**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].

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

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].
