COVID-19 neurological manifestations: a narrative review on the mechanisms, pathogenesis, and clinical management

Coronaviruses are a large viral family, whose infections are recognized since 1960, varying from the common cold to more critical respiratory conditions. Regarding coronavirus 2019 (COVID-19), a wide spectrum of neurological manifestations among infected patients were reported, raising concerns whether Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) had tropism for the central nervous system. To clarify these questions, this bibliographic review was carried out by searching for articles based on national and international data during the period from December 2019 to June 2020. Thus, this review summarizes the current evidence on the transmission routes, focusing on the olfactory bulb and the hematogenic pathways, as well as the direct and indirect pathological mechanisms through which SARS-CoV-2 causes neurological damage. Moreover, clinical, laboratorial, and therapeutic aspects to manage patients with COVID-19 related neurological symptoms are outlined. Finally, development of treatments tackling specific structures and pathways related to viral entry and cardiovascular regulation on the brain are expected, in addition to monitoring of patients affected by the COVID-19 to assess long-term consequences on the nervous system.

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Modern aspects of neuropathogenesis and neurological manifestations of COVID-19

INTERNATIONAL NEUROLOGICAL JOURNAL ◽

10.22141/2224-0713.17.2.2021.229887 ◽

2021 ◽

Vol 17 (2) ◽

pp. 6-15

Author(s):

L.A. Dziak ◽

O.S. Tsurkalenko ◽

K.V. Chekha ◽

V.M. Suk

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Psychiatric Symptoms ◽

Clinical Manifestations ◽

The Body ◽

Altered Level ◽

Wide Range ◽

The Central Nervous System ◽

The Brain

Coronavirus infection is a systemic pathology resulting in impairment of the nervous system. The involvement of the central nervous system in COVID-19 is diverse by clinical manifestations and main mechanisms. The mechanisms of interrelations between SARS-CoV-2 and the nervous system include a direct virus-induced lesion of the central nervous system, inflammatory-mediated impairment, thrombus burden, and impairment caused by hypoxia and homeostasis. Due to the multi-factor mechanisms (viral, immune, hypoxic, hypercoagulation), the SARS-CoV-2 infection can cause a wide range of neurological disorders involving both the central and peripheral nervous system and end organs. Dizziness, headache, altered level of consciousness, acute cerebrovascular diseases, hypogeusia, hyposmia, peripheral neuropathies, sleep disorders, delirium, neuralgia, myalgia are the most common signs. The structural and functional changes in various organs and systems and many neurological symptoms are determined to persist after COVID-19. Regardless of the numerous clinical reports about the neurological and psychiatric symptoms of COVID-19 as before it is difficult to determine if they are associated with the direct or indirect impact of viral infection or they are secondary to hypoxia, sepsis, cytokine reaction, and multiple organ failure. Penetrated the brain, COVID-19 can impact the other organs and systems and the body in general. Given the mechanisms of impairment, the survivors after COVID-19 with the infection penetrated the brain are more susceptible to more serious diseases such as Parkinson’s disease, cognitive decline, multiple sclerosis, and other autoimmune diseases. Given the multi-factor pathogenesis of COVID-19 resulting in long-term persistence of the clinical symptoms due to impaired neuroplasticity and neurogenesis followed by cholinergic deficiency, the usage of Neuroxon® 1000 mg a day with twice-day dosing for 30 days. Also, a long-term follow-up and control over the COVID-19 patients are recommended for the prophylaxis, timely determination, and correction of long-term complications.

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Acute Disseminated Encephalomyelitis

10.1093/med/9780199937837.003.0089 ◽

2017 ◽

Author(s):

Benjamin M. Greenberg ◽

Allen Desena

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Supportive Care ◽

Acute Disseminated Encephalomyelitis ◽

Autoimmune Response ◽

Inflammatory Disorder ◽

The Central Nervous System ◽

The Brain

Acute disseminated encephalomyelitis (ADEM) is a rare inflammatory disorder of the central nervous system (CNS) that can be fatal or lead to long-term disability. Various triggers have been identified in children and adults, which presumably cause an autoimmune response targeting myelin. The resulting inflammation causes demyelination and edema of the brain, spinal cord, and optic nerves. Depending on which portion of the CNS is affected, patients will experience a variety of symptoms including weakness, numbness, ataxia, encephalopathy, and seizures. Treatment is currently focused on reducing the amount of inflammation and supportive care.

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Neurological involvement of COVID-19: from neuroinvasion and neuroimmune crosstalk to long-term consequences

Reviews in the Neurosciences ◽

10.1515/revneuro-2020-0092 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Dian Eurike Septyaningtrias ◽

Rina Susilowati

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Immune Responses ◽

Nerve Degeneration ◽

Neurological Involvement ◽

Neurological Manifestations ◽

The Central Nervous System ◽

Coronavirus Infection ◽

Long Term Consequences

Abstract As the coronavirus disease 2019 (COVID-19) pandemic continues to be a multidimensional threat to humanity, more evidence of neurological involvement associated with it has emerged. Neuroimmune interaction may prove to be important not only in the pathogenesis of neurological manifestations but also to prevent systemic hyperinflammation. In this review, we summarize reports of COVID-19 cases with neurological involvement, followed by discussion of possible routes of entry, immune responses against coronavirus infection in the central nervous system and mechanisms of nerve degeneration due to viral infection and immune responses. Possible mechanisms for neuroprotection and virus-associated neurological consequences are also discussed.

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Neurological symptoms due to Coronavirus disease 2019

Neurology International ◽

10.4081/ni.2020.8639 ◽

2020 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Farage Ftiha ◽

Moshe Shalom ◽

Henry Jradeh

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Neuromuscular Disorders ◽

Neurological Manifestations ◽

Full Extent ◽

The Central Nervous System ◽

Neurological Effects ◽

Brain And Spinal Cord ◽

The Brain

In this review, we focus on summarizing everything that is known about the neurological effects of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2). It has been shown that Coronavirus Disease 2019 (Covid-19) may result in neuromuscular disorders or damage to nerves outside of the brain and spinal cord, which may lead to weakness, numbness, and pain. Published literature has stated that SARS-COV-1 may infect the central nervous system and due to its similarities to SARS-COV-2, we suspect that SARS-COV-2 has the same potential. We conclude that Covid-19 has neurological manifestations. Further research should be done in this field to understand the full extent of this virus.

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Intravenous delivery of adeno-associated viral gene therapy in feline GM1 gangliosidosis

Brain ◽

10.1093/brain/awab309 ◽

2021 ◽

Author(s):

Amanda L Gross ◽

Heather L Gray-Edwards ◽

Cassie N Bebout ◽

Nathan L Ta ◽

Kayly Nielsen ◽

...

Keyword(s):

Gene Therapy ◽

Central Nervous System ◽

Cerebrospinal Fluid ◽

Nervous System ◽

Galactosidase Activity ◽

Gm1 Gangliosidosis ◽

The Central Nervous System ◽

Imaging And Spectroscopy ◽

The Brain

Abstract GM1 gangliosidosis is a fatal neurodegenerative disease caused by a deficiency of lysosomal β-galactosidase. In its most severe form, GM1 gangliosidosis causes death by 4 years of age, and no effective treatments exist. Previous work has shown that injection of the brain parenchyma with an adeno-associated viral vector provides pronounced therapeutic benefit in a feline GM1 model. To develop a less invasive treatment for the brain and increase systemic biodistribution, intravenous injection of AAV9 was evaluated. AAV9 expressing feline β-galactosidase was intravenously administered at 1.5x1013 vector genomes/kilogram body weight to six GM1 cats at approximately 1 month of age. The animals were divided into two cohorts: 1) a long-term group, which was followed to humane endpoint, and 2) a short-term group, which was analyzed 16-weeks post treatment. Clinical assessments included neurological exams, cerebrospinal fluid and urine biomarkers, and 7-Telsa magnetic resonance imaging and spectroscopy. Postmortem analysis included β-galactosidase and virus distribution, histological analysis, and ganglioside content. Untreated GM1 animals survived 8.0 ± 0.6 months while intravenous treatment increased survival to an average of 3.5 years (n = 2) with substantial improvements in quality of life and neurologic function. Neurological abnormalities, which in untreated animals progress to the inability to stand and debilitating neurological disease by 8 months of age, were mild in all treated animals. Cerebrospinal fluid biomarkers were normalized, indicating decreased central nervous system cell damage in the treated animals. Urinary glycosaminoglycans decreased to normal levels in the long-term cohort. Magnetic resonance imaging and spectroscopy showed partial preservation of the brain in treated animals, which was supported by postmortem histological evaluation. β-galactosidase activity was increased throughout the central nervous system, reaching carrier levels in much of the cerebrum and normal levels in the cerebellum, spinal cord and cerebrospinal fluid. Ganglioside accumulation was significantly reduced by treatment. Peripheral tissues such as heart, skeletal muscle, and sciatic nerve also had normal β-galactosidase activity in treated GM1 cats. GM1 histopathology was largely corrected with treatment. There was no evidence of tumorigenesis or toxicity. Restoration of β-galactosidase activity in the central nervous system and peripheral organs by intravenous gene therapy led to profound increases in lifespan and quality of life in GM1 cats. This data supports the promise of intravenous gene therapy as a safe, effective treatment for GM1 gangliosidosis.

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Literature Study: The Effectiveness of Aromatherapy on Reducing Anxiety in Chronic Kidney Failure Patients Undergoing Hemodialysis

Jurnal Ilmu Keperawatan (Journal of Nursing Science) ◽

10.21776/ub.jik.2021.009.02.4 ◽

2013 ◽

Vol 9 (2) ◽

pp. 168-177

Author(s):

Eka Agustin ◽

◽

Dian Hudiyawati

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Cerebral Cortex ◽

Kidney Disease ◽

The Body ◽

Future Research ◽

Long Term Treatment ◽

The Central Nervous System ◽

The Brain

Chronic Kidney Disease (CKD) is a progressive and irreversible decline in kidney function that results in the decreased ability of the body to retain fluids and electrolytes. Treatment methods in end-stage kidney disease are long-term treatment with hemodialysis and kidney transplantation. Hemodialysis therapy in the long term can cause anxiety. Aromatherapy can assist patients in coping with anxiety. The goal of this study was to determine the efficacy of aromatherapy in reducing anxiety in patients with hemodialysis. Articles were obtained through online databases such as PubMed, Google Scholar, and Science Direct. There are seven articles obtained after going through data screening and will be identified for critical review. The findings show that inhalation aromatherapy was effective in reducing anxiety levels among hemodialysis patients. Inhaled aromatherapy affects the central nervous system and has a balancing effect on the cerebral cortex and nerves in the brain. Inhaled aroma compounds will interact quickly through the central nervous system and olfactory nerves and then stimulate the nerves in the brain under the balance of the cerebral cortex to produce the release of the hormone melatonin, serotonin, which can cause a feeling of relaxation or sedative. Future research should include a variety of aromatherapy variants that can be used based on patient preferences, as well as an assessment of possible side effects.

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Neuroinflammation in Sepsis: Molecular Pathways of Microglia Activation

Pharmaceuticals ◽

10.3390/ph14050416 ◽

2021 ◽

Vol 14 (5) ◽

pp. 416

Author(s):

Carolina Araújo Moraes ◽

Camila Zaverucha-do-Valle ◽

Renaud Fleurance ◽

Tarek Sharshar ◽

Fernando Augusto Bozza ◽

...

Keyword(s):

Central Nervous System ◽

Current Knowledge ◽

Brain Dysfunction ◽

Regulatory Mechanisms ◽

Molecular Pathways ◽

Neurological Manifestations ◽

The Central Nervous System ◽

The Brain

Frequently underestimated, encephalopathy or delirium are common neurological manifestations associated with sepsis. Brain dysfunction occurs in up to 80% of cases and is directly associated with increased mortality and long-term neurocognitive consequences. Although the central nervous system (CNS) has been classically viewed as an immune-privileged system, neuroinflammation is emerging as a central mechanism of brain dysfunction in sepsis. Microglial cells are major players in this setting. Here, we aimed to discuss the current knowledge on how the brain is affected by peripheral immune activation in sepsis and the role of microglia in these processes. This review focused on the molecular pathways of microglial activity in sepsis, its regulatory mechanisms, and their interaction with other CNS cells, especially with neuronal cells and circuits.

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Current Evidence on the Effect of Dietary Polyphenols Intake on Brain Health

Current Nutrition & Food Science ◽

10.2174/1573401316999200714160126 ◽

2020 ◽

Vol 16 (8) ◽

pp. 1170-1182 ◽

Cited By ~ 3

Author(s):

Stefania D'Angelo

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Dietary Intake ◽

Neurodegenerative Diseases ◽

Health Benefits ◽

Current Evidence ◽

Brain Health ◽

Dietary Polyphenols ◽

The Central Nervous System ◽

The Brain

Background: In recent years, the possibility of favorably influencing the cognitive capacity through the promotion of lifestyle modifications has been increasingly investigated. In particular, the relationship between nutritional habits and brain health has attracted special attention. Polyphenols are secondary metabolites of plants. These phytochemicals are present in vegetables, fruits, legumes, olive oil, nuts. They include several antioxidant compounds and are generally considered to be involved in defense against chronic human diseases. In recent years, there has been a growing scientific interest in their potential health benefits to the brain. Objective: In this mini-review, we focus on the current evidence defining the position of polyphenols dietary intake in the prevention/slowdown of human neurodegenerative diseases. Methods: A literature research was performed using the keywords “polyphenols”, “brain”, “nutrition”, individually or all together, focusing on human trials. Results: The available clinical studies on the effect of polyphenols on cognitive functions are quite convincing. Regular dietary intake of polyphenols would seem to reduce the risk of neurodegenerative diseases. Moreover, beyond their beneficial power on the central nervous system, these phytochemicals seem also to be able to work on numerous cellular targets. They show different biological actions, that however, have to be confirmed in long-term randomized clinical trials. Currently, most data propose that a combination of phytonutrients instead of any single polyphenol is responsible for health benefits. Conclusions: Evolving indications suggest that dietary polyphenols may exercise beneficial actions on the central nervous system, thus representing a possible tool to preserve cognitive performance. Key questions to improve the coherence and reproducibility in the development of polyphenols as a possible future therapeutic drug require a better understanding of the sources of polyphenols, their treatment and more standardized tests including bioavailability of bioactive metabolites and studies of permeability of the brain.

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Neurological complications and infection mechanism of SARS-COV-2

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00818-7 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Dandan Wan ◽

Tingfu Du ◽

Weiqi Hong ◽

Li Chen ◽

Haiying Que ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Respiratory Diseases ◽

Neurological Diseases ◽

Neurological Complications ◽

Experimental Models ◽

Current Evidence ◽

Global Pandemic ◽

The Central Nervous System ◽

The Brain

AbstractCurrently, SARS-CoV-2 has caused a global pandemic and threatened many lives. Although SARS-CoV-2 mainly causes respiratory diseases, growing data indicate that SARS-CoV-2 can also invade the central nervous system (CNS) and peripheral nervous system (PNS) causing multiple neurological diseases, such as encephalitis, encephalopathy, Guillain-Barré syndrome, meningitis, and skeletal muscular symptoms. Despite the increasing incidences of clinical neurological complications of SARS-CoV-2, the precise neuroinvasion mechanisms of SARS-CoV-2 have not been fully established. In this review, we primarily describe the clinical neurological complications associated with SARS-CoV-2 and discuss the potential mechanisms through which SARS-CoV-2 invades the brain based on the current evidence. Finally, we summarize the experimental models were used to study SARS-CoV-2 neuroinvasion. These data form the basis for studies on the significance of SARS-CoV-2 infection in the brain.

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Anosmia: a missing link in the neuroimmunology of coronavirus disease 2019 (COVID-19)

Reviews in the Neurosciences ◽

10.1515/revneuro-2020-0039 ◽

2020 ◽

Vol 31 (7) ◽

pp. 691-701 ◽

Cited By ~ 6

Author(s):

Niloufar Yazdanpanah ◽

Amene Saghazadeh ◽

Nima Rezaei

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Innate Immune ◽

Neurological Manifestations ◽

Innate Immune Responses ◽

Neurotropic Viruses ◽

The Central Nervous System ◽

Olfactory Cells ◽

Novel Coronavirus ◽

The Brain

AbstractJust before 2020 began, a novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), brought for humans a potentially fatal disease known as coronavirus disease 2019 (COVID-19). The world has thoroughly been affected by COVID-19, while there has been little progress towards understanding the pathogenesis of COVID-19. Patients with a severe phenotype of disease and those who died from the disease have shown hyperinflammation and were more likely to develop neurological manifestations, linking the clinical disease with neuroimmunological features. Anosmia frequently occurs early in the course of COVID-19. The prevalence of anosmia would be influenced by self-diagnosis as well as self-misdiagnosis in patients with COVID-19. Despite this, the association between anosmia and COVID-19 has been a hope for research, aiming to understand the pathogenesis of COVID-19. Studies have suggested differently probable mechanisms for the development of anosmia in COVID-19, including olfactory cleft syndrome, postviral anosmia syndrome, cytokine storm, direct damage of olfactory sensory neurons, and impairment of the olfactory perception center in the brain. Thus, the observation of anosmia would direct us to find the pathogenesis of COVID-19 in the central nervous system, and this is consistent with numerous neurological manifestations related to COVID-19. Like other neurotropic viruses, SARS-CoV-2 might be able to enter the central nervous system via the olfactory epithelium and induce innate immune responses at the site of entry. Viral replication in the nonneural olfactory cells indirectly causes damage to the olfactory receptor nerves, and as a consequence, anosmia occurs. Further studies are required to investigate the neuroimmunology of COVID-19 in relation to anosmia.

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