COVID-19 and its effects on neurological functions.

Ever since the first reported case series on SARS-CoV-2-induced neurological manifestation in Wuhan, China in April 2020, various studies reporting similar as well as diverse symptoms of COVID-19 infection relating to the nervous system were published. Since then, scientists started to uncover the mechanism as well as pathophysiological impacts it has on the current understanding of the disease. SARS-CoV-2 binds to the ACE2 receptor which is present in certain parts of the body which are responsible for regulating blood pressure and inflammation in a healthy system. Presence of the receptor in the nasal and oral cavity, brain, and blood allows entry of the virus into the body and cause neurological complications. The peripheral and central nervous system could also be invaded directly in the neurogenic or hematogenous pathways, or indirectly through overstimulation of the immune system by cytokines which may lead to autoimmune diseases. Other neurological implications such as hypoxia, anosmia, dysgeusia, meningitis, encephalitis, and seizures are important symptoms presented clinically in COVID-19 patients with or without the common symptoms of the disease. Further, patients with higher severity of the SARS-CoV-2 infection are also at risk of retaining some neurological complications in the long-run. Treatment of such severe hyperinflammatory conditions will also be discussed, as well as the risks they may pose to the progression of the disease. For this review, articles pertaining information on the neurological manifestation of SARS-CoV-2 infection were gathered from PubMed and Google Scholar using the search keywords "SARS-CoV-2", "COVID-19", and "neurological dysfunction". The findings of the search were filtered, and relevant information were included.

Are we sure that the neurological impact of COVID 19 in childhood has not been underestimated?

BACKGROUND: Presently, it is known that, even if less frequently than in adults, children can develop a severe new coronavirus disease 2019 (COVID-19). Children with the SARS-CoV-2 infection can have neurological signs and symptoms of disease more frequently than previously thought, revealing the involvement of the central nervous system, the peripheral nervous system, or both. Aim of this manuscript is to highlight the neurologic complications associated with SARS-CoV-2 among pediatric patients with COVID-19, suggesting when to monitor carefully neurologic development. MAIN FINDINGS: Children with a severe chronic underlying disease, infants and toddlers and those who develop the so-called multisystem inflammatory syndrome (MIS-C) are those with the highest incidence of neurological complications. Fortunately, in most of the cases, neurological manifestations, mainly represented by headache and anosmia, are mild and transient and do not significantly complicate the COVID-19 course. However, in some cases, very severe clinical problems associated with relevant alterations of neuroimaging, electroencephalography, nerve conduction studies and electromyography findings can develop. Generally, almost all the children with COVID-19 and neurological manifestations till now described have made a complete recovery, although in some cases this has occurred after several weeks of treatment. Moreover, COVID-19 infection during pregnancy has been found associated with an increased risk of obstetric complications that can lead to neurological acute and long-term manifestations in neonates. CONCLUSIONS: Based on data showing the neurologic impact of COVID-19 in pediatric age, we suggest monitoring neurological development a few months after healing in pediatric patients who have presented MIS-C, seizures or other neurological manifestations and in children of pregnant women with COVID-19 in order to detect overt and subtle deficits.

[Neurology and COVID-19: Case Series of Neurological Complications in 96 patients Admitted at a University Hospital]. / Neurología hospitalaria y COVID-19: serie de 96 pacientes evaluados en un hospital universitario.

BACKGROUND: There are multisystemic consequences secondary to SARS- CoV-2 infection. AIM: To characterize neurological complications in patients admitted due to SARS-CoV-2 infection. METHODS: Review of medical records of patients aged over 15 years with COVID-19 evaluated by the neurology team between April and August 2020 at a university hospital. Severity of the infection, referral reasons, neurological diagnoses and laboratory results were registered. The diagnoses were defined by consensus among the members of the hospital neurology group. Cerebrovascular and inflammatory diseases of the central and peripheral nervous system were defined as "probably associated" or "possibly associated" to COVID-19. RESULTS: Ninety-six patients had at least 1 new neu- rological complication. 74% were admitted due to pneumonia and 20% due to a neurological disease. The most common reasons for neurological referral were impaired consciousness (39%), focal neurological deficit (24%), headache (9%) and seizures (5%). The most relevant neurological diagnoses were delirium in 48 patients, stroke in 24, critical illness polyneuropathy and myopathy in 17, seizures in 14, brachial plexopathy in 3, compressive neuropathies in 5, encephalitis in 1, possible vasculitis in 1 and Guillain-Barré syndrome in 1. Stroke and epilepsy were associated with increased length of hospital stay, but without differences in mortality. CONCLUSIONS: The spectrum of neurological complications of COVID-19 is wide. There are clinical entities typical of critically ill patients and also diseases associated directly and indirectly with the SARS-CoV2 infection.

NEUROLOGICAL DYSFUNCTION ASSOCIATED WITH COVID-19. / Disfunção neurológica associada à COVID-19.

COVID-19 was declared a pandemic by the World Health Organization on March 11, 2020. The clinical presentation is predominantly respiratory symptoms; however, in the current literature, several neurological manifestations associated with SARS-CoV-2 infection have been described. The authors present the clinical case of a 45-year-old man hospitalized for pneumonia with a positive test result for SARS-CoV-2, without a neurological history, who, on the sixteenth day of hospitalization, presented a sudden change in his state of consciousness accompanied by conjugated right gaze deviation and myoclonus of the face and thoracic region to the left, followed by generalized tonic-clonic seizures associated with persistent left hemiparesis. The present study highlights a positive RT-PCR test for SARS-CoV-2 in cerebrospinal fluid. The patient progressed with gradual improvement, and the outcome was favorable.

A COVID-19 foi declarada pandemia pela Organização Mundial de Saúde no dia 11 de março de 2020. O quadro clínico apresenta predominantemente sintomatologia respiratória, no entanto, na literatura atual, têm sido descritas diversas manifestações neurológicas associadas à infeção por SARS-CoV-2. Os autores apresentam o caso clínico de um homem de 45 anos internado por pneumonia com resultado positivo para SARS-CoV-2, sem antecedentes neurológicos, que, ao décimo sexto dia de internamento, apresentou alteração súbita do estado de consciência acompanhada de desvio conjugado do olhar para a direita e mioclonias da face e da região torácica à esquerda, seguidas de crise convulsiva tônico-clônica generalizada, associadas à hemiparesia esquerda persistente. Do estudo realizado salienta-se a existência de RT-PCR para SARS-CoV-2 no líquido cefalorraquidiano positiva. O doente apresentou evolução clínica com melhoria gradual, tendo o desfecho sido favorável.

COVID-19-Associated Cerebral White Matter Injury in a Newborn Infant With Afebrile Seizure.

Coronavirus disease 2019 (COVID-19) symptoms in newborn infants are incompletely described. We present the first case of neuroradiologic abnormality associated with COVID-19 in a newborn infant with afebrile seizure. This case underlines the possible neurologic involvement of severe acute respiratory syndrome coronavirus 2 in this age group.

COVID-19 as a Cause of Acute Neonatal Encephalitis and Cerebral Cytotoxic Edema.

The majority of coronavirus disease 2019 (COVID-19) have been confirmed in adults, with only a few reported cases in children. In the pediatric population, COVID-19 infection appears to be often unremarkable or associated with mild respiratory symptoms. Little is known about neurologic complications related to COVID-19 in newborns. We present a case of severe encephalitis with cytotoxic brain edema in a newborn with COVID-19.

Disfunção neurológica associada à COVID-19 / Neurological dysfunction associated with covid-19

RESUMO A COVID-19 foi declarada pandemia pela Organização Mundial de Saúde no dia 11 de março de 2020. O quadro clínico apresenta predominantemente sintomatologia respiratória, no entanto, na literatura atual, têm sido descritas diversas manifestações neurológicas associadas à infeção por SARS-CoV-2. Os autores apresentam o caso clínico de um homem de 45 anos internado por pneumonia com resultado positivo para SARS-CoV-2, sem antecedentes neurológicos, que, ao décimo sexto dia de internamento, apresentou alteração súbita do estado de consciência acompanhada de desvio conjugado do olhar para a direita e mioclonias da face e da região torácica à esquerda, seguidas de crise convulsiva tônico-clônica generalizada, associadas à hemiparesia esquerda persistente. Do estudo realizado salienta-se a existência de RT-PCR para SARS-CoV-2 no líquido cefalorraquidiano positiva. O doente apresentou evolução clínica com melhoria gradual, tendo o desfecho sido favorável.

ABSTRACT COVID-19 was declared a pandemic by the World Health Organization on March 11, 2020. The clinical presentation is predominantly respiratory symptoms; however, in the current literature, several neurological manifestations associated with SARS-CoV-2 infection have been described. The authors present the clinical case of a 45-year-old man hospitalized for pneumonia with a positive test result for SARS-CoV-2, without a neurological history, who, on the sixteenth day of hospitalization, presented a sudden change in his state of consciousness accompanied by conjugated right gaze deviation and myoclonus of the face and thoracic region to the left, followed by generalized tonic-clonic seizures associated with persistent left hemiparesis. The present study highlights a positive RT-PCR test for SARS-CoV-2 in cerebrospinal fluid. The patient progressed with gradual improvement, and the outcome was favorable.

Neurología hospitalaria y COVID-19: serie de 96 pacientes evaluados en un hospital universitario / Neurology and COVID-19: Case Series of Neurological Complications in 96 patients Admitted at a University Hospital

Background: There are multisystemic consequences secondary to SARS- CoV-2 infection. Aim: To characterize neurological complications in patients admitted due to SARS-CoV-2 infection. Methods: Review of medical records of patients aged over 15 years with COVID-19 evaluated by the neurology team between April and August 2020 at a university hospital. Severity of the infection, referral reasons, neurological diagnoses and laboratory results were registered. The diagnoses were defined by consensus among the members of the hospital neurology group. Cerebrovascular and inflammatory diseases of the central and peripheral nervous system were defined as "probably associated" or "possibly associated" to COVID-19. Results: Ninety-six patients had at least 1 new neu- rological complication. 74% were admitted due to pneumonia and 20% due to a neurological disease. The most common reasons for neurological referral were impaired consciousness (39%), focal neurological deficit (24%), headache (9%) and seizures (5%). The most relevant neurological diagnoses were delirium in 48 patients, stroke in 24, critical illness polyneuropathy and myopathy in 17, seizures in 14, brachial plexopathy in 3, compressive neuropathies in 5, encephalitis in 1, possible vasculitis in 1 and Guillain-Barré syndrome in 1. Stroke and epilepsy were associated with increased length of hospital stay, but without differences in mortality. Conclusions: The spectrum of neurological complications of COVID-19 is wide. There are clinical entities typical of critically ill patients and also diseases associated directly and indirectly with the SARS-CoV2 infection.

Detection of SARS-coronavirus-2 in the central nervous system of patients with severe acute respiratory syndrome and seizures.

This study was designed to evaluate whether severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can directly target the central nervous system (CNS). We present four patients suffering from the loss of consciousness and seizure during the clinical course of COVID-19 infection. In addition to positive nasopharyngeal swab tests, SARS-CoV-2 has been detected in their cerebrospinal fluid. This report indicates the neuroinvasive potential of SARS-CoV-2, suggesting the ability of this virus to spread from the respiratory tract to the CNS.

CNS implications of COVID-19: a comprehensive review.

COVID-19 was first reported in December 2019 in the Wuhan city of China, and since then it has spread worldwide taking a heavy toll on human life and economy. COVID-19 infection is commonly associated with symptoms like coughing, fever, and shortness of breath, besides, the reports of muscle pain, anosmia, hyposmia, and loss of taste are becoming evident. Recent reports suggest the pathogenic invasion of the SARS-CoV-2 into the CNS, that could thereby result in devastating long term complications, primarily because some of these complications may go unnoticed for a long time. Evidence suggest that the virus could enter the CNS through angiotensin-converting enzyme-2 (ACE-2) receptor, neuronal transport, haematogenous route, and nasal route via olfactory bulb, cribriform plate, and propagates through trans-synaptic signalling, and shows retrograde movement into the CNS along nerve fiber. COVID-19 induces CNS inflammation and neurological degenerative damage through a diverse mechanism which includes ACE-2 receptor damage, cytokine-associated injury or cytokine storm syndrome, secondary hypoxia, demyelination, blood-brain barrier disruption, neurodegeneration, and neuroinflammation. Viral invasion into the CNS has been reported to show association with complications like Parkinsonism, Alzheimer's disorder, meningitis, encephalopathy, anosmia, hyposmia, anxiety, depression, psychiatric symptoms, seizures, stroke, etc. This review provides a detailed discussion of the CNS pathogenesis of COVID-19. Authors conclude that the COVID-19 cannot just be considered as a disorder of the pulmonary or peripheral system, rather it has a significant CNS involvement. Therefore, CNS aspects of the COVID-19 should be monitored very closely to prevent long term CNS complications, even after the patient has recovered from COVID-19.

Human Herpesvirus 6 Encephalitis in Immunocompetent and Immunocompromised Hosts.

OBJECTIVE: The aim of this study was to analyze the clinical, radiologic, and biological features associated with human herpesvirus 6 (HHV-6) encephalitis in immunocompetent and immunocompromised hosts to establish which clinical settings should prompt HHV-6 testing. METHODS: We performed a retrospective research in the virology database of Fondazione IRCCS Policlinico San Matteo (Pavia, Italy) for all patients who tested positive for HHV-6 DNA in the CSF and/or in blood from January 2008 to September 2018 and separately assessed the number of patients meeting the criteria for HHV-6 encephalitis in the group of immunocompetent and immunocompromised hosts. RESULTS: Of the 926 patients tested for HHV-6 during the period of interest, 45 met the study criteria. Among immunocompetent hosts (n = 17), HHV-6 encephalitis was diagnosed to 4 infants or children presenting with seizures or mild encephalopathy during primary HHV-6 infection (CSF/blood replication ratio <<1 in all cases). Among immunocompromised hosts (n = 28), HHV-6 encephalitis was diagnosed to 7 adolescents/adults with hematologic conditions presenting with altered mental status (7/7), seizures (3/7), vigilance impairment (3/7), behavioral changes (2/7), hyponatremia (2/7), and anterograde amnesia (1/7). Initial brain MRI was altered only in 2 patients, but 6 of the 7 had a CSF/blood replication ratio >1. CONCLUSIONS: The detection of a CSF/blood replication ratio >1 represented a specific feature of immunocompromised patients with HHV-6 encephalitis and could be of special help to establish a diagnosis of HHV-6 encephalitis in hematopoietic stem cell transplant recipients lacking radiologic evidence of limbic involvement.

A Review on the Neurological Manifestations of COVID-19 Infection: a Mechanistic View.

There is increasing evidence of neurological manifestations and complications in patients with coronavirus disease 19 (COVID-19). More than one-quarter of patients with COVID-19 developed various neurological symptoms, ranging from headache and dizziness to more serious medical conditions, such as seizures and stroke. The recent investigations introduced hyposmia as a potential early criterion of infection with COVID-19. Despite the high mortality and morbidity rate of COVID-19, its exact mechanism of action and pathogenesis is not well characterized. The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could interact with angiotensin-converting enzyme 2 (ACE2) in the endothelial, neural, and glial cells. In the present study, we reviewed the most common neurological manifestations and complications that emerged after infection with the SARS-CoV-2 and discussed their possible relation to the expression and function of ACE2. Comprehensive and detailed studies are required to uncover how this virus invades the neural system as well as other critical organs.

Multiple Neuroinvasive Pathways in COVID-19.

COVID-19 is a highly infectious viral disease caused by the novel coronavirus SARS-CoV-2. While it was initially regarded as a strictly respiratory illness, the impact of COVID-19 on multiple organs is increasingly recognized. The brain is among the targets of COVID-19, and it can be impacted in multiple ways, both directly and indirectly. Direct brain infection by SARS-CoV-2 may occur via axonal transport via the olfactory nerve, eventually infecting the olfactory cortex and other structures in the temporal lobe, and potentially the brain stem. A hematogenous route, which involves viral crossing of blood-brain barrier, is also possible. Secondary mechanisms involve hypoxia due to respiratory failure, as well as aberrant immune response leading to various forms of encephalopathy, white matter damage, and abnormal blood clotting resulting in stroke. Multiple neurological symptoms of COVID-19 have been described. These involve anosmia/ageusia, headaches, seizures, mental confusion and delirium, and coma. There is a growing concern that in a number of patients, long-term or perhaps even permanent cognitive impairment will persist well after the recovery from acute illness. Furthermore, COVID-19 survivors may be at increased risk for developing neurodegenerative diseases years or decades later. Since COVID-19 is a new disease, it will take months or even years to characterize the exact nature, scope, and temporal extent of its long-term neurocognitive sequelae. To that end, rigorous and systematic longitudinal follow-up will be required. For this effort to succeed, appropriate protocols and patient registries should be developed and put in place without delay now.

Neonatal Rotavirus-Associated Leukoencephalopathy Is One of the Main Causes of Fifth-Day Fits.

Our province recently experienced an outbreak of neonatal rotavirus-associated leukoencephalopathy. This study aimed to verify whether rotavirus-associated leukoencephalopathy constituted fifth-day fits, which prevailed in Europe and Australia between the 1970s and mid-1980s. Of 118 full-term neonates who were admitted between 2008 and 2017 due to seizures, those who fulfilled the following criteria for fifth-day fits were included: healthy full-term neonates prior to seizures; absence of perinatal asphyxia; seizure onset during 4-6 days of age; and no known cause of neonatal seizures. Overall, 54 patients (45.8%) met the criteria for fifth-day fits. Of them, 44 patients (81.5%) also had rotavirus-associated leukoencephalopathy. The mean annual incidence of fifth-day fits was 5.4 cases, which peaked in 2012-2013 (13 cases) and became zero in 2017. Fifth-day fits with rotavirus-associated leukoencephalopathy accounted for 37.2% of neonatal seizures, which peaked at 70.6% in 2012, and gradually reduced to zero in 2017. Concordance of clinical features between rotavirus-associated leukoencephalopathy and fifth-day fits and their epidemic-like features suggest that rotavirus-associated leukoencephalopathy is one of the main causes of fifth-day fits.

New-Onset Seizures in Three COVID-19 Patients: A Case Series.

SUMMARY: Neurological manifestations of coronavirus disease 2019 most commonly present in severe cases and range from mild complications, such as headache and dizziness, to severe complications, such as encephalopathy and acute cerebrovascular disease. Seizures, however, are an underreported neurological manifestation of this disease. We present three critically ill coronavirus disease 2019 patients with EEG monitoring who developed new-onset seizures and encephalopathy up to three-and-a-half weeks after symptom onset. There are several speculated etiologies for the development of new-onset seizures; however, the pathogenic mechanism remains unknown. Testing of coronavirus disease 2019 in the cerebrospinal fluid in addition to extensive research on neurological manifestations is warranted.

Neurological, neuropsychiatric and neurodevelopmental complications of COVID-19.

Although COVID-19 is predominantly a respiratory disease, it is known to affect multiple organ systems. In this article, we highlight the impact of SARS-CoV-2 (the coronavirus causing COVID-19) on the central nervous system as there is an urgent need to understand the longitudinal impacts of COVID-19 on brain function, behaviour and cognition. Furthermore, we address the possibility of intergenerational impacts of COVID-19 on the brain, potentially via both maternal and paternal routes. Evidence from preclinical models of earlier coronaviruses has shown direct viral infiltration across the blood-brain barrier and indirect secondary effects due to other organ pathology and inflammation. In the most severely ill patients with pneumonia requiring intensive care, there appears to be additional severe inflammatory response and associated thrombophilia with widespread organ damage, including the brain. Maternal viral (and other) infections during pregnancy can affect the offspring, with greater incidence of neurodevelopmental disorders, such as autism, schizophrenia and epilepsy. Available reports suggest possible vertical transmission of SARS-CoV-2, although longitudinal cohort studies of such offspring are needed. The impact of paternal infection on the offspring and intergenerational effects should also be considered. Research targeted at mechanistic insights into all aspects of pathogenesis, including neurological, neuropsychiatric and haematological systems alongside pulmonary pathology, will be critical in informing future therapeutic approaches. With these future challenges in mind, we highlight the importance of national and international collaborative efforts to gather the required clinical and preclinical data to effectively address the possible long-term sequelae of this global pandemic, particularly with respect to the brain and mental health.

Neurological Complications Of Hand, Foot And Mouth Disease In Children: A Review.

BACKGROUND: Hand-Foot-and-Mouth disease (HFMD) is a viral illness commonly seen in young children, characterized by fever, vomiting, ulcerative lesions in oral mucosa, and vesicles on hands and feet. The early symptoms resolve but sometimes, it leads to more harsh neurological complications and even death. Therefore, the objective of this review was set to provide an overview of the symptoms, pathogenic agents, and treatment of neurological complications associated with HFMD. METHODS: We reviewed literature from PubMed and Science Direct covering at least one of our objectives from inception to 4th March 2018. RESULTS: This review represents 6 countries including China, Vietnam, Cambodia, South Korea, Taiwan, and Australia. Fifteen studies with a total of 1043 patients were included. The majority of HFMD cases with neurological complications were reported in China, predominance in boys as compared to girls, with 97% cases under 15 years of age. Meningoencephalitis and brainstem encephalitis contributed 70% of all neurological complications related to HFMD. Human Enterovirus71 genotype C, especially C4a was a causative agent associated with severe complications. Among symptoms, fever, vomiting, myoclonic jerks or seizure, headache, convulsion, and rashes were reported in almost all neurological complications. The common and supportive treatments were the administration of intravenous immunoglobulin and glucocorticoid therapies. CONCLUSIONS: Early detection and appropriate treatment of severe neurological complications can minimize the risk of adverse health outcomes. Evidence based clinical practice guidelines for early detection and treatment would be significant in the management of these devastating neurological complications.

EEG findings and clinical prognostic factors associated with mortality in a prospective cohort of inpatients with COVID-19.

PURPOSE: Our objective is to describe the most prevalent electroencephalographic findings in COVID-19 hospitalized patients, and to determine possible predictors of mortality including EEG and clinical variables. METHODS: A multicentric prospective observational study in patients with COVID-19 requiring EEG during hospitalization. RESULTS: We found 94 EEG from 62 patients (55 % men, mean age 59.7 ± 17.8 years) were analyzed. Most frequent comorbidity was cardiac (52 %), followed by metabolic (45 %) and CNS disease (39 %). Patients required ICU management by 60 %, with a mortality of 27 % in the whole cohort. The most frequent EEG finding was generalized continuous slow-wave activity (66 %). Epileptic activity was observed in 19 % including non-convulsive status epilepticus, seizures and interictal epileptiform discharges. Periodic patterns were observed in 3 patients (3.2 %). Multivariate analysis found that cancer comorbidity and requiring an EEG during the third week of evolution portended a higher risk of mortality CONCLUSION: We observed that the most prevalent EEG finding in this cohort was generalized continuous slow-wave activity, while epileptic activity was observed in less than 20 % of the cases. Mortality risk factors were comorbidity with cancer and requiring an EEG during the third week of evolution, possibly related to the hyperinflammatory state.