Neurological associations of COVID-19

Abstract

Background: The COVID-19 pandemic, caused by severe acute respiratory 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 respiratory 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 emerging 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 non-specific complications of severe disease (eg, hypoxic encephalopathy 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.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Approximate timeline for positive diagnostic tests, clinical presentation, and pathogenesis in COVID-19-associated neurological disease Approximate values are based on currently published data. Bars are faded to indicate uncertainty about specific ranges. Blue bars represent the period in which SARS-CoV-2 viral RNA and anti-SARS-CoV-2 IgM or IgG antibodies are detectable on either RT-PCR or antibody testing., , , , , Red bars represent the time of clinical presentation, including the duration of systemic or respiratory symptoms of COVID-19 and the time interval between onset of COVID-19 symptoms and symptoms of encephalitis,, , , , , , myelitis, acute disseminated encephalomyelitis,, Guillain-Barré syndrome,, , , , , , , , , , , , , or cerebrovascular disease., , , , , , A small number of patients who presented with neurological disease and never had respiratory features of COVID-19 are not represented in the figure. Green bars represent pathological mechanisms that might result in neurological disease in COVID-19, as in other viruses (appendix p 4). The dynamics of anti-SARS-CoV-2 IgG antibody production are not known beyond a few weeks, although by analogy with other viruses, it might be expected to persist for months to years. ADEM=acute disseminated encephalomyelitis. SARS-CoV-2=severe acute respiratory syndrome coronoavirus 2.

Figure 2

Brain imaging in patients with neurological disease associated with COVID-19 (A) Hyperintensity along the wall of inferior horn of right lateral ventricle on diffusion-weighted imaging, indicating ventriculitis. (B) hyperintense signal changes in the right mesial temporal lobe and hippocampus with slight hippocampal atrophy on FLAIR MRI, consistent with encephalitis, in a patient with COVID-19. (C) Hyperintensity within the bilateral medial temporal lobes and thalami on T2/FLAIR MRI. (D) Evidence of haemorrhage, indicated by hypointense signal on susceptibility-weighted images, consistent with acute necrotising encephalopathy in a patient with confirmed COVID-19. (E) CT showing ischaemic lesions involving the left occipital lobe. (F) Right frontal precentral gyrus of the brain in a man aged 64 years who deteriorated neurologically after admission to hospital with COVID-19 and was diagnosed with acute stroke. FLAIR=fluid-attenuated inversion recovery. Panels A and B reproduced from Moriguchi et al with permission from Elsevier under a creative commons CC BY-NC-ND license; panels C and D reproduced from Poyiadji et al with permission from The Radiological Society of North America; and panels E and F reproduced from Morassi et al with permission from Springer Nature.