Understanding the Neuropathogenesis of SARS-CoV-2: A Review

Introduction

The novel severe acute respiratory syndrome coronavirus 2, known as SARS-CoV-2, causing COVID-19 infection, gave the world an unprecedented health blow, and in this regard, a lot of scientific inquiries on the biology of the disease were undertaken. In fact, though most of the focus has been upon respiratory issues, considerable neurological involvement is well supported by increasingly growing data. Neurotropism and the capability of SARS-CoV-2 to enter the CNS have raised an alert for its potential long-term neurological consequence. This article reviews the current understanding of neuropathogenesis caused by the novel coronavirus SARS-CoV-2, with a special focus on neurological symptoms, mechanisms of neuroinvasion, and potential long-term consequences.

Mechanisms of neuroinvasion

Its entry to the brain is thought to be via several routes. One hypothesis is that the virus enters the brain through the olfactory nerve, bypassing the blood-brain barrier. A high number of anosmias or loss of smell in COVID-19 patients supports this theory. Another possible route of dissemination is hematogenous: through infection of the virus in the blood-brain barrier endothelial cells, leading to increased permeability and allowing access of the virus into the central nervous system. The virus may also use the vagus nerve or other peripheral nerves to enter the brainstem and other parts of the central nervous system.

Once inside, these infections spread by hijacking the transport system, moving along axons inside neurons. Several infections also carry out cell-to-cell spread that avoids immune surveillance and extracellular space. Elucidation of these routes is essential in developing therapeutic strategies to prevent or reduce the outcomes of neuroinvasive diseases.

Because these ACE2 receptors are expressed in a general manner by several parts of the brain, including both neurons and glial cells, their neuropathogenesis might depend on the capability of SARS-CoV-2 to bind with these ACE2 receptors. One of the most likely mechanisms for neurotoxicity is a direct viral attack mediated by the spike viral protein through the ACE2 receptors. Moreover, severe manifestations of COVID-19 feature a hyperinflammatory status, also known as a “cytokine storm,” which leads to further CNS involvement because of an increase in the pervasive inflammation and oxidative stress, causing a further lesion of neural structures. Such knowledge is essential to treat neurological symptoms in COVID-19 patients and gives a chance for targeted therapy that may protect the nervous system from the long-term consequences of SARS-CoV-2 infection.

Neurological manifestations

Neurological manifestations of COVID-19 range from minor symptoms such as headache and dizziness to severe diseases such as encephalitis, stroke, and Guillain-Barre syndrome. Symptoms could be divided into three major categories: musculoskeletal issues, peripheral nervous system manifestations, and central nervous system complications.

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Central nervous system complications

Encephalitis and encephalopathy: Confusion, seizures, and altered consciousness have been reported in a number of studies among COVID-19-infected individuals, with many having abnormalities in imaging consistent with encephalitis.

Stroke: Covid-19 has been linked to elevated chances of cerebrovascular accidents, including hemorrhagic and ischemic strokes. It is one of the potential speculated mechanisms responsible for the increased stroke risk in these cohorts of patients due to the combination of endothelial dysfunction and the hypercoagulable state it can cause.

Acute disseminated encephalomyelitis (ADEM), an immune-mediated illness that almost invariably follows a preceding infectious phase, has also been noted in patients with COVID-19; it presents as demyelination and multifocal neurological deficits.

Peripheral nervous system complications

Guillain-Barre Syndrome: This is a very rare but possibly fatal disease that has been reported in COVID-19 patients. An immune attack on peripheral nerves results in paralysis and muscle weakness in the GBS.

Cranial nerve palsy: COVID-19 is considered to be associated with cranial neuropathy, which causes loss of hearing, facial paralysis, and a reduction in taste.

Symptoms related to the musculoskeletal system

Muscle aches and rhabdomyolysis: The most common complications among COVID-19 sufferers are muscle aches and weakness; some of them are also suffering from rhabdomyolysis, a severe breakdown of muscle tissue that may cause renal injury.

Guillain-Barre syndrome: This is a less common but more dangerous disease that has also been reported in COVID-19 patients. GBS is an immune attack by the human body against peripheral nerves leading to paralysis and muscle weakness.

Neurological manifestations: Cranial nerve palsy There is involvement of cranial nerves due to the COVID-19 infection, which can eventually lead to hearing loss, facial paralysis, and loss of taste.

Symptoms of musculoskeletal systems:

Myalgia and Rhabdomyolysis: One of the common symptoms of COVID-19 includes muscle ache and weakness. In severe cases, they may show rhabdomyolysis—a disastrous breakdown of muscles that might lead to renal injury.

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Long-term neurological sequelae

Long-term neurological effects of COVID-19 are still being studied, yet judging from the results so far, it is now becoming apparent that in some chronic patients there might be some long-standing problems. Such “long haulers” may come up. with a variety of other problems, though, including anxiety, sadness, and chronic fatigue, and cognitive dysfunction described as “brain fog.” The mechanisms of such prolonged deficiency are not clear and may include not only direct viral effects on the neurological system but also immunological reactions, long-lasting inflammation, or direct viral effects on the nervous system.

Pathophysiological insights from related coronaviruses

Such SARS-CoV-2 neuropathogenesis mechanisms were further elucidated by studies contrasting them with other coronaviruses, in particular with MERS-CoV and SARS-CoV-1, which shared similar neuroinvasive properties. MERS-CoV and SARS-CoV-1 have been demonstrated to cause peripheral neuropathies and encephalitis. This special spike characteristic of the SARS-CoV-2 may have neuropathogenic pathways equal or comparable by structure and action but may carry further neuroinvasive features.

Conclusion

The virus SARS-CoV-2 has proved to have the potential for severe impacts on the nervous system and may lead to further wide variations of neurological symptoms and issues. Understanding neuroinvasion processes and subsequent pathophysiology becomes very important to manage such issues and reduce long-term consequences. It will require further study to better elucidate the full neuropathogenic potential of SARS-CoV-2 and to provide specific treatment strategies aimed at halting and treating neurological injury in COVID-19.

References

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