Neurological Sequelae of COVID-19.

BACKGROUND: Though primarily a pulmonary disease, Coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus can generate devastating disease states that affect multiple organ systems including the central nervous system (CNS). The various neurological disorders associated with COVID-19 range in severity from mild symptoms such as headache, or myalgias to more severe symptoms such as stroke, psychosis, and anosmia. While some of the COVID-19 associated neurological complications are mild and reversible, a significant number of patients suffer from stroke. Studies have shown that COVID-19 infection triggers a wave of inflammatory cytokines that induce endothelial cell dysfunction and generate coagulopathy that increases the risk of stroke or thromboses. Inflammation of the endothelium following infection may also destabilize atherosclerotic plaque and induce thrombotic stroke. Although uncommon, there have also been reports of hemorrhagic stroke associated with COVID-19. The proposed mechanisms include a blood pressure increase caused by infection leading to a reduction in angiotensin converting enzyme-2 (ACE-2) levels that results in an imbalance of the renin-angiotensin system ultimately manifesting inflammation and vasoconstriction. Coagulopathy, as demonstrated by elevated prothrombin time (PT), has also been posited as a factor contributing to hemorrhagics stroke in patients with COVID-19. Other neurological conditions associated with COVID-19 include encephalopathy, anosmia, encephalitis, psychosis, brain fog, headache, depression, and anxiety. Though there are several hypotheses reported in the literature, a unifying pathophysiological mechanism of many of these disorders remains unclear. Pulmonary dysfunction leading to poor oxygenation of the brain may explain encephalopathy and other disorders in COVID-19 patients. Alternatively, a direct invasion of the CNS by the virus or breach of the blood-brain barrier by the systemic cytokines released during infection may be responsible for these conditions. Notwithstanding, the relationship between the inflammatory cytokine levels and conditions such as depression and anxiety is contradictory and perhaps the social isolation during the pandemic may in part be a contributing factor to some of the reported CNS disorders. OBJECTIVE: In this article, we review the current literature pertaining to some of the most significant and common neurological disorders such as ischemic and hemorrhagic stroke, encephalopathy, encephalitis, brain fog, Long COVID, headache, Guillain-Barre syndrome, depression, anxiety, and sleep disorders in the setting of COVID-19. We summarize some of the most relevant literature to provide a better understanding of the mechanistic details regarding these disorders in order to help physicians monitor and treat patients for significant COVID-19 associated neurologic impairments. METHODS: A literature review was carried out by the authors using PubMed with the search terms "COVID-19" and "Neurology", "Neurological Manifestations", "Neuropsychiatric Manifestations", "Stroke", "Encephalopathy", "Headache", "Guillain-Barre syndrome", "Depression", "Anxiety", "Encephalitis", "Seizure", "Spasm", and "ICUAW". Another search was carried out for "Long-COVID" and "Post-Acute COVID-19" and "Neurological Manifestations" or "Neuropsychiatric Manifestations". Articles such as case reports, case series, and cohort studies were included as references. No language restrictions were enforced. In the case of anxiety and depression, attempts were made to focus mainly on articles describing these conditions in infected patients. RESULTS: A total of 112 articles were reviewed. The incidence, clinical outcomes, and pathophysiology of selected neurological disorders are discussed below. Given the recent advent of this disease, the incidence of certain neurologic sequelae was not always available. Putative mechanisms for each condition in the setting of COVID-19 are outlined.

Brain Inflammation and Intracellular α-Synuclein Aggregates in Macaques after SARS-CoV-2 Infection.

SARS-CoV-2 causes acute respiratory disease, but many patients also experience neurological complications. Neuropathological changes with pronounced neuroinflammation have been described in individuals after lethal COVID-19, as well as in the CSF of hospitalized patients with neurological complications. To assess whether neuropathological changes can occur after a SARS-CoV-2 infection, leading to mild-to-moderate disease, we investigated the brains of four rhesus and four cynomolgus macaques after pulmonary disease and without overt clinical symptoms. Postmortem analysis demonstrated the infiltration of T-cells and activated microglia in the parenchyma of all infected animals, even in the absence of viral antigen or RNA. Moreover, intracellular α-synuclein aggregates were found in the brains of both macaque species. The heterogeneity of these manifestations in the brains indicates the virus' neuropathological potential and should be considered a warning for long-term health risks, following SARS-CoV-2 infection.

Catching hold of COVID-19-related encephalitis by tracking ANGPTL4 signature in blood: An Editorial Highlight for "Endothelial cell biomarkers in critically ill COVID-19-patients with encephalitis": An Editorial Highlight for "Endothelial cell biomarkers in critically ill COVID-19-patients with encephalitis" on page 492.

Infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in humans is characterized by a plethora of symptoms varying in intensity, such as non-specific febrile illness, dry cough, dyspnea, hypoxemia to severe lung damage, and even death. In addition to pulmonary complications associated with coronavirus disease-19 (COVID-19), perturbations in the physiology of multiple other organ systems have been reported, resulting in multiorgan failure (MoF) that is frequently observed in severe COVID-19 cases. Central nervous system (CNS) infection by SARS-CoV-2 is characterized by neurological impairments in patients with COVID-19, with the development of encephalopathy at the severe end of the spectrum. While mechanistic investigations of SARS-CoV-2-related encephalitis may reveal promising therapeutic candidates for reducing COVID-19-associated disease morbidity, the discovery of biomarkers capable of diagnosing and predicting prognosis in patients with encephalitis upon SARS-CoV-2 infection will afford significant value for the rapid detection of encephalitis and predicting disease outcomes. This will ultimately enable appropriate modifications of therapeutic regimens aimed at reducing disease morbidity and mortality. In this editorial, we highlight a study by Le Guennec and colleagues, entitled "Endothelial cell biomarkers in critically ill COVID-19-patients with encephalitis", reporting the association of increased serum angiopoietin-like 4 (ANGPTL4) abundance with COVID-19-related encephalitis. The study highlights ANGPTL4 as a potential molecular marker for this disease. These novel findings may catalyze developments in the field of COVID-19-associated encephalitis by facilitating accurate and rapid diagnosis of encephalitis and timely treatment initiation, thus improving patient outcomes by ameliorating disease burden.

Endothelial cell biomarkers in critically ill COVID-19 patients with encephalitis.

COVID-19 is associated with encephalitis in critically ill patients and endothelial dysfunction seems to contribute to this life-threatening complication. Our objective was to determine the hallmark of endothelial activation in COVID-19-related encephalitis. In an observational study in intensive care unit (ICU), we compared vascular biomarkers of critically ill COVID-19 patients with or without encephalitis. To be classified in the encephalitis group, patients had to have new onset of central neurologic symptom, and pathological findings on either brain magnetic resonance imaging (MRI) and/or electroencephalogram (EEG). Among the 32 critically ill COVID-19 consecutive patients, 21 were categorized in the control group and 11 in the encephalitis group. Encephalitis patients had a longer ICU stay than control patients (median length [25th-75th percentile] of 52 [16-79] vs. 20.5 [11-44] days, respectively, p = 0.04). Nine-month overall follow-up mortality reached 21% (7/32 patients), with mortality rates in the encephalitis group and the control group of 27% and 19%, respectively. Encephalitis was associated with significant higher release of soluble endothelial activation markers (sE-selectin, tumor necrosis factor-α (TNF-α), interleukin 6, placental growth factor, and thrombomodulin), but these increases were correlated with TNF-α plasmatic levels. The hypoxia-inducible protein angiopoietin-like 4 (ANGPTL4) was at significantly higher levels in encephalitis patients compared to control patients (p = 0.0099), and in contrary to the other increased factors, was not correlated with TNF-α levels (r = 0.2832, p = 0.1163). Our findings suggest that COVID-19-related encephalitis is a cytokine-associated acute brain dysfunction. ANGPTL4 was the only elevated marker found in encephalitis patients, which was not correlated with systemic inflammation, suggesting that ANGPTL4 might be a relevant factor to predict encephalitis in critically ill COVID-19 patients.

Activation of Endogenous Retrovirus, Brain Infections and Environmental Insults in Neurodegeneration and Alzheimer's Disease.

Chronic neurodegenerative diseases are complex, and their pathogenesis is uncertain. Alzheimer's disease (AD) is a neurodegenerative brain alteration that is responsible for most dementia cases in the elderly. AD etiology is still uncertain; however, chronic neuroinflammation is a constant component of brain pathology. Infections have been associated with several neurological diseases and viruses of the Herpes family appear to be a probable cause of AD neurodegenerative alterations. Several different factors may contribute to the AD clinical progression. Exogeneous viruses or other microbes and environmental pollutants may directly induce neurodegeneration by activating brain inflammation. In this paper, we suggest that exogeneous brain insults may also activate retrotransposons and silent human endogenous retroviruses (HERVs). The initial inflammation of small brain areas induced by virus infections or other brain insults may activate HERV dis-regulation that contributes to neurodegenerative mechanisms. Chronic HERV activation in turn may cause progressive neurodegeneration that thereafter merges in cognitive impairment and dementia in genetically susceptible people. Specific treatment for exogenous end endogenous pathogens and decreasing pollutant exposure may show beneficial effect in early intervention protocol to prevent the progression of cognitive deterioration in the elderly.

[Encephalitis as a neurological manifestation of COVID-19]. / Encefalitis como manifestación neurológica del COVID-19.

INTRODUCTION: In the context of the global COVID-19 pandemic, the different clinical manifestations of this infection pose a challenge for healthcare professionals. Respiratory involvement, the main symptom of SARS-CoV-2 infection, means that other manifestations, such as neurological, take a back seat, with the consequent delay in diagnosis and treatment. MATERIAL AND METHODS: All COVID-19 patients admitted with neurological symptoms or diagnosed with encephalitis since March 2020 in a tertiary hospital in Zaragoza, Spain. RESULTS: Two patients with COVID-19 infection confirmed by nasopharyngeal PCR and whose clinical picture consisted of neurological alterations compatible with encephalitis. Cerebrospinal fluid (CSF) microbiology was negative for bacteria and viruses, including SARS-CoV-2 but, given the clinical suspicion of encephalitis due to the latter, antiviral treatment with immunoglobulins and plasmapheresis was started early. Despite this, the evolution was not satisfactory. CONCLUSIONS: COVID-19 encephalitis is a recently described clinical entity, whose pathophysiology is still unknown and no treatment with clinical evidence is available to date.

A Review of Neurological Involvement in Patients with SARS-CoV-2 Infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen of the recent pandemic of coronavirus disease 19 (COVID-19). As the infection spreads, there is increasing evidence of neurological and psychiatric involvement in COVID-19. Headache, impaired consciousness, and olfactory and gustatory dysfunctions are common neurological manifestations described in the literature. Studies demonstrating more specific and more severe neurological involvement such as cerebrovascular insults, encephalitis and Guillain-Barre syndrome are also emerging. Respiratory failure, a significant condition that leads to mortality in COVID-19, is hypothesized to be partly due to brainstem impairment. Notably, some of these neurological complications seem to persist long after infection. This review aims to provide an update on what is currently known about neurological involvement in patients with COVID-19 due to SARS-CoV-2 infection. In this review, we demonstrate invasion routes of SARS-CoV-2, provide evidence to support the neurotropism hypothesis of the virus, and investigate the pathological mechanisms that underlie neurological complications associated with SARS-CoV-2.

Neurological Manifestation of SARS-CoV-2 Induced Inflammation and Possible Therapeutic Strategies Against COVID-19.

There are regular reports of extrapulmonary infections and manifestations related to the ongoing COVID-19 pandemic. Coronaviruses are potentially neurotropic, which renders neuronal tissue vulnerable to infection, especially in elderly individuals or in those with neuro-comorbid conditions. Complaints of ageusia, anosmia, myalgia, and headache; reports of diseases such as stroke, encephalopathy, seizure, and encephalitis; and loss of consciousness in patients with COVID-19 confirm the neuropathophysiological aspect of this disease. The brain is linked to pulmonary organs, physiologically through blood circulation, and functionally through the nervous system. The interdependence of these vital organs may further aggravate the pathophysiological aspects of COVID-19. The induction of a cytokine storm in systemic circulation can trigger a neuroinflammatory cascade, which can subsequently compromise the blood-brain barrier and activate microglia- and astrocyte-borne Toll-like receptors, thereby leading to neuronal tissue damage. Hence, a holistic approach should be adopted by healthcare professionals while treating COVID-19 patients with a history of neurodegenerative disorders, neuropsychological complications, or any other neuro-compromised conditions. Imperatively, vaccines are being developed at top priority to contain the spread of the severe acute respiratory syndrome coronavirus 2, and different vaccines are at different stages of development globally. This review discusses the concerns regarding the neuronal complications of COVID-19 and the possible mechanisms of amelioration.

Clinical Presentation and Outcomes of Severe Acute Respiratory Syndrome Coronavirus 2-Related Encephalitis: The ENCOVID Multicenter Study.

BACKGROUND: Several preclinical and clinical investigations have argued for nervous system involvement in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Some sparse case reports have described various forms of encephalitis in coronavirus disease 2019 (COVID-19) disease, but very few data have focused on clinical presentations, clinical course, response to treatment, and outcomes. METHODS: The SARS-CoV-2 related encephalopaties (ENCOVID) multicenter study included patients with encephalitis with full infectious screening, cerebrospinal fluid (CSF), electroencephalography (EEG), and magnetic resonance imaging (MRI) data and confirmed SARS-CoV-2 infection recruited from 13 centers in northern Italy. Clinical presentation and laboratory markers, severity of COVID-19 disease, response to treatment, and outcomes were recorded. RESULTS: Twenty-five cases of encephalitis positive for SARS-CoV-2 infection were included. CSF showed hyperproteinorrachia and/or pleocytosis in 68% of cases whereas SARS-CoV-2 RNA by reverse-transcription polymerase chain reaction resulted negative. Based on MRI, cases were classified as acute demyelinating encephalomyelitis (ADEM; n = 3), limbic encephalitis (LE; n = 2), encephalitis with normal imaging (n = 13), and encephalitis with MRI alterations (n = 7). ADEM and LE cases showed a delayed onset compared to the other encephalitis cases (P = .001) and were associated with previous, more severe COVID-19 respiratory involvement. Patients with MRI alterations exhibited worse response to treatment and final outcomes compared to those with other encephalitis. CONCLUSIONS: SARS-CoV-2 infection is associated with a wide spectrum of encephalitis characterized by different clinical presentation, response to treatment, and outcomes.

A role for pathogen risk factors and autoimmunity in encephalitis lethargica?

The encephalitis lethargica (EL) epidemic swept the world from 1916 to 1926 and is estimated to have afflicted between 80,000 to one million people. EL is an unusual neurological illness that causes profound sleep disorders, devastating neurological sequalae and, in many cases, death. Though uncommon, EL is still occasionally diagnosed today when a patient presents with an acute or subacute encephalitic illness, where all other known causes of encephalitis have been excluded and criteria for EL are met. However, it is impossible to know whether recent cases of EL-like syndromes result from the same disease that caused the epidemic. After more than 100 years of research into potential pathogen triggers and the role of autoimmune processes, the aetiology of EL remains unknown. The epidemic approximately coincided with the 1918 H1N1 influenza pandemic but the evidence of a causal link is inconclusive. This article reviews the literature on the causes of EL with a focus on autoimmune mechanisms. In light of the current pandemic, we also consider the parallels between the EL epidemic and neurological manifestations of COVID-19. Understanding how pathogens and autoimmune processes can affect the brain may well help us understand the conundrum of EL and, more importantly, will guide the treatment of patients with suspected COVID-19-related neurological disease, as well as prepare us for any future epidemic of a neurological illness.

Acute myelitis and SARS-CoV-2 infection. A new etiology of myelitis?

The etiological agent of coronavirus disease-19 (COVID-19), SARS-coronavirus-2 (SARS-CoV-2), emerged in Wuhan, China, and quickly spread worldwide leading the World Health Organization (WHO) to recognize it not only as a pandemic but also as an important thread to public health. Beyond respiratory symptoms, new neurological manifestations are being identified such as headache, ageusia, anosmia, encephalitis or acute cerebrovascular disease. Here we report the case of an acute transverse myelitis (TM) in a patient with SARS-CoV-2 infection detected by the nasopharyngeal swab technique but not in cerebrospinal fluid (CSF) analysis. Anti-herpes simplex virus (HSV) 1 and varicella-zoster IgM antibodies were not detected in serum samples and spinal and brain magnetic resonance imaging (MRI) showed no abnormal findings. This case remarks that COVID-19 nervous system damage could be caused by immune-mediated mechanisms.

Neurological manifestations of COVID-19: available evidences and a new paradigm.

The recent pandemic outbreak of coronavirus is pathogenic and a highly transmittable viral infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2). In this time of ongoing pandemic, many emerging reports suggested that the SARS-CoV-2 has inimical effects on neurological functions, and even causes serious neurological damage. The neurological symptoms associated with COVID-19 include headache, dizziness, depression, anosmia, encephalitis, stroke, epileptic seizures, and Guillain-Barre syndrome along with many others. The involvement of the CNS may be related with poor prognosis and disease worsening. Here, we review the evidence of nervous system involvement and currently known neurological manifestations in COVID-19 infections caused by SARS-CoV-2. We prioritize the 332 human targets of SARS-CoV-2 according to their association with brain-related disease and identified 73 candidate genes. We prioritize these 73 genes according to their spatio-temporal expression in the different regions of brain and also through evolutionary intolerance analysis. The prioritized genes could be considered potential indicators of COVID-19-associated neurological symptoms and thus act as a possible therapeutic target for the prevention and treatment of CNS manifestations associated with COVID-19 patients.

[Neurologic compromise in pediatric COVID-19 infection]. / Compromiso neurológico en infección por COVID-19 en pacientes pediátricos.

Coronavirus disease has extended its involvement beyond the respiratory system, with increasing reports of involving different systems, such as Nervous System. The neuroinvasive potential of this pathogen would be explained by its neurotropism given the presence of ACE2 receptors in the brain and spinal cord, in addition to the important systemic inflammatory involvement. The neu rological involvement due to infection is divided between the central nervous system, highlighting non-specific and mild symptoms such as dizziness and headache, as well as severe symptoms with encephalitis and cerebrovascular pathology, and the peripheral nervous system, which mainly pre sents anosmia, ageusia, and myositis. Clinical symptomatology in pediatric patients seems to be less than in adults, but there is a growing report in the literature regarding these findings. There fore, it is very important to have an adequate registry and anamnesis that allow early identification of neurological involvement.

[Encephalitis associated with COVID-19 in a 13-year-old girl: A case report]. / Encefalitis asociada a COVID-19 en una niña de 13 años: reporte de caso.

There are limited reports of neurological symptoms in the pediatric population with COVID-19. We report a 13-year-old girl with three days of illness characterized by headache, non-explosive vomiting, fever, and sudden-onset sensory disorder associated with difficulty in standing and hemiparesis in limbs without evidence of meningeal signs. Brain tomography revealed diffuse brain edema, and the cerebrospinal fluid study was consistent with a viral infection. COVID-19 was diagnosed based on serology. The patient had an untoward clinical course despite treatment with hydroxychloroquine, azithromycin, and corticosteroids, dying on the third day of hospitalization. Encephalitis in a patient with COVID-19 is not frequently reported in the pediatric population. It should be considered in the differential diagnosis in patients who arrives at the emergency with a sensory disorder or neurological symptomatology in the context of the COVID-19 pandemic.

Existen limitados reportes de síntomas neurológicos en la población pediátrica con COVID-19. Reportamos el caso de una niña de 13 años con tres días de enfermedad caracterizada por cefalea, vómitos no explosivos, fiebre y trastorno del sensorio de inicio brusco asociado a dificultad para la bipedestación y hemiparesia en extremidades, sin evidencia de signos meníngeos. La tomografía cerebral reveló edema cerebral difuso y el estudio de líquido cefalorraquídeo era concordante con una infección viral. El diagnóstico de COVID-19 fue mediante pruebas serológicas. La paciente tuvo una evolución clínica desfavorable a pesar del tratamiento con hidroxicloroquina, azitromicina y corticoides, falleciendo al tercer día de hospitalización. La encefalitis en un paciente con COVID-19 es una asociación poco descrita en la población pediátrica. Esta infección debe ser considerado como diagnóstico diferencial en los pacientes que llegan a la emergencia con trastorno de sensorio o sintomatología neurológica en el contexto de la actual pandemia.

SARS-CoV-2-Associated Acute Hemorrhagic, Necrotizing Encephalitis (AHNE) Presenting with Cognitive Impairment in a 44-Year-Old Woman without Comorbidities: A Case Report.

BACKGROUND Acute hemorrhagic necrotizing encephalitis (AHNE) is a rare manifestation of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. AHNE usually involves the subcortical white matter but not the cortical grey matter. This study describes the disruptive effects of AHNE associated with SARS-CoV-2 on cognitive function in a previously healthy and sound middle-aged woman resulting from alterations in cortical areas involved in the cognitive network. CASE REPORT A 44-year-old previously healthy woman with a history of inter-state travel developed a flu-like illness, followed by acute, steadily progressive cognitive impairment. She was admitted in a comatose state after a first tonic-clonic seizure. Blood tests were non-informative. Cerebral magnetic resonance imaging (MRI) was indicative of AHNE. Cerebrospinal fluid analysis showed mild lymphocytosis with normal protein and normal glucose but an elevated IgG index. After testing positive for SARS-CoV-2, she was administered steroids. Treatment was ineffective, and the patient died. CONCLUSIONS SARS-CoV-2 is a potential central nervous system (CNS) pathogen, which may manifest as AHNE. These patients may present with generalized tonic-clonic seizures and frontal dysexecutive syndrome, with cognitive impairment being the presenting feature of neuro-coronavirus disease-2019 (COVID-19). The patient described in this report is unique for acute-onset and isolated cognitive impairments due to SARS-CoV-2 infection in the absence of clinical or radiological respiratory manifestations. These findings may help in the early detection and diagnosis of neuro-COVID-19, especially among clinicians and neurologists working in areas of endemic SARS-CoV-2 infection.