Symptoms and Neurological Manifestations among COVID-19 Patients: Comparison
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Please note this is a comparison between Version 2 by Wendy Huang and Version 1 by Wissam AbouAlaiwi.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a newly emerged coronavirus, has sparked a global pandemic with its airborne transmission and ability to infect with asymptomatic patients. The disease state, including its pneumonia-like symptoms, is called COVID-19, as it was a coronavirus discovered in 2019. The pathophysiology is thought to relate to the binding of angiotensin converting enzyme 2 (ACE2) receptors in the body. These receptors are widely expressed in various body organs such as the lungs, the heart, the gastrointestinal tract (GIT), and the brain.

  • SARS-CoV-2
  • COVID-19
  • pneumonia-like symptoms
  • neurological symptoms
  • anosmia
  • demyelination

1. Introduction

SARS-CoV-2 is one of seven known coronaviruses and is a member of the beta-coronavirus (βCoV) clade, which also includes Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV) [2][1]. It appears to have similarities to other coronaviruses in symptoms and biological targets. SARS-CoV-2 is a virus with a single positive-stranded RNA genome that shares about 79.6% of its genome with SARS-CoV [3,4][2][3]. It is composed of four proteins, the spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins. The S protein is the structure that binds to the host cell receptor in order to enter and fuse with the host cell [5][4]. Due to similarities in their genome, both SARS-CoV-2 and SARS-CoV bind to the ACE2 receptor, an extracellular enzyme on various organ tissues needed to enter the cell.

The symptoms for SARS-CoV-2 infection range from fever and cough to anosmia and encephalopathy in severe cases. The flu symptoms are the predominant symptoms that physicians detect when diagnosing COVID-19 infections, but there are also neurological impacts of this virus that are as pertinent. Understanding the pathology of the SARS-CoV-2 virus throughout the body will improve the knowledge of its symptoms and improve efforts to develop a treatment.

2. General Symptoms

SARS-CoV-2 is a type of coronavirus (CoV), which have been known for years—SARS, which is caused by SARS-CoV-1, appeared in 2003, and middle eastern respiratory syndrome (MERS), caused by MERS-CoV, appeared in 2012 [11,12][5][6]. The common manifestation of COVID-19 in patients are pneumonia-like symptoms, such as fever, cough, chills, and fatigue. Because it targets the lower respiratory tract, it can also lead to acute respiratory distress syndrome (ARDS) and dyspnea (or difficulty breathing) [2][1]. Lung injury caused by SARS-CoV-2 involves direct viral damage and inflammatory responses [13][7]. The virus attaches to ACE-2, which is expressed on the alveolar epithelium and vascular endothelium, and both are then taken into the cell. Similar to alveolar flooding in ARDS, cellular damage is caused by interstitial edema and alveolar fluid filling [13][7]. However, symptoms are not restricted to respiratory illnesses, there are reports of patients with gastrointestinal distress, kidney dysfunction, as well as neurological manifestations [2][1]. Records from previous pandemics and epidemics caused by viruses, including influenza (H1N1 and Spanish influenza), MERS-CoV, and SARS-CoV-1, have shown significant notable neuropsychiatric symptoms, such as anxiety, depression, insomnia, mania, psychosis, suicidality, and delirium, as well as central nervous system inflammatory disorders, such as encephalitis lethargica [12[6][8],14], narcolepsy, seizures, encephalopathy, and Guillain–Barre syndrome (GBS) [15][9]. One systematic review found that SARS-CoV-2 causes an indirect, proinflammatory effect that leads to intracranial, endothelial dysfunction and encephalopathy [16][10].

3. Statistics on Neurological Symptoms

Although there are limited data on the involvement of SARS-CoV-2 in the central nervous system neurological manifestations, evidence from new case reports and studies is showing the significant relationship between them, especially in patients with severe infection [15][9]. In a pooled study of 13,232 patients who had experienced long term COVID-19, 22% experienced cognitive impairment for at least 12 weeks [17][11]. In addition, many reports from Wuhan, China, have shown that approximately 20% of patients in a 799-patient retrospective study had alterations in their consciousness, meaning that they have shown encephalopathies symptoms, caused by cytokine storms [18][12]. Another study documented that 36.4% of 214 SARS-CoV-2 patients developed neurological symptoms such as headache, consciousness disorders, and paresthesia [6][13]. Additionally, there have been new reports pinpointing the symptoms of loss of smell (anosmia) and taste (dysgeusia) in COVID-19 patients [15][9]. These symptoms, ranging from headaches and dizziness to ischemic stroke and cerebral hemorrhage, impact both the central and peripheral nervous systems [19][14]. One case study reported a woman confirmed with SARS-CoV-2 with symmetric lesions in the thalami region of her brain shown through CT and MRI scans. This was due to a complication called acute necrotizing encephalopathy, which can occur from a viral infection, and leads to altered mental state and, thus, the breakdown of the BBB [20][15].

4. Anosmia

One of the most common otorhinolaryngological manifestations in COVID-19 patients is anosmia [12][6]. Anosmia is defined as the loss or inability to smell, and it is common in sinonasal diseases, some viral infections caused by some coronaviruses, parainfluenza, the Epstein–Barr virus, and many more [21][16], as well as in neurodegenerative diseases [22][17]. In a 417-patient study of patients of different ethnicities, 88% of COVID-19 patients reported olfactory dysfunction, and 80% of these patients had anosmia [23][18]. The mechanism by which SARS-CoV-2 adheres to the olfactory system leading to anosmia is still debatable [21[16][18],23], but many studies have shown viral infection’s ability to invade the central nervous system through receptor neurons in olfactory epithelium [24][19]. Human neuronal cells contain the angiotensin-converting enzyme 2 (ACE2) receptor, which is classified as a target and entry point for coronaviruses to the healthy cell, most importantly in SARS-CoV and SARS-CoV-2, at which the spike of the virus interacts with the receptor-binding domain, leading to their entry into the cell [6,8,10][13][20][21]. Another potential mechanism is inflammation in the olfactory epithelium [25][22]. Similar to the previous theory, high ACE2 receptor expression was reported in the olfactory epithelium (OE); cytokine release is caused by the virus binding to these cells, leading to a promotion in OE inflammation. Another theory about COVID-19-induced anosmia concerns the Nsp-13 protein and nasal cilia. The Nsp-13 protein damages the physiological interactions of the cilia structure by competing with endogenous-binding compounds of the centrosome proteins, leading to deciliation [25][22]. Anosmia as an olfactory impairment in SARS-CoV-2 patients might be the viral entry path to the CNS, leading to other neurological manifestations [12,14][6][8].

5. Cerebrovascular Manifestations

Cerebrovascular manifestations, such as strokes, are increasingly recognized in COVID-19 patients [10][21]. A cerebrovascular event refers to an acute compromise of the cerebral perfusion or vasculature, can be ischemic or hemorrhage, and is the fifth leading cause of death in the US [26][23]. In addition, a variety of CNS infections lead to strokes, such as the herpes virus [27][24]. It is not clear yet how SARS-CoV-2 infection leads to strokes, but epidemiological data and research evidence suggest that inflammation-triggering infections in the upper respiratory system, as with COVID-19, can lead to acute ischemic stroke, suggesting that this might be occurring because of the activation of thrombocytes as an immunological response to the infection alongside endothelial dysfunction [28][25]. This has been proven in the human influenza A (H1N1) virus that stimulates strokes as well; the inflammatory response was mostly the leading cause of strokes in H1N1 patients, through elevated cytokines levels [29][26]. One theory linking strokes to COVID-19 is that the virus induces acute ischemic strokes by promoting hypercoagulability [30][27]. Previous studies have found that some patients with severe COVID-19 had increased levels of pro-inflammatory cytokines, which can cause inflammation and hypercoagulability. Another theory is related to damaged endothelial cells being closely related to acute ischemic strokes. COVID-19 may damage brain endothelial cells by promoting cerebral thrombosis through inducing hypercoagulability [30][27].

6. Inflammatory Demyelinating Mechanisms

Myelin is crucial for the proper functioning of neurons as they encase the neuron and speed up the rate of electrical impulses. There is an increasing amount of evidence that contracting the SARS-CoV-2 viral infection includes a risk factor of demyelination in the central and peripheral nervous systems [31][28]. This is not surprising as demyelination has been seen in other coronavirus infections. The destruction of myelin, known as primary demyelination, is classified into various categories, but the most relevant category to COVID-19 is demyelination caused by inflammatory processes [32][29]. Inflammatory demyelination is usually caused by the immune system attacking the myelin sheath. The main mechanism behind this immune response occurs when T-lymphocytes stimulate an inflammatory cascade when they pierce the BBB, leading to demyelination [33][30]. The process of inflammatory demyelination looks very similar in COVID-19, as it does in multiple sclerosis. An early phase of COVID-19 is characterized by high-levels of pro-inflammatory cytokines in the blood, generating an overactive immune response [33][30]. The high levels of cytokines in COVID-19 are also referred to as a cytokine storm; characterized by a high expression of interlukin-6 and tumor necrosis factor α [34][31]. In normal conditions, the angiotensin-converting enzyme II (ACE2) receptors on the cell surface are occupied by angiotensin 2 (ANG II). However, in COVID-19, the ACE2 receptors are occupied by SARS-CoV-2. The levels of ANG II increase in the serum as a result of ACE2-mediated degradation [35][32]. SARS-CoV-2 activates NF-κB and STAT3 using pattern recognition receptors and the accumulated ANG II induces inflammatory cytokines. This is followed via the activation of the interluken-6 amplifier, which hyperactivates NF-κB and STAT3 [35][32].

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