Neurological Complications of COVID-19

The neurological complications of COVID-19 are an expansive and heterogeneous topic. This chapter discusses the neuropathophysiology of COVID-19 and the potential mechanisms through which the disease leads to neurological manifestations while also exploring historical viruses that have also led to neurological sequelae. These complications are then characterized and classified into several groups with support from contemporaneous evidence. In addition to this we examine common neurological imaging and their findings and finally discuss the greatest needs moving forward with regard to evidence and research through collaborative efforts. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

SARS-CoV-2 and the nervous system: current perspectives.

SARS-CoV-2 infection frequently causes neurological impairment in both adults and children. Recent publications have described significant aspects of the viral pathophysiology associated with neurological dysfunction. In theory, neurological manifestations following SARS-CoV-2 infection may be caused directly by the effects of the virus infecting the brain or indirectly by the local and systemic immune responses against the virus. Neurological manifestations can occur during the acute phase as well as in the post-acute phase of the infection. In this review, we discuss recent literature describing the association of nervous system disorders with COVID-19.

A Rare Case Report of Acute Neurologic Sequelae in a Young Primigravida With Recent COVID Pneumonia.

Post-infectious neurological sequelae, particularly in the pediatric population, are a rarely observed and under-explored complication of COVID-19. Few case reports exist detailing severe neurological sequelae following acute infection with COVID-19, such as encephalopathy, stroke, and coma. This case report details the diagnosis and treatment of a 16-year-old primigravida with no past medical history who presented to the emergency department with rhythmic tremors, urinary incontinence, and generalized weakness two weeks following initial COVID-19 diagnosis with admission for pneumonia and sepsis. Vital signs were remarkable for tachycardia and normotension. Shortly following admission, she experienced generalized tonic-clonic seizure activity. Neurologic evaluation was remarkable for electroencephalogram with frontally predominant generalized periodic discharges and magnetic resonance imaging of the head showing bilateral parafalcine restricted diffusion. Cerebrospinal fluid analysis and magnetic resonance imaging of the spine were unremarkable. The patient was ultimately diagnosed with reversible cerebral vasoconstriction syndrome and an anterior cerebral artery stroke. Throughout the patient's recovery, she demonstrated incoherent, delirious, and disinhibited behavior that resolved within several days. She was ultimately discharged to a skilled rehabilitation facility with follow-up in a neurology clinic.

Neurological and Neuropsychiatric Impacts of COVID-19 Pandemic.

BACKGROUND: Albeit primarily a disease of respiratory tract, the 2019 coronavirus infectious disease (COVID-19) has been found to have causal association with a plethora of neurological, neuropsychiatric and psychological effects. This review aims to analyze them with a discussion of evolving therapeutic recommendations. METHODS: PubMed and Google Scholar were searched from 1 January 2020 to 30 May 2020 with the following key terms: "COVID-19", "SARS-CoV-2", "pandemic", "neuro-COVID", "stroke-COVID", "epilepsy-COVID", "COVID-encephalopathy", "SARS-CoV-2-encephalitis", "SARS-CoV-2-rhabdomyolysis", "COVID-demyelinating disease", "neurological manifestations", "psychosocial manifestations", "treatment recommendations", "COVID-19 and therapeutic changes", "psychiatry", "marginalised", "telemedicine", "mental health", "quarantine", "infodemic" and "social media". A few newspaper reports related to COVID-19 and psychosocial impacts have also been added as per context. RESULTS: Neurological and neuropsychiatric manifestations of COVID-19 are abundant. Clinical features of both central and peripheral nervous system involvement are evident. These have been categorically analyzed briefly with literature support. Most of the psychological effects are secondary to pandemic-associated regulatory, socioeconomic and psychosocial changes. CONCLUSION: Neurological and neuropsychiatric manifestations of this disease are only beginning to unravel. This demands a wide index of suspicion for prompt diagnosis of SARS-CoV-2 to prevent further complications and mortality.

Les impacts neurologiques et neuropsychiatriques d'une infection à la COVID-19. CONTEXTE: Bien qu'il s'agisse principalement d'une maladie des voies respiratoires, la maladie infectieuse à coronavirus apparue en 2019 (COVID-19) s'est avérée avoir un lien de causalité avec une pléthore d'impacts d'ordre neurologique, neuropsychiatrique et psychologique. Cette étude entend donc analyser ces impacts tout en discutant l'évolution des recommandations thérapeutiques se rapportant à cette maladie. MÉTHODES: Les bases de données PubMed et Google Scholar ont été interrogées entre les 1er janvier et 30 mai 2020. Les termes clés suivants ont été utilisés : « COVID-19 ¼, « SRAS ­ CoV-2 ¼, « Pandémie ¼, « Neuro ­ COVID ¼, « AVC ­ COVID ¼, « Épilepsie ­ COVID ¼, « COVID ­ encéphalopathie ¼, « SRAS ­ CoV-2 ­ encéphalite ¼, « SRAS ­ CoV-2 ­ rhabdomyolyse ¼, « COVID ­ maladie démyélinisante ¼, « Manifestations neurologiques ¼, « Manifestations psychosociales ¼, « Recommandations thérapeutiques ¼, « COVID-19 et changement thérapeutiques ¼, « Psychiatrie ¼, « Marginalisés ¼, « Télémédecine ¼, « Santé mentale ¼, « Quarantaine ¼, « Infodémique ¼ et « Médias sociaux ¼. De plus, quelques articles de journaux relatifs à la pandémie de COVID-19 et à ses impacts psychosociaux ont également été ajoutés en fonction du contexte. RÉSULTATS: Il appert que les manifestations neurologiques et neuropsychiatriques des infections à la COVID-19 sont nombreuses. Les caractéristiques cliniques d'une implication des systèmes nerveux central et périphérique sautent désormais aux yeux. Ces caractéristiques ont fait l'objet d'une brève analyse systématique à l'aide de publications scientifiques. En outre, la plupart des impacts d'ordre psychologique de cette pandémie se sont révélés moins apparents que les changements réglementaires, socioéconomiques et psychosociaux. CONCLUSION: Les manifestations neurologiques et neuropsychiatriques de cette maladie ne font que commencer à être élucidées. Cela exige donc une capacité accrue de vigilance en vue d'un diagnostic rapide, et ce, afin de prévenir des complications additionnelles et une mortalité accrue.

Lactoferrin for Mental Health: Neuro-Redox Regulation and Neuroprotective Effects across the Blood-Brain Barrier with Special Reference to Neuro-COVID-19.

Overall mental health depends in part on the blood-brain barrier, which regulates nutrient transfer in-and-out of the brain and its central nervous system. Lactoferrin, an innate metal-transport protein, synthesized in the substantia nigra, particularly in dopaminergic neurons and activated microglia is vital for brain physiology. Lactoferrin rapidly crosses the blood-brain barrier via receptor-mediated transcytosis and accumulates in the brain capillary endothelial cells. Lactoferrin receptors are additionally present on glioma cells, brain micro-vessels, and neurons. As a regulator of neuro-redox, microglial lactoferrin is critical for protection/repair of neurons and healthy brain function. Iron imbalance and oxidative stress are common among patients with neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, dementia, depression, and multiple sclerosis. As an endogenous iron-chelator, lactoferrin prevents iron accumulation and dopamine depletion in Parkinson's disease patients. Oral lactoferrin supplementation could modulate the p-Akt/PTEN pathway, reduce Aß deposition, and ameliorate cognitive decline in Alzheimer's disease. Novel lactoferrin-based nano-therapeutics have emerged as effective drug-delivery systems for clinical management of neurodegenerative disorders. Recent emergence of the Coronavirus disease-2019 (COVID-19) pandemic, initially considered a respiratory illness, demonstrated a broader virulence spectrum with the ability to cross the blood-brain barrier and inflict a plethora of neuropathological manifestations in the brain - the Neuro-COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are widely reported in Parkinson's disease, Alzheimer's disease, dementia, and multiple sclerosis patients with aggravated clinical outcomes. Lactoferrin, credited with several neuroprotective benefits in the brain could serve as a potential adjuvant in the clinical management of Neuro-COVID-19.

Late neurological consequences of SARS-CoV-2 infection: New challenges for the neurologist.

Objective: In this study, a systematic review of the literature was performed to study the frequency of neurological symptoms and diseases in adult patients with COVID-19 that may be late consequences of SARS-CoV-2 infection. Methods: Relevant studies were identified through electronic explorations of Scopus, PubMed, and Google Scholar. We followed PRISMA guidelines. Data were collected from studies where the diagnosis of COVID-19 was confirmed and its late neurological consequences occurred at least 4 weeks after initial SARS-CoV-2 infection. Review articles were excluded from the study. Neurological manifestations were stratified based on frequency (above 5, 10, and 20%), where the number of studies and sample size were significant. Results: A total of 497 articles were identified for eligible content. This article provides relevant information from 45 studies involving 9,746 patients. Fatigue, cognitive problems, and smell and taste dysfunctions were the most frequently reported long-term neurological symptoms in patients with COVID-19. Other common neurological issues were paresthesia, headache, and dizziness. Conclusion: On a global scale of patients affected with COVID-19, prolonged neurological problems have become increasingly recognized and concerning. Our review might be an additional source of knowledge about potential long-term neurological impacts.

Golgi localization of SARS-CoV-2 spike protein and interaction with furin in cerebral COVID-19 microangiopathy: a clue to the central nervous system involvement?

In a neuropathological series of 20 COVID-19 cases, we analyzed six cases (three biopsies and three autopsies) with multiple foci predominantly affecting the white matter as shown by MRI. The cases presented with microhemorrhages evocative of small artery diseases. This COVID-19 associated cerebral microangiopathy (CCM) was characterized by perivascular changes: arterioles were surrounded by vacuolized tissue, clustered macrophages, large axonal swellings and a crown arrangement of aquaporin-4 immunoreactivity. There was evidence of blood-brain-barrier leakage. Fibrinoid necrosis, vascular occlusion, perivascular cuffing and demyelination were absent. While no viral particle or viral RNA was found in the brain, the SARS-CoV-2 spike protein was detected in the Golgi apparatus of brain endothelial cells where it closely associated with furin, a host protease known to play a key role in virus replication. Endothelial cells in culture were not permissive to SARS-CoV-2 replication. The distribution of the spike protein in brain endothelial cells differed from that observed in pneumocytes. In the latter, the diffuse cytoplasmic labeling suggested a complete replication cycle with viral release, notably through the lysosomal pathway. In contrast, in cerebral endothelial cells the excretion cycle was blocked in the Golgi apparatus. Interruption of the excretion cycle could explain the difficulty of SARS-CoV-2 to infect endothelial cells in vitro and to produce viral RNA in the brain. Specific metabolism of the virus in brain endothelial cells could weaken the cell walls and eventually lead to the characteristic lesions of COVID-19 associated cerebral microangiopathy. Furin as a modulator of vascular permeability could provide some clues for the control of late effects of microangiopathy.

Neuro-COVID-19 With or Without the Multisystem Inflammatory Syndrome (MIS-C): A Single-Center Study : COVID-19: Neurologic Manifestations in Children.

This study evaluates the range of neurological manifestation in children with COVID-19 (neuro-COVID-19) both with and without the multisystem inflammatory syndrome (MIS-C) and the persistence of symptoms after hospital discharge. The study was conducted as a prospective study of children and adolescents under 18 years of age who were admitted to a children's hospital for infectious diseases from January 2021 to January 2022. The children had no previous neurological or psychiatric disorders. Out of the 3021 patients evaluated, 232 were confirmed to have COVID-19 and 21 of these patients (9%) showed neurological manifestations associated with the virus. Of these 21 patients, 14 developed MIS-C, and 7 had neurological manifestations unrelated to MIS-C. There was no statistical difference regarding the neurological manifestations during hospitalization and outcomes between patients with neuro-COVID-19 who had or did not have MIS-C, except for seizures that occurred more frequently in patients with neuro-COVID-19 without MIS-C (p-value = 0.0263). One patient died, and 5 patients still had neurological or psychiatric manifestations at discharge, which persisted for up to 7 months. The study highlights that SARS-CoV-2 infection can affect the central and peripheral nervous system, particularly in children and adolescents with MIS-C, and that it is crucial to be vigilant for long-term adverse outcomes, as the neurological and psychiatric effects of COVID-19 in children are emerging during an important stage of brain development.

Time-dependent recovery of brain hypometabolism in neuro-COVID-19 patients.

PURPOSE: We evaluated brain metabolic dysfunctions and associations with neurological and biological parameters in acute, subacute and chronic COVID-19 phases to provide deeper insights into the pathophysiology of the disease. METHODS: Twenty-six patients with neurological symptoms (neuro-COVID-19) and [¹⁸F]FDG-PET were included. Seven patients were acute (< 1 month (m) after onset), 12 subacute (4 ≥ 1-m, 4 ≥ 2-m and 4 ≥ 3-m) and 7 with neuro-post-COVID-19 (3 ≥ 5-m and 4 ≥ 7-9-m). One patient was evaluated longitudinally (acute and 5-m). Brain hypo- and hypermetabolism were analysed at single-subject and group levels. Correlations between severity/extent of brain hypo- and hypermetabolism and biological (oxygen saturation and C-reactive protein) and clinical variables (global cognition and Body Mass Index) were assessed. RESULTS: The "fronto-insular cortex" emerged as the hypometabolic hallmark of neuro-COVID-19. Acute patients showed the most severe hypometabolism affecting several cortical regions. Three-m and 5-m patients showed a progressive reduction of hypometabolism, with limited frontal clusters. After 7-9 months, no brain hypometabolism was detected. The patient evaluated longitudinally showed a diffuse brain hypometabolism in the acute phase, almost recovered after 5 months. Brain hypometabolism correlated with cognitive dysfunction, low blood saturation and high inflammatory status. Hypermetabolism in the brainstem, cerebellum, hippocampus and amygdala persisted over time and correlated with inflammation status. CONCLUSION: Synergistic effects of systemic virus-mediated inflammation and transient hypoxia yield a dysfunction of the fronto-insular cortex, a signature of CNS involvement in neuro-COVID-19. This brain dysfunction is likely to be transient and almost reversible. The long-lasting brain hypermetabolism seems to reflect persistent inflammation processes.

Opsoclonus Myoclonus Ataxia Syndrome Due to SARS-CoV-2.

Opsoclonus myoclonus syndrome (OMS)/opsoclonus myoclonus ataxia syndrome (OMAS), also known as Kinsbourne's syndrome or 'dancing eyes-dancing feet' syndrome, is a rare central nervous system manifestation of COVID-19 but an increasing number of articles have reported patients in whom COVID-19 was complicated by OMS/OMAS. This narrative review aims at summarising and discussing current knowledge about the clinical presentation, diagnosis, treatment and outcome of SARS-CoV-2 associated OMS/OMAS. Altogether, 29 articles reporting 45 patients with SARS-CoV-2 associated OMS/OMAS were retrieved. Their ages ranged from 2 to 88 years. Three patients were children and the remainder adults. Gender was male in 32 patients and female in 13 patients. Opsoclonus was described in 29 patients, which was associated with myoclonus in 28 cases. Myoclonus was described in 43 patients, which was associated with opsoclonus and ataxia in 18 patients. Cerebral magnetic resonance imaging and cerebrospinal fluid investigations were not informative in the majority of the cases. OMS/OMAS was treated with steroids in 28 patients and with intravenous immunoglobulin (IVIG) in 15 patients. Clonazepam was given to 18 patients, levetiracetam to 13 patients, and sodium valproate to eight patients. Complete recovery was achieved in 12 cases and incomplete recovery in 22 cases. Diagnosing SARS-CoV-2 associated OMS/OMAS requires extensive neurological work up and exclusion of various differentials. SARS-CoV-2 associated OMS/OMAS may not always present with the full spectrum of manifestations but as an abortive syndrome. OMS/OMAS should not be missed as it usually responds favourably to steroids or IVIG.

Neurological Manifestations of Non-Severe COVID-19-A Multidirectional Approach.

COVID-19 remains a significant clinical issue worldwide, with frequent neurological manifestations. In this study, the authors combine data obtained from the patient's medical history, physical examinations, and additional test results in the pursuit of any clinically relevant connections. Fifty-eight adult patients hospitalized in the Department of Neurology and Infectiology over a five-months period were retrospectively enrolled in this study. On admission, all patients included in this study were classified as mild or moderate COVID-19 cases, according to the World Health Organization (WHO) guidelines. Laboratory tests, Electroencephalography (EEG), and Magnetic Resonance Imaging (MRI) were performed. There was no statistically significant difference in the Neutrophil-Lymphocyte Ratio (NLR), C-reactive protein (CRP), and Interleukin 6 (IL-6) in patients who reported to the hospital within a week from the symptoms' onset and in those who reported later. In total, 49.06% of patients with eligible EEG recordings presented abnormal brain activity, while 27.59% of the study population had COVID-19-associated MRI findings. EEG and MRI abnormality occurrence did not correlate with the incidence of mild neurological symptoms (headache, olfactory, and gustatory disorders) of the SARS-CoV-2 infection. In three patients in this study population, unprovoked generalized epileptic seizures occurred for the first time in their life. Non-severe SARS-CoV-2 infection causes functional and structural abnormalities within the central nervous system. Brain microhemorrhages are frequently present in non-severe COVID-19 patients. There is no significant association between mild neurological symptoms of COVID-19 and additional test abnormalities. The time from SARS-CoV-2 infection's onset to hospital admission does not seem to influence the prognostic value of CRP, IL-6, and NLR in non-severe COVID-19. Mild-to-moderate SARS-CoV-2 infection can be a trigger factor for epilepsy and epileptic seizures.

Neurovisual Manifestations in Children with Mild COVID-19: An Association to Remember.

Neurovisual involvement has been reported in a number of patients with severe SARS-CoV-2 disease (COVID-19), mainly among adult patients. In children, such involvement has been reported in rare cases, often in those presenting with severe forms of COVID-19. The aim of this work is to explore the association between mild COVID-19 and neurovisual manifestations. We report the cases of three previously healthy children who developed neurovisual manifestations following mild acute COVID-19, analysing the clinical phenotype, the latency between the onset of acute COVID-19 and neurovisual involvement, and the kinetic of resolution. Our patients developed different clinical patterns, including visual impairment and ophthalmoplegia. In two cases, these clinical features occurred during acute COVID-19, while in the third patient their development was delayed after 10 days from disease onset. Furthermore, the dynamics of resolution were different, with one patient showing remission after 24 hours, the second after 30 days, and the third showing persistence of the strabismus after 2 months of follow-up. The spreading of COVID-19 among the paediatric population will probably lead to an increase of atypical disease forms, including those presenting with neurovisual involvement. Therefore, a better knowledge of the pathogenic and clinical features of these manifestations is warranted.

Underlying Causes and Treatment Modalities for Neurological Deficits in COVID-19 and Long-COVID.

With reports of diverse neurological deficits in the acute phase of COVID-19, there is a surge in neurological findings in Long-COVID─a protracted phase of SARS-CoV-2 infection. Very little is known regarding the pathogenic mechanisms of Neuro-COVID in the above two settings in the current pandemic. Herein, we hint toward the possible molecular mechanism that can contribute to the signs and symptoms of patients with neurological deficits and possible treatment and prevention modalities in the acute and chronic phases of COVID-19.

Neuro-Axonal Damage and Alteration of Blood-Brain Barrier Integrity in COVID-19 Patients.

Neurofilament light chain (NfL) is a specific biomarker of neuro-axonal damage. Matrix metalloproteinases (MMPs) are zinc-dependent enzymes involved in blood-brain barrier (BBB) integrity. We explored neuro-axonal damage, alteration of BBB integrity and SARS-CoV-2 RNA presence in COVID-19 patients with severe neurological symptoms (neuro-COVID) as well as neuro-axonal damage in COVID-19 patients without severe neurological symptoms according to disease severity and after recovery, comparing the obtained findings with healthy donors (HD). Overall, COVID-19 patients (n = 55) showed higher plasma NfL levels compared to HD (n = 31) (p < 0.0001), especially those who developed ARDS (n = 28) (p = 0.0005). After recovery, plasma NfL levels were still higher in ARDS patients compared to HD (p = 0.0037). In neuro-COVID patients (n = 12), higher CSF and plasma NfL, and CSF MMP-2 levels in ARDS than non-ARDS group were observed (p = 0.0357, p = 0.0346 and p = 0.0303, respectively). SARS-CoV-2 RNA was detected in four CSF and two plasma samples. SARS-CoV-2 RNA detection was not associated to increased CSF NfL and MMP levels. During COVID-19, ARDS could be associated to CNS damage and alteration of BBB integrity in the absence of SARS-CoV-2 RNA detection in CSF or blood. CNS damage was still detectable after discharge in blood of COVID-19 patients who developed ARDS during hospitalization.

DJ-1-Nrf2 axis is activated upon murine ß-coronavirus infection in the CNS.

Coronaviruses have emerged as alarming pathogens owing to their inherent ability of genetic variation and cross-species transmission. Coronavirus infection burdens the endoplasmic reticulum (ER.), causes reactive oxygen species production and induces host stress responses, including unfolded protein response (UPR) and antioxidant system. In this study, we have employed a neurotropic murine ß-coronavirus (M-CoV) infection in the Central Nervous System (CNS) of experimental mice model to study the role of host stress responses mediated by interplay of DJ-1 and XBP1. DJ-1 is an antioxidant molecule with established functions in neurodegeneration. However, its regulation in virus-induced cellular stress response is less explored. Our study showed that M-CoV infection activated the glial cells and induced antioxidant and UPR genes during the acute stage when the viral titer peaks. As the virus particles decreased and acute neuroinflammation diminished at day ten p.i., a significant up-regulation in UPR responsive XBP1, antioxidant DJ-1, and downstream signaling molecules, including Nrf2, was recorded in the brain tissues. Additionally, preliminary in silico analysis of the binding between the DJ-1 promoter and a positively charged groove of XBP1 is also investigated, thus hinting at a mechanism behind the upregulation of DJ-1 during MHV-infection. The current study thus attempts to elucidate a novel interplay between the antioxidant system and UPR in the outcome of coronavirus infection.

SARS-CoV-2 infection in multiple sclerosis patients: interaction with treatments, adjuvant therapies, and vaccines against COVID-19.

The SARS-CoV-2 pandemic has raised particular concern for people with Multiple Sclerosis, as these people are believed to be at increased risk of infection, especially those being treated with disease-modifying therapies. Therefore, the objective of this review was to describe how COVID-19 affects people who suffer from Multiple Sclerosis, evaluating the risk they have of suffering an infection by this virus, according to the therapy to which they are subjected as well as the immune response of these patients both to infection and vaccines and the neurological consequences that the virus can have in the long term. The results regarding the increased risk of infection due to treatment are contradictory. B-cell depletion therapies may cause patients to have a lower probability of generating a detectable neutralizing antibody titer. However, more studies are needed to help understand how this virus works, paying special attention to long COVID and the neurological symptoms that it causes.