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Severe acute respiratory syndrome coronavirus 2 and seizure: An insight into the pathophysiologic mechanisms

Based on previous studies, seizure has been reported to accompany coronavirus disease 2019 (COVID-19). Underlying mechanisms are those leading to the direct central nervous system (CNS) invasion through hematogenous spread or trans-synaptic retrograde invasion, causing meningoencephalitis. On the other hand, there are pathophysiologic mechanisms that seizure would be one of their early consequences, such as cytokine storm, hypoxemia, metabolic derangement, and structural brain lesions. Herein, we focused on available evidence to provide an insight into the pathophysiologic mechanisms that link seizure and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as a better understanding of pathophysiology would lead to better diagnosis and treatment.


Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel species from the beta-coronavirus genus, has led to the most recent outbreak of severe acute respiratory syndrome (SARS). The symptomatology and underlying signaling pathway of two previous highlypathogenic coronaviruses species, known as SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), was studied in 2002 and 2012, respectively. However, SARS-CoV-2 seems to possess the most malignant epidemic impact among Coronaviridae with many reported neurologic manifestations.
Seizure has been reported in numerous coronavirus disease 2019 (COVID- 19) cases. Based on a retrospective study in China, one patient with severe COVID-19 out of 214 patients had seizure, http://cjn.tums.ac.ir 04 January while for other coronaviruses (such as MERS-CoV), this occurrence had greater prevalence up to 8.6 percent in a report in Saudi Arabia. 1,2 Accepting the similarities between coronaviruses would improve alertness about the expected complications among involved physicians.
Although the hypotheses for SARS-CoV-2 neuroinvasion are mainly based on previous evidence on the coronavirus family and shared similar characteristics, unique SARS-CoV-2 signaling pathways have to be clarified in future studies. Herein, we review possible mechanisms associated with COVID-19 infection that result in seizure as a presenting symptom. For this purpose, we categorize these mechanisms into direct and indirect pathways.

Direct pathway
Seizure is a well-described complication of meningitis and/or encephalitis. Accordingly, Moriguchi et al. reported a case of SARS-CoV-2 meningoencephalitis predominantly presented with generalized seizures. 3 Based on cellular, animal, and clinical studies on previous coronavirus infections, possible central nervous system (CNS) involvement of SARS-CoV-2 has been postulated. Previous studies showed the presence of sporadic epileptiform discharges (EDs) and frontal sharp waves in critically-ill patients with COVID-19, which confirm the involvement of the brain in these patients. 4 Viral meningoencephalitis and acute necrotizing encephalitis (ANE) have been reported as histopathologic evidence of brain invasion in SARS-CoV-2. 5 To unveil these findings, we have to explore the direct entry of the virus into the brain with two classic pathways, trans-synaptic and hematologic.
Trans-synaptic spread of the virus throughout the CNS is one of the possible direct pathways of SARS-CoV-2 neuroinvasion. Prospective epidemiologic studies reported that up to 80% of patients with COVID-19 had significant olfactory dysfunction. 6 Moreover, studies on rats and humans have been carried out to describe the way viruses can enter the brain through the olfactory nerve to cause meningoencephalitis. Apart from the olfactory nerve pathway, there are studies suggesting neuroinvasion and retrograde transsynaptic propagation of the virus to the brain after its inoculation to the cornea, retina, lung, and gut, making the neuroinvasion more possible. 7 Hematogenous spread is another pathway proposed as a mechanism of SARS-CoV-2 invasion to the brain. A post-mortem study by Paniz-Mondolfi et al. has shown the presence of SARS-CoV-2 in the endothelial cells and frontal lobe of an infected patient with encephalopathy who died of COVID-19 complications. 8 SARS-CoV-2 seems to be present in blood circulation. In fact, the capillary endothelium of CNS microcirculation expresses angiotensinconverting enzyme 2 (ACE-2), which is the receptor for SARS-COV2. Thus, the interaction between the virus and cells is guaranteed, which then results in subsequent damage of endothelium and virus entry to the brain. Another proposed mechanism is the passage of leukocytes into the brain tissue. In other words, the virus uses them as its reservoir to enter the brain tissue. 9 Besides, transmembrane serine protease II (TMPRSS2), as a host cell factor for spike protein priming, is crucial for the spread of several clinically-similar viruses, including influenza A viruses and coronaviruses. 10 Hoffmann et al. indicated that SARS-CoV-2 spread also depended on TMPRSS2 activity. 11

Indirect mechanisms
Systemic complications of SARS-CoV-2 infection affect almost every organ, resulting in multi-organ failure in critically-ill patients. Here, we discuss current evidence on various possible mechanisms of COVID-19 systemic complications, presenting with seizure.

Cytokine storm
The overwhelming evidence proposes that seizure is associated with inflammation and elevated levels of cytokines. In this regard, neuronal hyperexcitability has been widely studied concerning elevated circulatory and cerebrospinal fluid (CSF) certain cytokines. Interleukin 1 beta (IL-1β), IL-6, and tumor necrosis factor alpha (TNF-α) activities have extensively been investigated in the context of their pro-convulsive effects. 12 Regarding COVID-19, cytokine release syndrome (CRS) includes elevated levels of inflammatory cytokines, such as IL-6 and TNF-α. 13 Interestingly, Karimi et al. reported frequent compulsive seizures in a case of COVID-19, which have been attributed to pro-inflammatory cytokine storm. 14 On the other hand, the blood-brain barrier (BBB) breakdown is another hypothesis that has been discussed regarding circulatory cytokine elevation and seizure provocation. 15 It is worth mentioning that the cytokine storm has also been http://cjn.tums.ac.ir 04 January reported in connection with ANE, which is mentioned as a complication of COVID- 19. 16 Hypoxia and other mechanisms Respiratory failure in patients with COVID-19 may be justified by various rationales. First of all, extended lung involvement is present after being infected with SARS-COV-2 which is evident in lung imaging. This may cause decreased oxygen levels in the case of diffuse alveolar involvement. Furthermore, as explained in SARS, myopathy, neuropathy, and involvement of respiratory centers have been assumed which may lessen the respiratory function. 17 Acquired acute porphyria due to viral hemoglobin (Hb) 1-beta chain invasion is another hypothesis for SARS-CoV-2-induced hypoxemia, although doubtful methodology precludes its widespread acceptance. 18 Moreover, suggested mechanisms of hypoxic damages include astrocyte swelling and gammaaminobutyric acid (GABA) ergic deficit in the synapses, which could explain the occurrence of post-hypoxic myoclonic jerks and seizures. 19 Lippi et al. in a pooled analysis of 1415 patients with COVID-19 reported that sodium, calcium, and potassium were significantly lower in patients with severe COVID-19 compared to those with the non-severe disease. 20 In addition, consequent changes in sodium and calcium level have been shown to bring about neuronal irritability which can potentially provoke seizure in these patients. 21 Finally, hypercoagulable state and thrombotic microangiopathy (TMA) in patients with COVID-19 might be responsible for the significant rate of cerebrovascular accident (CVA) in these patients. 22,23 Following CVA, there is a risk of acute symptomatic seizure that should be considered in SARS-CoV-2 infection presented with seizure.
Mechanisms of seizure in COVID-19 are summarized in figure 1.

Reported COVID-19-associated seizures
Numerous cases of COVID-19-associated seizures have been reported in the literature. These seizures were documented in a broad range of age groups, from infancy to elderly patients. Generalized tonicclonic seizures (GTCSs), focal motor seizures, and status epilepticus (SE) have been observed in subjects with COVID-19. Besides, several pathologies have been found in these patients justifying the occurrence of seizure, including encephalopathy, meningitis, ANE, and venous sinus thrombosis (VST). The outcome of these patients varied from complete resolution to death in severe cases. Some cases of COVID-19associated seizures are summarized in table 1.

Conflict of Interests
The authors declare no conflict of interest in this study.