Impact of COVID 19 on the Nervous System

Original Editor - Srishti Banerjee

Top Contributors - Srishti Banerjee, Kim Jackson, Aminat Abolade and Rishika Babburu

One Page Owner - Srishti Banerjee as part of the One Page Project

Introduction

With the outbreak of coronavirus, the major areas of concern were the respiratory system. However, it has been established that coronavirus affection can extend beyond the respiratory system and one of the deadly areas of affection is the effect of the virus on the nervous system. A wide range of neurological manifestations have been reported during and post covid conditions.

Pathophysiology

Invasion via the olfactory route.

Loss of smell has been reported as one of the earliest symptoms of covid infection. It has been established by the evidence of an increase in MRI signal to the olfactory cortex suggestive of infection in the nervous system. The virus gains access to the central nervous system via the bloodstream, infecting the endothelial cells. Secondly the virus can enter the peripheral nervous system through retrograde neuronal routes. The virus could be internalized in nerve terminals by endocytosis, transported retrogradely, and spread trans-synaptically to other brain regions

Angiotensin-converting enzyme -2 ( ACE-2) receptor present in the nasal mucosa is exploited by the virus. ACE-2 receptor is also present in organs such as kidneys , lungs, and in tissues of the nervous system. The presence of ACE-2 receptors in the tissues of the nervous system is hypothesized to be the reason that the virus leads to neurological manifestations.

The virus from the general circulation can pass into the cerebral circulation, where due to sluggish movement of the blood in the microcirculation along with the high rate of the load from the initial sites of infection facilitates the interaction of a protein present in the coronavirus known as spike protein ( S protein ) with the ACE-2 receptors present in the capillary endothelium. Following this, there is the budding of the virus in the capillary endothelium leading to the spread of the virus in areas of the brain and brainstem via Virchow-Robin spaces surrounding arterioles and venules.

Cytokine Storm is another mechanism reported to be responsible for neurological manifestations in covid infection. Cytokine storm is defined as dysfunctional, uncontrolled, continuous activation of inflammation. This leads to acute respiratory distress syndrome, renal failure, myocardial injury, the severity of illness, the requirement of intensive care unit admission, the requirement of mechanical ventilation, and mortality. The presence of inflammatory markers such as C-reactive protein and leukocytes confirm the presence of cytokine storm. Diffuse illness of CNS has been reported and temporal association between inflammatory markers and CNS dysfunction is yet to be established. However, it is known that the release of interleukin-6 causes vascular leakage and activation of complement and coagulation cascades, in addition to this patients with severe covid infection presents with higher levels of D-dimer, which is a marker of a hypercoagulable state and endogenous fibrinolsis . These may be the factors that cause acute cerebrovascular disease. Cytokine storm is also responsible for causing arthralgia.

Pneumonia is a common clinical feature of covid infection, however, the systemic hypoxia occurirng due to pneumonia causes damage to the brain cells and other nerve cells.

Peripheral vasodilatation, hypercarbia, hypoxia, and anaerobic metabolism, which ultimately result in neuronal swelling and brain edema, which leads to raised intracranial pressure resulting in headache, impaired consciousness, seizure, and irritation of the trigeminal nerve.

Immune dysregulation by the hypothalamus: Several cytokines such as IL-6, IL-1β, and TNF are secreted during the covid infection and are powerful activators of the hypothalamic-pituitary-adrenocortical (HPA) axis The HPA axis is central to the regulation of systemic immune activation and is activated by blood-brain barrier dysfunction and neurovascular inflammation. The Covid infection leads to immunosuppression and lymphopenia which leads to activation of the HPA, leading to the release of norepinephrine and glucocorticoids. These mediators act synergistically to induce splenic atrophy, T cell apoptosis, and Natural killer cell deficiency. Downregulation of these factors, in concert with calprotectin release from damaged lungs, may increase hematopoietic stem cell proliferation skewed towards  emergency myelopoiesis ( production of the bone marrow) which results in lymphopenia and neutrophilia, two key hematological features of COVID.

Covid infection can cause multi-system failure leading to systemic water, electrolyte imbalance, hormonal dysfunction, accumulation of toxic metabolites which is hypothesized to cause neurological manifestations such as headaches, confusion, agitation etc.

However, apart from the neurological manifestations during the active infection, it has been established that following the clearance of the infection also there are few neurological manifestations reported such as several cases of Guillain-Barre syndrome, neuropathy caused by an immune attack on peripheral

nerves, have been reported in patients with recent COVID-19 Most reported cases describe classic features of this syndrome, such as generalized weakness, evidence of demyelination on nerve conduction studies and elevated proteins without white blood cells in CSF.The Miller-Fisher variant of Guillain-Barre syndrome, characterized by cranial nerve involvement, has also been reported, including at least one case with detectable anti-ganglioside antibodies suggesting an immune attack on the peripheral nerves

Neurological manifestations,,

The neurological manifestations during and after the infection include:

• Encephalopathy manifests as an alteration in mental status which includes, confusion, disorientation, agitation, and somnolence. Encephalopathy also presents as delirium and coma which is due to hypoxia, renal failure, hypotension, high dose of sedatives, prolonged immobility and isolation.
• Encephalitis manifests as fever, altered mental state, siezures, white blood cells in cerebrospinal fluid, and focal brain abnormalities on neuroimaging.
• Acute cerebrovascular disease and brain perfusion abnormalities are due to hypercoagulable states during and following the infection. Presence of patchy microthrombi and infarction is present.
• Brain leptomeningeal enhancement [1]
• Dysexecutive syndrome [2]
• Ataxia
• Meningitis
• Myelitis

Neurological manifestations related to the stay in the intensive care units(ICU).

Altered mental status has been reported in patients with critical illness and prolonged ICU stay. Critically ill patients with acute respiratory distress syndrome ( ARDS) who are mechanically ventilated experience delirium due to hypoxemia and administration of a high dose of sedatives.

Post infectious neurological complications

There are delayed effects as the infection leads to dysregulation in the systemic immune system response. After the acute phase of the infection subsides the dysregulated immune system response affects both the central and peripheral nervous system. Acute disseminated encephalomyelitis and acute necrotizing hemorrhagic encephalopathy are reported in the CNS after the infection. Peripherally, several cases of Guillain-Barre syndrome, neuropathy caused by an immune attack on peripheral nerves, have been reported in patients with recent COVID-19. The Miller-Fisher variant of Guillain-Barre syndrome, characterized by cranial nerve involvement, has also been reported,