Signs and Symptoms of Central Nervous System Involvement and Their Pathogenesis in COVID-19 According to The Clinical Data (Review)

Detailed clinical assessment of the central nervous system involvement in SARS-CoV-2 infection is relevant due to the low speciﬁcity of neurological manifestations, the complexity of evaluation of patient complaints, reduced awareness of the existing spectrum of neurological manifestations of COVID-19, as well as low yield of the neurological imaging. The in COVID-19 its based on clinical data. nervous system and the mechanisms of nervous tissue damage. Based on the literature analysis, a high frequency and variability of central nervous system manifestations of COVID-19 were revealed, and an important role of vascular brain damage and neurodegeneration in the pathogenesis of COVID-19 was highlighted.

Therefore, the aim of this review is to reveal the clinical manifestations of central nervous system involvement in COVID-19 and their mechanisms based on the analysis of clinical data.
Analysis of Russian and international literature shows mainly descriptive studies (including international multicenter studies), lack of a unified pathogenesis concept of SARS-CoV-2-associated nervous system damage and insufficient data on the long-term neurological consequences of COVID-19.
The symptoms of COVID-19 traditionally considered as intoxication-related and possibly associated with CNS damage include fever (over 90% of cases), fatigue (45%), headache (8-70%), and dizziness (up to 20% of cases). Fever is a frequent sign of infection-related intoxication in acute respiratory diseases, but in COVID-19 the efficacy of antipyretics is low, which suggests a predominantly central origin of hyperthermia.
Smell disorders are among the most common signs of nervous system involvement in COVID-19 (up to 98% of cases) . Hypo-and anosmia usually occur in the first days of the disease [2, 6, 7, 15,19] and persist for an average of 1-2 weeks [6-8, 13, 15, 17, 19]. The study by Lechien J. R. et al. (2020) (1420 patients with the mean age of 39 years), the frequency of hypo-and anosmia was 70% [8]. All the studies included in the analysis were performed at the same time (first half of 2020), so the wide variation in the frequency of olfactory disorders is unlikely to be explained by altered properties of the SARS-CoV-2 over time. In studies with a sample size of more than 100 observations in East Asian countries, the frequency of olfactory disorders was less than 50% [2,11], while in Western countries it was as high as 86% [3,5,8].
In COVID-19, virus-induced inflammation may be a possible cause of the high frequency of olfactory and gustatory disorders, however there is no such association in other acute respiratory diseases [4,22]. Given the high frequency of smell (up to 98% of cases) and taste disorders (up to 89% of cases) and their obvious predominance among clinical manifestations of CNS involvement, the large proportion of severe disorders (anosmia and ageusia), as well as their short duration and reversibility, the key mechanism of olfactory and taste disorders could most likely be the damage to the receptors.
Altered consciousness is an extremely variable and multifaceted condition seen in many diseases. Its frequency in COVID-19 is 3-8% [2, [23][24][25], but can reach up to 53% in the elderly with severe disease [26]. Importantly, the prevalence of this sign did not differ between East Asian and Western countries.
Bulbar disorders in COVID-19 were reported only by Lechien J. R. et al. (2020), who included patients from Europe (mean age 39 years): the frequency of dysphonia was 28%, the one of dysphagia was 19% [5]. In other studies included in the analysis, dysphonia and dysphagia were not reported, which is most probably attributable to the targeted assessment of swallowing and vocalization done by specialized otolaryngological examination in the study by Lechien J. R. et al.
Dysphonia and dysphagia may be part of bulbar and pseudobulbar syndromes, which, in turn, result from either brainstem or bilateral supranuclear damage. According to Helms J. et al. (2020), patients with COVID-19 rarely demonstrate acute brain lesions on MRI [27], therefore dysphonia and dysphagia are unlikely to be caused by pseudobulbar syndrome. However, dysphonia and dysphagia as part of bulbar syndrome without focal brain abnormalities on MRI are often found in neurodegenerative diseases, primarily amyotrophic lateral sclerosis, which suggests a role of neurodegeneration in CNS damage by SARS-CoV-2. Taking into account the previous data on highly contagious coronavirus infections and extrapolating them to SARS-CoV-2, we should note that, in experiments with mice, the MERS virus when injected intranasally was able to reach the brain stem and thalamus through olfactory nerves [28], whereas the SARS-CoV virus triggers neuronal death with no signs of inflammation in brain [29] suggesting a typical neurodegenerative process. Several studies have confirmed the association between SARS-CoV and a higher risk of Parkinson's disease and multiple sclerosis [30][31][32][33][34][35][36][37]. Another probable cause of dysphonia and dysphagia in COVID-19 may be pre-гии не были представлены, что наиболее вероятно объясняется прицельной оценкой глотания и голосообразования в рамках оториноларингологического осмотра в исследовании Lechien J. R. с соавт.
Potential routes of SARS-CoV-2 entry into the brain include hematologic spread combined with increased permeability of the blood-brain barrier, retrograde transport via olfactory neurons [2] or vagal nerve afferents from lungs or gastrointestinal tract [72]. In retrograde entry through mechanoreceptors and chemoreceptors of lungs, SARS-CoV-2 could affect respiratory and vasomotor centers of medulla oblongata, causing neurogenic respiratory failure [72,73].  presented the most detailed concept of mechanisms responsible for the brain damage in coronavirus infection [74]. According to the authors, the main mechanisms of neuronal damage resulting in toxic infectious encephalopathy, viral encephalitis and acute cerebrovascular events can include: • direct viral damage causing impaired circulation and demyelination; • hypoxic damage and increased anaerobic metabolism; • interaction with angiotensin-converting enzyme-2 (ACE2) receptors; • immune damage leading to systemic inflammatory response syndrome.
ACE2 receptors are found in the cerebral microcirculatory system, which may contribute to brain vulnerability in COVID-19 [75,76].
Analysis of the literature data highlighted the following significant mechanisms of the impact of highly contagious coronaviruses (including SARS-CoV-2) on central nervous system: neurodegeneration (including cytokine-induced), cerebral thrombosis and thromboembolism, damage to the neurovascular unit, immune-mediated damage of nervous tissue, leading to the infection-induced and allergic demyelination.
Few reports of neuroimaging features of SARS-CoV-2 associated brain damage were made available. In March 2020, radiological evidence of COVID-19 brain damage manifested as acute hemorrhagic necrotizing encephalopathy was published. Politi L. S. et al. (2020) demonstrated topically correlated cortical changes in COVID-19-induced anosmia for the first time in vivo using neuroimaging studies [78], which in combination with the above-mentioned assumed leading role of receptor damage suggests a secondary injury of olfactory neurons involved in the pathogenesis of COVID-19-induced anosmia.
COVID-19 can associate with an increased risk of cerebrovascular accidents and subsequent adverse clinical outcome. In medical and surgical practice, the perioperative period has a similar pattern. Among intrahospital strokes, 30% are perioperative, which can be considered as a clinical model of cerebrovascular accident because this type of stroke has a pre-defined time of onset. Pathogenesis, prevention and treatment of perioperative stroke have been studied in detail, as well as the pattern of postoperative cerebral dysfunction [79,80] (see figure).
В литературе представлены немногочисленные наблюдения нейровизуализационных of the main therapeutic targets makes it possible to use the results of studies on the prevention and treatment of perioperative stroke and postoperative cerebral dysfunction (including the preventive use of a combination succinic acid-based antihypoxic drug) [79] to outline the preventive and therapeutic strategies for cerebral vascular damage in COVID-19.

Conclusion
Thus, the analysis of available literature has shown a high frequency and variability of neurological COVID-19 manifestations, as well as an important role of cerebral vascular damage and neurodegeneration in the pathogenesis of COVID-19.