COVID-19 disease is a significant risk factor for cerebrovascular complications. The causes of stroke in COVID-19 are essential hypertension, heart-rhythm disorders, inflammation of the myocardium, rheology and blood coagulation system disorders appearing in patients with severe pneumonia or acute respiratory distress syndrome. The diversity of pathogenetic mechanisms determines the heterogeneity of the clinical forms of stroke. The predisposing factors are elderly and senile age, cardiac pathology, intubation, mechanical ventilation, systemic hemodynamic instability, elevated levels of cardiac troponins, D-dimer, fibrin, the presence of atherosclerotic plaques, stenosis of the main arteries of the head and neck [36, 61].

In some observation studies, ischemic stroke (IS) is considered to be cryptogenic in more than 50–65% of cases [46]. In a meta-analysis including 18 studies and 70 thousand patients, cryptogenic IS occurred more often in COVID-19 inpatients than in the uninfected control group [51]. Though this high index can represent incomplete diagnostic assessment of the state of some patients, it suggests that COVID-19 can cause a stroke with the involvement of atypical or new mechanisms, including hypercoagulation and a proinflammatory state related to the new coronavirus infection.

According to L. Mao et al., COVID-19 related stroke is a relatively rare phenomenon. For inpatients, the incidence of COVID-19 related IS ranges from 0.4 to 2.7% and the incidence of intracranial hemorrhage is 0.2–0.9% [46]. The risk of stroke can vary depending on the severity of COVID-19. It is less than 1% for patients with mild disease and can reach 6% for patients of intensive-care units [46].

According to S. Fridman et al., the average age of patients with COVID-19 and stroke is approximately the same as that of patients without COVID-19. The systematic analysis of 10 studies involved 160 patients with COVID-19 and stroke with a mean age of 65 years [26].

Some studies have shown that the mean age of patients with stroke due to COVID-19-related large vessel occlusion is lower than the age of patients without COVID-19, including young individuals without traditional risk factors [32, 57]. Younger patients without risk factors seem to be the minority of COVID-19 related stroke cases.

A retrospective study performed in China and for 221 patients showed the development of IS in 11 people (5% of all patients in the sample), cerebral venous sinus thrombosis in one patient, and intracerebral hemorrhage in one more patient [43]. In another prospective examination of 288 patients, IS was diagnosed in 9 patients (2.5% of the total number of subjects) [44]. Nine published works describe a total of 21 patients (16 men and 5 women) with an average age of 59.8 years (63.1 years for men and 49.8 years for women). Most strokes (19 out of 21) were ischemic, though 3 patients went through the hemorrhagic transformation of IS, and hemorrhagic stroke was diagnosed in two cases. Among the 19 patients with IS, 4 patients died, 6 patients continued to be treated at the intensive-care unit, 3 patients were transferred to the rehabilitation unit, 5 patients quickly recovered, and the fate of one patient is unknown. It is interesting that significantly elevated levels of D-dimer were recorded in 14 cases; among them, 9 patients had variable results of the tests for anti-cardiolipin antibodies [65].

The survey published in 2020, which involved 121 patients of the St. Petersburg city mutiprofile hospital no. 2, was devoted to the analysis of clinical features of stroke against the background of community-acquired pneumonia caused by COVID-19 [1]. Two groups were formed depending on lung damage. The main group included 84 patients with clinically and instrumentally diagnosed novel coronavirus infection in combination with stroke. The control group included 37 patients: cases of ischemic and hemorrhagic stroke without symptoms of SARS-CoV-2. The average age of the patients was 73.5 years. The patients with the comorbidity of cerebral stroke and COVID-19 demonstrated the predominance of IS cases (86.4%), including unspecified (41.4%) and cardioembolic (35.7%) pathogenetic subtypes (according to TOAST) with localization in the carotid system (89.7%). The control group showed different distribution of patients with the following proportion of stroke subtypes: atherothrombotic, 32%; cardioembolic, 40%; unspecified, 24%. The stroke severity according to the National Institutes of Health Stroke Scale (NIHSS) was 13.2 (8.8) points on average in the main group, i.e., less than in the control: 23.1 (9.7) points. The total severity score for brain injury according to the Glasgow Coma Scale upon admission to hospital was 14 (12; 15) on average in the main group, i.e., more than in the control group: 10 (5; 15). The symptoms of pneumonia were revealed in 91.2% of cases in patients of the main group and only in 18.9% of cases in the control group. The assessment of laboratory parameters has shown the following peculiarities: the main group had a higher value of С-RB (11.1 (10.2) mg/L) compared to the control group (10.15 (8) mg/L) and more marked fasting blood glucose levels (8.65 (6.85; 10.45) mmol/L in the main group and 7.30 (6.20; 8.95) mmol/L in the control). There was no reliable increase in the number of cases of clinically significant manifestations of systemic and organ-specific hypercoagulation [1].

In a report of one of New York’s hospitals, the average NIHSS score was higher in patients with the comorbidity of stroke and COVID-19 compared to the control group of patients with stroke but without COVID-19 (NIHSS score 19 vs. 8) [64]. In another study with a combined sample of COVID-19 patients from 28 centers in 16 countries from around the world, the NIHSS score was higher in 174 patients with stroke and COVID-19 compared to patients with stroke without COVID-19 (NIHSS score 10 vs. 6) [54]. In addition, the parameters of mortality and disability after IS were higher in patients with COVID-19 compared to those without it [55].

According to S. Fridman et al., the in-hospital lethality among 160 patients with COVID-19 and stroke was 34% [26]. This result probably represents the greater severity of stroke and/or diverse concomitant pathology as respiratory and other systemic complications of COVID-19 [54, 64].

The analysis of clinical data shows that patients suffer from stroke in the acute period of the novel coronavirus infection against the background of hyperthermia and often pneumonia. Stroke is characterized by large focal lesions in the carotid vascular system, which is more like large-artery thrombotic occlusion syndrome. An essential difference between COVID-dependent and atherothrombotic IS, according to D. McNamara, is the absence of a relationship between a thrombus and an atherosclerotic plaque and the presence of symptoms of vascular-wall inflammation [48]. It is noteworthy that the inflammation and edema of arteries of the vascular system, where cerebral infarction develops, can be considered as acute vasculitis [48].

Should it be considered that there is a special pathogenetic subtype of IS: COVID-19-dependent stroke? Probably yes. This is an ACVA caused by acute inflammatory angiopathy and thrombosis of large arteries of the brain. The acknowledgment of a new IS subtype does not exclude the development of other ACVA variants in COVID-19 patients. The hypercoagulation status of patients with novel coronavirus infection is one more important factor of changes in the stable course of diseases associated with atherosclerosis [12]. The disorders of hemostasis, permeability of the hemovasal barrier in case of inflammatory vasculopathy and uncontrolled arterial hypertension are of primary importance for the initiation of hemorrhagic complications, in particular, hemorrhagic stroke [18, 58]. The peculiar feature of clinical manifestations of intracerebral hemorrhage, i.e., hemorrhagic infarct in cerebral venous sinus thrombosis, is the predominance of cerebral symptoms over focal symptoms [29].

The cases of spontaneous parenchymal and cortical subarachnoid hemorrhage in coagulopathy and anticoagulation have been described [41]. Some of these hemorrhages may be undiagnosed ischemic events followed by hemorrhagic conversion. In the report of S. Dogra et al., who summarized the experience of treating 3824 COVID-19 patients, intracerebral hemorrhage was diagnosed in 33 people (0.9%) [23]. On the basis of X-ray data, the researchers arrived at the conclusion that about 3/4 of them could be a result of hemorrhagic transformation of IS. The publication of E. Lin et al. describes the results of treating 278 COVID-19 patients who underwent neurovisualization. The authors reported the diagnosis of intracerebral hemorrhage in 10 (3.6%) patients. In both reports, most patients underwent full-dose anticoagulation therapy [23, 41].

When characterizing the mechanisms of encephalopathy, we should note that neurological disorders caused by viral infections can be different. On the one hand, acute encephalopathy is a reversible brain dysfunction as a result of systemic toxemia, metabolic disorders and hypoxemia, while viral encephalitis is related to inflammatory parenchymal lesions caused by a virus, which is detected in the cerebrospinal fluid or tissues. COVID-19 patients often suffer from severe hypoxia, which can lead to neurological disorders in the form of impaired consciousness up to coma. Impaired gas exchange in alveoli, pulmonary edema and inflammation result in the development of hypoxia of the CNS; the mitochondria of the brain cells increase anaerobic metabolism; the accumulation of lactic acid leads to vascular dilatation, cellular and interstitial edema, obstruction of blood flow, ischemia and tissue congestion. If hypoxia is not stopped, it will lead to increased intracranial pressure.

In the study of M. Kennedy et al., encephalopathy was diagnosed in 229 (28%) out of 817 elderly and senile patients (average age of 78 years) with confirmed COVID-19. Among these patients, 37% had no typical COVID-19 symptoms such as fever or short breath. The risk factors for encephalopathy included old age, visual impairment, Parkinson’s disease or stroke in past history, as well as the previous use of psychoactive drugs [34].

The distinctive feature of toxic–metabolic encephalopathy is attention deficit and hyperactivity accompanied by confusion, torpor, delirium or coma. The widespread risk factors that predispose patients to delirium are old age, dementia or cognitive disorders, multiple comorbidities, infection, and malnutrition [15].

In COVID-19, there is the possibility of the development of acute hemorrhagic necrotizing encephalopathy. Patients with clinical signs of infection of the upper air passages (cough, short breath) have headaches, behavioral disorders (disorientation, motor anxiety, incomprehension and ignoring speech), loss of consciousness, convulsions, and hyperkinesis. The focal and meningeal symptoms are not always present. Neurovisualization of the brain (CT scan, MRI of the brain) demonstrate symmetric distribution or limited lesion of the temporal-lobe white matter, the island of Reil, the basal ganglions, the thalamus with signs of hemorrhage, and encephalomalacia (softening of the brain), which is typical of necrotic encephalopathy. The brainstem and the cerebellum are affected less frequently [2].

The Chinese experts T. Chen et al. in a retrospective study of clinical characteristics of 113 COVID-19 patients diagnosed hypoxic encephalopathy in 20 (17.7%) patients [19]. L. Мао et al. reported the appearance of headaches and hypoxic encephalopathy in 40% of patients with the novel coronavirus infection, but they did not use detailed data and generally accepted diagnostic criteria [46].

Severe hypoxemia widespread in COVID-19 patients probably plays a role in many cases, just as metabolic disorders, due to organ failure and drug exposure. The neurochemical evidence of astrocyte and neuronal damage recorded in the blood plasma of patients with medium-severe and severe COVID-19 do not confirm particular data on the pathogenesis of encephalopathy. The etiology of encephalopathy in COVID-19 patients is often multifactorial. A series of autopsies from 18 patients with encephalopathy who died of COVID-19 showed acute hypoxic injury in all patients and chronic pathology of the nervous system (arteriosclerosis, Alzheimer’s disease) in most of them [40].

Guillain–Barré syndrome (GBS) is an acute autoimmune lesion of the peripheral nervous system, which manifests itself in muscle weakness and sensory impairment. Since the onset of the pandemic, more than 90 patients with GBS that could be associated with SARS-CoV-2 have been recorded [22, 24]. However, it is still unclear whether SARS-CoV-2 is one more potential infectious agent or the recorded phenomena are random.

In an international prospective cohort study, L.W.G. Luijten et al. examined 49 patients with GBS from China, Denmark, France, Italy, the Netherlands, Spain, Switzerland and Great Britain [45]. The number of such patients was shown to increase only in Switzerland (6 compared to the average value of 1–3 per month one year before the pandemic). The patients were classified into three groups: “potential, ” if they had at least one clinical sign of the SARS-CoV-2 infection; “probable,” if they had deviations on X-ray images with suspected SARS-CoV-2 infection, or if they had both clinical signs: and “confirmed,” in case of laboratory-confirmed SARS-CoV-2 infection. The average age of “confirmed” and “probable” patients was 63 and 53 years, respectively. Most of the “confirmed” patients had a sensorimotor variant of GBS, and all patients had a severe form of the disease. Common early neurological peculiarities were facial nerve palsy, sensory deficit and autonomic dysfunction. Among the “confirmed” patients, 55% had to be admitted to intensive-care units and 36% required mechanical ventilation. All patients at intensive-care units had SARS-CoV-2-related complications (pneumonia, acute respiratory distress syndrome, sepsis, pulmonary embolism); 5 patients had acute tetraparesis, with cranial nerve lesions in 4 of them. All “confirmed” patients received immunomodulatory therapy: immunoglobulins and plasmapheresis. Three patients died: two from pneumonia and one from pulmonary embolism. Thus, the authors came to the conclusion that the expected clinical and electrophysiological phenotype of GBS associated with the SARS-CoV-2 virus is not evidence of their causal relationship, in spite of the presence of COVID-19 in the overwhelming majority of patients. If SARS-CoV-2 can really cause GBS, it is due to the mechanism of post-infectious disease but not due to direct invasion of the virus, because the time between the appearance of SARS-CoV-2 and GBS symptoms is 2.5–3.5 weeks [45].

The authors of several other recently published studies on determination of the relationship between SARS-CoV-2 and GBS have arrived at different conclusions [24, 25]. A retrospective multicenter study performed in Italy showed an increase in the incidence of GBS in March and April of 2020 (30 patients) compared to the same period of 2019 (17 patients) [24]. The findings lead to the conclusion that the incidence of GBS is 47.9 per 100 thousand cases of the SARS-CoV-2 infection. However, this parameter is most likely overestimated due to underestimation of the total number of COVID-19 infected people.

A retrospective “case–control” study in patients of intensive-care units in Spain showed that the probability of GBS development was 6-fold higher in patients with SARS-CoV-2 than in patients without COVID-19 throughout March and April of 2020. However, the total number of GBS cases in this study was actually lower than for the same period of the previous year [25].

Though these results assume a potential relationship between GBS and COVID-19, they per se cannot be reliable evidence of the cause-and-effect relation between these diseases. Both studies included a small number of patients; they were carried out within a short period of time and had numerous potential factors [24].

The review of 37 cases of comorbidity of GBS and COVID-19 published by A.A. Pinto et al. showed that the average period of time between the appearance of symptoms of the new coronavirus infection and the development of acute polyradiculoneuritis was 11 days [56]. In 50% of cases, GBS patients demonstrated the signs of demyelination. Disturbed albumin levels corresponding to impairment of the blood–brain barrier were detected in the cerebrospinal fluid of 76% of the patients. Despite the above, the test of cerebrospinal fluid samples for SARS-CoV-2 RNA was negative in all subjects. Anti-ganglioside antibodies in blood serum were absent in 15 out of the 17 patients under study. The patients received a single course of intravenous injections of immunoglobulin G, and in most cases their state was shown to improve within the first 8 weeks [56].

The Russian authors S.A. Bondar et al. presented two clinical studies of GBS development in men aged 58 years. The period between the first manifestations of COVID-19 and the manifestation of GBS was 5 and 13 days, respectively. In the cases described, GBS had a severe course: both patients required the invasive ventilation of the lungs, with the development of sepsis and acute kidney injury, resulting in the death of one of them. The test for anti-ganglioside antibodies was performed only in one patient, but they were not detected [3].

The prevalence of sleep disorders during the COVID-19 pandemic strongly varied in different groups of examined people: from 3 to 88%. The most affected group was COVID-19 patients (74.8%), followed by healthcare personnel (36%) and the population as a whole (32.3%). COVID-19 patients had sleeping problems, depression and anxiety 6 months after acute coronavirus infection [53]. In the period of the pandemic, more and more publications were devoted to sleep disorders in the case of COVID-19 [8, 13, 21, 27, 28, 40, 47, 49, 50, 53, 60].

R. Gupta et al. have demonstrated that a cytokine storm, which is an immune response to COVID-19, results in inflammation and lesion of the CNS. The SARS-CoV-2 virus affects mainly the prefrontal cortex, the basal ganglions and the hypothalamus, i.e., the areas involved in sleep regulation and cognitive processes [28]. It should be taken into consideration that the situation of the COVID-19 pandemic per se caused significant stress, “indirect injury,” “coronaphobia” and concerns about health, social isolation, changes in employment, financial wellbeing, as well as the problem of combining work and family duties, and adaptation to a new way and rhythm of life. Such a large-scale stressful life event, together with the particular psychological characteristics of a person, resulted in sleep and circadian-rhythm disorders, impeded flexible adaptation to the crisis and increased uncertainty about the future [13].

M. Lauriola et al. have confirmed the presence of a bidirectional relationship between solitude and insomnia. The authors have proven that the fear of being infected by СOVID-19 is directly associated with insomnia. The anxiety of waiting causes cognitive arousal and therefore affects sleep. The subjective feeling of loneliness is also related to the symptoms of insomnia [39]. Solitude may intensify the feeling of vulnerability, cognitive and behavioral hyperexcitation, restless and shallow sleep. On the contrary, decreasing satisfaction with the quality of sleep enhances frustration associated with the feeling of loneliness and can interfere with contacts with other people, e.g., because of sleep–wake schedule disruption [27].

The study by A. Abdelhady has shown that the main sleep disorders in people having COVID-19 are insomnia (presomnic disorders accompanied by emotional and cognitive mobilization) and “secondary” restless legs syndrome. It can be directly associated with infection, hypoxia and mental state. The low quality and longer latency of sleep (trouble falling asleep), restless, shallow sleep full of dreams and nightmares are the main symptoms of insomnia. They are observed during acute coronavirus infection; in the period of rehabilitation, they are associated with immune processes promoting the appearance of pathological forms of sleep disorder. It is probable that the high incidence of sleep disorders during the COVID-19 pandemic can be attributed to asymptomatic infection by the virus [13].

In addition, A. Abdelhady has shown that patients with PCR-confirmed COVID-19 infection demonstrate intensification of somatic phenomena (tachycardia, nausea, etc.) as a form of stress regression; sleep duration decreases in the incubation period and increases in the symptomatic phase, being referred to as COVID-19 associated sleep disorders. At the same time, a combined approach including somatotropic therapy, psychopharmacotherapy (if necessary) and cognitive behavioral therapy for insomnia, both face-to-face and digital cognitive behavioral therapy, restored the normal sleep regime and improved the general condition of COVID-19 patients [13].

G. Das et al. have noted that effective therapy results in a rapid return to the initial duration of sleep [21]. P. Markku has shown that sleep suppresses the activity of the hypothalamic–pituitary–adrenal axis (the stress response axis), which mediates several aspects of responses to most stresses, some stressors, and psychological factors suppress sleep and increase the period of wakefulness by creating cognitive (the stream of thoughts “what if…,” “if… then”) and behavioral hyperexcitation (overcautious behavior, fussiness, searching behavior for sleep improvement) [47].

Some authors note that insomnia symptoms are also observed in the period of rehabilitation after COVID-19, which may be caused by anticipatory anxiety regarding relapse. However, clinical experience shows that, in spite of reduced systemic inflammation and hypoxemia in patients, sleep remains disturbed even after recovery. This fact suggests the presence of a post-covid stress disorder. It has been shown that there is no relationship between COVID-19 morbidity/mortality and insomnia [21, 28, 47, 59].

The gender factor revealed in the pre-covid period also proved to be important, demonstrating that women are more predisposed to sleep disorders in the pandemic period. This conclusion is in agreement with evidence that women are more sensitive to stress-related pathologies such as post-traumatic stress disorder and anxiety-spectrum disorders [16, 42].

The personnel of ambulance teams and “red zones” of hospitals run the maximum risk of insomnia during the COVID-19 pandemic. A higher workload, round-the-clock shift work, and fear of being infected by the coronavirus became significant risk factors for these people. It resulted in higher psychosocial stress and emotional burnout, including those due to sleep disorders [30].

The Russian researcher A.I. Melekhin has described specificity of the forms of sleep disorders during the COVID-19 pandemic, which includes a range of sleep alterations, from insomnia and restless legs syndrome to behavioral disorders in the REM sleep phase. The author has demonstrated different effects of the coronavirus, COVID-associated stress on the sleep disorders of patients and their psychoneurological status; described the specific diagnostic clinical and psychological manifestations of COVID-associated sleep disorders; presented models of relations between COVID-associated anxiety, the perception of situations as stress, insomnia, suicidal thinking, anxiety-spectrum disorders and depression; proved that the predictable insomnia during the COVID-19 pandemic arises from a patient’s intolerance to uncertainty, COVID-associated anxiety, the feeling of loneliness, the presence (both previously and currently) of symptoms of depression and anxiety [8].

As a result of a study including 920 residents of Moscow and St. Petersburg who stayed in 10-day isolation (75.3% women and 24.8% men, 18–37 years old), A.I. Melekhin was the first one in Russia to describe the general tactics of psychological examination of an infected patient or a COVID-19 survivor in the presence of insomnia and alterations in mental state. The author arrived at the following conclusions [8].

— The question regarding the relationship between the coronavirus (viral load) and sleep disorders remains open. A person who has fallen ill with or is recovering from COVID-19 may have COVID-associated sleep disorders (chronic insomnia, “secondary” restless legs syndrome). At the same time, there may be anxiety-spectrum disorders with the anticipation of repeated infection resulting in chronic insomnia. The COVID-19 pandemic per se, with the particular psychological peculiarities of a person (high neuroticism, tendency to catastrophizing), can also lead to sleep and circadian-rhythm disorders.

— The phenomenon of COVID-somnia includes a whole set of changes in sleep: specific nightmares, insomnia (presomnic and intrasomnic disorders), restless legs syndrome, sleep apnea, night terror, nighttime panic attacks, maternal insomnia and behavioral disorders during the REM sleep phase.

— The factors affecting sleep disorders during the COVID-19 pandemic are as follows: changes in tolerance to uncertainty, COVID-associated anxiety, the perception of situations as stresses, the subjective feeling of loneliness, anxiety and depression symptoms. Women and elderly people (55+) are more disposed to insomnia during the pandemic.

— The psychological examination of a patient with post-covid sleep disorder should be performed by a clinical psychologist, with assessment of the symptoms of insomnia (ISI) and excessive daytime sleepiness (ESS), and dysfunctional beliefs about sleep (DBAS-16). Attention should be paid to assessing the general health concern, COVID-associated anxiety, assessment of depression symptoms, taking into account the risk factors for suicide, cyberchondriac manifestations, tolerance to uncertainty and changes in emotional regulation. Additionally, there are studies of the specificity of patients’ perception of situations as stresses, the presence of problem-oriented personality type and COVID-associated victimity.

— For COVID-associated sleep disorders (chronic insomnia, restless legs syndrome) and coronaphobia accompanied by episodes of insomnia, it is recommended to use the protocol of short-term digital cognitive behavioral therapy for anxiety and insomnia associated with the СOVID-19 pandemic. It is necessary to pay attention to cyberchondriac manifestations in a patient, with minimization of excess negative information search, and health concern with avoiding and overcautious behavior.

The initial randomized studies showed the high efficiency of vaccines against the new coronavirus infection COVID-19. In addition to direct protection against COVID-19 infection, available vaccines substantially reduce transmission, partially by protecting against both symptomatic and asymptomatic infection. However, the main goal of vaccines against COVID-19 is protection against severe disease but not infection. Numerous studies have shown stable efficiency of the vaccine against severe COVID-19 disease for most of adults [20, 35].

At the same time, there are short-term side effects and potential medium- and long-term unfavorable complications of vaccination, which cannot be detected due to the absence of research results. In long-term studies of vaccine safety (e.g., with regard to the potential initiation of neoplasms or Alzheimer’s disease), decades may be required to obtain trustworthy results. Thus, there is incompatibility between the short terms of the development and production of vaccines, which the government and industry strive for, and the time necessary for the validation of control measures providing vaccine safety [35].

According to L. Adeline et al., in the autumn of 2020, 2 patients had transverse myelitis after using the Oxford/AstraZeneca vaccine [14]. A. Allen et al. have described a single case of post-vaccination transverse myelitis in a patient with the previously diagnosed multiple sclerosis. The relationship between transverse myelitis and vaccination has been assessed as highly unlikely, while the other case of myelitis is referred to as immune-mediated [