**6. Etiopathogenetic evaluation for understanding and treatment of the disease**

It is important to know the causality and etiopathogenesis of COVID-19-related cognitive impairment before the treatment phase. All mechanisms are explained in 3 major pathways. The first is the direct neurotropism of SARS-CoV-2 and is explained by past SARS-CoV studies. The virus may invade the brain by direct neuronal or indirect immune cells-mediated hematogenous pathway. One of the main steps of treatment is to prevent the infiltration of virus-infected immune cells into the central nervous system. It is aimed to prevent cytokine storm with immunosuppression treatment. However, it is important that immunosuppression therapy does not induce infection. The second important step is to prevent the invasion of infiltrating cells with SARS-CoV-2 into the impaired blood-brain barrier structure. At this stage, it should be aimed to stabilize the blood-brain barrier structure [57, 58]. The main aim of treatment is to prevent immune reactivation. Viruses can cause retrograde brain invasion via olfactory neurons. However, there is not enough data about this subject. Invasion has been demonstrated to be associated with ACE2 and TMPRSS2 [12]. Therefore, these proteins and receptors should be targeted in therapy to prevent direct neuronal invasion [12]. Therefore, these proteins and receptors should be targeted during the treatment phase to prevent direct neuronal invasion.

Increased hyperinflammation is detected after cytokine storm in patients with COVID-19. Cytokine storm causes systemic inflammation and vascular damage. Thus, over-induced neuroinflammation is triggered. In addition, mechanical ventilation, cardiopulmonary failure and hypoxia also induce the neuropathological process. Prevention of hypoxia and increased proinflammation is important in the prevention of cognitive impairment. As a result of these mechanisms, cerebral microvascular dysfunction is tried to be prevented [57, 58].

Neuropsychiatric factors have been demonstrated to be important in the pathogenesis. Evaluation of neuropsychiatric disorders in the treatment phase is one of the main strategic steps. Therefore, all patients with and without neurological diseases should be evaluated for neuropsychiatric diseases. The major neuropsychiatric disorders in the COVID-19 disease process are anxiety and depression. These diseases should also be treated [6, 45, 68]. Evaluation of psychiatric and neurocognitive status is important in these patients.

The most important step of this process is the prevention of viral transmission. SARS-CoV-2 spread primarily via respiratory droplets during close face-to-face contact. Personal hygiene, social distance (at least 1 meter, optimum 2 meters) and personal protective equipment are important for protection from COVID-19 disease [57].

Neurocognitive disorders associated with coronavirus infection may have iatrogenic aetiology. Favipiravir and hydroxychloroquine are safe drugs for cognitive dysfunction. No cognitive impairment has been reported as an adverse reaction to tocilizumab. Azithromycin may cause somlonans, insomnia or agitation [57].
