Neurobiology of COVID-19

Abstract

Anosmia, stroke, paralysis, cranial nerve deficits, encephalopathy, delirium, meningitis, and seizures are some of the neurological complications in patients with coronavirus disease-19 (COVID-19) which is caused by acute respiratory syndrome coronavirus 2 (SARS-Cov2). There remains a challenge to determine the extent to which neurological abnormalities in COVID-19 are caused by SARS-Cov2 itself, the exaggerated cytokine response it triggers, and/or the resulting hypercoagulapathy and formation of blood clots in blood vessels throughout the body and the brain. In this article, we review the reports that address neurological manifestations in patients with COVID-19 who may present with acute neurological symptoms (e.g., stroke), even without typical respiratory symptoms such as fever, cough, or shortness of breath. Next, we discuss the different neurobiological processes and mechanisms that may underlie the link between SARS-Cov2 and COVID-19 in the brain, cranial nerves, peripheral nerves, and muscles. Finally, we propose a basic "NeuroCovid" classification scheme that integrates these concepts and highlights some of the short-term challenges for the practice of neurology today and the long-term sequalae of COVID-19 such as depression, OCD, insomnia, cognitive decline, accelerated aging, Parkinson's disease, or Alzheimer's disease in the future. In doing so, we intend to provide a basis from which to build on future hypotheses and investigations regarding SARS-Cov2 and the nervous system.

Keywords: Alzheimer’s disease; COVID-19; SARS-Cov2; anosmia; cerebrovascular disease; cytokines; seizure; vasculitis.

Fig. 1.

SARS-Cov2: Cellular mechanism of action. SARS-Cov2 binds ACE2 to enter epithelial cells of blood vessels and cells in multiple other organs. 1) Once internalized, it can cause damage to mitochondria and lysosomes which in turn may result in increased reactive oxygen species (ROS), protein misfolding, protein aggregation, and cell death. 2) By binding to ACE2, SARS-Cov2 also downregulates and inhibits the metabolic conversion of Angiotensin 2 (AT2) to AT(1–7). The resulting higher levels of AT2 is associated with pro-inflammatory markers, vasoconstriction, vascular permeability and edema, vascular injury to cells in the lungs, brain, heart, and kidneys as well as processes involved in pro-apoptosis and aging.

Fig. 2.

SARS-Cov2: Pathophysiology of action in the nose, cranial nerves and the brain. SARS-Cov2 can cause a variety of neurological symptoms in patients with COVID-19 such as anosmia, strokes, encephalopathy, meningitis, and cranial nerve injury. 1) By binding and inhibiting nasal (and gustatory - not shown) epithelial cells, it reduces the sense of smell and taste. 2) By activating the cytokines and hypercoagulation pathways in the blood, it results in the formation of small and large vessel occlusion in cerebral arteries. 3) Formation of blood clots in the cerebral veins can results in cerebral venous thrombosis. 4) High levels of cytokines in the cerebral vessels can damage the blood-brain barrier, and once infiltrate the brain, damage neurons and glia which results in seizures and/or encephalopathy. 5) Damage to arteries in meninges can result in meningitis. 6) Formation of auto-antibodies, known as molecular mimicry, may lead to damage to cranial nerves (see Fig. 3).

Fig. 3.

SARS-Cov2: Pathophysiology of action in peripheral nerves and muscle. 1) SARS-Cov2 activation of cytokines causes inflammatory injury to epithelial cells in the blood vessels (vasculitis) and muscles cells (myositis). In cardiac arteries and muscles (not shown), cytokine storm, triggered by SARS-Cov2, can result in hypercoagulopathy and formation of blood clots (myocardial infarction) or endocarditis. 2) SARS-Cov2 can trigger the formation of autoantibodies (such as GD1a) which react with antigens on axons and myelin cells to cause Guillain-Barre syndrome (GBS).

Fig. 4.

NeuroCovid Stage I, II, and III. SARS-Cov2’s neurological manifestation can be grouped into three stages. In NeuroCovid Stage I, the virus damage is limited to epithelial cells of nose and mouth. In NeuroCovid Stage II, patients may experience blood clots in their brain or have auto-antibodies that damage their peripheral nerves and muscles. In NeuroCovid Stage III, the cytokine storm damages the blood-brain barrier and patients may develop seizures, coma, or encephalopathy.