Open access peer-reviewed chapter

COVID-19 and Seizures

Written By

Rafael Jesus, Carolina Azoia, Paulo Coelho and Pedro Guimarães

Submitted: 13 November 2021 Reviewed: 07 January 2022 Published: 07 February 2022

DOI: 10.5772/intechopen.102540

From the Edited Volume

COVID-19, Neuroimmunology and Neural Function

Edited by Thomas Heinbockel and Robert Weissert

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The past two years were deeply marked by the emergence of a global pandemic caused by the worldwide spread of the virus severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection. The plethora of repercussions on the health of those affected is extensive, ranging from asymptomatic individuals, mild flu-like disease, and severe respiratory failure, eventually leading to death. Despite this predilection for the respiratory system, the virus is responsible for multisystemic manifestations and soon became clear that neurological involvement was a frequent issue of coronavirus disease 2019 (COVID-19). Much have been pointed out about the neurotropic nature of the virus, the ways by which it invades and targets specific structures of the central nervous system, and the physiopathology behind the neurologic manifestations associated with it (namely encephalomyelitis, Guillain-Barré syndrome, lacunar infarcts, and vascular dysfunction, just to list a few). This chapter aims to raise light about the association between COVID-19 and the mechanisms of acute symptomatic seizures, through neurotropism and neuroinvasion features of SARS-CoV-2, and to review the variety of clinical presentations reported so far.


  • COVID-19
  • neurotropism
  • central nervous system infection
  • acute symptomatic seizure
  • electroencephalogram

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].

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].


3. SARS-CoV-2 infection and acute symptomatic seizures

Seizure is a relatively uncommon neurological complication of SARS-CoV-2 infection, accounting for less than 1% of patients [17, 24, 25], despite a significant proportion of patients presenting risk factors such as hypoxia, acute cerebrovascular disease, and metabolic derangements [26]. Prevalence was lower compared with previous MERS-CoV and SARS-CoV (8,6% and 2,7%, respectively) [24, 27].

Acute symptomatic seizures can occur in infection setting particularly in patients with poor general condition and fever [25], but a few case reports stated it as a presenting symptom of SARS-CoV-2 infection without the classical respiratory symptoms [27, 28, 29]. No study has yet clarified any direct relation between COVID-19 and the potentiation of epileptic seizures. At least in some patients with a history of epilepsy, they could merely reflect unprovoked seizures [26].

Nonetheless, several mechanisms were proposed for seizure generation and epileptogenesis in SARS-CoV-2 infection setting.

3.1 Pro-convulsant effect of angiotensin II

Some reports suggested that ACE2 could also be part of a specific mechanism for seizure induction by SARS-CoV-2, with upregulation of components of the renin-angiotensin-aldosterone in the hippocampus of patients with temporal lobe epilepsy. Downregulation of ACE2 would lead to higher concentration of angiotensin II with angiotensin II receptor type 1 (AT1) activation, which is known to cause vasoconstriction and promote inflammatory cascade. ACE2 also plays a role in kallikrein-kinin system, important for maintenance of cardiovascular system homeostasis. These findings point to a pro-convulsant effect of angiotensin II, theoretically increasing susceptibility to seizure occurrence in COVID-19. However, no experimental or clinical data have yet supported this hypothesis yet [26].

3.2 Neuroinflammation and BBB dysfunction

CSF SARS-CoV-2 PCR was reported positive in some patients with clinical and imagiological evidence of encephalitis. This suggests that the virus is able to invade and infect CNS, causing meningitis and encephalitis with possible concurrent seizures [15]. Neuroinflammation may also be acquired from systemic circulation through BBB dysfunction [30, 31]. Glial cells assume an important role in this process by releasing inflammatory mediators and by modulating neuronal function. Seizure generation and epileptogenesis have been associated with neuronal damage and gliosis and, for some time, with an inflammatory state in neural tissue [30].

After CNS invasion, SARS-CoV-2 triggers a large inflammatory cycle that leads to chronic inflammation and neural hyperexcitability, promoting neuronal apoptosis, astrogliosis, and tissue necrosis [32]. There are several proinflammatory cytokines involved in this process, namely IL-1β, TNF-α, IL-6, but also nitric oxide, prostaglandin-E2 (PGE2), and free radicals. IL-1β, expressed in active microglia and astrocytes, increases availability of glutamate in the synapses and increases the number of GluN2B subunits in NMDA receptors of postsynaptic cells leading to hyperexcitability and possibly causing seizures [30, 32]. TNF-α also plays a role in lowering seizure threshold through induction of glutamate release from glia, increasing excitatory glutamate receptors, and decreasing the number of inhibitory GABA receptors and hyperregulating AMPA receptors (leading to calcium over-uptake and neuronal toxicity) [30, 32]. IL-6 is typically found in low amounts in the CNS, but its levels increase with activation of astrocytes and microglia. This upregulation decreases hippocampal neurogenesis and contributes to initiation of epileptogenesis. PGE2 stimulates EP3 receptors on astrocytes also promoting glutamate release and neuronal hyperexcitability and death [30]. In response to neuronal depolarization and upregulation of these proinflammatory cytokines, matrix metalloproteinase-9 (MMP-9) transcription increases. MMP-9 is responsible for structural modification in synapses, reducing its plasticity, increasing susceptibility to seizure occurrence and epileptogenesis [30, 33]. Chemokines, expressed by microglia, astrocytes, and endothelial cells, can also modify neuronal physiology, modulating ion channels and promoting the release of certain neurotransmitters, contributing to the ictal phenomena [30].

Central and peripheral inflammation and hypoxia contribute to BBB breakdown and dysfunction, through upregulation of inflammatory mediators [31]. Similar to other infectious diseases, COVID-19 infection can affect BBB integrity. This leads to migration of blood cells and proteins and to expression of adherence molecules allowing immune cells to enter [30, 32]. Leucocytes also secrete MMP-9 with the subsequent upregulation of inflammatory mediators, which enhance BBB dysfunction, recruit even more immune cells and astrocyte, and activate glia cells, perpetuating a chronic inflammatory process. The ultimate consequence of this cascade of events is the disruption of osmotic balance in CNS leading to neuronal damage, alteration of membrane potential, hyperexcitable status, and seizure genesis [32].

Hyperthermia is another cause of BBB disruption and a potential seizure inducer. In the brain, severe hyperthermia promotes glial cells activation and increases BBB permeability, per se, and indirectly through the release of inflammatory mediators (as IL-1β) [32].

Several studies show that “cytokine storm” and systemic inflammation are responsible for severe cases of acute respiratory distress syndrome and multiorganic failure [34, 35]. Neuroinflammation seems to be a crucial mechanism for seizure occurrence and epileptogenesis in COVID-19 patients [30].

In patients with epilepsy history, infections (mainly respiratory) are a frequent precipitant of relapsing seizures, particularly in pediatric setting [27].

3.3 Metabolic and electrolytic imbalance, hypoxia, and organ failure

Acute symptomatic seizures can occur in patients with metabolic derangements, as the result of COVID-19 multiorganic dysfunction or aggravation of previous comorbidities.

Several works reported metabolic and electrolytic abnormalities in patients with COVID-19, mainly in those patients with severe disease. The most common disorders are decreased serum concentrations of sodium, potassium, calcium, and magnesium, but the pathophysiology is not well elucidated [36, 37]. Some authors propose hypokalemia could result from elevated angiotensin II levels and consequent promotion of renal potassium excretion. Other potential causes for electrolyte imbalance are renal failure, syndrome of inappropriate anti-diuretic hormone secretion (SiADH), iatrogenic (as use of diuretics) and gastrointestinal losses when vomiting and diarrhea are present [36]. Electrolyte disturbances are important causes of acute symptomatic seizures, mainly in patients with hyponatremia, hypocalcaemia, and hypomagnesemia. The successful treatment of these patients is achieved through a correct diagnosis of underlying disturbance and the respective correction, preventing inadequate use of anti-seizure drugs [32, 38].

COVID-19 can also influence glucose metabolism predisposing to higher risk of ketoacidosis in diabetic patients [39]. Even though nonketotic hyperosmolar coma more commonly results in seizures than ketoacidosis, this is a hypothesis to consider in these patients [40].

Systemic inflammatory cascade with endothelial dysfunction and increased brain vasculature permeability and edema can originate a form of posterior reversible encephalopathy syndrome (PRES) concurring as another mechanism for seizure generation. Hypertension and renal disease are predisposing factors for PRES, aggravated by COVID-19 [41].

Severe respiratory disease results in devastating hypoxia that can potentiate hypoxic encephalopathy and contribute to development of seizures. Multiorganic failure as systemic complication of COVID-19 with associated metabolic disorders (namely uremia and metabolic acidosis) could also lead to seizure occurrence [42]. These situations reduce the seizure threshold mostly in susceptible patients (with brain structural lesions or neurodegenerative diseases, for example), potentially causing new-onset seizures or decompensating disease control in patients with previous epilepsy [32].

3.4 Hypercoagulability and cerebrovascular disease

Coagulation disorders and cerebrovascular disease were described soon in a significant number of COVID-19 patients [15]. COVID-19 patients have shown increased levels of D-dimers, which is thought to be associated to the hypercoagulable state and predisposition to thrombosis [22]. One study found much higher rates of diffuse intravascular coagulation in non-survivors compared with survivors, setting that coagulopathy is related to worst prognosis [43, 44]. Different factors can contribute to coagulation disorders. Persistent inflammatory and “cytokine storm” status activates coagulation cascade and suppresses the fibrinolytic system. The resulting endothelial damage by direct effect of the virus (remember ACE2 is expressed in endothelial cells) [22] and aggravated by systemic inflammatory response can activate coagulation system. On the other hand, coagulation cascade can potentiate immune response giving rise to a vicious cycle that progressively increases hypercoagulable state [32, 43].

Thereby, cerebrovascular disease, mainly ischemic events, is a serious complication of COVID-19, occurring in 1–3% of infections (with higher incidence in severe infection setting) [9, 24, 45]. It seems to be the result of hypercoagulable state, direct endothelial damage by SARS-CoV-2, higher levels of angiotensin II associated vasoconstriction, and higher vascular resistance and multiorganic dysfunction that often lead to cardiac malfunction and hypotension, promoting brain ischemia and hypoxia [15, 22].

A seizure can occur as a manifestation of stroke setting with several contributing factors that include hypoxia, metabolic disorders, and imbalance of blood perfusion. In the acute ischemia, damaged cells release potassium and glutamate into the extracellular space, which may activate AMPA and NMDA receptors potentiating neuronal death and contributing for seizure occurrence. Chronic inflammation, gliosis, and neuronal death with alteration of synapses structure and loss of synaptic plasticity contribute to occurrence of late seizures, as well [32, 46].

3.5 Role of mitochondrial dysfunction

Mitochondria play a key role, not only in assuring energy homeostasis, but also in calcium homeostasis, production of reactive oxygen species (ROS), modulation of neurotransmitters in CNS, and regulation of cell apoptosis [47].

COVID-19 infection is associated with oxidative stress, as inflammatory cascade increases production of ROS. High concentrations of ROS can damage mitochondrial respiratory chain, alteration of its membrane permeability and its structure and induce mitochondrial DNA mutations. Due to the important role of these organelles in maintaining normal electrical activity of neuronal and synaptic transmission, any disturbance may lead to abnormal electrical activity of neurons and occurrence of seizures [32, 47].

3.6 Iatrogenic induced seizures

Iatrogenics is another way by which SARS-CoV-2 can be related to acute symptomatic seizures in the context of COVID-19. Drugs used to treat infectionnamely chloroquine and hydroxychloroquinemay cause seizures, along with headache, lightheadedness, and paresthesia; liponavir-ritonavir may also cause peripheral and perioral paresthesia, headache, confusion, and reduction of the epileptic threshold [48].

Certain antibiotics were also associated with acute symptomatic seizures. Despite COVID-19 being a viral infection, some patients can evolve with bacterial superinfection and initiate treatment with antibiotics that predispose for seizures, as it is the case for quinolones [49].


4. Clinical features of seizures associated with COVID-19

As mentioned above, in addition to respiratory symptoms, COVID-19 has been associated with neurologic complications, but minimal literature exists about seizures in these patients [50]. Seizures have been described as direct consequence of SARS-CoV infection in the context of encephalitis [51] or indirectly as a consequence of hypoxemia, metabolic derangement, medications, multiorganic failure, or even brain damage [52]. The evidence available points to the fact that the virus by itself does not carry an increased risk of seizure [50], and it is common to find accompanying seizure-triggering comorbidities in patients with a first seizure and COVID-19, mainly metabolic and electrolytic disturbances and ischemic stroke [27].

New-onset seizures in COVID-19 patients should be considered acute symptomatic, and long-term anti-seizure medication is usually not necessary, unless a subsequent episode occurs or a brain lesion is found to raise the risk for seizure recurrence [53].

COVID-19 may present in many different ways making early diagnosis difficult and delaying proper treatment in atypical cases [27]. Even though seizures are not a common manifestation of COVID-19, they have been described in a variety of forms, as focal motor, generalized motor, convulsive and nonconvulsive status epilepticus (CSE and NCSE, respectively) [52]. In most cases, they are not the presenting symptom and arise mostly in patients with severe disease [26].

New-onset seizures had been described as a possible early symptom of COVID-19 in patients with no preceding symptoms suggestive of that diagnosis and, in some cases, seizure is in fact the symptom that prompts presentation to the emergency room, mainly in children [27]. Fasano and colleagues [28] reported a case of first motor seizure as presenting symptom of SARS-CoV-2 infection; Kadono and coworkers [54] described a case of a patient presenting an acute symptomatic seizure with a recurrence of severe brain edema post cerebral venous thrombosis who was later found to have a COVID-19 infection.

Change in mental status has been reported in about 10% of patients with severe COVID-19, but electroencephalogram (EEG) has not been done as routine to investigate or exclude NCSE in patients with altered responsiveness and COVID-19 [4, 53]. Several studies report that, due to the contagious nature of the disease, COVID-19 patients had limited access to diagnostic investigations, including EEG, and this could seriously underestimate the incidence of non-motor seizures and NCSE [55]. According to semiology, CSE predominates over NCSE [56]. Nonetheless, COVID-19 patients with unexplained altered mental status should be studied for the possibility of NCSE [42]. Some authors recommend continuous EEG monitoring in patients with COVID-19 and altered mental status to rule out NCSE [8].


5. Complementary studies in SARS-CoV-2 infected patients with seizures

5.1 CSF findings

There are only a few reports with CSF findings in COVID-19 patients, as it is not systematically accessed for every patient. One systematic review reported CSF findings in COVID-19 patients who presented seizures in infection setting, including 69 patients. They found that only 13% had positive CSF SARS-CoV-2 PCR. Pleocytosis was found in one-third of them, and nearly half had increased proteinorachia. Postictal pleocytosis and hyperproteinorachia were already described, so these findings may be secondary to seizures itself as opposed to an intrathecal process related to SARS-CoV-2. Autoimmune antibodies were tested in 11 patients and were positive in only two (NMDA antibodies and Caspr2 antibodies). It remained unclear if these findings were related to COVID-19 (as some cases of autoimmune encephalitis can be preceded by infection that works as a trigger of autoimmunity) or if it was purely coincidental [57].

5.2 Electroencephalographic findings

There are some reports of electroencephalogram (EEG) findings in patients with SARS-CoV-2 infection. Altered mental status and seizures are the most common indication for EEG. Most of patients performed routine EEG, with a few cases submitted to continuous video-EEG monitoring [42, 58]. A systematic review found that continuous EEG studies reported more abnormalities than routine EEG [59].

Even though EEG abnormalities are frequent, none of available studies showed specific findings in COVID-19 patients. The most commonly described abnormalities are diffuse slow activity (accounting for 60% of findings in these patients) and, less frequently, focal slow activity [56]. One study showed that brain reactivity was reduced or absent more often in COVID-19 patients with poor prognosis [27, 60]. Confusion and seizures seem to be the most frequent predictors of encephalopathy [58].

According to available literature, epileptiform abnormalities and periodic patterns account for 13–20% of EEG findings in COVID-19 patients, more often found in critically ill patients and in those whose presented seizures [42, 56, 59]. Several EEG patterns were reported in status epilepticus (SE) associated to COVID-19, including periodic discharges (lateralized, bilateral, and generalized) and rhythmic discharges, but no single pattern appears to be specific. EEG findings localized to frontal lobe were described in almost half of SE [59].

Just a few patients had focal abnormalities explained by structural focal lesions as ischemic stroke, encephalitis, and unspecified gliosis [56].

One report found severity of EEG findings may be correlated with oxygen saturation at admission and with severity of COVID-19 [59]. It is difficult to relate EEG findings with CSF and neuroimaging findings as just a few patients underwent a complete screening for all modalities. One study was able to obtain records of thoracic CT scan, CSF SARS-CoV-2 PCR, and EEG of a subgroup of 13 patients, and no correlations were found between those variables [58].

There are some limitations to obtain information in this field. Timing of EEG is difficult to recall, as it is usually performed according to onset of neurological complication and not COVID-19 classical symptoms. Information about disease severity and anti-seizure medication and sedatives at time of EEG is not always clear [56].

5.3 Neuroimaging findings

Neuroimaging findings in COVID-19 patients are heterogeneous, varying according to disease severity and neurological concomitant complications [42]. Available cases and reviews suggest more than two-thirds of COVID-19 patients, who undergo brain imaging (CT or MRI), do not show abnormalities presumably associated to infection [61].

Among those who present abnormalities, the most common findings were unspecific diffuse white matter (WM) abnormality (accounting for about 75% of reported findings) and acute or subacute ischemic strokes. WM signal abnormality is usually described as subcortical and periventricular, in association with microhemorrhages. Cerebellar, midline, and deep brain structures involvement is uncommon [61, 62]. Leukoaraiosis is one important finding attributable to aging, and one review suggested its prevalence was higher in COVID-19 patients than expected for age. However, relationship between COVID-19 infection and structural brain lesions is not clear yet. Cortical FLAIR signal abnormality was described in a vast differential diagnosis, including patients with encephalitis, post-ictal state, PRES, and acute ischemia [61].

In a cohort of patients with SE, MRI revealed abnormalities in about 43% of patients, mainly inflammatory lesions, and lesions suggestive of PRES, brain atrophy, cerebral hemorrhage, and brain tumor. Inflammatory lesions did not reveal a specific localization nor a specific cortical involvement in most of cases [55].


6. Conclusions

SARS-CoV-2 seems to have neurotropism and neuroinvasion mechanisms, similar to previous known human coronavirus infections, and neurological complications are frequent [22]. Despite of all new information constantly being published about this issue, robust and complete data are lacking about seizures in patients with COVID-19.

Systemic infection may be a trigger for breakthrough seizures in patients with a history of epilepsy and respiratory infection in particular is a well-known precipitant of acute symptomatic seizures in such individuals [27]. Severe systemic illness, metabolic derangements, emotional stress, the eventual inability to obtain anti-seizure drugs (as patients may avoid hospitals and pharmacies and have more difficulty to get their medications), or gastrointestinal symptoms impeding absorption of oral medications are just examples of the diversity of ways through which COVID-19 may be associated with recurrence of seizures in the epileptic population [25, 27]. As any other infectious disease, COVID-19 can present with significant electrolytic and metabolic imbalance, as hyponatremia or uremic state, both potentially responsible for lowering the seizure threshold in susceptible, non-epileptic, patients. Acute symptomatic seizure can also occur in the context of cerebrovascular disease [27].

Nevertheless, seizure occurrence in COVID-19 is uncommon. Most of the available reviews report an incidence lower than 1% of SARS-CoV-2 infections, even lower than that described in previous human coronaviruses. Higher risk is appointed for patients with poor general condition and severe COVID-19 symptoms [26, 27].

Regardless of etiology, COVID-19 should be considered in the differential diagnosis for patients presenting with seizures during the pandemic, as early consideration may lead to earlier detection and appropriate precautions [27]. Particular attention should rise for patients with altered mental status and the risk of nonconvulsive status epilepticus.



We dedicate this work to all victims of COVID-19 and their families, as well as to all health professionals specially those working with COVID-19 patients.


Conflict of interest

The authors declare no conflict of interest.


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Written By

Rafael Jesus, Carolina Azoia, Paulo Coelho and Pedro Guimarães

Submitted: 13 November 2021 Reviewed: 07 January 2022 Published: 07 February 2022