Neurological associations of COVID-19

Abstract

Background The COVID-19 pandemic, caused by severe acute respi ratory syndrome coronavirus 2 (SARS-CoV-2), is of a scale not seen since the 1918 influenza pandemic. Although the predominant clinical presentation is with respiratory disease, neurological manifestations are being recognised increasingly. On the basis of knowledge of other coronaviruses, especially those that caused the severe acute respiratory syndrome and Middle East respi ratory syndrome epidemics, cases of CNS and peripheral nervous system disease caused by SARS-CoV-2 might be expected to be rare.Recent developments A growing number of case reports and series describe a wide array of neurological manifestations in 901 patients, but many have insufficient detail, reflecting the challenge of studying such patients. Encephalopathy has been reported for 93 patients in total, including 16 (7%) of 214 hospitalised patients with COVID-19 in Wuhan, China, and 40 (69%) of 58 patients in intensive care with COVID-19 in France. Encephalitis has been described in eight patients to date, and Guillain-Barré syndrome in 19 patients. SARS-CoV-2 has been detected in the CSF of some patients. Anosmia and ageusia are common, and can occur in the absence of other clinical features. Unexpectedly, acute cerebrovascular disease is also emerg ing as an important complication, with cohort studies reporting stroke in 2-6% of patients hospitalised with COVID-19. So far, 96 patients with stroke have been described, who frequently had vascular events in the context of a pro-inflammatory hypercoagulable state with elevated C-reactive protein, D-dimer, and ferritin.Where next? Careful clinical, diagnostic, and epidemiological studies are needed to help define the manifestations and burden of neurological disease caused by SARS-CoV-2. Precise case definitions must be used to distinguish nonspecific complications of severe disease (eg, hypoxic encephalo pathy and critical care neuropathy) from those caused directly or indirectly by the virus, including infectious, para-infectious, and post-infectious encephalitis, hypercoagulable states leading to stroke, and acute neuropathies such as Guillain-Barré syndrome. Recognition of neurological disease associated with SARS-CoV-2 in patients whose respiratory infection is mild or asymptomatic might prove challenging, especially if the primary COVID-19 illness occurred weeks earlier. The proportion of infections leading to neurological disease will probably remain small. However, these patients might be left with severe neurological sequelae. With so many people infected, the overall number of neurological patients, and their associated health burden and social and economic costs might be large. Health-care planners and policy makers must prepare for this eventuality, while the many ongoing studies investigating neurological associations increase our knowledge base.

Reply to the Letter “COVID‐19‐Associated Encephalopathy and Cytokine‐Mediated Neuroinflammation”

“…The high levels of interleukins in CSF compared with serum, as well as the increase of CNS-specific GFAP, speak against passive leakage across the blood-brain barrier, and instead suggest an intrathecally active inflammatory process. Several works reported similar cases during the last months, [4][5][6] showing that many patients with SARS-CoV-2 encephalitis exhibited clinical and imaging findings highly consistent with previously reported inflammatorymediated neurotoxicity, 1,2 whereas direct invasion and autoimmune responses appeared to be a rare condition. Despite the interesting insights given by this case report, larger studies are urgently needed to confirm cytokine-induced neuroinflammation as a main driver of SARS-CoV-2 related encephalitis, as this issue has deep consequences for the management and treatment of this growing condition worldwide.…”

Broad transcriptional dysregulation of brain and choroid plexus cell types with COVID-19

“…The observed transcriptional response to COVID-19 in the brain could arise from direct neurotropism or indirect damage via peripheral inflammation 15,16 . We thus stained for the SARS-CoV-2 spike glycoprotein 20,41 in medial frontal cortex and choroid plexus tissue immediately adjacent to tissue used in snRNA-seq.…”

“…Cellular and molecular approaches are required to understand the neurological changes that may contribute to symptoms reported in COVID-19 patients. Fundamentally, pathology can arise from the direct infection of neurons and glia or indirectly from peripheral infection and its attendant immune response 15,16 . Viral RNA has been detected in the olfactory mucosa and cerebrospinal fluid (CSF) in some cases, but the consequences for brain cells remain unclear 17–20 .…”

Coronavirus Disease 2019 and Parkinsonism: A Non‐post‐encephalitic Case

“…Neurologic manifestations in COVID-19 most commonly described include headache, seizures, stroke, hyposmia, and altered mental status. 2,3 As they may occur regardless of respiratory symptoms, most likely there is direct viral neurotoxicity. 4 Since the outbreak of encephalitis lethargica in the 1920s, 5 an ever-growing number of viruses have been implicated in postencephalitic parkinsonism, including influenza, Epstein-Barr, West Nile, and Japanese encephalitis.…”