A systematic review of neurological symptoms and complications of COVID-19

Abstract

Objective: To study the frequency of neurological symptoms and complications in COVID-19 patients in a systematic review of the literature.

Methods: Relevant studies were identified through electronic explorations of PubMed, medRxiv, and bioRxiv. Besides, three Chinese databases were searched. A snowballing method searching the bibliographies of the retrieved references was applied to identify potentially relevant articles. Articles published within 1 year prior to April 20th, 2020, were screened with no language restriction imposed. Databases were searched for terms related to SARS-CoV-2/COVID-19 and neurological manifestations, using a pre-established protocol registered on the International Prospective Register of Systematic Reviews database (ID: CRD42020187994).

Results: A total of 2441 articles were screened for relevant content, of which 92 full-text publications were included in the analyses of neurological manifestations of COVID-19. Headache, dizziness, taste and smell dysfunctions, and impaired consciousness were the most frequently described neurological symptoms, the latter more often among patients with a severe or critical disease course. To date, only smaller cohort studies or single cases have reported cerebrovascular events, seizures, meningoencephalitis, and immune-mediated neurological diseases, not suitable for quantitative analysis.

Conclusion: The most frequent neurological symptoms reported in association with COVID-19 are non-specific for the infection with SARS-CoV-2. Although SARS-CoV-2 may have the potential to gain direct access to the nervous system, so far, SARS-CoV-2 was detected in the cerebrospinal fluid in two cases only. Standardized international registries are needed to clarify the clinical relevance of the neuropathogenicity of SARS-CoV-2 and to elucidate a possible impact of SARS-CoV-2 infection on common neurological disease, such as Alzheimer's, Parkinson's disease or multiple sclerosis.

Keywords: COVID-19; Nervous system; Neuro-COVID; SARS-CoV-2.

Fig. 1

Neurotropism of SARS-CoV-2. SARS-CoV-2 spike (S) proteins bind angiotensin-converting enzyme 2 (ACE-2) receptor of target cell. Cleavage of the S protein by type II transmembrane serine protease (TMPRSS2), facilitates viral entry. ACE-2 mRNA expression and double-positive ACE-2 + TMPRSS2 + cells have been identified, amongst others, on neurons and glial cells, in the cerebral cortex, striatum, hypothalamus, substantia nigra and brain stem, making the CNS potential direct targets of SARS-CoV-2 infection ( Adapted from Servier Medical Art, https://smart.servier.com)

Fig. 2

Neuropathogenesis of SARS-CoV-2. a Three potential mechanisms of SARS-CoV-2 invasion into the CNS. (1) CNS entry through the transcribial route, involving infection of the olfactory epithelium [13], (2) axonal transport and trans-synaptic transfer, including infection of various peripheral nerve terminals [17] and the spread along nerves [15] and (3) viral spread through the bloodstream or lymphatic system [18]. b Factors indirectly influencing neurotoxicity. Immune-mediated pathogenesis, associated with, amongst others, lymphocytopenia [2] and T-helper 1 cell-mediated neuroinflammation [20, 21] coagulation dysfunction including higher D-dimer levels, prolonged prothrombin time, and decreased platelet counts [22], as well as hypoxia [26], disturbances of the gut microbiome during gastrointestinal SARS-CoV-2 infection [27] and cardiovascular-metabolic comorbidities like hypertension, diabetes [23] and altered glucose and lipid metabolism [24, 25] might all influence SARS-CoV-2 neuropathogenicity ( Adapted from Servier Medical Art, https://smart.servier.com)

Fig. 3

Study identification PRISMA flow diagram