**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 infection**—**namely chloroquine and hydroxychloroquine**—**may 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].
