• Pathogenesis Underlying Neurological Manifestations of Long COVID Syndrome and Potential Therapeutics – “Neurological manifestations of long COVID exist as a major complication of COVID-19 post-infection, affecting up to one third of patients with COVID symptoms lasting longer than four weeks. Although SARS-CoV-2 neurotropism, viral-induced coagulopathy, endothelial disruption, systemic inflammation, cytokine overactivation and neuroglial dysfunction have been hypothesized as mechanisms associated with pathogenesis of long COVID condition, further clinical, neuropathological, and experimental models are needed to address many of the unknown questions about pathogenesis. Similarly, current and potential therapeutics to target these hypothesized pathogenic mechanisms using anti-inflammatory, anti-viral, and neuro-regenerative agents are potentially able to reverse neurological sequelae but still require well designed clinical trials studies to prove their efficacy.”
  • The SARS-CoV-2 main protease induces neurotoxic TDP-43 cleavage and aggregates – “SARS-CoV-2 infection results in multilineage neural cell dysregulation, decreased new neuron generation, and a reduction in overall brain size in patients, even those with mild respiratory COVID-19.2 The infectivity of SARS-CoV-2 in neural cells has been confirmed in human neural progenitor cells, brain organoids and nonhuman primates.3,9,10 Overall, there is a critical need to determine which viral factors contribute to central nervous system (CNS) disorders. Hence, our identification of Nsp5 as cytotoxic towards neuroblasts and glial cells demonstrates a direct killing effect of SARS-CoV-2 infection on neuronal cells through TDP-43 cleavage, which may lead to further CNS dysfunction, including neuroinflammation. Nevertheless, the effects of TDP-43 cleavage by the viral protease Nsp5 on host neural damage still need to be further confirmed in organoids, animal models, and infected patients.”
  • Dissecting the Molecular Mechanisms Surrounding Post-COVID-19 Syndrome and Neurological Features – “Post-COVID-19 syndrome shows high prevalence and multisystem involvement among survivors. The syndrome overlaps with ME/CFS and previous post-SARS syndromes. Nonetheless, a lack of consensus on the characterization of PCS needs to be addressed. The syndrome is likely to involve many immunological processes. Manifestations of PCS may be partially explained by a neuroinflammatory process involving the activation of astrocytes and microglia. The hypothalamus and its network are implicated in the ongoing neuroinflammation and might be a major cause of some of the persistent symptoms. As vaccine rollout increases and the world is looking into a post-COVID era, developing accurate laboratory and clinical guidelines for PCS is crucial to define and identify PCS. Long-term specialized brain imaging and glial marker studies are urgently needed to determine whether PCS exhibits a specific imprint in the CNS. There are several clinical trials on various anti-inflammatory agents—such as corticosteroids—currently being performed, and these studies may help to improve our understanding—especially if they are aided by extensive measurements of the relevant biomarkers.”
  • SARS-CoV-2 promotes microglial synapse elimination in human brain organoids – “Neuropsychiatric manifestations are common in both the acute and post-acute phase of SARS-CoV-2 infection, but the mechanisms of these effects are unknown. In a newly established brain organoid model with innately developing microglia, we demonstrate that SARS-CoV-2 infection initiate neuronal cell death and cause a loss of post-synaptic termini.”
  • Longitudinal evaluation of neurologic-post acute sequelae SARS-CoV-2 infection symptoms – “Early in the neuro-PASC syndrome, fatigue and headache are the most commonly reported symptoms. At 6 months, memory impairment and decreased concentration were most prominent. Only one-third of participants had completed resolution of neuro-PASC at 6 months, although persistent symptoms trended toward improvement at follow-up.”
  • Neurological complications of COVID-19 in children and the associated immunological responses – “Neonates and children infected with SARS-CoV-2 or COVID-19 infection are thought to be at higher risk of inflammatory responses leading to injury and critical illness. Examination of the peripheral blood may be important for identifying seriously ill patients or patients with severe COVID-19 disease as well as patients with MIS-C. This peripheral blood examination is important as it can allow the investigators to understand the values of neutrophil toxic granulations, burr cells, and schistocytes, and cytokines. Several children have indicated COVID-19 mediated complications including stroke, and encephalopathy, suggesting that COVID-19 can impose a severe impact on children. This severe COVID-19 disease in children is associated with an inflammatory response mediated by the immune system, associated with MIS-C. Considering all these aspects, cytokine storms should be given primary importance while developing the treatment and preventive options against COVID-19 in children.”
  • More than 50 long-term effects of COVID-19: a systematic review and meta-analysis – “This systematic review and meta-analysis shows that 80% (95% CI 65–92) of individuals with a confirmed COVID-19 diagnosis continue to have at least one overall effect beyond 2 weeks following acute infection. In total, 55 effects, including symptoms, signs, and laboratory parameters, were identified, with fatigue, anosmia, lung dysfunction, abnormal chest X-ray/CT, and neurological disorders being the most common.”
  • SARS-CoV-2 Spike Protein Accumulation in the Skull-MeningesBrain Axis: Potential Implications for Long-Term Neurological Complications in post-COVID-19 – “The accumulation of SARS-CoV-2 spike protein in the skull-meninges-brain axis presents potential molecular mechanisms and therapeutic targets for neurological complications in long-COVID-19 patients.”
  • Characterizing long COVID in an international cohort: 7 months of symptoms and their impact – “Patients with Long COVID report prolonged, multisystem involvement and significant disability. By seven months, many patients have not yet recovered (mainly from systemic and neurological/cognitive symptoms), have not returned to previous levels of work, and continue to experience significant symptom burden.”
  • Acute encephalitis in pediatric multisystem inflammatory syndrome associated with COVID-19 – “Patients with MIS-C may present acute encephalitis characterized by rapid-onset encephalopathy and EEG abnormalities (slow wave activity and/or epileptic abnormalities), in some cases associated with focal neurological signs that disappear with immunomodulatory therapy. The detection through neurological evaluation of sentinel neurological signs and distinctive EEG patterns documentable at disease onset will allow timely diagnosis and treatment of these cases.”
  • Prevalence and Risk Factors of Neurologic Manifestations in Hospitalized Children Diagnosed with Acute SARS-CoV-2 or MIS-C – “In this multicenter study, 44% of children hospitalized with SARS-CoV-2-related conditions experienced neurological manifestations, which were associated with ICU admission and pre-existing neurological condition. Posthospital assessment for, and support of, functional impairment and neuroprotective strategies are vitally needed.”
  • Direct and indirect impact of SARS-CoV-2 on the brain – “Although COVID-19 is mostly a pulmonary disease, it is now well accepted that it can cause a much broader spectrum of signs and symptoms and affect many other organs and tissue. From mild anosmia to severe ischemic stroke, the impact of SARS-CoV-2 on the central nervous system is still a great challenge to scientists and health care practitioners. Besides the acute and severe neurological problems described, as encephalopathies, leptomeningitis, and stroke, after 2 years of pandemic, the chronic impact observed during long-COVID or the post-acute sequelae of COVID-19 (PASC) greatly intrigues scientists worldwide. Strikingly, even asymptomatic, and mild diseased patients may evolve with important neurological and psychiatric symptoms, as confusion, memory loss, cognitive decline, chronic fatigue, associated or not with anxiety and depression. Thus, the knowledge on the correlation between COVID-19 and the central nervous system is of great relevance. In this sense, here we discuss some important mechanisms obtained from in vitro and in vivo investigation regarding how SARS-CoV-2 impacts the brain and its cells and function.”
  • Brain Disorders: Impact of Mild SARS-CoV-2 May Shrink Several Parts of the Brain – “This article aims to describe the prolonged neurological clinical consequences related to brain changes in people with mild COVID-19 infection. When compared to a control group, people those who tested positive for COVID-19 had more brain shrinkage, grey matter shrinkage, and tissue damage. The damage occurs predominantly in areas of the brain that are associated with odour, ambiguity, strokes, reduced attention, headaches, sensory abnormalities, depression, and mental abilities for few months after the first infection. Therefore, in patients after a severe clinical condition of COVID-19, a deepening of persistent neurological signs is necessary.”
  • Neurological involvement associated with COVID-19 infection in children – “n these MIS-C cases, 46% and 92% of children were reported positive COVID-19 reverse transcription polymerase chain reaction (RT-PCR) and serum antibody (IgG and/or IgM), respectively. This evidence suggests that while MIS-C occurred, most children might not have an active COVID-19 infection”
  • Neurological Manifestations of COVID-19 in Children: Time to Be More Vigilant – “Several neurological presentations have been documented in children and adults with COVID-19 infections. Parainfectious complications include autoimmune encephalitis, autoimmune epilepsy, central nervous system demyelination, Guillain-Barre syndrome, and acute necrotizing encephalopathy. With inflammation playing a major role, these conditions probably share a final common pathway; this also explains the benefit of immunotherapy in these conditions. Because these parainfectious neurological syndromes have an infectious trigger (herpes, dengue, etc.), COVID-19 testing may be appropriate in patients with these disorders.”
  • Cortical Grey matter volume depletion links to neurological sequelae in post COVID-19 “long haulers” – “The results demonstrate a statistically significant depletion of CGM volume in 24 COVID-19 infected patients. Reduced CGM volume likely influences their long term neurological sequelae and may impair post COVID-19 patient’s quality of life and productivity.” – “This study contributes to understanding effects of COVID-19 infection on patient’s neurocognitive and neurological function, with potential for producing serious long term personal and economic consequences, and ongoing challenges to public health systems.”
  • Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis – “A significant proportion of individuals experience persistent fatigue and/or cognitive impairment following resolution of acute COVID-19. The frequency and debilitating nature of the foregoing symptoms provides the impetus to characterize the underlying neurobiological substrates and how to best treat these phenomena.”
  • Frequency and phenotype of headache in covid-19: a study of 2194 patients – “In this study, headache occurred in one of every four confirmed COVID-19 cases. Headache is a common symptom in systemic viral infections. In addition, in our sample, we estimated that headache was the first symptom of COVID-19 in 6% of patients, with an early onset in most of the cases. The phenotype of headache attributed to acute SARS-CoV-2 infection shows a bilateral headache predominantly affecting the forehead, with pressing quality, with severe intensity, and frequently accompanied by typical migraine symptoms, in line with previously published studies.”
  • Headache as a Symptom of COVID-19: Narrative Review of 1-Year Research – “Headache is a common symptom of COVID-19, resulting from mechanisms involving individual factors and SARS-CoV-2 characteristics such as its neuro-invasive potential and ability to produce inflammation. Although several questions still need to be answered, studies on COVID-19 have helped to regain interest in 9.2.2 headache attributed to systemic viral infection. However, COVID-19 headache research represents a unique opportunity to better understand COVID-19 in general and advance in the knowledge of both secondary and primary headaches.”
  • Long COVID Neuropsychological Deficits after Severe, Moderate, or Mild Infection – “This study demonstrates the presence of long-term neuropsychological sequelae following SARS-CoV-2 infection, regardless of the severity of the respiratory disease in the acute phase. Some of the cognitive deficits could be explained by psychiatric variables, emphasizing the importance of considering a broad range of psychiatric symptoms. However, not all neuropsychological sequelae could be explained by these variables. The presence of correlations between olfaction, emotion recognition, and episodic memory, which share common functional and anatomical substrates, reinforces the hypothesis that the virus targets the CNS (notably the limbic system). Finally, the data support the notion of different clinical phenotypes, paving the way for clinical guidelines and recommendations for the management of long-term neurological impairment following SARS-CoV-2 infection.”
  • Long-Term Brain Disorders in Post Covid-19 Neurological Syndrome (PCNS) Patient – “The alterations of the cerebral parenchyma found and documented in our patient, with the recent study of MRI, are findings completely similar to those that are recognized in about 40–45% of patients suffering from migraine to system immune disorders, as well as inflammation of the connective tissue. These conditions, which have as their common denominator a vascular microsuffering caused by vasoconstriction, generate microthrombosis with consequent microvascular alterations, leading to neuronal degeneration and subsequent gliosis. These areas evolve in minute focal areas of altered signal intensity recognizable in neuroimaging with Magnetic Resonance as signal hyperintensity in long TR images, especially in FLAIR, expression of gliosis reactive to neuronal damage. These additional aspects of COVID-19 infection can further evidence the harmful action of COVID-19 in the central nervous system.”
  • Long-term neurologic outcomes of COVID-19 – “In conclusion, our report provides a comprehensive analysis of neurologic outcomes at 12 months. We show increased risk of an array of neurologic disorders spanning several neurologic disease categories including stroke (both ischemic and hemorrhagic), cognition and memory disorders, peripheral nervous system disorders, episodic disorders, extrapyramidal and movement disorders, mental health disorders, musculoskeletal disorders, sensory disorders, and other disorders including Guillain–Barré syndrome, and encephalitis or encephalopathy. The risks were evident in all examined subgroups and were evident even in people who were not hospitalized during the acute phase of the disease. Altogether, the findings call for attention to the long-term neurologic consequences of SARS-CoV-2 infection. Both healthcare system planning, and more broadly, public policy making, should take into account the long-term neurologic (and other) consequences of infection with SARS-CoV-2.”
  • Mid and long-term neurological and neuropsychiatric manifestations of post-COVID-19 syndrome: A meta-analysis – “Findings: In a meta-analysis of 18 studies encompassing 10,530 patients (hospitalised and non-hospitalised), overall prevalence for neurological symptoms three months after COVID-19 onset was: fatigue (37%), brain fog (32%), memory issues (28%), attention disorder (22%), myalgia (17%), anosmia (12%), dysgeusia (10%), and headache (15%). The prevalence of neuropsychiatric symptoms was sleep disturbances (31%), anxiety (23%), and depression (17%).”
  • Molecular Imaging Findings on Acute and Long-Term Effects of COVID-19 on the Brain: A Systematic Review – “Molecular imaging techniques such as PET and SPECT have been used to shed light on how coronavirus disease 2019 (COVID-19) affects the human brain. We provide a systematic review that summarizes the current literature according to 5 predominant topics”
  • Neurobiology of COVID-19 – “Patients with COVID-19 can present with a wide range of neurological manifestations that can be due to the injury to central and peripheral nervous system via a cytokine storm, blood clots, direct damage by SARS-Cov2, and/or molecular mimicry. This review, while presenting what is currently known about this virus and the related clinical neurology, represents only the base of what will eventually become a separate active field of research.”
  • Neuropsychologic Profiles and Cerebral Glucose Metabolism in Neurocognitive Long COVID Syndrome – “The present study reports a prospective assessment of 31 patients self-presenting to our outpatient clinic because of neurocognitive symptoms more than 6 mo after a SARS-CoV-2 infection with long COVID syndrome. Although 39% of patients report a relevant disability at work and everyday life due to these symptoms, an exhaustive assessment including a detailed cognitive battery showed only mild impairment in individual patients, and cerebral 18F-FDG PET failed to reveal a distinct pathologic signature.”
  • Neurovascular injury with complement activation and inflammation in COVID-19 – “Injury to the microvasculature by immune complexes with complement activation is the key central event that results in breakdown of the blood–brain barrier, microthromboses, perivascular inflammation and neuronal injury. We postulate that these events are central to the development of the neurological manifestations seen in acute COVID-19 and possibly in long-COVID. Importantly, these studies suggest that therapeutic approaches targeted against the development of immune complexes should be considered.”
  • Persistent neurologic symptoms and cognitive dysfunction in non-hospitalized Covid-19 “long haulers” – “Non-hospitalized Covid-19 “long haulers” experience prominent and persistent “brain fog” and fatigue that affect their cognition and quality of life.”
  • Persistent Symptoms in Adult Patients 1 Year After Coronavirus Disease 2019 (COVID-19): A Prospective Cohort Study – “Neurocognitive long-COVID symptoms can persist ≥1 year after COVID-19 symptom onset and reduce life quality significantly. Several neurocognitive symptoms were associated with ANA titer elevations. This may indicate autoimmunity as a cofactor in etiology of long COVID.”
  • Plasma Biomarkers of Neuropathogenesis in Hospitalized Patients With COVID-19 and Those With Postacute Sequelae of SARS-CoV-2 Infection – “We enrolled a total of 64 study participants, including 9 hospitalized patients with COVID-19 encephalopathy (CE), 9 posthospitalization neuro-PASC (PNP) patients, 38 nonhospitalized neuro-PASC (NNP) patients, and 8 HC subjects. Patients with CE were older, had higher pNfL and pGFAP concentrations, and more frequent pN Ag detection than all neuro-PASC groups. PNP and NNP patients exhibited similar PASC symptoms, decreased quality-of-life measures, and cognitive dysfunction, and 1 of the 38 (2.6%) NNP patients had pN Ag detectable 3 weeks postsymptoms onset. Patients with neuro-PASC presenting with anxiety/depression had higher neuroglial scores, which were correlated with increased anxiety on quality-of-life measures.”
  • The neurobiology of long COVID – “Persistent neurological and neuropsychiatric symptoms affect a substantial fraction of people after COVID-19 and represent a major component of the post-acute COVID-19 syndrome, also known as long COVID. Here, we review what is understood about the pathobiology of post-acute COVID-19 impact on the CNS and discuss possible neurobiological underpinnings of the cognitive symptoms affecting COVID-19 survivors. We propose the chief mechanisms that may contribute to this emerging neurological health crisis.”
  • Assessing Brain Capillaries in Coronavirus Disease 2019 – “Multiple lines of evidence indicate endothelial dysfunction may contribute to severe COVID-19 illness. Lung examination demonstrates megakaryocytes,5 and the cells have now been reported in other organs.6 One possibility is that altered endothelial or other signaling is recruiting megakaryocytes into the circulation and somehow permitting them to pass through the lungs. Although this initial study does not investigate mechanism, it is notable that we found megakaryocytes in cortical capillaries in 33% of cases examined. Because the standard brain autopsy sections taken sampled at random only a minute portion of the cortical volume, finding these cells suggests the total burden could be considerable. By occluding flow through individual capillaries, these large cells could cause ischemic alteration in a distinct pattern, potentially resulting in an atypical form of neurologic impairment.”
  • Brain autopsies of critically ill COVID-19 patients demonstrate heterogeneous profile of acute vascular injury, inflammation and age-linked chronic brain diseases – “Acute tissue injuries and microglial activation were the most common abnormalities in COVID-19 brains. Focal evidence of encephalitis-like changes was noted despite the lack of detectable virus. The majority of older subjects showed age-related brain pathologies even in the absence of known neurologic disease. Findings of this study suggest that acute brain injury superimposed on common pre-existing brain disease may put older subjects at higher risk of post-COVID neurologic sequelae.”
  • COVID-19 and stroke: A review – “COVID-19 patients have presented with a wide range of neurological disorders, among which stroke is the most devastating. SARS-CoV-2 infection induces coagulopathy, disrupts endothelial function, and promotes hypercoagulative state. Severe COVID-19 infection renders patients bedridden, and in certain cases requiring instrumental support. Collectively, it predisposes patients to cerebrovascular events. Due to the unprecedented strain on the healthcare system, stroke care has been inevitably compromised from initial encounter, treatment, to rehabilitation. The understanding of the underlying mechanism between COVID-19 and stroke warrants further study, so does the development of an effective therapeutic or preventive intervention.”
  • The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings – “The widespread effects of COVID-19 include neurological disorders but there have been, to date, no detailed clinical reports of their nature (Guan et al., 2020; Helms et al., 2020; Mao et al., 2020; Varatharaj et al., 2020). Our London and regional cohort describes a range of neurological syndromes including encephalopathies, para- and post-infectious CNS syndromes including encephalitis, ADEM with haemorrhage and necrotic change, transverse myelitis, ischaemic stroke and GBS.”
  • Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions – “Neurological and neuropsychiatric symptoms are common in COVID-19 patients. Emerging neuroimaging and neurochemical evidence indicate neuroimmune dysfunction and brain injury in severe COVID-19 patients, especially those with neuropsychiatric manifestations. These neuropsychiatric complications are recognized as critical contributors to morbidity and mortality during the COVID-19 pandemic and have become major public health challenges. SARS-CoV-2 infection can directly invade the CNS through the blood circulation and neuronal pathways, and indirectly affect the innate and adaptive immune system and cause neuroinflammation. Both of these disruptions to immune functioning and neuroinflammation ultimately lead to brain lesions and accelerate the progression and worsening of the clinical outcomes of neuropsychiatric disorders.”
  • Multiple Neuroinvasive Pathways in COVID-19 – “SARS-CoV-2, the virus that causes COVID-19, is one of several human viruses that affect the brain. We are only beginning to learn the exact mechanisms by, and the extent to which, it impacts the brain. Considering the rapid accumulation of knowledge about multiple neurological and neurocognitive symptoms in COVID-19 patients, Neuro-COVID-19 has been increasingly recognized as a useful clinical/scientific construct in the evolving discourse about the development of systematic approaches to the diagnosis, management, and treatment of the neurological and neurocognitive aspects of COVID-19.”
  • Human Pluripotent Stem Cell-Derived Neural Cells and Brain Organoids Reveal SARS-CoV-2 Neurotropism Predominates in Choroid Plexus Epithelium – “Neurological complications are common in patients with COVID-19. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal pathogen of COVID-19, has been detected in some patient brains, its ability to infect brain cells and impact their function is not well understood. Here, we investigated the susceptibility of human induced pluripotent stem cell (hiPSC)-derived monolayer brain cells and region-specific brain organoids to SARS-CoV-2 infection. We found that neurons and astrocytes were sparsely infected, but choroid plexus epithelial cells underwent robust infection.”
  • Neurocognitive and psychiatric symptoms following infection with COVID-19: Evidence from laboratory and population studies – “Converging findings from laboratory and population survey data support the conclusion that symptomatic COVID-19 infection is associated with task-related, functional imaging and self-reported indices of cognitive dysfunction as well as psychiatric symptoms. In some cases, these findings appear to be more amplified among women than men, and among older women than younger.”
  • Mechanisms of Stroke in COVID-19 – “A number of mechanisms are involved in stroke in COVID-19, including a hypercoagulable state, DIC, necrotizing encephalopathy, vasculitis, and cardiomyopathy. It seems likely that anticoagulation will play a substantial role in the management of stroke in COVID-19. Further evidence is needed from larger studies.”
  • COVID-19 virus may have neuroinvasive potential and cause neurological complications: a perspective review – “Here, we reviewed the evidence of the neuroinvasive potential of coronaviruses and discussed the possible pathogenic processes in CNS infection by COVID-19 to provide a precise insight for future studies.”
  • Brain Disorders: Impact of Mild SARS-CoV-2 May Shrink Several Parts of the Brain – “This article aims to describe the prolonged neurological clinical consequences related to brain changes in people with mild COVID-19 infection. When compared to a control group, people those who tested positive for COVID-19 had more brain shrinkage, grey matter shrinkage, and tissue damage. The damage occurs predominantly in areas of the brain that are associated with odour, ambiguity, strokes, reduced attention, headaches, sensory abnormalities, depression, and mental abilities for few months after the first infection. Therefore, in patients after a severe clinical condition of COVID-19, a deepening of persistent neurological signs is necessary.”
  • Chronic cough in post-COVID syndrome: Laryngeal electromyography findings in vagus nerve neuropathy – “LEMG studies suggest the existence of postviral vagus nerve neuropathy after SARS-CoV-2 infection that could explain chronic cough in post-COVID syndrome.”