**1. Introduction**

When SARS-CoV-2 emerged in a seafood wholesale market in Wuhan, a city in the Hubei Province of China, back in December 2019, the world was far from foreseeing the real dimensions of the challenge ahead. What was first considered as just a local outbreak causing a cluster of cases of a "deadly viral pneumonia," soon became a global concern as it spread throughout the five continents in a matter of few months. While reaching pandemic proportions, in 2020, it revealed to have catastrophic healthcare and socioeconomic effects, being responsible for more than 3 million of confirmed cases worldwide and over 200.000 deaths, all in less than six months. The actual number of infections led to more than 299 million cases and over 5.4 million deaths worldwide (data from Johns Hopkins University Coronavirus Resource Center).

SARS-CoV-2 belongs to the family *Coronaviridae*, a large family of viruses that cause illness ranging from the common cold to more severe diseases [1]. Coronaviruses are enveloped positive-stranded RNA viruses, with crown-like thorns on their surface (the Latin word for crown is *coronam*); full-genome sequencing and phylogenic analysis indicate that SARS-CoV-2 is a betacoronavirus in the same subgenus as its older relative SARS-CoV, both distantly related with the *Middle East respiratory syndrome* (MERS) virus [2, 3]. The analysis of the SARS-CoV-2 genome suggests that a natural evolutionary process between a bat-CoV and a pangolin-CoV could have been important in creating the new zoonotic virus, but the closest RNA sequence similarity is to bat coronaviruses, making bats the most probable primary source of human transmission [1, 4]. SARS-CoV-2 enters host cells via the angiotensin-converting enzyme 2 (ACE2) receptor, which is widely expressed in various human organs, particularly in neurons and glia, and to which it binds through the receptor-binding domain of its spike protein [1, 5].

According to the World Health Organization, COVID-19 symptoms can be divided in *most common*, *less common,* and *serious* [6]. Most common symptoms include fever, cough, tiredness, and loss of taste or smell. Less common symptoms include sore throat, headache, generalized aches and pains, diarrhea, rash, and even red, irritated eyes. When it comes to serious symptoms, these include shortness of breath, chest pain, and some neurologic complications such as loss of speech or mobility and confusion. Gladly, the majority of infected people will develop mild to moderate illness and recover without hospitalization; for those who experience severe manifestations, big effort is put on preventing lethal respiratory failure [6].

Recent reports have drawn attention to the neurotropic behavior shown by the virus, as it affects both the central and the peripheral nervous system (CNS and PNS, respectively), as well as skeletal muscle [7]. The neurological diseases affecting the PNS and muscle in COVID-19 are less frequent than those related to the CNS invasion by the virus and include Guillain-Barré syndrome; Miller Fisher syndrome; multiple cranial neuropathies; and rare instances of viral myopathy with rhabdomyolysis [7].

Most frequently described CNS manifestations include headache and agitation, delirium, impaired consciousness, anosmia, hyposmia, hypogeusia, and dysgeusia, some of which are early symptoms of coronavirus infection [7]. Even the respiratory infection has a probable neurogenic origin and may result from the viral invasion of the olfactory nerve, progressing into rhinencephalon and brainstem respiratory centers [7]. Cerebrovascular disease seems to be due to a prothrombotic state induced by viral attachment to ACE2 receptors in endothelium, causing widespread endotheliitis, coagulopathy, arterial and venous thrombosis; acute hemorrhagic necrotizing encephalopathy has also been documented secondary to the cytokine storm involved in the immune response against the virus [7].

To date, literature is still very scarce when it comes to reports of encephalopathy, meningitis, encephalitis, myelitis, and seizures. Given the already proven neurotropism as a common feature of coronaviruses, it is reasonable to expect that some patients infected with SARS-CoV-2 develop seizures as a consequence of hypoxia, metabolic derangements, organ failure, or even cerebral damage that may occur in the context of COVID-19 [8]. This chapter focuses on the specific matter of acute symptomatic seizures associated with COVID-19 with particular interest in the neurologic mechanisms explaining the epileptogenic activity of SARS-CoV-2.

## **2. About neurotropism: how SARS-CoV-2 affects nervous system**

As soon as the scientific community became aware of the multitude and magnitude of neurological complications of SARS-CoV-2 infection, as well as of the fact that virus is detectable in the cerebrospinal fluid (CSF) of patients infected, much effort was put on finding out the many possible ways the virus can enter and affect the nervous system, for a better understanding of pathophysiology and possible treatment targets [9].

#### *COVID-19 and Seizures DOI: http://dx.doi.org/10.5772/intechopen.102540*

Nervous system invasion has already been demonstrated as a feature of previously identified human coronavirus (namely MERS-CoV and SARS-CoV) [10], but it is not clear yet whether neurological symptoms are a direct result of virus infection of nervous system cells, parainfectious or postinfectious immune-related disease, or a consequence of systemic illness, with possible concurring mechanisms [11].

There have been described two different ways for the virus to reach the central nervous system: using a hematogenous route or by a retrograde axonal route. In the hematogenous route, virus circulating in blood vessels gains access to the CNS through infection of endothelial cells at the blood–brain barrier (BBB), epithelial cells at the choroid plexus and immune cells that eventually enter the CNS (the so called "Trojan horse" method). In the retrograde axonal route, the virus travels backward through the axons to reach neuron cell bodies in the peripheral nervous system or in the CNS through neural-mucosal interface [9, 12].

Several ways have been proposed by which SARS-CoV-2 originates neurological damage, including direct damage through receptors in neurons and glia, or indirectly *via* systemic inflammation with cytokine-mediated injury, secondary hypoxia, and retrograde travel through nerve fibers [9].

### **2.1 The role of angiotensin-converting enzyme 2 (ACE2)**

Early in the pandemic, several studies identified ACE2 expressing cells as targets for SARS-CoV-2 infection. Superficial ACE2 works as a functional receptor for the virus to enter into host cells, similarly as for the previously known SARS-CoV, but with higher binding affinity [12, 13].

ACE2 is a carboxy-peptidase responsible for the synthesis of vasodilator peptides as angiotensin-(1-7) [12] and is widely expressed in almost all human organs in varying degrees. It is present in the brain tissue (both neuronal and glial cells) and endothelial cells of BBB allowing viral binding and entry into CNS [5].

Thereby, in the beginning, it was assumed by some authors that ACE2 deficiency could reduce the impact of SARS-CoV-2 infection [14]. Further studies rejected this hypothesis as they concluded that the interaction between ACE2 and SARS-CoV-2 ultimately leads to substantial loss of ACE2 receptor activity on membrane surface, mainly through its internalization, downregulation, and malfunction. Consequently, there is dysregulation of the protective renin-angiotensin-aldosterone system axis inducing higher levels of angiotensin II and less generation of (protective) angiotensin-(1-7). This gives rise to angiotensin II "storm" triggering vasoconstriction and inflammation, kidney failure, heart disease, apoptosis, and oxidative processes that promote brain degeneration and contribute to the poor outcome seen in many patients with COVID-19 and giving rise to some neurological complications [15, 16].

The binding of SARS-CoV-2 with ACE2 receptor gained more significance in cerebrovascular disease in COVID-19 patients as the imbalance of renin-angiotensin-aldosterone axis results in vascular dysfunction leading to atherosclerosis, arterial hypertension, and cardiovascular disease. Along with the prothrombotic effect of inflammatory cascade, it contributes to a higher risk for stroke and venous thrombosis in these patients [12, 15, 17].

#### **2.2 Neuronal retrograde dissemination and neural-mucosal interface**

Hyposmia and dysgeusia soon started to be widely reported in patients with SARS-COV-2 infection. One study with 417 patients with mild to moderate COVID-19 found olfactory and gustatory dysfunction in 85,6% and 88% of patients, respectively [18]. These symptoms do not seem to be related to traditional nasal symptoms, as

seen in other viral infections (as influenza and rhinovirus), as COVID-19 patients do not present significant nasal congestion or rhinorrhea [15]. Therefore, scientific community postulated that anosmia and dysgeusia could be a consequence of viral infection targeting olfactory system. Further studies suggested that SARS-CoV-2 could directly affect the olfactory nerve and bulb and trigeminal afferents in nasal mucosa and vagus nerve afferents in the respiratory tract, traveling retrogradely along these structures, being a highway between the nasal epithelium and central nervous system [9, 12, 15, 19]. One study assessed viral load of olfactory mucosa and its nervous projections as several other CNS regions in postmortem COVID-19 patients. Higher levels of viral RNA for SARS-CoV-2 were found within the olfactory mucosa directly beneath the cribriform plate, but also in lower levels in the cornea, conjunctiva, and oral mucosa, pointing these as potential sites for SARS-CoV-2 CNS entry. Virus detection in CNS regions with no direct connection to the olfactory mucosa suggests the contribution of other mechanisms in combination with axonal transport, as SARS-CoV-2-containing-leukocyte migrating across the BBB and viral entry along CNS endothelia [19].

Against this theory, some authors showed two important genes for SARS-CoV-2 cellular entry, ACE2 and transmembrane serine protease 2 (TMPRSS2), which were expressed in the olfactory and nasal airway epithelial cells, but not in olfactory afferent neurons, raising questions about the olfactory bulb as a pathway for CNS invasion by SARS-CoV-2 [20]. Frequent and early alterations of taste and smell in patients with COVID-19 reinforce the contribution of a neural-mucosal interface possibly relating to other molecular ways than ACE2 receptor [9, 19].

#### **2.3 Systemic inflammatory response and hypoxia**

Neuronal damage can be either the result of viral replication effects or the aberrant immunological response, consequently giving rise to neurological signs and symptoms [12].

The binding of SARS-CoV-2 to pulmonary epithelial cells gives rise to a systemic inflammatory response (SIRS), mediated by increased levels of interleukin (IL), namely IL-6, IL-12, IL-15, and tumor necrosis factor alpha (TNF-α), the so-called "cytokine storm" [9, 21]. The infiltrated immune cells, which include activated astrocytes and microglia, produce even more inflammatory mediators (including cytokines and matrix metalloproteases) resulting in severe brain inflammation. Besides the chemokine role in host defense, they also are responsible for immune damage by attracting activated T cells, NK cells, and monocytes to the brain tissue. TNF-α and Monocyte Chemoattractant Protein-1 (MCP-1) contribute to disruption of tight junctions of the BBB, increasing vascular permeability and leukocyte migration [12, 22], and all this inflammatory cascade causes even more damage to BBB facilitating SARS-CoV-2 invasion of brain cells [10, 15, 22].

Some authors defend that SARS-CoV-2 has antigenic determinants similar to some of myelinated neurons, and a cross-reaction of immunological response to the virus could lead to a postinfectious autoimmune demyelinating disease as encephalomyelitis or acute demyelinating polyneuropathy [22, 23].

Additionally to the systemic inflammatory response, diffuse alveolar and interstitial inflammatory exudation leads to disruption of alveolar gas exchange causing hypoxia in the CNS. This process can also complicate with hemodynamic changes leading to septic (distributive) shock and CNS hypoperfusion. Consequently, this increases anaerobic metabolism in the brain cells with accumulation of acid metabolites that lead to vasodilation, brain edema, and possibly obstruction of blood flow with consequent hypoxic and ischemic lesions of brain tissue [9, 10].
