The lungs are the most severely affected organ in COVID-19, which manifests as diffuse alveolar damage, hyaline membrane formation, inflammatory cell infiltration, and microvascular damage [
20]. Although SARS-CoV-2 infection was initially thought to be limited to the respiratory tract, causing severe respiratory syndrome, it was later found that the virus can invade other organs, including the CNS [
10,
21]. After analysing data from 214 patients from 67 studies, Motalvan et al. [
22] found that 36.4% of patients with COVID-19 developed neurological symptoms (Table
1). Multiple retrospective cohort studies of COVID-19 survivors found that one-third of the patients developed neurological or psychiatric symptoms 6 months after SARS-CoV-2 infection [
23,
24]. In addition, multiple studies have shown a high incidence of cognitive impairment in post-COVID-19 patients, exceeding 50% in all studies reporting prevalence [
25‐
30] (Table
1). Notably, cognitive impairment appears to be more common in critically ill patients. In a cohort study of 1438 COVID-19 survivors, Liu et al. found that 10% of severe COVID-19 survivors had dementia and 26.54% had MCI at 6 months after discharge [
31]. At 12 months, the number of dementia patients increased to 15%, while the number of MCI patients remained at 26.15%, higher than nonsevere cases (0.76%) and MCI (5.35%) [
31] (Table
1). The presence of abnormal brain magnetic resonance imaging (MRI) findings in COVID-19 patients and the detection of SARS-CoV-2 RNA in cerebrospinal fluid may support the possibility that SARS-CoV-2 has neuroinvasive ability [
32‐
35]. Taken together, SARS-CoV-2 enters the brain parenchyma, which may lead to damage and loss of brain neurons and endothelial cells, thereby causing COVID-19-related neurological symptoms.
Table 1
Summary of neurological involvement in COVID-19 patients in existing studies
214 | – | Headache, disturbance of consciousness, neuralgia, ataxia, acute cerebrovascular disease, seizures | |
29 | 59–65% (at 4 months) | Executive dysfunction (33%) | |
2103 | 61.5–80% (at 3 months) | – | |
53 | 61.5% | Hyposmia (26%), headache (21%), ischaemic stroke (11.1%), coordination deficits (74%), paresis (47%), abnormal reflex status (45%), sensory abnormalities (45%) | |
26 | 69.2% | Anosmia (34%), hyposmia (52%), hypogeusia (100%) | |
179 | 58.7% (at 2 months) | Impaired immediate verbal memory and learning (38%), delayed verbal memory (11.8%), verbal fluency (34.6%) and working memory (executive function) (6.1%) | |
226 | 78% | Impaired executive function (50%), impaired psychomotor coordination (57%) | |
1438 | Dementia: 10% (at 6 months)–15% (at 12 months) MCI: 26.54% (at 6 months)–26.1% (at 12 months) | – | |
Furthermore, in severe cases of COVID-19, SARS-CoV-2 infection can trigger systemic inflammation and cytokine storms [
36]. Significantly elevated levels of interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) were found in the cerebrospinal fluid of patients affected by COVID-19 [
37‐
39]. In vivo and in vitro studies have shown that IL-6 and TNF-⍺ can trigger stress response mechanisms that disrupt synaptic plasticity, memory formation, and hippocampal neurogenesis [
40‐
42]. Viruses can cause brain dysfunction and neuronal damage through direct cytolysis or secondary inflammatory responses (indirect effects) [
43]. Regardless of whether the brain is affected by SARS-CoV-2 through primary or secondary pathways, the neurological complications of COVID-19 may be related to the invasive effects of SARS-CoV-2 on brain tissue.