Acute and chronic neurological disorders in COVID-19: potential mechanisms of disease

Abstract

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.

Keywords: COVID-19; SARS-CoV-2; encephalopathy; nervous system; stroke.

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.

Figure 2

Microvascular diseases with COVID-19. (A) Multiple congested blood vessels and microhaemorrhages are observed in the basal ganglia at post-mortem. (B) MRI of the same block of tissue shows hyper and hypointense signals corresponding to the blood vessels in A. The hyperintense signals represent fibrin clots while the hypointense signals are microhaemorrhages. (C) MRI of the pons shows similar punctate hypointense signals (arrows).

Figure 3

Chronic neurological sequelae of COVID-19. Several long-term neurological syndromes result from SARS-CoV-2 among hospital- and community-treated patients, termed long COVID or post-acute sequelae of COVID-19 (PASC). These syndromes include neurocognitive, mood and sleep disorders, dysautonomia, diverse pain syndromes, as well as marked exercise intolerance and fatigue. These protracted syndromes remain to be fully defined in longitudinal cohort studies.