COVID‐19–Associated Encephalopathy and Cytokine‐Mediated Neuroinflammation

Muccioli, Lorenzo; Pensato, Umberto; Cani, Ilaria; Guarino, Maria; Cortelli, Pietro; Bisulli, Francesca

doi:10.1002/ana.25855

Cited by 65 publications

(63 citation statements)

References 5 publications

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“…An autoantibody-mediated mechanism is unlikely to explain CNS involvement, based on the brief temporal interval between CNS and infection-related symptom onset, negative testing for anti-neuronal antibodies, and the prompt and sustained response to IVIg [15]. Cytokine-mediated neuroinflammation has been implicated in the underlying pathogenic mechanism of COVID-19-associated encephalopathy, and may have contributed to disease course in our patients [5][6][7][8][9][10]. Except the third case, all patients suffered acute respiratory distress secondary to CRS induced by SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 84%

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Intravenous immunoglobulin therapy in COVID-19-related encephalopathy

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Objective To report on efficacy and safety of intravenous immunoglobulin (IVIg) therapy in a case series of patients with COVID-19-related encephalopathy. Methods We retrospectively collected data on all patients with COVID-19 hospitalized at two Italian hospitals who developed encephalopathy during disease course and were treated with IVIg. Results Five patients (two females, mean age 66.8 years) developed encephalopathy after a mean of 12.6 days, since the onset of respiratory/constitutional symptoms related to COVID-19. Four patients suffered severe respiratory distress, three of which required invasive mechanical ventilation. Neurological manifestations included impaired consciousness, agitation, delirium, pyramidal and extrapyramidal signs. EEG demonstrated diffuse slowing in all patients. Brain MRI showed non-specific findings. CSF analysis revealed normal cell count and protein levels. In all subjects, RT-PCR for SARS-CoV-2 in CSF tested negative. IVIg at 0.4 g/kg/die was commenced 29.8 days (mean, range: 19–55 days) after encephalopathy onset, leading to complete electroclinical recovery in all patients, with an initial improvement of neuropsychiatric symptoms observed in 3.4 days (mean, range: 1–10 days). No adverse events related to IVIg were observed. Conclusions Our preliminary findings suggest that IVIg may represent a safe and effective treatment for COVID-19-associated encephalopathy. Clinical efficacy may be driven by the anti-inflammatory action of IVIg, associated with its anti-cytokine qualities.

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Section: Discussionmentioning

confidence: 84%

“…Cytokines may drive neuroinflammation even without severe CRS, possibly as a consequence of local CNS production [5,6,20]. The IVIg anti-cytokine effects documented peripherally may independently and directly act on the CNS.…”

Section: Discussionmentioning

confidence: 99%

Intravenous immunoglobulin therapy in COVID-19-related encephalopathy

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“…CSF analysis showed a slightly increased cellularity and negative PCR for SARS-CoV-2. Even though these findings cannot rule out CNS viral invasion with certainty, we believe more likely an immuno-mediated para-infectious pathogenic mechanism underlying the neurological manifestations of our patient, also according to the emerging evidence supporting an inflammatory, cytokine-mediated, pathogenesis in a subset of patients with COVID-19-related encephalopathy (Beach et al, 2020;Cani et al, 2020;Muccioli et al, 2020;Pilotto et al, 2020). The relationship between the disclosed oligoclonal bands in the present report and COVID-19 remains unclear.…”

Section: Discussionmentioning

confidence: 49%

“…Neurological manifestations of COVID-19 are being increasingly reported, including a spectrum of encephalitis with distinguished underlying pathogenic mechanisms. Among well-known entities such as acute disseminated encephalomyelitis, limbic encephalitis and acute necrotizing encephalopathy, SARS-CoV-2 may cause viral encephalitis secondary to CNS invasion and, notably, a type of encephalopathy that appears related to cytokine-mediated neuroinflammation (Pilotto et al, 2020;Muccioli et al, 2020;Beach et al, 2020;Koralnik and Tyler, 2020). This has not been clearly phenotyped thus far, however it appears characterized by altered mental status ranging from mild confusion to delirium, language disturbances including akinetic mutism, as weel as other various CNS manifestations (Koralnik and Tyler, 2020).…”

Section: Introductionmentioning

confidence: 99%

COVID-19-related encephalopathy presenting with aphasia resolving following tocilizumab treatment

Muccioli

Pensato

Cani

et al. 2020

Journal of Neuroimmunology

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Encephalopathy is emerging as a recurrent complication of COVID-19 yet remains poorly characterized. We report the case of a middle-aged woman with COVID-19-related encephalopathy presenting as expressive aphasia and inattentiveness, subsequently progressing to agitation and marked confusion. Brain MRI and CSF analysis were unremarkable, while EEG showed slowing with frontal sharp waves. Neuropsychiatric symptoms resolved following treatment with tocilizumab. CNS involvement in COVID-19 may present as a subacute encephalopathy characterized by prominent frontal lobe dysfunction, with language disturbances as first neurological manifestation. Future studies should further investigate the role of tocilizumab in treating COVID-19-related encephalopathy.

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“…Неврологические симптомы при инфицировании SARS-CoV-2 регистрируются у 30-40% пациентов [2,36,55,63]. Дисфункция ЦНС при COVID-19 увеличивает неблагоприятный исход у пациентов [42].…”

Section: неврологческие проявления Covid-19 как предпосылки для изучеunclassified

Molecular and cellular mechanisms of central nervous system alteration in COVID-19

Алексеева

Sokolov

Никитюк

et al. 2020

Žurnal anatomii i gistopatologii

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The ongoing coronavirus disease 2019 (COVID-19) pandemic dictates the need to study the molecular and cellular mechanisms of interaction between the pathogen and the human body. The manifestation of neurological symptoms in some patients with COVID-19 is a problem for neuroscientists due to the insufficiently understood pathomorphogenesis of the disease. This review systematizes the literature data reflecting the ways of penetration of SARS-CoV-2 into the brain, features of its interaction with neurons, neuroglia, and immune cells. It has been shown that the main mechanisms of SARS-CoV-2 neuroinvasion are presumably retrograde axonal transport along the fibers of the olfactory and vagus nerves; penetration through the damaged blood-brain barrier (BBB) or migration of immunocompetent cells containing viral particles through the intact BBB. It was found that virusinducible neuronal death is caused not only by a direct cytotoxic effect, but also due to dysregulation of the reninangiotensin system of the brain and the release of a large amount of inflammatory cytokines as a manifestation of a “cytokine storm”. The participation of neuroglial cells in the initiation and maintenance of neuroinflammatory and neurodegenerative processes due to the activation of their proinflammatory phenotype has been demonstrated. The role of mast cells in antiviral defense mechanisms and inflammatory reactions is discussed.

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COVID‐19–Associated Encephalopathy and Cytokine‐Mediated Neuroinflammation

Cited by 65 publications

References 5 publications

Intravenous immunoglobulin therapy in COVID-19-related encephalopathy

Intravenous immunoglobulin therapy in COVID-19-related encephalopathy

COVID-19-related encephalopathy presenting with aphasia resolving following tocilizumab treatment

Molecular and cellular mechanisms of central nervous system alteration in COVID-19

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