Acute and Chronic Neurological Disorders in COVID-19

Potential Mechanisms of Disease

Erin F. Balcom; Avindra Nath; Christopher Power


Brain. 2022;144(12):3576-3588. 

In This Article

Abstract and Introduction


Coronavirus disease 2019 (COVID-19) is a global pandemic caused by SARS-CoV-2 infection and is associated with both acute and chronic disorders affecting the nervous system. Acute neurological disorders affecting patients with COVID-19 range widely from anosmia, stroke, encephalopathy/encephalitis, and seizures to Guillain–Barré syndrome. Chronic neurological sequelae are less well defined although exercise intolerance, dysautonomia, pain, as well as neurocognitive and psychiatric dysfunctions are commonly reported. Molecular analyses of CSF and neuropathological studies highlight both vascular and immunologic perturbations. Low levels of viral RNA have been detected in the brains of few acutely ill individuals. Potential pathogenic mechanisms in the acute phase include coagulopathies with associated cerebral hypoxic-ischaemic injury, blood–brain barrier abnormalities with endotheliopathy and possibly viral neuroinvasion accompanied by neuro-immune responses. Established diagnostic tools are limited by a lack of clearly defined COVID-19 specific neurological syndromes. Future interventions will require delineation of specific neurological syndromes, diagnostic algorithm development and uncovering the underlying disease mechanisms that will guide effective therapies.


Since its discovery in Wuhan, China in late 2019, coronavirus disease 2019 (COVID-19), the illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 3 million deaths ( and placed unprecedented pressure on social, economic and health care systems worldwide. Many survivors of the acute infection experience persistent and incapacitating neurological symptoms, which can have socio-economic and personal consequences.[1] It is thus imperative that there is a thorough understanding of the evolving clinical syndromes and the underlying pathophysiological mechanisms, enabling rational therapeutic interventions to be expeditiously deployed.

Retrospective cohort studies from around the world report neurological signs and symptoms such as headache, altered mental status, seizures and stroke, in over a third of patients during the acute phase of the illness,[2–4] positioning SARS-CoV-2 as an emerging neuro-pathogen. A similar proportion of infected individuals develop a post-infectious viral syndrome with diverse neuropsychiatric manifestations. Viral infections cause neurological impairments through multiple mechanisms,[5] including direct infection of neurons, glia or endothelial cells within the nervous system resulting in acute cell death, as observed in herpes simplex virus type-1 (HSV-1) encephalitis.[6] Alternatively, viruses, e.g. the human immunodeficiency virus type-1 (HIV-1), can persist in cellular reservoirs within the central (CNS) and perhaps peripheral (PNS) nervous system resulting in chronic inflammation and insidious progressive neurological damage.[7] Among non-neurotropic viruses such as influenza and other respiratory viruses, systemic infection is associated with inflammation, metabolic and hormonal derangements, with vascular injury resulting in neurological disease.[8] The host immune responses triggered during or following viral infections can also result in autoimmune damage of neural tissues, as observed in the PNS [e.g. Guillain–Barré syndrome (GBS)] and in the CNS [e.g. acute disseminated encephalomyelitis (ADEM) or acute transverse myelitis (ATM)]. Each of these mechanisms are implicated in SARS-CoV-2 infection and are addressed next. Of note, a multisystem inflammatory syndrome in children (MIS-C) has been described in paediatric cohorts with COVID-19; several cohort studies of children infected with SARS-CoV-2 report neurological disorders resembling those observed in adults including headache, encephalopathy, demyelinating disorders and stroke.[9–13] This review provides an update on neurological manifestations of COVID-19 that concentrates on adults while also examining contemporary evidence for the neuropathogenic mechanisms implicated in SARS-CoV-2 infection (Figure 1) and their relationship to current and potential therapies (Table 1).

Figure 1.

Potential mechanisms of acute neurological disease in COVID-19. (A) Multiple pathogenic processes result in injury to the brain during COVID-19 including vascular abnormalities resulting in thromboembolism, microhaemorrhage and endotheliopathy with associated antiphospholipid antibodies (αPL) and disruption of the blood–brain barrier (BBB) leading to bioenergy failure, autoantibodies (e.g. αGQ1b, α-NMDA-R, α-CASPR2 and αLGI2) that target a range of neural antigens, and neuroinvasion with infection of neurons and astrocytes via ACE2 as well as associated systemic inflammation and innate neuroimmune responses (cytokine, chemokine, protease and reactive oxygen species production and release by microglia and astrocytes). Therapeutic interventions that have been reported or proposed are indicated with an asterisk. (B) In the PNS and spinal cord, GBS associated with anti-glycan antibodies (αGL), T-cell mediated transverse myelitis, as well as myositis have been reported in patients with COVID-19 that may be responsive to different therapies. PLEX = plasma exchange.