused by SARS-CoV-2, termed COVID-19 by the World Health Organization, the acronym derived from "coronavirus disease 2019'', occurred and quickly became a pandemic [1,2]. The impact of the pandemic on public health caused psychological and psychiatric difficulties globally. ...
... The psychiatrist, in addition to what was done by psychology during the first consultation, could request diagnostic aids, and ultimately recommended a pharmacological and/or non-pharmacological treatment, depending on the patient's health condition. This initial consultation lasted for one (1) hour. ...
Background:
The SARS-CoV2 global pandemic impacted participants in the Alzheimer's Prevention Initiative (API) Autosomal Dominant Alzheimer's Disease (ADAD) clinical trial, who faced three stressors: 1) fear of developing dementia; 2) concerns about missing treatment; and 3) the possibility of becoming infected with SARS-CoV2.
Objective:
To describe the frequency of psychological disorders among the participants of the API ADAD Colombia clinical study, treated by a holistic mental health team during the COVID-19 pandemic. Possibility of utilizing the mental health team services was explored, considering different risk factors, and comparing between users and non-users of these services.
Methods:
Participants had free and optional access to psychology and psychiatry services, outside of the study protocol. Descriptive statistics were used to analyze the frequency of the mental health difficulties. A multivariable logistic regression model has been used to assess associations with using this program.
Results:
66 participants were treated by the Mental Health Team from March 1, 2020, to December 31, 2020. Before and after the start of the pandemic, the most common psychological problems were anxiety (36.4% before, 63.6% after) and depression (34.8% before, 37.9% after). 70% of users assisted by psychology and 81.6% of those assisted by psychiatry felt that the services were useful for them. Female sex, depression, and anxiety before the pandemic were positively associated with being assisted by either psychology or psychiatry, while hyperlipidemia history association was negative.
Conclusions:
A holistic mental health program, carried out in the context of a study, could mitigate psychopathology during pandemics such as COVID-19.
... Neurological manifestations, known as "neuroCOVID, " have been noted in adults. Meanwhile, children, including those with no history of febrile seizures, have presented with seizures when infected with the Omicron variant [1][2][3]. Febrile seizures, which typically occur in children aged 6 months to 5 years, can arise during viral infection [4][5][6]. Seizures induced by fever associated with COVID-19 have been linked to status epilepticus or increased seizure frequency in patients with pre-existing epilepsy [7]. ...
... SARS-CoV-2 is a coronavirus that gave rise to COVID-19, which spread rapidly throughout the world, resulting in the death of more than 6.9 million people during the pandemic of 2019-21 [16]. Neurologic side effects have been reported in numerous patients both with SARS-CoV-2 infections and its predecessors, SARS (severe acute respiratory syndrome) and MERS (Middle Eastern Respiratory Syndrome) [23,46,78]. Viruses enter the central nervous system (CNS) either through hematogenous transport, the blood-brain barrier (BBB), or retrograde axonal transport [81]. ...
The SARS-CoV-2 virus that led to COVID-19 is associated with significant and long-lasting neurologic symptoms in many patients, with an increased mortality risk for people with Alzheimer’s disease (AD) and/or Down syndrome (DS). However, few studies have evaluated the neuropathological and inflammatory sequelae in postmortem brain tissue obtained from AD and people with DS with severe SARS-CoV-2 infections. We examined tau, beta-amyloid (Aβ), inflammatory markers and SARS-CoV-2 nucleoprotein in DS, AD, and healthy non-demented controls with COVID-19 and compared with non-infected brain tissue from each disease group (total n = 24). A nested ANOVA was used to determine regional effects of the COVID-19 infection on arborization of astrocytes (Sholl analysis) and percent-stained area of Iba-1 and TMEM 119. SARS-CoV-2 antibodies labeled neurons and glial cells in the frontal cortex of all subjects with COVID-19, and in the hippocampus of two of the three DS COVID-19 cases. SARS-CoV-2-related alterations were observed in peri-vascular astrocytes and microglial cells in the gray matter of the frontal cortex, hippocampus, and para-hippocampal gyrus. Bright field microscopy revealed scattered intracellular and diffuse extracellular Aβ deposits in the hippocampus of controls with confirmed SARS-CoV-2 infections. Overall, the present preliminary findings suggest that SARS-CoV-2 infections induce abnormal inflammatory responses in Down syndrome.
... So, the lesions may need to detoxify at least for 4 months and needs to be followed up. Also, neurologic pathologies such as near paralysis of extremities, diffi cult to walk, sudden unknown convulsive movements, and autonomic palpitations of the extremities, were improved with detoxifi cation methods written in the table 1. Abnormal neurologic features may include anosmia, stroke, paralysis, decreased eye function, facial numbness, and depression were diffi cult to cure by the usual and classic rehabilitation methods [11]. Intensity, frequency, and duration of myopericarditis symptoms aft er the COVID-19 vaccinations such as dyspnea, chest For the whole-body immersion bathing, 4.5 kg of bay salt is melted with a 500 ml vinegar in the half-hot water-fi lled bath. ...
Korea Veritas Doctors for COVID-19 are reporting two important fi ndings: (a) actively moving unknown live micro-organisms were found
in the COVID-19 Vaccine vials (b) a treatment cocktail for 44 COVID-19 outbreak patients was administered and worked successfully. In our
opinion all the contents of the COVID-19 vaccines should be thoroughly studied and irrational and harmful COVID-19 vaccinations should
be stopped. As a result baseless Vaccine Pass Policy should be stopped. COVID-19 prevention and treatment cocktails should replace the
harmful COVID-19 vaccines for the prevention and treatment of COVID-19. Sequels and the harmful eff ects of the COVID-19 vaccines should
be addressed by detoxifi cations methods.
... Від початку пандемії вчені різних країн повідомляли про те, що коронавірус спричиняє не лише проблеми фізичного здоров'я, але й зміни у психічних і емоційних реакціях у багатьох людей [8][9][10][11][12]. Рівень стресу, тривожності та депресії підвищився, і багато хто зіткнувся зі складнощами у впорядкуванні свого психологічного стану [13]. ...
Дослідження присвячене вивченню психофізіологічних аспектів в осіб, які перехворіли на COVID-19, і тих, хто отримав вакцину Pfizer. В обстеженні брали участь жінки, середній вік яких становив 47,34 ± 0,66 років. Комплексне дослідження включало аналіз рівня депресії в зазначених вище осіб за методикою «Шкала депресії Бека», виявлення ступеня денної сонливості за діагностичним опитувальником «Шкала сонливості Епворта» й оцінку якості сну протягом останнього місяця за Пітсбурзьким опитувальником якості сну. Результати анкетування та спостережень обстежених щодо їхнього психічного стану, зокрема й рівень депресії та показники якості сну, показали, що захворювання COVID-19 чинить суттєвий вплив на психофізіологічні параметри жінок. Показано, що постковідний синдром спричиняє депресію, втрату інтересу або задоволення, зниження енергії, порушення концентрації уваги, апетиту, якості та кількості сну. Спричинене вірусом порушення імунної системи може сприяти розвитку психопатології через посилення психологічного стресу внаслідок перенесення потенційно смертельної хвороби та стрес-зумовленого запалення. Взаємодія між вродженою й адаптивною імунними системами та нейромедіаторами є механізмом, який лежить в основі розладів настрою, психозів і тривожних розладів. Стрес, який супроводжує хворобу, може призводити до змін у сні та бадьорості під час дня. Зайва енергія в умовах відсутності фізичної активності може поглибити метаболічні порушення, що внаслідок цього підвищує ризик виникнення різних хронічних захворювань. Кишковий мікробіом є потенційно ключовим чинником у розвитку психічних розладів, як-от депресія та тривога, особливо в умовах пандемії. Також наявний взаємозв’язок, де мікробні метаболіти й ендотоксини можуть впливати на легені через кров, запалення в легенях може взаємодіяти з мікробіотою кишечника. Особи, які отримали вакцину, можуть мати більше відчуття безпеки щодо можливості уникнути тяжкого перебігу COVID-19 або передачі вірусу іншим особам. Це може позитивно вплинути на їхній психологічний стан. Результати дослідження можуть бути корисними для лікарів і психологів, щоб покращити підтримку та лікування осіб, які перехворіли на COVID-19, та допомогти їм відновитися після цього захворювання.
... In certain instances, LOC cannot be attributed to respiratory, metabolic, or other systemic disorders and may likely be a result of pro-inflammatory mechanisms leading to the release of cytokines within the central nervous system (CNS). 4,5 In cases of LOC-related disorders, various CNS-stimulating drugs, benzodiazepine receptor antagonists, or opioid receptor antagonists have been employed. Some of these treatments have resulted in improvements in alertness, attention, and neurocognitive function. ...
Aim
COVID‐19 can lead to encephalopathy and loss of consciousness. This double‐blinded randomized clinical trial conducted in Tehran, Iran, aimed to assess the potential effectiveness of modafinil in patients with COVID‐19‐related encephalopathy.
Methods
Nineteen non‐intubated COVID‐19 patients with encephalopathy were randomized into two groups: a treatment group receiving crushed modafinil tablets and a placebo group receiving starch powder. Modafinil was administered at a dose of 100 mg every 2 h, reaching a peak dosage of 400 mg. The level of consciousness was assessed using the Glasgow Coma Score (GCS) at multiple time points on the day of medication administration. The trial was registered under IRCT20170903036041N3 on 23/5/2021.
Results
The average age in the modafinil and placebo groups was 75.33 and 70 years, respectively. No significant differences were observed between the two groups in terms of chronic conditions, clinical symptoms, or laboratory data. GCS scores were similar between the groups at baseline ( p ‐value = 0.699). After four doses of modafinil, GCS scores were slightly higher in the treatment group, but this difference was not statistically significant ( p ‐value = 0.581). GCS scores after each round of drug administration didn't significantly differ between the treatment and placebo groups ( p ‐value = 0.908).
Conclusion
Modafinil exhibited a slight improvement in the level of consciousness among COVID‐19 patients with encephalopathy, although this improvement did not reach statistical significance when compared to the control group. Further research with larger sample sizes and longer treatment durations is recommended to explore modafinil's potential benefits in managing altered consciousness in COVID‐19 patients.
... can affect various organs. SARS-COV-2 infection leads to various diseases such as taste dysfunction, meningitis, myocarditis, and arterial and venous thromboembolism [2][3][4][5]. The mechanisms by which COVID-19 leads to thrombosis and thromboembolism have remained unclear. ...
The effects of Covid-19 vaccines on vascular function are still controversial. We evaluated the effects of BNT162b2 vaccine (BioNTech and Pfizer) on endothelial function assessed by flow-mediated vasodilation (FMD) and vascular smooth muscle function assessed by nitroglycerine-induced vasodilation (NID). This study was a prospective observational study. A total of 23 medical staff at Hiroshima University Hospital were enrolled in this study. FMD and NID were measured before vaccination and two weeks and six months after the 2 nd dose of vaccination. FMD was significantly smaller two weeks after the 2 nd dose of vaccination than before vaccination (6.5±2.4% and 8.2±2.6%, p = 0.03). FMD was significantly larger at six months than at two weeks after the 2 nd dose of vaccination (8.2±3.0% and 6.5±2.4%, p = 0.03). There was no significant difference between FMD before vaccination and that at six months after the 2 nd dose of vaccination (8.2±2.6% to 8.2±3.0%, p = 0.96). NID values were similar before vaccination and at two weeks, and six months after vaccination (p = 0.89). The BNT162b2 Covid-19 vaccine temporally impaired endothelial function but not vascular smooth muscle function, and the impaired endothelial function returned to the baseline level within six months after vaccination.
... SARS-CoV-2 is predominantly a respiratory disease affecting the lungs yet can have wide-ranging impacts throughout the body such as abnormal blood coagulation, fibrinolytic disturbances, neurodegeneration in the brain, and AA amyloidosis [66][67][68][69] . While some recent studies have proposed putative links between SARS-COV-2 proteins and amyloidosis 43,44 , including induction . ...
SARS CoV-2 infection can affect a surprising number of organs in the body and cause symptoms such as abnormal blood coagulation, fibrinolytic disturbances, and neurodegeneration. Our study delves into the intricate pathogenic potential of a SARS-CoV-2 envelope protein peptide, shedding light on its implications for multi-organ effects and amyloid formation. Specifically, we focus on the peptide SK9 or ⁵⁴ SFYVYSRVK ⁶² derived from the C-terminus of human SARS coronavirus 2 envelope protein. We demonstrate that SK9 containing peptides readily form classic amyloid structures consistent with predictions of amyloid aggregation algorithms. In vivo , overexpression of proteases such as neutrophil elastase during inflammation can potentially lead to C-terminal peptides containing SK9. We also demonstrate that SK9 can promote the fibrillization of SAA, a protein marker of acute inflammation. Our investigations reveal that the aromatic residues Phe2 and Tyr3 of SK9 play a pivotal role in its amyloidogenic function. We show that the primary sites of SK9-SAA binding lie in the amyloidogenic hotspots of SAA itself. Our results highlight two possible complications of SARS CoV-2 infection in individuals with hyper-inflammation either due to amyloids arising from SK9 containing peptides or SK9-induced AA amyloidosis.
... The cytokine storm in severe COVID-19 cases may cause systemic inflammation and endothelial dysfunction, 74 impairing the blood supply and oxygen delivery to the brain. 75,76 The cytokines may also cross the blood-brain . Neurodegenerative diseases, such as Alzheimer's disease (AD), are characterized by the loss of neurons and synapses in the brain, resulting in cognitive and functional decline. ...
COVID-19 is a respiratory infection caused by SARS-CoV-2 that can also have neurological manifestations and complications. There is growing evidence that COVID-19 may be associated with an increased risk of neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, and Amyotrophic lateral sclerosis. The mechanisms underlying this association are not fully understood but may involve direct viral invasion of the brain, systemic inflammation, endothelial dysfunction, and amyloid formation. These factors may trigger or accelerate the neuronal damage and debilitation that characterize neurodegenerative disorders. Hence, this study aims to review the highlighted connections between SARS-COV-2 and NDDs, considering new technologies in treating challenging diseases. To put it better, CRISPR-Cas9 is a genome editing tool that targets and modifies specific DNA sequences in living cells. It has been used to create animal models, study gene function, and develop gene therapies for various diseases. CRISPR-Cas9 may also be a promising tool to combat COVID-19 and prevent or treat its neurological complications by targeting either the viral genome or the host factors essential for viral infection. It has been concluded that there are still some questions and limitations to the clinical application of CRISPR-Cas9, such as delivery efficiency, specificity, safety, and immunogenicity, which require further investigation and biological and medical observation to be accepted as a stable alternative treatment in this field.
... COVID-19 increases the risk of ischemic stroke 7.8 times in the first three days after respiratory distress [5]. The pathophysiology of stroke in COVID-19 is related to viral affinity towards the Angiotensin Converting Enzyme (ACE-2) receptors, which directly causes brain neuron damage [6], activation on the immune system in the form of cytokine storms, which increases the incidence of inflammation [7], a combination of hypercoagulability and endothelial dysfunction [8], and hypoxemia due to respiratory distress. [9] Death is more common in acute stroke patients with COVID-19 [4,5]. ...
Background
Stroke is one of the neurological manifestations of COVID-19, leading to a significant risk of morbidity and mortality. Clinical manifestations and laboratory parameters were investigated to determine mortality predictors in this case.
Method
The case control study was conducted at Dr. Sardjito General Hospital,Yogyakarta, Indonesia, with data collected between July 2020 and August 2021. All recorded clinical and laboratory data from acute stroke patients with confirmed COVID-19 were collected. Baseline characteristics, bivariate, and multivariate analyses were assessed to determine significant predictors for mortality.
Result
This study involved 72 subjects with COVID-19 and stroke. The majority experienced ischemic stroke, with hypertension as the most prevalent comorbidity. Notably, 45.8% of subjects (p < 0.05) loss of consciousness and 72.2% of exhibited motor deficits (p < 0.05). Severe degree of COVID-19 was observed in 52.8% of patients, with respiratory distress and death rates of 56.9% and 58.3%. Comparison of surviving and deceased groups highlighted significant differences in various clinical and laboratory characteristics differences. Hazard ratio (HR) analysis identified loss of consciousness (HR = 2.68; p = 0.01), motor deficit (HR = 2.34; p = 0.03), respiratory distress (HR = 81.51; p < 0.001), and monocyte count (HR:1.002; p = 0.04) as significant predictors of mortality.
Conclusion
Mortality in COVID-19 patients with stroke was significantly associated with loss of consciousness, motor deficit, respiratory distress, and raised monocyte count. The risk of mortality is heightened when multiple factors coexist.
... It has been estimated that about 80% of symptomatic patients do not need medical assistance or hospitalization, but the mortality rate among patients admitted to the ICU varies from 39% to 72% (Verity et al., 2020). Furthermore, the COVID-19 virus particles can impair the function of sensory receptor cells (blocking olfaction) by binding to the angiotensinconverting enzyme 2 or ACE2 receptors, which are highly expressed in the olfactory epithelial cells and oral mucosa (Fotuhi et al., 2020). ...
Exosomes are small vesicles that carry molecules from one cell to another. They have many features that make them interesting for research, such as their stability, low immunogenicity, size of the nanoscale, toxicity, and selective delivery. Exosomes can also interact with viruses in diverse ways. Emerging research highlights the significant role of exosomes in viral infections, particularly in the context of diseases like COVID-19, HIV, HBV and HCV. Understanding the intricate interplay between exosomes and the human immune system holds great promise for the development of effective antiviral therapies. An important aspect is gaining clarity on how exosomes influence the immune system and enhance viral infectivity through their inherent characteristics. By leveraging the innate properties of exosomes, viruses exploit the machinery involved in exosome biogenesis to set replication, facilitate the spread of infection, and eliminate immune responses. They can either help or hinder viral infection by modulating the immune system. This review summarizes the recent findings on how exosomes mediate viral infection and how they can be used for diagnosis or therapy. This could lead to new clinical applications of exosomes in disease management.
... When COVID-19 struck, there was a desperate need for research on the disease, its effects on the brain and body and on the development of new treatments for patients with the disease. Early in the disease it was noticed that those with the disease suffered a loss of smell and taste, as well as neurological and psychiatric symptoms, some of which lasted long after the patients had "survived" the disease [9][10][11][12][13][14][15]. As soon as the pandemic started, there was a search for appropriate animal models in which to study this unknown disease [16,17]. ...
... One metaanalysis reported that the estimated prevalence of sleep problems among COVID-19 patients was 52.39% (Jahrami et al., 2022). Cytokine storm, blood clots, direct damage by SARS-CoV-2, and/or molecular mimicry were important causes for increased insomnia and sleep disturbances (Fotuhi, Mian, Meysami, & Raji, 2020). After infection, the virus in the cerebrospinal fluid and brain tissue post-mortem could further induce the priming of neuro-immunological substrates, leading to an exacerbated immune response and autoimmunity targeting structures in the central nervous system (Tizenberg et al., 2021). ...
Sleep disturbances are highly prevalent during the COVID-19 pandemic, especially among older adults. We aimed to evaluate sleep heath during COVID-19 pandemic and assess the differences among geographical regions and pandemic periods. We searched three databases (PubMed, Embase, Web of Science) to find articles up to March 12, 2023. We included observational studies that reported the prevalence of sleep disturbances among adults aged 60 years or older in any setting. Two researchers independently reviewed the literature and retrieved the data. We used Der Simonian-Laird random effects meta-analyses to pool the data, followed by subgroup analysis, sensitivity analysis, and meta-regression. A total of 64 studies with 181,224 older adults during the pandemic were included. The prevalence of poor sleep quality, short sleep duration, long sleep duration, and insomnia symptoms were 47.12% (95% CI: 25.97%, 68.27%), 40.81% (95% CI: 18.49%, 63.12%), 31.61% (95% CI: 24.83%, 38.38%), and 21.15% (95% CI: 15.30%, 27.00%), respectively. The prevalence of sleep problems reported by self-constructed items was 26.97% (95% CI: 20.73%, 33.22%). When compared to America (64.13%), Europe (20.23%) and the Western Pacific (21.31%) showed a lower prevalence of sleep problems (all P < 0.0001). The prevalence of worsened sleep problems was 27.88% (95% CI: 11.94%, 43.82%). Compared to 2020 (15.14%), it increased to 47.42% in 2021 (P < 0.05). Eight studies on sleep disturbances among 672 older COVID-19 patients were included. The prevalence of sleep problems and insomnia symptoms among older COVID-19 patients were 41.58% (95% CI: 21.97%, 61.20%) and 41.56% (95% CI: 28.11%, 58.02%), respectively. A significant burden related to poor sleep has been observed among older adults worldwide over the past three years, with variations across different regions and time periods. It is important to make more efforts in prevention and intervention to identify the risk factors, treatment, and rehabilitation of sleep disturbances for healthy aging.
... Alzheimer's disease (AD) is one of the most prevalent CNS disorders associated with the comorbidity of COVID-19 [20,21]. AD is complex and affected by age, heredity, lifestyle, and environmental factors [22]. ...
Background
The neurological effects of the coronavirus disease of 2019 (COVID-19) raise concerns about potential long-term consequences, such as an increased risk of Alzheimer's disease (AD). Neuroinflammation and other AD-associated pathologies are also suggested to increase the risk of serious SARS-CoV-2 infection. Anosmia is a common neurological symptom reported in COVID-19 and in early AD. The olfactory mucosa (OM) is important for the perception of smell and a proposed site of viral entry to the brain. However, little is known about SARS-CoV-2 infection at the OM of individuals with AD.
Methods
To address this gap, we established a 3D in vitro model of the OM from primary cells derived from cognitively healthy and AD individuals. We cultured the cells at the air–liquid interface (ALI) to study SARS-CoV-2 infection under controlled experimental conditions. Primary OM cells in ALI expressed angiotensin-converting enzyme 2 (ACE-2), neuropilin-1 (NRP-1), and several other known SARS-CoV-2 receptor and were highly vulnerable to infection. Infection was determined by secreted viral RNA content and confirmed with SARS-CoV-2 nucleocapsid protein (NP) in the infected cells by immunocytochemistry. Differential responses of healthy and AD individuals-derived OM cells to SARS-CoV-2 were determined by RNA sequencing.
Results
Results indicate that cells derived from cognitively healthy donors and individuals with AD do not differ in susceptibility to infection with the wild-type SARS-CoV-2 virus. However, transcriptomic signatures in cells from individuals with AD are highly distinct. Specifically, the cells from AD patients that were infected with the virus showed increased levels of oxidative stress, desensitized inflammation and immune responses, and alterations to genes associated with olfaction. These results imply that individuals with AD may be at a greater risk of experiencing severe outcomes from the infection, potentially driven by pre-existing neuroinflammation.
Conclusions
The study sheds light on the interplay between AD pathology and SARS-CoV-2 infection. Altered transcriptomic signatures in AD cells may contribute to unique symptoms and a more severe disease course, with a notable involvement of neuroinflammation. Furthermore, the research emphasizes the need for targeted interventions to enhance outcomes for AD patients with viral infection. The study is crucial to better comprehend the relationship between AD, COVID-19, and anosmia. It highlights the importance of ongoing research to develop more effective treatments for those at high risk of severe SARS-CoV-2 infection.
Graphical Abstract
... From the long-lasting neurological effects of COVID-19 infections to the impacts of social isolation and loneliness endured by millions during the pandemic, to worldwide disruptions in research on the treatment and prevention of neurodegenerative disorders will all have enduring effects on brain health. [1][2][3][4] What is clear in the aftermath of the COVID-19 pandemic is a need for far greater cooperation and collaboration across national borders to address global health threats. This is highly instructive for achieving the goal of maintaining and improving global brain health in the 21st Century. ...
Maintaining and improving brain health, one of the most critical global challenges of this century, necessitates innovative, interdisciplinary, and collaborative strategies to address the growing challenges in Latin America and the Caribbean. This paper introduces Brain Health Diplomacy (BHD) as a pioneering approach to bridge disciplinary and geographic boundaries and mobilize resources to promote equitable brain health outcomes in the region. Our framework provides a toolkit for emerging brain health leaders, equipping them with essential concepts and practical resources to apply in their professional work and collaborations. By providing case studies, we highlight the importance of culturally sensitive, region-specific interventions to address unique needs of vulnerable populations. By encouraging dialogue, ideation, and cross-sector discussions, we aspire to develop new research, policy, and programmatic avenues. The novel BHD approach has the potential to revolutionize brain health across the region and beyond, ultimately contributing to a more equitable global cognitive health landscape.
... 10,11 Although the precise mechanisms through which SARS-CoV-2 affects the nervous system are yet to be elucidated, 12 the widespread distribution of angiotensin-converting enzyme 2 in the nervous system is plausible to make it vulnerable to SARS-CoV-2 infection. 13 Accumulating evidence has suggested the neuroinvasive potential of SARS-CoV-2. [14][15][16] Neurological manifestations, including the involvement of the central nervous system (CNS), the peripheral nervous system (PNS), and skeletal muscles, are observed in up to one third of patients with COVID-19. ...
Background
COVID-19 patients with neurological manifestations have poorer outcomes. We investigated the association between clinicodemographic and laboratory findings with poorer outcomes among COVID-19 inpatients with neurological manifestations.
Methods
This was a retrospective study of consecutive medical records (March–April 2020). Neurological manifestations (altered level of consciousness, acute cerebrovascular disease, ataxia, seizure, headaches, dizziness/vertigo, muscle weakness, and peripheral neuropathies) were categorized into serious and nonserious.
Results
Of 119 COVID-19 inpatients, 38 with neurological manifestations were included (age, 63.7 ± 13.4 years; male, 65.8%), of whom 27 (71.1%) had serious manifestations. Muscle weakness (57.9%), impaired consciousness (47.4%), and acute cerebrovascular disease (23.7%) were the most frequent manifestations. The in-hospital mortality rate was 28.9%. Patients with serious manifestations were significantly older (66.9 vs 55.7, P = 0.018), with significantly higher white blood cell count (6.8 vs 5.1 × 10 ³ /μL, P = 0.023), direct bilirubin (0.3 vs 0.2 mg/dL, P = 0.030), prothrombin time (PT) (15.4 vs 14.4 seconds, P = 0.006), international normalized ratio (1.2 vs 1.1, P = 0.005), and model for end-stage liver disease (MELD) scores (10 vs 7, P = 0.011), compared with those with nonserious manifestations. In addition, the nonsurvivors had higher potassium (4.5 vs 4.0 mEq/L, P = 0.021), total bilirubin (1.1 vs 0.6 mg/dL, P = 0.008), and MELD scores (12 vs 8, P = 0.025) compared with the survivors. After adjustment, we found significant impacts of age (adjusted odds ratio [aOR], 1.11; P = 0.032), PT (aOR, 5.04; P = 0.019), and MELD score (aOR, 1.27, P = 0.047) on poorer outcomes.
Conclusions
Older age, higher white blood cell count, bilirubin, PT, international normalized ratio, potassium, and MELD scores were associated with poorer outcomes in COVID-19 inpatients with neurological manifestations.
... The COVID-19 infection may cause damage to brain structure and function leading to multi-domain cognitive impairment including memory, executive functions, verbal fluency, processing speed, and visuospatial processing (11,14,19,20). One possible reason for the impact of the COVID-19 infection on cognition could be neurotropism (21)(22)(23)(24)(25)(26)(27)(28)(29). SARS-CoV-2 can enter the central nervous system and infect neuronal cells overcoming the blood-brain barrier (21,30). ...
Background
COVID-19 patients can report ‘brain fog’ and may exhibit cognitive symptoms for months after recovery (Cognitive COVID). However, evidence on whether and the extent to which SARS-CoV-2 infection impacts cognition irrespective of COVID-19 course and severity is limited to clinical samples and mainly comes from prognostic studies. We aimed to explore the association between serologically confirmed SARS-CoV-2 infection and cognitive functioning in community-based and institutionalized older adults, irrespective of COVID-19 symptoms.
Methods
We conducted a case-control study nested into two cohorts in Southern Switzerland. Eligible subjects were Italian speaking older adults, without a previous diagnosis of dementia, who underwent serological testing for anti-SARS-CoV-2 antibodies between November 2020 and July 2021. We manually selected age-, sex- and education-matched cases (i.e., individuals with a serologically confirmed SARS-CoV-2 infection), with seronegative controls, and we conducted in-person neuropsychological assessments using validated, highly sensitive cognitive tests.
Results
We completed 38 neuropsychological assessments in a mostly female sample of older adults (Mean age: 83.13 ± 8.95; 86.8% women). 17 were community dwelling individuals while 21 lived in a nursing home. As expected, socio-demographic characteristics of age, gender and educational level were similarly distributed between cases (n = 14) and controls (n = 24). In linear regression models, cases had significantly lower scores in cognitive tasks of memory (β = −0.367, p = 0.023), attention (β = 0.428, p = 0.008) and executive functions (β = 0.326, p = 0.046). We found no significant difference in tests of language and spatial-temporal orientation (all p values > 0.05).
Conclusions
SARS-CoV-2 infection was associated with cognitive impairment in memory, attention, and executive functions in older adults. Our findings are consistent with mechanistic evidence of the neurotropism of the virus and provide empirical support for the “Cognitive COVID” construct also in non-clinical samples. With nearly 800 million COVID-19 cases (in April 2023), and many more infections worldwide, the clinical and public health implications of Cognitive COVID due to SARS-CoV-2 infection may be massive and warrant further epidemiological investigations.
... Neurological symptoms have been reported in patients with COVID-19, ranging from mild symptoms such as headaches and anosmia, to severe symptoms such as neurovascular events and cognitive impairment (Harapan & Yoo, 2021). Additionally, it has been suggested that these neurological symptoms may increase the risk of developing neurodegenerative conditions (Fotuhi et al., 2020). ...
Although COVID-19 is primarily considered a respiratory pathology, it has been observed to impact other bodily systems, including the nervous system. While several studies have investigated anatomical changes in brain structures, such as volume or thickness post-COVID-19, there are no comprehensive reviews of these changes using imaging techniques for a holistic understanding. The aim of this study was to systematically analyze the literature on brain changes observed through neuroimaging after COVID-19. We conducted a systematic review according to PRISMA guidelines using Web of Science, Scopus, Medline, Pubmed, Sciencedirect, and LitCOVID. We selected studies that included adult patients during or after COVID-19 development, a control group or pre-infection images, and morphometric measurements using neuroimaging. We used the MSQ scale to extract information on sample characteristics, measured anatomical structures, imaging technique, main results, and methodological quality for each study. Out of 1126 identified articles, we included 19 in the review, encompassing 1155 cases and 1284 controls. The results of these studies indicated a lower volume of the olfactory bulb and variable increases or decreases in cortical and limbic structures' volumes and thicknesses. Studies suggest that brain changes occur post-COVID-19, primarily characterized by a smaller olfactory bulb. Additionally, there may be variations in cortical and limbic volumes and thicknesses due to inflammation or neuroplasticity, but these findings are not definitive. These differences may be attributed to methodological, geographical, and temporal variations between studies. Thus, additional studies are required to provide a more comprehensive and quantitative view of the evidence.
... It is crucial to stress that each of these processes plays a role in the development of different neurodegenerative illnesses, including ALS, PD, and Alzheimer's disease (AD). 85,86 Various biomarkers were found to be present in long-COVID neurological symptoms such as albumin, CRP, ferritin, IL-4, IL-6, tumor necrosis factor-α (TNF-α), glial fibrillary acidic protein (GFAP), and neurofilament light (NFL). Exosomes were found to play a major role in the long-COVID symptoms as they decorated with viral spikes (virus-like structure), carry viral RNA in their cargo, transfer viral receptors between different cells, and exaggerate inflammation, as presented in Figure 2. ...
With the decline in the number of new Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) infections, the World Health Organization announced the end of the SARS‐CoV‐2 pandemic. However, the repercussions of this viral pandemic may remain with us for a longer period of time, as it has remodeled the lives of humankind in many ways, including social and economic. Of course, its most important repercussions remain on the human health level. Long‐coronavirus disease (COVID) or post‐COVID is a state for which we do not have a concrete definition, a specific international classification of diseases Code, clear diagnostic tools, or well‐known effective cures as of yet. In this second article from the Intrinsic Factors behind long‐COVID Series, we try to link long‐COVID symptoms with their causes, starting from the nervous system. Extracellular vesicles (ECVs) play very complex and ramified roles in the bodies of both healthy and not‐healthy individuals. ECVs may facilitate the entry of many bioactive molecules and pathogens into the tissues and cells of the nervous system across the blood–brain barrier. Based on the size, quantity, and quality of their cargo, ECVs are directly proportional to the pathological condition and its severity through intertwined mechanisms that evoke inflammatory immune responses typically accompanied by pathological symptoms over variable time periods according to the type of these symptoms.
... The pos si ble course of the COVID-19 dis ease can be di vided into three "NeuroCovid Stages" based on the analy sis of the po ten tial pathophysiological mech a nisms involved in neu ro log i cal man i fes ta tions of SARS-Cov-2 (Ta ble) [11]. ...
Introduction. COVID-19 can damage the nervous system by direct viral damage to the neural cells or by immunopathology. More serious medical conditions such as cerebral edema, neuronal degeneration, encephalitis, acute disseminated encephalomyelitis, Guillain-Barre syndrome, Bickerstaff’s brainstem encephalitis, Miller-Fisher syndrome, polyneuritis, toxic encephalopathy, and stroke can occur.Case report. We report a case of a 40-year-old patient with previous history of hypertension and no other chronic disease who was admitted to the hospital with respiratory distress due to SARS-CoV-2-induced bilateral pneumonia. A few days later, he developed worsening respiratory function with an acute seizure episode. Head CT scan revealed subarachnoid hemorrhage with diffuse cerebral edema as a lethal neurological complication, possibly secondary to COVID-19.Discussion. COVID-19 induces CNS damage through various mechanisms including ACE-2 receptor damage, cytokine storm syndrome, secondary hypoxia, blood-brain barrier disruption, and neuroinflammation. Neurological symptoms correlate with the severity of COVID-19 disease and may range from asymptomatic infection to severe and lethal forms. Acute cerebral edema, as illustrated by our case, may result from a combination of diffuse en dothelial dysfunction, cytokine release syndrome, and hypoxic damage from pulmonary dysfunction.
... Neurological symptoms have been reported in patients with COVID-19, ranging from mild symptoms such as headaches and anosmia, to severe symptoms such as neurovascular events and cognitive impairment (Harapan & Yoo, 2021). Additionally, it has been suggested that these neurological symptoms may increase the risk of developing neurodegenerative conditions (Fotuhi et al., 2020). ...
MORALES-VERDUGO, J.; LOZANO-LOZANO, J. A.; PÉREZ-ROJAS, F.; MENDEZ-REBOLLEDO, G.; CARREÑO VÁSQUEZ, A. Structural brain alterations in individuals post-COVID-19: a systematic review. Int. J. Morphol., 41(5):1310-1316, 2023. SUMMARY: Although COVID-19 is primarily considered a respiratory pathology, it has been observed to impact other bodily systems, including the nervous system. While several studies have investigated anatomical changes in brain structures, such as volume or thickness post-COVID-19, there are no comprehensive reviews of these changes using imaging techniques for a holistic understanding. The aim of this study was to systematically analyze the literature on brain changes observed through neuroimaging after COVID-19. We conducted a systematic review according to PRISMA guidelines using Web of Science, Scopus, Medline, Pubmed, Sciencedirect, and LitCOVID. We selected studies that included adult patients during or after COVID-19 development, a control group or pre-infection images, and morphometric measurements using neuroimaging. We used the MSQ scale to extract information on sample characteristics, measured anatomical structures, imaging technique, main results, and methodological quality for each study. Out of 1126 identified articles, we included 19 in the review, encompassing 1155 cases and 1284 controls. The results of these studies indicated a lower volume of the olfactory bulb and variable increases or decreases in cortical and limbic structures' volumes and thicknesses. Studies suggest that brain changes occur post-COVID-19, primarily characterized by a smaller olfactory bulb. Additionally, there may be variations in cortical and limbic volumes and thicknesses due to inflammation or neuroplasticity, but these findings are not definitive. These differences may be attributed to methodological, geographical, and temporal variations between studies. Thus, additional studies are required to provide a more comprehensive and quantitative view of the evidence.
... Neurologists are faced with the challenge of LOC in covid-19 patients. In some cases, the LOC cannot be explained by respiratory, metabolic, or other systemic disorders and in all likelihood is secondary to the effect of pro-in ammatory mechanisms leading to the release of cytokines into the central nervous system (CNS) (4,5). In several LOC disorders, CNS stimulating drugs, benzodiazepine receptor antagonists or opioid receptor antagonists have been utilized, which in some cases resulted in improvement of alertness, attention, and neurocognitive function (6, 7). ...
Background
Covid-19 may cause encephalopathy leading to loss of consciousness. This study aimed to address this issue using modafinil.
Methods
This study was a double-blinded Randomized Clinical Trial conducted in The Rasoul Akram Hospital in Tehran, Iran. A total of 19 non-intubated Covid-related encephalopathy patients were divided into two treatment and placebo groups, receiving crushed Modafinil tablets and placebo starch powder, respectively. The drug was administered on a basis of a dose of 100 mg every two hours until reaching a peak dosage of 400 mg. In both groups, the level of consciousness was evaluated based on the Glasgow Consciousness Score (GCS) at 10, 8, 12, 14 and 16 hours on the day of medication administration. The trial registration number for this study is: IRCT20170903036041N3 which was registered on 23/5/2021. The obtained data were analyzed and compared between the two groups using SPSS version 26.
Results
The average age in the modafinil group and placebo group was 75.33 years and 70 years, respectively. There were no significant differences between the treatment and placebo groups in terms of chronic conditions, clinical symptoms, or laboratory data. GCS score was similar between the two groups (P-value = 0.699). GCS score was slightly higher in treatment group after four doses of Modafinil, which wasn’t meaningful (P-value = 0.581). GCS score after each round of drug administration wasn’t significantly different between treatment and placebo groups (P-value = 0.908).
Conclusion
Modafinil slightly improved the level of consciousness in patients with Covid-19 encephalopathy, which was not statistically significant compared to the control group.
... Como regla general, las formas graves de covid-19 tienen más probabilidades de producir complicaciones neurológicas en comparación con las formas leves en 45.5% contra 30%, respectivamente, y se ha documentado que aproximadamente 20% de los pacientes con covid-19 requieren ingresar a una unidad de cuidados intensivos para el manejo de complicaciones de tipo neurológico, condición que incrementa el riesgo de fallecer (Fotuhi et al., 2020). ...
... About 20% of patients infected with SARS-CoV-2 develop a post-acute syndrome [20] within months after the infection, named "Long-COVID" [20][21][22][23][24][25][26][27]. This condition is characterized by persistent fatigue, neurological [28][29][30][31][32][33][34][35][36], neurodegenerative [31,37,38], psychiatric [39][40][41][42][43][44][45], and cognitive [40][41][42][43][44][45][46][47][48][49][50][51] symptoms, especially brain fog [20,22,23,39,[52][53][54][55][56]. In one study, most hospitalized patients had neurological symptoms that lasted at least 6 months [57]. ...
SARS-CoV-2 infects cells via its spike (S) protein binding to its surface receptor angiotensin converting enzyme 2 (ACE2) on target cells and results in acute symptoms involving especially the lungs known as COVID-19. However, increasing evidence indicates that SARS-CoV-2 infection produces neuroinflammation associated with neurological, neuropsychiatric, and cognitive symptoms persists well past the resolution of the infection, known as post-COVID-19 sequalae or long-COVID. The neuroimmune mechanism(s) involved in long-COVID have not been adequately characterized. In this study, we show that recombinant SARS-CoV-2 full-length S protein stimulates release of pro-inflammatory IL-1b, CXCL8, IL-6, and MMP-9 from cultured human microglia via TLR4 receptor activation. Instead, recombinant receptor-binding domain (RBD) stimulates release of TNF-α, IL-18, and S100B via ACE2 signaling. These results provide evidence that SARS-CoV-2 spike protein contributes to neuroinflammation through different mechanisms that may be involved in CNS pathologies associated with long-COVID.
Introduction
The COVID-19 pandemic, with over 83 million confirmed cases and 1.8 million deaths, has raised concerns about long-term cognitive issues, especially in populations facing disparities. Despite a few years since Peru’s first COVID-19 wave, the cognitive effects on adults remain unclear. This study is the first in Peru to explore COVID-19’s impact on general cognition and executive function.
Methods
A retrospective cross-sectional study compared individuals with COVID-19 history to controls, assessing general cognition, verbal fluency, attention, and executive function. Among 240 assessed, 154 met the study inclusion criteria, with about 60% female and an average age of 38.89 ± 16.001 years. Groups included controls ( n = 42), acute phase (AP, n = 74) (1–14 days of symptoms), and hyperinflammatory phase (HP, n = 38) (>14 days of symptoms).
Results
Significant cognitive differences were observed. The HP group exhibited lower general cognitive performance ( p = 0.02), working memory ( p = 0.01), and executive function (planning; p < 0.001; flexibility; p = 0.03) than controls. Those with <14 days of illness (AP vs. HP) had deficits in general cognitive performance ( p = 0.02), working memory ( p = 0.02), and planning ( p < 0.001), mainly during the hyperinflammatory phase, showing differences in working memory ( p = 0.003) and planning ( p = 0.01). Gender differences emerged, with males in the HP phase having poorer working memory ( p = 0.003) and planning ( p = 0.01).
Discussion
This study underscores COVID-19’s negative impact on cognitive function, even in mild cases, with potential heightened effects in men during acute or hyperinflammatory phases. The findings provide Peru’s first evidence, highlighting the vulnerability of populations facing socioeconomic disparities.
Objective
Although Coronavirus disease 2019 (COVID-19) is primarily a respiratory infectious disease, it has also been associated with a wide range of other clinical manifestations. It is widely accepted in the scientific community that many patients after recovery continue to experience COVID-19-related symptoms, including cognitive impairment. The aim of this systematic review was to investigate the cognitive profile of patients with long-COVID syndrome.
Methods
A systematic search of empirical studies was conducted through the PubMed/Medline and Scopus electronic databases. Cross-sectional and longitudinal studies published between 2020 and 2023 were included.
Results
Of the 516 studies assessed for eligibility, 36 studies met the inclusion criteria. All included studies support the presence of persistent cognitive changes after COVID-19 disease. Executive function, memory, attention, and processing speed appear to be the cognitive domains that are predominantly associated with long-COVID syndrome, whereas language is an area that has not been sufficiently investigated.
Conclusions
In this review, the high frequency of cognitive impairment after COVID-19 is evident. If we consider that cognitive functioning affects our ability to live independently and is a key determinant of our quality of life, it is imperative to precisely define those factors that may induce cognitive impairment in COVID-19 survivors, with the ultimate goal of early diagnosis of cognitive changes and, consequently, the development of targeted rehabilitation interventions to address them.
Autopsy followed by histopathological examination is foundational in clinical and forensic medicine for discovering and understanding pathological changes in disease, their underlying processes, and cause of death. Imaging technology has become increasingly important for advancing clinical research and practice, given its noninvasive, in vivo and ex vivo applicability. Medical and forensic autopsy can benefit greatly from advances in imaging technology that lead toward minimally invasive, whole-brain virtual autopsy. Brain autopsy followed by histopathological examination is still the hallmark for understanding disease and a fundamental modus operandi in forensic pathology and forensic medicine, despite the fact that its practice has become progressively less frequent in medical settings. This situation is especially relevant with respect to new diseases such as COVID-19 caused by the SARS-CoV-2 virus, for which our neuroanatomical knowledge is sparse. In this narrative review, we show that ad hoc clinical autopsies and histopathological analyses combined with neuroimaging of the principal circumventricular organs are critical to gaining insight into the reconstruction of the pathophysiological mechanisms and the explanation of cause of death (ie, atrium mortis ) related to the cardiovascular effects of SARS-CoV-2 infection in forensic and clinical medicine.
The pandemic of severe-acute-respiratory-syndrome-related coronavirus (SARS-Cov-2) has shown a wide spectrum of possible consequences in children, ranging from asymptomatic patients to the development of severe conditions, such as multisystem inflammatory syndrome in children and encephalopathies related to cytokine storm. Specifically, neurological and neuroimaging abnormalities, ranging from mild-to-the severe ones, have been documented in children as well, such as postinfectious immune-mediated acute disseminated encephalomyelitis, myelitis, neural enhancement, cranial nerve enhancement, and cortical injury, also without neurological symptoms. Considering the neurotropism of coronaviruses and SARS-Cov-2, which has been well described in the literature, we reviewed the literature reporting possible cerebral malformation in neonates due to the infection of SARS-Cov-2 in pregnancy. Coronavirus disease 2019 (COVID-19) during pregnancy might develop cerebral disorders in several ways. Articles in English in the literature were screened using the following search terms: (1) “brain malformations” AND “COVID-19”; (2) “cerebral malformations” AND “COVID-19”; (3) brain malformations AND “Sars-Cov-2”; (4) “cerebral malformations “AND “Sars-Cov-2.” Considering the congenital brain malformation found in newborns exposed to infection of SARS-Cov-2 pre- or neonatally, we identified one paper which reported three neonates with cerebral malformation. Although sporadic, cerebral malformations like atypical signals in white matter with delayed myelination, brain dysplasia/hypoplasia with delayed myelination, and unusual signals in the periventricular regions have been documented.
The article introduces a comprehensive review of theoretical and experimental studies in the field of psychophysiological predictors of cognitive impairments in post-COVID-19 patients. The data obtained made it possible to design a model of psychological correction and prevention of post-COVID-19 cognitive dysfunction. This condition affects cognitive, behavioral, and psycho-emotional areas of mental activity. Functional changes involve poor mobility of nervous processes and short attention span, as well as changes in coping behavior and personality characteristics. Unlike older patients, teenagers experience fewer consequences for cardiovascular system and cognitive functions. As for gender differences, men restored their cognitive functions better when they came to grasp with their past experience. For women, recovery was associated with life meaning, planning, and goal setting. The resulting model for the prevention and psychological correction of post-COVID-19 cognitive dysfunction integrated the principles of systemic, information, cognitive, and personality-oriented approaches. It consisted of several structural elements that made it possible to support COVID-19 patients through all treatment stages, i.e., psychodiagnostics, psychocorrection, psychotherapy, and social and lifestyle adaptation.
The bacteriophage behavior of SARS‐CoV‐2 during the acute and post‐COVID‐19 phases appears to be an important factor in the development of the disease. The early use of antibiotics seems to be crucial to inhibit disease progression—to prevent viral replication in the gut microbiome, and control toxicological production from the human microbiome. To study the impact of specific antibiotics on recovery from COVID‐19 and long COVID (LC) taking into account: vaccination status, comorbidities, SARS‐CoV‐2 wave, time of initiation of antibiotic therapy and concomitant use of corticosteroids and nonsteroidal anti‐inflammatory drugs (NSAIDs). A total of 211 COVID‐19 patients were included in the study: of which 59 were vaccinated with mRNA vaccines against SARS‐CoV‐2 while 152 were unvaccinated. Patients were enrolled in three waves: from September 2020 to October 2022, corresponding to the emergence of the pre‐Delta, Delta, and Omicron variants of the SARS‐CoV‐2 virus. The three criteria for enrolling patients were: oropharyngeal swab positivity or fecal findings; moderate symptoms with antibiotic intake; and measurement of blood oxygen saturation during the period of illness. The use of antibiotic combinations, such as amoxicillin with clavulanic acid (875 + 125 mg tablets, every 12 h) plus rifaximin (400 mg tablets every 12 h), as first choice, as suggested from the previous data, or azithromycin (500 mg tablets every 24 h), plus rifaximin as above, allows healthcare professionals to focus on the gut microbiome and its implications in COVID‐19 disease during patient care. The primary outcome measured in this study was the estimated average treatment effect, which quantified the difference in mean recovery between patients receiving antibiotics and those not receiving antibiotics at 3 and 9 days after the start of treatment. In the analysis, both vaccinated and unvaccinated groups had a median illness duration of 7 days (interquartile range [IQR] 6–9 days for each; recovery crude hazard ratio [HR] = 0.94, p = 0.700). The median illness duration for the pre‐Delta and Delta waves was 8 days (IQR 7–10 days), while it was shorter, 6.5 days, for Omicron (IQR 6–8 days; recovery crude HR = 1.71, p < 0.001). These results were confirmed by multivariate analysis. Patients with comorbidities had a significantly longer disease duration: median 8 days (IQR 7–10 days) compared to 7 days (IQR 6–8 days) for those without comorbidities (crude HR = 0.75, p = 0.038), but this result was not confirmed in multivariate analysis as statistical significance was lost. Early initiation of antibiotic therapy resulted in a significantly shorter recovery time (crude HR = 4.74, p < 0.001). Concomitant use of NSAIDs did not reduce disease duration and in multivariate analysis prolonged the disease ( p = 0.041). A subgroup of 42 patients receiving corticosteroids for a median of 3 days (IQR 3–6 days) had a longer recovery time (median 9 days, IQR 8–10 days) compared to others (median 7 days, IQR 6–8 days; crude HR = 0.542, p < 0.001), as confirmed also by the adjusted HR. In this study, a statistically significant reduction in recovery time was observed among patients who received early antibiotic treatment. Early initiation of antibiotics played a crucial role in maintaining higher levels of blood oxygen saturation. In addition, it is worth noting that a significant number of patients who received antibiotics in the first 3 days and for a duration of 7 days, during the acute phase did not develop LC.
Currently, there exists a limited comprehension regarding the correlation between COVID-19 and Alzheimer’s disease (AD). To elucidate the interrelationship and its impact on outcomes, a comprehensive investigation was carried out utilising time-unrestricted searches of reputable databases such as Scopus, PubMed, Web of Science, and Google Scholar. Our objective was to evaluate the impact of various medical conditions on severe COVID-19-related events. We focused on identifying and analysing articles that discussed the clinical characteristics of COVID-19 patients, particularly those pertaining to severe events such as ICU admission, mechanical ventilation, pneumonia, mortality and acute respiratory distress syndrome (ARDS) a serious lung condition that causes low blood oxygen. Through careful data analysis and information gathering, we tried to figure out how likely it was that people with conditions, like AD, would have serious events. Our research investigated potential mechanisms that link AD and COVID-19. The ability of the virus to directly invade the central nervous system and the role of ACE-2 receptors were investigated. Furthermore, the OAS1 gene served as the genetic link between AD and COVID-19. In the context of COVID-19, our findings suggest that individuals with AD may be more susceptible to experiencing severe outcomes. Consequently, it is crucial to provide personalised care and management for this demographic. Further investigation is required to attain a comprehensive comprehension of the intricate correlation between Alzheimer’s disease and COVID-19, as well as its ramifications for patient outcomes.
An infection with SARS-CoV‑2 can affect the central nervous system, leading to neurological as well as psychiatric symptoms. In this respect, mechanisms of inflammation seem to be of much greater importance than the virus itself. This paper deals with the possible contributions of organic changes to psychiatric symptomatology and deals especially with delirium, cognitive symptoms, depression, anxiety, posttraumatic stress disorder and psychosis. Processes of neuroinflammation with infection of capillary endothelial cells and activation of microglia and astrocytes releasing high amounts of cytokines seem to be of key importance in all kinds of disturbances. They can lead to damage in grey and white matter, impairment of cerebral metabolism and loss of connectivity. Such neuroimmunological processes have been described as a organic basis for many psychiatric disorders, as affective disorders, psychoses and dementia. As the activation of the glia cells can persist for a long time after the offending agent has been cleared, this can contribute to long term sequalae of the infection.
Background
Assessing and following up the clinical status of patients with COVID-19 can provide useful information for developing treatment algorithms to clarify treatment recommendations and improve patients’ stability after discharge. This study aimed to address the clinical course of patients with COVID-19 and its relationship with administration of recommended vaccines.
Methods
This cross-sectional study focused on 140 patients with COVID-19, selected based on convenience sampling, who were discharged from Vasei Hospital affiliated with Sabzevar University of Medical Sciences in between February 2022 and July 2022. Using a questionnaire, we assessed the recovery process and clinical course of patients 4 and 12 weeks after discharge. The data were analyzed in SPSS v. 24 at the significance level of 5%.
Results
Administration of the recommended vaccine doses and the recovery rate had a significant relationship in the second follow-up (P = 0.026), but not in the first follow-up. There was a significant relationship between the results of the PCR test in second period and the recovery rate in the first follow-up (P = 0.002), but there was no such significant relationship in the second follow-up (P = 0.51).
Conclusion
The results of this study showed that vaccination affects the level of immunity and the long-term recovery of patients with COVID-19.
Background: COVID-19, also known as the new coronavirus, has been linked to a variety of clinical outcomes, including moderate respiratory symptoms, severe respiratory failure, multi-organ failure, and death. The disease's severity can vary depending on a number of factors, including age, pre-existing medical disorders, and immunological function.
COVID-19 patients can exhibit a wide range of clinical manifestations affecting various organs and systems. Neurological symptoms have been reported in COVID-19 patients, both during the acute phase of the illness and in cases of long-term COVID. Moderate symptoms include ageusia, anosmia, altered mental status, and cognitive impairment, and in more severe cases can manifest as ischemic cerebrovascular disease and encephalitis. In this narrative review, we delve into the reported neurological symptoms associated with COVID-19, as well as the underlying mechanisms contributing to them. These mechanisms include direct damage to neurons, inflammation, oxidative stress, and protein misfolding. We further investigate the potential of small molecules from natural products to offer neuroprotection in models of neurodegenerative diseases. Through our analysis, we discovered that flavonoids, alkaloids, terpenoids, and other natural compounds exhibit neuroprotective effects by modulating signaling pathways known to be impacted by COVID-19. Some of these compounds also directly target SARS-CoV-2 viral replication. Therefore, molecules of natural origin show promise as potential agents to prevent or mitigate nervous system damage in COVID-19 patients. Further research and the evaluation of different stages of the disease are warranted to explore their potential benefits.
Aralık 2019’da Çin’den gelen bir haberle başlayan COVID-19 pandemi süreci, zaman zaman sönüyor gibi görünse de farklı alt türlerini oluşturması ile yeniden alevlenerek yoluna devam ediyor. Çin'de ve dünya genelinde vaka sayısındaki hızlı artış nedeniyle DSÖ, 11 Mart 2020'de SARS-CoV-2’nin neden olduğu COVID-19 hastalığı için, pandemi ilan etti. Salgın, COVID-19 hastalarının öksürme veya hapşırma sırasında çıkardıkları solunum damlacıkları yoluyla bulaşıyor ve öncelikle akciğer parankimini etkiliyor. Etkilenen hastalar, asemptomatik enfeksiyonlardan ölümle sonuçlanan ciddi süreçlere kadar çeşitli klinik belirtiler gösterebiliyor. COVID-19 hastalarında en çok solunum tutulumu görülse de, virüs diğer organ sistemlerini de etkileyebiliyor. Virüsün hücrelere girerken bir kapı gibi kullandığı reseptör ACE2’dir ve birçok hücre tipinde eksprese olmaktadır. Virüsün neden olduğu sistemik inflamasyon, gastrointestinal, kardiyovasküler, hematolojik, renal, kas-iskelet, nöroloji, üriner ve üreme sistemini etkileyen ekstra pulmoner semptomların ortaya çıkışını açıklamaktadır. Sonuç olarak, çeşitli dokulardaki klinik durumları anlamak, klinisyenlerin COVID-19'u erken bir aşamada teşhis etmesine ve hastalığın daha fazla yayılmasını önlemek için uygun önlemlerin alınmasının sağlamasına, yardımcı olabilir.
Background
Stroke is one of the neurological manifestations of COVID-19. Acute stroke patients with COVID-19 had a significant morbidity and mortality. The clinical and laboratory data of these patients were investigated to determine the key factors in predicting mortality.
Method
This retrospective case-control study was conducted at Dr. Sardjito General Hospital Yogyakarta, Indonesia using data from July 2020 - August 2021. All acute stroke patients with confirmed COVID-19 were included. Patients’ medical records were used to collect the clinical and laboratory data. For baseline characteristics, univariate tests were used, followed by bivariate and multivariate analyses to determine significant predictors of mortality.
Result
We included a total of 72 subjects, consisting of 65 (90.28%) subjects with ischemic stroke and 7 (9.72%) with hemorrhagic stroke. The overall mortality rate was 58.3%, which consisted of 50% ischemic and 8.3% hemorrhagic stroke cases. Lowered Glasgow Coma Scale (GCS), loss of consciousness, generalized seizures, worsened modified Ranking Scale (mRS), history of dyslipidemia, worsened clinical severity of COVID-19 infection, respiratory distress, higher neutrophil count, C-Reactive Protein levels (> 41mg/dl), Blood Urea Nitrogen (> 29.05mg/dl), and Random Blood Glucose level (> 111.5mg/dl) at admission were all significantly associated with mortality (p < 0.05). Cox regression analysis revealed a 17.535 higher risk of mortality in individuals with severe COVID-19 (p = 0.032). Higher mRS scores more than doubled the probability of mortality (p = 0.001).
Conclusion
The poorer functional status assessed by mRS and the greater degree of COVID-19 on admission should be carefully identified since they may increase the risk of mortality in stroke patients with COVID-19.
The COVID-19 pandemic posed a significant impediment to experimental research, leading several researchers to adapt psychophysical data acquisition. With the development and proliferation of information technology, paper-based organizational processes have gradually begun to be replaced by computer-based equivalents. This study describes how we developed, analyzed data, and validated the temporal bisection task in a remote data acquisition scenario. We implemented the data acquisition using the open science software OpenSesame, in conjunction with the JATOS platform. We described in detail all the steps to use our codes, which we made available for reuse. We acquired data from 28 participants using the remote acquisition system and compared them with data obtained in person (from Penney et al., 2000). Our remote data showed compatible results with live experiments, suggesting that the modality of data acquisition (remote or live) does not influence the results.
Patients with coronavirus disease 2019 (COVID-19) infection can suffer from a variety of neurological disorders; therefore, there is a demand to investigate specific treatments. As a part of this endeavor, academic databases related to clinical, neuropathological, and immunological biomarkers were examined for searching promising drugs to treat neurological disorders in the COVID-19 group. Also, the neuroprotective potential of herbs for patients with post-COVID-19 has been evaluated using PubMed, MEDLINE, Scopus, EMBASE, Google Scholar, EBSCO, Web of Science, Cochrane Library, WHO database, and ClinicalTrials.gov. The terms used for the Boolean search were Indian herbs and neuroprotective potential, post-COVID-19 symptoms, and so on. Based on our knowledge, nervous system immunity is an inherent characteristic of the nervous system because it is highly immunologically active. It was found that patients infected with COVID-19 often experience neurological symptoms such as muscle pain, headaches, confusion, dizziness, and loss of smell and taste. The most commonly used herbs for neurological disorders are Bacopa monnieri, Mucuna pruriens, Withania somnifera, Acorus calamus, Phyllanthus emblica, Blumea balsamifera, Asparagus racemosus, Cannabis sativa, Convolvulus prostratus, Swertia chirata, Vitex negundo, Nyctanthes arbor-tristis Linn, Centella asiatica, Curcuma longa, Ocimum tenuiflorum. It is widely recognized that herbal drugs have the potential for treating neurological diseases such as Parkinson’s, Alzheimer’s, and cerebrovascular diseases in COVID-19 patients. However, clinical trials are still limited. The suitability of drugs depends on the investigation of biomarkers and pathobiological mechanisms. Thus, it is necessary to use modern scientific approaches and technologies to conduct comprehensive mechanistic studies to understand the therapeutic potential of herbs for neurological disorders associated with the SARS-CoV-2 infection.
Background: Objective data on chemosensitive disorders during COVID-19 are lacking in the Literature.
Methods: Multicenter cohort study that involved four Italian hospitals. Three hundred and forty-five COVID-19 patients underwent objective chemosensitive evaluation.
Results: Chemosensitive disorders self-reported by 256 patients (74.2%) but the 30.1% of the 89 patients who did not report dysfunctions proved objectively hyposmic. Twenty-five percentage of patients were seen serious long-lasting complaints. All asymptomatic patients had a slight lowering of the olfactory threshold. No significant correlations were found between the presence and severity of chemosensitive disorders and the severity of the clinical course. On the contrary, there is a significant correlation between the duration of the olfactory and gustatory symptoms and the development of severe COVID-19. Conclusions: Patients under-report the frequency of chemosensitive disorders. Contrary to recent reports, such objective testing refutes the proposal that the presence of olfactory and gustatory dysfunction may predict a milder course, but instead suggests that those with more severe disease neglect such symptoms in the setting of severe respiratory disease.
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.
This review intends to provide an overview of the current knowledge on neurologic sequelae of COVID-19 and their possible etiology, and, based on available data, proposes possible improvements in current medical care procedures. We conducted a thorough review of the scientific literature on neurologic manifestations of COVID-19, the neuroinvasive propensity of known coronaviruses (CoV) and their possible effects on brain structural and functional integrity. It appears that around one third of COVID-19 patients admitted to intensive care units (ICU) for respiratory difficulties exhibit neurologic symptoms. This may be due to progressive brain damage and dysfunction triggered by severe hypoxia and hypoxemia, heightened inflammation and SARS-CoV-2 dissemination into brain parenchyma, as suggested by current reports and analyses of previous CoV outbreaks. Viral invasion of the brain may particularly target and alter brainstem and thalamic functions and, consequently, result in sensorimotor dysfunctions and psychiatric disorders. Moreover, data collected from other structurally homologous CoV suggest that SARS-CoV-2 infection may lead to brain cell degeneration and demyelination similar to multiple sclerosis (MS). Hence, current evidence warrants further evaluation and long-term follow-up of possible neurologic sequelae in COVID-19 patients. It may be particularly relevant to evaluate brainstem integrity in recovered patients, as it is suspected that this cerebral area may particularly be dysfunctional following SARS-CoV-2 infection. Because CoV infection can potentially lead to chronic neuroinflammation and progressive demyelination, neuroimaging features and signs of MS may also be evaluated in the long term in recovered COVID-19 patients.
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), has caused a global pandemic in only 3 months. In addition to major respiratory distress, characteristic neurological manifestations are also described, indicating that SARS-CoV-2 may be an underestimated opportunistic pathogen of the brain. Based on previous studies of neuroinvasive human respiratory coronaviruses, it is proposed that after physical contact with the nasal mucosa, laryngopharynx, trachea, lower respiratory tract, alveoli epithelium, or gastrointestinal mucosa, SARS-CoV-2 can induce intrinsic and innate immune responses in the host involving increased cytokine release, tissue damage, and high neurosusceptibility to COVID-19, especially in the hypoxic conditions caused by lung injury. In some immune-compromised individuals, the virus may invade the brain through multiple routes, such as the vasculature and peripheral nerves. Therefore, in addition to drug treatments, such as pharmaceuticals and traditional Chinese medicine, non-pharmaceutical precautions, including facemasks and hand hygiene, are critically important.
Background:
Emergence of the novel corona virus (severe acute respiratory syndrome (SARS)-CoV-2) in December 2019 has led to the covid-19 pandemic. The extent of covid-19 involvement in the central nervous system is not well established, and the presence or the absence of SARS-CoV-2 particles in the cerebrospinal fluid (CSF) is a topic of debate.
Case description:
We present two patients with covid-19 and concurrent neurological symptoms. Our first patient is a 31-year-old man who had flu-like symptoms due to covid-19 and later developed an acute-onset severe headache and loss of consciousness and was diagnosed with a Hunt and Hess grade 3 subarachnoid haemorrhage from a ruptured aneurysm. Our second patient is a 62-year-old woman who had an ischaemic stroke with massive haemorrhagic conversion requiring a decompressive hemicraniectomy. Both patients' CSF was repeatedly negative on real-time PCR analysis despite concurrent neurological disease.
Conclusion:
Our report shows that patients' CSF may be devoid of viral particles even when they test positive for covid-19 on a nasal swab. Whether SARS-CoV-2 is present in CSF may depend on the systemic disease severity and the degree of the virus' nervous tissue tropism and should be examined in future studies.
Background: Since its discovery in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 2 180 000 people worldwide and has caused more than 150 000 deaths as of April 16, 2020. SARS-CoV-2, which is the virus causing coronavirus disease 2019 (COVID-19), uses the angiotensin-converting enzyme 2 (ACE2) as a cell receptor to invade human cells. Thus, ACE2 is the key to understanding the mechanism of SARS-CoV-2 infection. This study is to investigate the ACE2 expression in various human tissues in order to provide insights into the mechanism of SARS-CoV-2 infection.
Methods: We compared ACE2 expression levels across 31 normal human tissues between males and females and between younger (ages ≤ 49 years) and older (ages > 49 years) persons using two-sided Student’s t test. We also investigated the correlations between ACE2 expression and immune signatures in various tissues using Pearson’s correlation test.
Results: ACE2 expression levels were the highest in the small intestine, testis, kidneys, heart, thyroid, and adipose tissue, and were the lowest in the blood, spleen, bone marrow, brain, blood vessels, and muscle. ACE2 showed medium expression levels in the lungs, colon, liver, bladder, and adrenal gland. ACE2 was not differentially expressed between males and females or between younger and older persons in any tissue. In the skin, digestive system, brain, and blood vessels, ACE2 expression levels were positively associated with immune signatures in both males and females. In the thyroid and lungs, ACE2 expression levels were positively and negatively associated with immune signatures in males and females, respectively, and in the lungs they had a positive and a negative correlation in the older and younger groups, respectively.
Conclusions: Our data indicate that SARS-CoV-2 may infect other tissues aside from the lungs and infect persons with different sexes, ages, and races equally. The different host immune responses to SARS-CoV-2 infection may partially explain why males and females, young and old persons infected with this virus have markedly distinct disease severity. This study provides new insights into the role of ACE2 in the SARS-CoV-2 pandemic.
The novel coronavirus, SARS-CoV-2-causing Coronavirus Disease 19 (COVID-19), emerged as a public health threat in December 2019 and was declared a pandemic by the World Health Organization in March 2020. Delirium, a dangerous untoward prognostic development, serves as a barometer of systemic injury in critical illness. The early reports of 25% encephalopathy from China are likely a gross underestimation, which we know occurs whenever delirium is not monitored with a valid tool. Indeed, patients with COVID-19 are at accelerated risk for delirium due to at least seven factors including (1) direct central nervous system (CNS) invasion, (2) induction of CNS inflammatory mediators, (3) secondary effect of other organ system failure, (4) effect of sedative strategies, (5) prolonged mechanical ventilation time, (6) immobilization, and (7) other needed but unfortunate environmental factors including social isolation and quarantine without family. Given early insights into the pathobiology of the virus, as well as the emerging interventions utilized to treat the critically ill patients, delirium prevention and management will prove exceedingly challenging, especially in the intensive care unit (ICU). The main focus during the COVID-19 pandemic lies within organizational issues, i.e., lack of ventilators, shortage of personal protection equipment, resource allocation, prioritization of limited mechanical ventilation options, and end-of-life care. However, the standard of care for ICU patients, including delirium management, must remain the highest quality possible with an eye towards long-term survival and minimization of issues related to post-intensive care syndrome (PICS). This article discusses how ICU professionals (e.g., physicians, nurses, physiotherapists, pharmacologists) can use our knowledge and resources to limit the burden of delirium on patients by reducing modifiable risk factors despite the imposed heavy workload and difficult clinical challenges posed by the pandemic.
Coronaviruses (CoVs) possess an enveloped, single, positive-stranded RNA genome which encodes for four membrane proteins, namely spike (S), envelope (E), membrane (M) and nucleocapsid (N) proteins 3-5 [1]. With regard to pathogenicity, S proteins are essential for viral entry into host cells [2, 3]. SARS-CoV binds to the angiotensin-converting enzyme (ACE)2 which is present on nonimmune cells, such as respiratory and intestinal epithelial cells, endothelial cells, kidney cells (renal tubules) and cerebral neurons and immune cells, such as alveolar monocytes/macrophages [4-6]. Of note, CD209L or liver/lymph node special intercellular adhesion molecule-3-grabbing non-integrin (SIGN) and dendritic cell (DC)-SIGN are alternative receptors for SARS-CoV but with lower affinity [7]. In the case of MERS-CoV, S proteins bind to the host cell receptor dipeptidyl peptidase 4 (DPP4 or CD26) which is broadly expressed on intestinal, alveolar, renal, hepatic and prostate cells as well as on activated leukocytes [8]. Then, viruses replicate in target cells with release of mature virions, which, in turn, invade new target cells [9]. Evidence has been provided that SARSCoV proteins are cleaved into two subunits, S1 and S2, respectively, and the amino acids 318-510 of the S1 represent the receptor-binding domain (RBD) which binds to ACE2 [10, 11]. Quite importantly, in the context of RBD there is the receptor-binding motif (RBM) (amino acids 424- 494), which accounts for complete binding to ACE2 [11]. Moreover, by means of two residues at positions 479 and 487 RBD allows virus progression and tropism [10, 11]. In the case of MERSCoV, its RBM binds to DPP4 with residues 484-567, thus, suggesting that its RBD differs from that of SARS-CoV [12, 13]. In a very recent paper, Wan and associates [14] have investigated the receptor recognition by COVID-19 (a new term to indicate the 2019-nCoV in Wuhan) on the bases of structural studies. In this respect, the sequence of COVID-19 RBM is similar to that of SARSCoV, thus, implicating that ACE2 may represent the binding receptors for COVID-19. Furthermore, gln493 residue of COVID-19 RBM seems to allow interaction with human ACE2, thus, suggesting the ability of this virus to infect human cells. According, to Wan and associates structural analysis [14], COVID-19 binds to human ACE2 with a lesser efficiency than human SARS-CoV (2002) but with higher affinity than human SARS-CoV (2003). Furthermore, same authors predicted that a single mutation at the 501 position may enhance the COVID-19 RBD binding capacity to human ACE2 and this evolution should be monitored in infected patients [14]. These predictive findings by Wan and associates [14] are confirmed by two contemporary studies by Letko and Muster [15] and Peng and associates [16]. In particular, the report by Peng and associates [16], points out the possible origin of COVID-19 from bats [16]. From a pathogenic point of view, evidence has been provided that binding of S2 to ACE2 receptor leads to its down-regulation with subsequent lung damage in the course of SARS-CoV infection [17]. Down-regulation of ACE2 causes excessive production of angiotensin (ANG) II by the related enzyme ACE with stimulation of ANG type 1a receptor (AT1R) and enhanced lung vascular permeability [18]. In particular, same authors have reported that recombinant ACE2 could attenuate severe acute lung injury in mice [18]. Moreover, Battle and associates [19] also proposed to use already available recombinant ACE2 for intercepting COVID-19 and attenuating infection. In the previous paragraphs, the presence of ACE2 on immune cells has been pointed out and, by analogy to epithelial cells, this receptor may also be down-regulated following viral entry. Therefore, in CoV-infected animal models and in infected humans further investigations are required to clarify a possible reduced expression of ACE2 on immune cells. In fact, in the course of SARS-CoV infection, a number of immune disorders have been detected. Three reports have demonstrated the ability of CoV to inhibit interferon (IFN)- production in the course of SARS acting as IFN antagonist [20-22]. In senescent Balb/c mice, depletion of T lymphocytes is associated to more severe interstitial pneumonitis and delayed clearance of SARS-CoV, thus, suggesting a protective role played by these cells [23]. In this connection, both SARS-CoV and MERS-CoV have been shown to induce T cell apoptosis, thus, aggravating the clinical course of disease [24, 25]. Quite interestingly, memory CD8+ T cells specific for SARS-CoV M and N proteins have been detected up to 11 years post-infection [26]. As far as humoral immune responsiveness is concerned, evidence has been provided that S1 subunit from MERS-CoV is highly immunogenic in mice [27]. Moreover, monoclonal antibodies have been shown to be highly neutralizing against MERS-CoV replication and endowed with post exposure effectiveness in susceptible mice [28, 29]. Human neutralizing antibodies have also been isolated from a recovered patient, thus, suggesting the role of humoral immunity in the control of the persistence of CoV in the host [30]. In particular, IgG response occurs early in infection and its prolonged production may serve for virus clearance during recovery also in view of the absence of viremia in convalescent sera from SARS patients [31]. According to current literature, severity of COVID-19 infection correlates with lymphopenia and patients who died from COVID-19 had lower lymphocyte counts when compared to survivors [32, 33]. These data suggest that lymphocyte-mediated anti-viral activity is poorly effective against COVID-19. Despite lymphopenia, evidence for an exaggerate release of proinflammatory cytokines [interleukin (IL)-1 and IL-6] has been reported in the course acute respiratory syndrome in COVID19 infected patients, thus, aggravating the clinical course of disease [34]. As recently reported, during COVID-19 pandemic in both Italy and China higher frequency of fatalities have been observed in the frail elderly population with previous comorbidities [35]. It is well known that decline of immunity occurs in ageing and, therefore, COVID-19 may gain easier access to the respiratory tract in frail elderly patients [36]. There is evidence that ACE2 protects from severe acute lung failure and operates as a negative regulator of the renin-angiotensin system (RAS) [18, 37]. It is well known that ANG II via activation of the AT1R promotes detrimental effects on the host, such as, vasoconstriction, reactive oxygen species generation, inflammation and matrix remodelling [38]. ACE2 counterbalances the noxious effects exhibited by ANG II and AT1R via activation of AT2R which arrests cell growth, inflammation and fibrosis [39]. In this framework, Gurwitz [40] proposed to use AT1R blockers, such as losartan, as a potential treatment of COVID-19 infection. In fact, losartan as well as olmesartan, used for treating hypertension in patients, were able to increase ACE2 expression after 28 days treatment of rats with myocardial infarction [41]. Then, Gurwitz suggests to evaluate severity of symptoms in COVID-19 infected patients under previous chronic treatment with AT1R blockers in comparison to COVID-19 infected patients who did not take AT1R blockers [40]. Quite interestingly, 75% of aged COVID-19 infected patients admitted to Italian hospitals had hypertension [unpublished data]. However, the putative effects of ACE-2 down-regulation on the cardiovascular system in the course of COVID-19 pandemic need more intensive studies. Taken together, these evidences suggest that CoV-induced down-regulation of ACE2 activates RAS with collateral damage to organs, such as lungs, in the course of SARS-related pneumonia. Then, putative therapeutic measures aimed at increasing ACE2 levels on respiratory epithelial cells should be taken into serious consideration. Quite interestingly, over the past few years, three key papers have demonstrated the ability of a polyphenol, resveratrol (RES), to experimentally deactivate the RAS system in maternal and post-weaning high fat diet, arterial ageing and high fat diet, respectively [42-44]. In all these experimental models, RES led to an increase of ACE2 with reduction of organ damage, such as liver steatosis and aorta media thickness and decrease of adipose tissue mass, respectively. As far as the mechanism of action of RES is concerned, this polyphenol is able to activate sirtuin (Sirt)1 [45-47]. In turn, Sirt1 down-regulates AT1R expression via ACE2 up-regulation [43, 48]. Of importance, Lin and associates [48] have demonstrated the ability of RES to in vitro inhibit MERS-CoV infection of Vero E6 cells, thus, prolonging cell survival in virtue of an anti-apoptotic mechanism. These findings suggest a direct antiviral effect exerted by RES. It would be very interestingly to evaluate the direct effects of RES on COVID-19, in vitro. The data above discussed strongly suggest, that RES, as an activators of ACE2, should be investigated in animal models of CoV-induced severe pneumonia, also taking into account the antioxidant, anti-inflammatory and immunomodulating effects exerted by polyphenols [49]. Then, successful animal studies may pave the way for RES-based human trials in COVID-infected patients. Note added in proof During the reviewing process of this perspective other related papers have been published. Hanff and associates [50] have discussed the possible association between COVID-19-associated cardiovascular mortality and dysregulation of the Renin Angiotensin System (RAS). From a pharmacologic point of view, RAS inhibition leads to upregulation of ACE2, thus, attenuating acute respiratory syndrome and myocarditis in COVID-19-infected patients. Conversely, increase in ACE2 expression may facilitate the access into the host of COVID-19, thus, aggravating the clinical picture. Such a dilemma would be solved by clinical trials based on RAS blockade or initiation and monitoring related effects. Contemporarily, Danser and associates [51] claim that there is no evidence to stop RAS blockers in the course of COVID-19 infection. In fact, there are no available data which support that ACE inhibitors or ANG II type I receptor blockers increase COVID-19 infection via its binding to ACE2. Finally, Kuster and associates [52] write that there are no data on the strict relationship between ACE2 activity and SARS-CoV2 mortality. Moreover, in the SARSCoV2, cells expressing ACE2 were not attacked by the virus, while cells lacking ACE2 were bound by the SARS-CoV2 virus [53]. These findings suggest that also in the case of RES effects on COVID-19 infection, the dual role of ACE2 should be taken into serious consideration.
From the first reports, ageusia and anosmia appear to be frequent clinical features in coronavirus disease 19 (COVID‐19) patients. We have performed a survey of the literature, analyzing the possible causes of these chemosensory alterations, which may be useful as a starting point for specific further studies.
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We investigated SARS-CoV-2 potential tropism by surveying expression of viral entry-associated genes in single-cell RNA-sequencing data from multiple tissues from healthy human donors. We co-detected these transcripts in specific respiratory, corneal and intestinal epithelial cells, potentially explaining the high efficiency of SARS-CoV-2 transmission. These genes are co-expressed in nasal epithelial cells with genes involved in innate immunity, highlighting the cells’ potential role in initial viral infection, spread and clearance. The study offers a useful resource for further lines of inquiry with valuable clinical samples from COVID-19 patients and we provide our data in a comprehensive, open and user-friendly fashion at www.covid19cellatlas.org. An analysis of single-cell transcriptomics datasets from different tissues shows that ACE2 and TMPRSS2 are co-expressed in respiratory, corneal and intestinal epithelial cell populations, and that respiratory expression of ACE2 is associated with genes involved in innate immunity.
We report a case of a 75-year-old woman diagnosed with severe coronavirus disease 2019 (COVID-19) complicated by acute cerebral infarction. The patient was admitted to our hospital on 5 February 2020 with severe COVID-19. On 20 February 2020, she was diagnosed with concomitant acute cerebral infarction via head computed tomography (CT) and deep vein thrombosis in both lower limbs. After symptomatic and supportive treatments, the patient was discharged on 13 March 2020. She will comply with quarantine for another 2 weeks and receive rehabilitation training from a specialist doctor. Cerebral infarction should be considered and promptly managed in patients with COVID-19.
Could COVID-19 represents a negative prognostic factor in patients with stroke? - Antonio Siniscalchi, Luca Gallelli
Coronavirus disease 2019 (COVID‐19) is widely spread and poses a critical threat to global health (Zhang et al). Prominent changes in coagulation function in severe patients of COVID‐19 have been reported in a recent study (Han, et al 2020). Therefore, we conducted this quantitative meta‐analysis to explore the difference in blood coagulation parameters between severe and mild cases of COVID‐19.
Our aim was to clarify the incidence and risk of acute symptomatic seizures in people with coronavirus disease 2019 (COVID‐19). This multicenter retrospective study enrolled people with COVID‐19 from January 18 to February 18, 2020 at 42 government‐designated hospitals in Hubei province, the epicenter of the epidemic in China; Sichuan province; and Chongqing municipality. Data were collected from medical records by 11 neurologists using a standard case report form. A total of 304 people were enrolled, of whom 108 had a severe condition. None in this cohort had a known history of epilepsy. Neither acute symptomatic seizures nor status epilepticus was observed. Two people had seizurelike symptoms during hospitalization due to acute stress reaction and hypocalcemia, and 84 (27%) had brain insults or metabolic imbalances during the disease course known to increase the risk of seizures. There was no evidence suggesting an additional risk of acute symptomatic seizures in people with COVID‐19. Neither the virus nor potential risk factors for seizures seem to be significant risks for the occurrence of acute symptomatic seizures in COVID‐19.
Objective
To report two patients infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) who acutely presented with Miller Fisher syndrome and polyneuritis cranialis, respectively.
Methods
Patient data were obtained from medical records from the University Hospital “Príncipe de Asturias”, Alcalá de Henares, Madrid, Spain and from the University Hospital “12 de Octubre”, Madrid, Spain.
Results
The first patient was a 50-year-old man who presented with anosmia, ageusia, right internuclear ophthalmoparesis, right fascicular oculomotor palsy, ataxia, areflexia, albuminocytologic dissociation and positive testing for GD1b-IgG antibodies. Five days before, he had developed a cough, malaise, headache, low back pain, and a fever. The second patient was a 39-year-old man who presented with ageusia, bilateral abducens palsy, areflexia and albuminocytologic dissociation. Three days before, he had developed diarrhea, a low-grade fever, and a poor general condition. The oropharyngeal swab test for coronavirus disease 2019 (COVID-19) by qualitative real-time reverse-transcriptase–polymerase-chain-reaction assay was positive in both patients and negative in the cerebrospinal fluid. The first patient was treated with intravenous immunoglobulin and the second, with acetaminophen. Two weeks later, both patients made a complete neurological recovery, except for residual anosmia and ageusia in the first case.
Conclusions
Our two cases highlight the rare occurrence of Miller Fisher syndrome and polyneuritis cranialis during the COVID-2 pandemic. Neurological manifestations may occur because of an aberrant immune response to COVID-19. The full clinical spectrum of neurological symptoms in patients with COVID-19 remains to be characterized.
The recent global severe acute respiratory distress syndrome coronavirus 2 pandemic is changing the world we live in. As we learn about the virus and the pandemic, it is becoming evident that it is an age‐associated problem that affects the human population. Severe acute respiratory distress syndrome coronavirus 2 is one of seven coronaviruses known to infect humans. These are large enveloped non‐segmented positive‐sense RNA viruses. Our knowledge of severe acute respiratory distress syndrome coronavirus 2 is extremely recent but is growing daily. There are currently no antiviral treatments against the virus or vaccines for its prevention. The long term consequences of the infection on human health remain uncertain but extrapolations can be made about the potential effects of the virus on cellular lifespan as well as on organismal healthspan. Here, we posit that severe acute respiratory distress syndrome coronavirus 2 infection may, in the long‐term, lead to accelerated aging phenotypes in survivors, not only in affected tissues but also in other organs, including the brain. Since some of the effects could manifest months or years after infection, it will be necessary to follow carefully people affected by coronavirus disease 2019. Keeping accurate registries may enable us to, in the future, establish connections with aging‐associated disorders, such as Parkinson's disease and other neurodegenerative disorders.
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Novel outbreak with coronavirus 2019 began since 31 December 2019. Coronaviruses can cause multiple systemic infections that respiratory complications are the most obvious symptoms. In this report, we describe the symptoms of Guillain Barre syndrome (GBS) in one infected patient with COVID-19, for the first time. We reported a 65-years- old male patient with complaints of acute progressive symmetric ascending quadriparesis. Two weeks prior to hospitalization, the patient suffered from cough, fever, and RT-PCR was reported positive for COVID-19 infection. The electrodiagnostic test showed that the patient is an AMSAN variant of GBS. COVID-19 stimulates inflammatory cells and produces various inflammatory cytokines and as a result, it creates immune-mediated processes. GBS is an immune-mediated disorder and molecular mimicry as a mechanism of autoimmune disorder plays an important role in creating it. It is unclear whether COVID-19 induces the production of antibodies against specific gangliosides. Further investigations should be conducted about the mechanism of GBS in patients with COVID-19, in the future.
The coronavirus-19 (COVID-19) pandemic has potential to disproportionately and severely affect patients with neuromuscular (NM) disorders. In a short period of time, it has already caused reorganization of neuromuscular clinical care delivery and education, which will likely have lasting impact on the field. This paper reviews 1) potential NM complications of COVID-19, 2) assessment and mitigation of COVID-19-related risk for patients with pre-existing NM disease, 3) guidance for management of immunosuppressive and immunomodulatory therapies, 4) practical guidance regarding NM care delivery, telemedicine and education, and 5) impact on neuromuscular research. We outline key unanswered clinical questions and highlight the need for team-based and inter-specialty collaboration. Primary goals of clinical research during this time are to develop evidence-based best practices and to minimize morbidity and mortality related to COVID-19 for patients with neuromuscular disorders.
Background
Rapid spread of the SARS‐CoV‐2 virus and concern for viral transmission by ambulatory patients with minimal to no symptoms underline the importance of identifying early or subclinical symptoms of Covid‐19 infection. Two such candidate symptoms include anecdotally reported loss of smell and taste. Understanding the timing and association of smell/taste loss in Covid‐19 may help facilitate screening and early isolation of cases.
Methods
A single‐institution, cross‐sectional study evaluating patient‐reported symptoms with a focus on smell and taste was conducted using an internet‐based platform on adult subjects who underwent testing for Covid‐19. Logistic regression was employed to identify symptoms associated with Covid‐19 positivity.
Results
A total of 1480 patients with influenza‐like symptoms underwent Covid‐19 testing between March 3 through 29, 2020. Our study captured 59 of 102 (58%) Covid‐19‐positive patients and 203 of 1378 (15%) Covid‐19‐negative patients. Smell and taste loss were reported in 68% (40/59) and 71% (42/59) of Covid‐19‐positive subjects, respectively, compared to 16% (33/203) and 17% (35/203) of Covid‐19‐negative patients (p<0.001). Smell and taste impairment were independently and strongly associated with Covid‐19‐positivity (anosmia: adjusted odds ratio [aOR] 10.9, 95%CI:5.08‐23.5; ageusia: aOR 10.2 95%CI:4.74‐22.1); whereas, sore throat was associated with Covid‐19‐negativity (aOR 0.23, 95%CI:0.11‐0.50). Of patients who reported Covid‐19‐associated loss of smell, 74% (28/38) reported resolution of anosmia with clinical resolution of illness.
Conclusions
In ambulatory individuals with influenza‐like symptoms, chemosensory dysfunction was strongly associated with Covid‐19 infection and should be considered when screening symptoms. Most will recover chemosensory function within weeks paralleling resolution of other disease‐related symptoms.
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Since the initial reports of the novel coronavirus disease (COVID-19) in December 2019 in Wuhan, China, and the declaration by the World Health Organization of the disease as a pandemic, increasing numbers of patients are diagnosed with COVID-19 globally on a daily basis. While initially fever, cough and dyspnea were thought to be the dominant symptoms, other unusual presentations of COVID-19 such as altered olfactory function have been increasingly recognized. Recently, isolated anosmia/hyposmia is reported as a marker of COVID-19. The onset of anosmia was sudden in majority of the cases and most had a concomitant decrease in taste sensation
Importance
The outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China, is serious and has the potential to become an epidemic worldwide. Several studies have described typical clinical manifestations including fever, cough, diarrhea, and fatigue. However, to our knowledge, it has not been reported that patients with COVID-19 had any neurologic manifestations.
Objective
To study the neurologic manifestations of patients with COVID-19.
Design, Setting, and Participants
This is a retrospective, observational case series. Data were collected from January 16, 2020, to February 19, 2020, at 3 designated special care centers for COVID-19 (Main District, West Branch, and Tumor Center) of the Union Hospital of Huazhong University of Science and Technology in Wuhan, China. The study included 214 consecutive hospitalized patients with laboratory-confirmed diagnosis of severe acute respiratory syndrome coronavirus 2 infection.
Main Outcomes and Measures
Clinical data were extracted from electronic medical records, and data of all neurologic symptoms were checked by 2 trained neurologists. Neurologic manifestations fell into 3 categories: central nervous system manifestations (dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia, and seizure), peripheral nervous system manifestations (taste impairment, smell impairment, vision impairment, and nerve pain), and skeletal muscular injury manifestations.
Results
Of 214 patients (mean [SD] age, 52.7 [15.5] years; 87 men [40.7%]) with COVID-19, 126 patients (58.9%) had nonsevere infection and 88 patients (41.1%) had severe infection according to their respiratory status. Overall, 78 patients (36.4%) had neurologic manifestations. Compared with patients with nonsevere infection, patients with severe infection were older, had more underlying disorders, especially hypertension, and showed fewer typical symptoms of COVID-19, such as fever and cough. Patients with more severe infection had neurologic manifestations, such as acute cerebrovascular diseases (5 [5.7%] vs 1 [0.8%]), impaired consciousness (13 [14.8%] vs 3 [2.4%]), and skeletal muscle injury (17 [19.3%] vs 6 [4.8%]).
Conclusions and Relevance
Patients with COVID-19 commonly have neurologic manifestations. During the epidemic period of COVID-19, when seeing patients with neurologic manifestations, clinicians should suspect severe acute respiratory syndrome coronavirus 2 infection as a differential diagnosis to avoid delayed diagnosis or misdiagnosis and lose the chance to treat and prevent further transmission.
Objective
To investigate the occurrence of olfactory and gustatory dysfunctions in patients with laboratory-confirmed COVID-19 infection.Methods
Patients with laboratory-confirmed COVID-19 infection were recruited from 12 European hospitals. The following epidemiological and clinical outcomes have been studied: age, sex, ethnicity, comorbidities, and general and otolaryngological symptoms. Patients completed olfactory and gustatory questionnaires based on the smell and taste component of the National Health and Nutrition Examination Survey, and the short version of the Questionnaire of Olfactory Disorders-Negative Statements (sQOD-NS).ResultsA total of 417 mild-to-moderate COVID-19 patients completed the study (263 females). The most prevalent general symptoms consisted of cough, myalgia, and loss of appetite. Face pain and nasal obstruction were the most disease-related otolaryngological symptoms. 85.6% and 88.0% of patients reported olfactory and gustatory dysfunctions, respectively. There was a significant association between both disorders (p < 0.001). Olfactory dysfunction (OD) appeared before the other symptoms in 11.8% of cases. The sQO-NS scores were significantly lower in patients with anosmia compared with normosmic or hyposmic individuals (p = 0.001). Among the 18.2% of patients without nasal obstruction or rhinorrhea, 79.7% were hyposmic or anosmic. The early olfactory recovery rate was 44.0%. Females were significantly more affected by olfactory and gustatory dysfunctions than males (p = 0.001).Conclusion
Olfactory and gustatory disorders are prevalent symptoms in European COVID-19 patients, who may not have nasal symptoms. The sudden anosmia or ageusia need to be recognized by the international scientific community as important symptoms of the COVID-19 infection.
We investigated SARS-CoV-2 potential tropism by surveying expression of viral entry-associated genes in single-cell RNA-sequencing data from multiple tissues from healthy human donors. We co-detected these transcripts in specific respiratory, corneal and intestinal epithelial cells, potentially explaining the high efficiency of SARS-CoV-2 transmission. These genes are co-expressed in nasal epithelial cells with genes involved in innate immunity, highlighting the cells’ potential role in initial viral infection, spread and clearance. The study offers a useful resource for further lines of inquiry with valuable clinical samples from COVID-19 patients and we provide our data in a comprehensive, open and user-friendly fashion at www.covid19cellatlas.org.
Background
Much of the focus regarding the global pandemic of coronavirus disease of 2019 (COVID-19) has been on the cardiovascular, pulmonary, and hematologic complications. However, neurologic complications have arisen as an increasingly recognized area of morbidity and mortality.
Objective
This brief report summarizes the neurologic complications associated with COVID-19 with an emphasis on the emergency medicine clinician.
Discussion
COVID-19 has infected over 3.5 million people and killed over 240,000 people worldwide. While pulmonary complications are profound, the neurologic system is also significantly impacted, with complications including acute cerebrovascular events, encephalitis, Guillain-Barré syndrome, acute necrotizing hemorrhagic encephalopathy, and hemophagocytic lymphohistiocytosis. Additionally, patients on immunosuppressive medications for pre-existing neurologic issues are at an increased risk for complications with COVID-19 infection, and many of the currently proposed COVID-19 therapies can interact with these medications.
Conclusions
When caring for COVID-19 patients, emergency medicine clinicians should be aware of the neurologic complications from COVID-19.
Objective
Acute stroke remains a medical emergency even during the COVID-19 pandemic. Most patients with COVID-19 present with constitutional and respiratory symptoms, some patients present with atypical symptoms including gastrointestinal, cardiovascular, or neurological symptoms. Here we present a series of four COVID-19 patients with acute stroke as a presenting symptom.
Methods
We searched the hospital databases for patients presenting with acute strokes and suspected COVID-19 features. All patients that had imaging confirmed strokes and PCR confirmed COVID-19 were included in the study. Patients admitted to the hospital with PCR confirmed COVID-19 disease whose hospital course was complicated with acute stroke while inpatient were excluded from the study. Retrospective patient data were obtained from electronic medical records. Informed consent was obtained.
Results
We identified four patients presenting with imaging confirmed acute strokes and PCR confirmed SARS-CoV-2 infection. We elucidate the clinical characteristics, imaging findings, and the clinical course.
Conclusions
Timely assessment and hyperacute treatment is the key to minimize mortality and morbidity of patients with acute stroke. Stroke teams should be wary of the fact that COVID-19 patients can present with cerebrovascular accidents and dawn appropriate personal protective equipment in every suspected patient. Further studies are urgently needed for a comprehensive understanding of the neurological pathology of COVID-19 and its effects on the nervous system.
The rapid spread of a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to an ongoing pandemic of coronavirus disease 2019 (COVID-19). Recently, angiotensin-converting enzyme 2 (ACE2) has been shown to be a functional receptor for SARS-CoV-2 to enter host target cells. Given that angiotensin receptor blockers (ARBs) and an ACE inhibitor (ACEI) upregulated ACE2 expression in animal studies, the concern might arise regarding whether ARBs and ACEIs would increase the morbidity and mortality of COVID-19. On the other hand, animal data suggested a potential protective effect of ARBs against COVID-19 pneumonia because an ARB prevented the aggravation of acute lung injury in mice infected with SARS-CoV, which is closely related to SARS-CoV-2. Importantly, however, there is no clinical or experimental evidence supporting that ARBs and ACEIs either augment the susceptibility to SARS-CoV-2 or aggravate the severity and outcomes of COVID-19 at present. Until further data are available, it is recommended that ARB and ACEI medications be continued for the treatment of patients with cardiovascular disease and hypertension, especially those at high risk, according to guideline-directed medical therapy based on the currently available evidence.
In late December 2019 an outbreak of a novel coronavirus (SARS-CoV-2) causing severe pneumonia (COVID-19) was reported in Wuhan, Hubei Province, China. A common finding in most COVID-19 patients is high D-dimer levels which are associated with a worse prognosis. We aimed to evaluate coagulation abnormalities via traditional tests and whole blood thromboelastometry profiles in a group of 22 (mean age 67 ± 8 years, M:F 20:2) consecutive patients admitted to the Intensive Care Unit of Padova University Hospital for acute respiratory failure due to COVID-19. Cases showed significantly higher fibrinogen and D-dimer plasma levels versus healthy controls (p < 0.0001 in both comparisons). Interestingly enough, markedly hypercoagulable thromboelastometry profiles were observed in COVID-19 patients, as reflected by shorter Clot Formation Time (CFT) in INTEM (p = 0.0002) and EXTEM (p = 0.01) and higher Maximum Clot Firmness (MCF) in INTEM, EXTEM and FIBTEM (p < 0.001 in all comparisons). In conclusion, COVID-19 patients with acute respiratory failure present a severe hypercoagulability rather than consumptive coagulopathy. Fibrin formation and polymerization may predispose to thrombosis and correlate with a worse outcome.
Angiotensin converting enzyme-2 (ACE2) receptors mediate the entry into the cell of three strains of coronavirus: SARS-CoV, NL63 and SARS-CoV-2. ACE2 receptors are ubiquitous and widely expressed in the heart, vessels, gut, lung (particularly in type 2 pneumocytes and macrophages), kidney, testis and brain. ACE2 is mostly bound to cell membranes and only scarcely present in the circulation in a soluble form. An important salutary function of membrane-bound and soluble ACE2 is the degradation of angiotensin II to angiotensin1-7. Consequently, ACE2 receptors limit several detrimental effects resulting from binding of angiotensin II to AT1 receptors, which include vasoconstriction, enhanced inflammation and thrombosis. The increased generation of angiotensin1-7 also triggers counter-regulatory protective effects through binding to G-protein coupled Mas receptors. Unfortunately, the entry of SARS-CoV2 into the cells through membrane fusion markedly down-regulates ACE2 receptors, with loss of the catalytic effect of these receptors at the external site of the membrane. Increased pulmonary inflammation and coagulation have been reported as unwanted effects of enhanced and unopposed angiotensin II effects via the ACE→Angiotensin II→AT1 receptor axis. Clinical reports of patients infected with SARS-CoV-2 show that several features associated with infection and severity of the disease (i.e., older age, hypertension, diabetes, cardiovascular disease) share a variable degree of ACE2 deficiency. We suggest that ACE2 down-regulation induced by viral invasion may be especially detrimental in people with baseline ACE2 deficiency associated with the above conditions. The additional ACE2 deficiency after viral invasion might amplify the dysregulation between the ‘adverse’ ACE→Angiotensin II→AT1 receptor axis and the ‘protective’ ACE2→Angiotensin1-7→Mas receptor axis. In the lungs, such dysregulation would favor the progression of inflammatory and thrombotic processes triggered by local angiotensin II hyperactivity unopposed by angiotensin1-7. In this setting, recombinant ACE2, angiotensin1-7 and angiotensin II type 1 receptor blockers could be promising therapeutic approaches in patients with SARS-CoV-2 infection.
The COVID-19 pandemic is causing global morbidity and mortality, straining health systems, and disrupting society, putting individuals with Alzheimer's disease and related dementias (ADRD) at risk of significant harm.
In this Special Article, we examine the current and expected impact of the pandemic on individuals with ADRD. We discuss and propose mitigation strategies for: the risk of COVID-19 infection and its associated morbidity and mortality for individuals with ADRD; the impact of COVID-19 on the diagnosis and clinical management of ADRD; consequences of societal responses to COVID-19 in different ADRD care settings; the effect of COVID-19 on caregivers and physicians of individuals with ADRD; mental hygiene, trauma, and stigma in the time of COVID-19; and the potential impact of COVID-19 on ADRD research.
Amid considerable uncertainty, we may be able to prevent or reduce the harm of the COVID-19 pandemic and its consequences for individuals with ADRD and their caregivers.
As the biomedical community races to disentangle the unknowns associated with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) – the virus responsible for causing coronavirus disease (COVID‐19) – the link between diminished immune function and individuals with obesity raises important questions about the possibility for greater viral pathogenicity in this population. Increased adiposity may undermine the pulmonary microenvironment wherein viral pathogenesis and immune cell trafficking could contribute to a maladaptive cycle of local inflammation and secondary injury. A further challenge to those with obesity during the current pandemic may involve vitamin D deficiency/insufficiency. In the interest of personal and public health, we caution decision/policy makers alike not to pin all hope on a proverbial ‘silver bullet.’ Until further breakthroughs emerge, we should remember that modifiable lifestyle factors like diet and physical activity should not be marginalized. Decades of empirical evidence supports both as key factors promoting health and wellness.
There has been a global outbreak of coronavirus disease 2019 (COVID‐19) since December 2019. In clinical practice, not only fever and respiratory tract symptoms but also multiple organ symptoms are observed in patients diagnosed with COVID‐19. Herein, we report a rare case of a patient diagnosed with COVID‐19 who manifested with concomitant neurological symptoms. The patient developed fever and respiratory symptoms at disease onset, followed by muscle soreness, and subsequently altered consciousness and psychiatric symptoms, with positive signs based on neurological examination. The patient tested positive for the severe acute respiratory syndrome corona virus 2 (SARS‐CoV‐2) nucleic acid (throat swab). Further, chest computed tomography (CT) revealed typical COVID‐19 findings, and head CT did not reveal significant abnormalities. The patient recovered after treatment and was discharged. This rare case indicates that SARS‐CoV‐2 can invade the central nervous system, thus causing neurological symptoms and signs.
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The novel SARS-CoV-2 virus has very high infectivity, which allows it to spread rapidly around the world. Attempts at slowing the pandemic at this stage depend on the number and quality of diagnostic tests performed. We propose that the olfactory epithelium from the nasal cavity may be a more appropriate tissue for detection of SARS-CoV-2 virus at the earliest stages, prior to onset of symptoms or even in asymptomatic people, as compared to commonly used sputum or nasopharyngeal swabs. Here we emphasize that the nasal cavity olfactory epithelium is the likely site of enhanced binding of SARS-CoV-2. Multiple non-neuronal cell types present in the olfactory epithelium express two host receptors, ACE2 and TMPRSS2 proteases, that facilitate SARS-CoV-2 binding, replication, and accumulation. This may be the underlying mechanism for the recently reported cases of smell dysfunction in patients with COVID-19. Moreover, the possibility of subsequent brain infection should be considered which begins in olfactory neurons. In addition, we discuss the possibility that olfactory receptor neurons may initiate rapid immune responses at early stages of the disease. We emphasize the need to undertake research focused on additional aspects of SARS-CoV-2 actions in the nervous system, especially in the olfactory pathway.
The coronavirus disease 19 (COVID-19) pandemic is a significant psychological stressor in addition to its tremendous impact on every facet of individuals’ lives and organizations in virtually all social and economic sectors worldwide. Fear of illness and uncertainty about the future precipitate anxiety- and stress-related disorders, and several groups have rightfully called for the creation and dissemination of robust mental health screening and treatment programs for the general public and front-line healthcare workers. However, in addition to pandemic-associated psychological distress, the direct effects of the virus itself (several acute respiratory syndrome coronavirus; SARS-CoV-2), and the subsequent host immunologic response, on the human central nervous system (CNS) and related outcomes are unknown. We discuss currently available evidence of COVID-19 related neuropsychiatric sequelae while drawing parallels to past viral pandemic-related outcomes. Past pandemics have demonstrated that diverse types of neuropsychiatric symptoms, such as encephalopathy, mood changes, psychosis, neuromuscular dysfunction, or demyelinating processes, may accompany acute viral infection, or may follow infection by weeks, months, or longer in recovered patients. The potential mechanisms are also discussed, including viral and immunological underpinnings. Therefore, prospective neuropsychiatric monitoring of individuals exposed to SARS-CoV-2 at various points in the life course, as well as their neuroimmune status, are needed to fully understand the long-term impact of COVID-19, and to establish a framework for integrating psychoneuroimmunology into epidemiologic studies of pandemics.
As coronavirus disease 2019 (COVID-19) spreads across the world, the intensive care unit (ICU) community must prepare for the challenges associated with this pandemic. Streamlining of workflows for rapid diagnosis and isolation, clinical management, and infection prevention will matter not only to patients with COVID-19, but also to health-care workers and other patients who are at risk from nosocomial transmission. Management of acute respiratory failure and haemodynamics is key. ICU practitioners, hospital administrators, governments, and policy makers must prepare for a substantial increase in critical care bed capacity, with a focus not just on infrastructure and supplies, but also on staff management. Critical care triage to allow the rationing of scarce ICU resources might be needed. Researchers must address unanswered questions, including the role of repurposed and experimental therapies. Collaboration at the local, regional, national, and international level offers the best chance of survival for the critically ill.
In a recent review, we have suggested a neuroinvasive potential of SARS‐CoV‐2 and its possible role in the causation of acute respiratory failure of COVID‐19 patients (J Med Viol doi: 10.1002/jmv.25728), based upon the clinical and experimental data available on the past SARS‐CoV‐1 and the recent SARS‐CoV‐2 pandemic. In this article, we provide new evidences recently reported regarding the neurotropic potential of SARS‐CoV‐2 and respond to several comments on our previously published article. In addition, we also discuss the peculiar manifestations of respiratory failure in COVID‐19 patients and the possible involvement of nervous system.
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