METHODS: We searched PubMed, Medline, Cochrane library, ClinicalTrials.gov, and EMBASE for studies from December 31, 2019, to December 15, 2020, enrolling consecutive patients with COVID-19 presenting with neurologic manifestations. Risk of bias was examined with the Joanna Briggs Institute scale. A random-effects meta-analysis was performed, and pooled prevalence and 95% confidence intervals (CIs) were calculated for neurologic manifestations. Odds ratio (ORs) and 95% CIs were calculated to determine the association of neurologic manifestations with disease severity and mortality. Presence of heterogeneity was assessed with I 2, meta-regression, and subgroup analyses. Statistical analyses were conducted in R version 3.6.2.

RESULTS: Of 2,455 citations, 350 studies were included in this review, providing data on 145,721 patients with COVID-19, 89% of whom were hospitalized. Forty-one neurologic manifestations (24 symptoms and 17 diagnoses) were identified. Pooled prevalence of the most common neurologic symptoms included fatigue (32%), myalgia (20%), taste impairment (21%), smell impairment (19%), and headache (13%). A low risk of bias was observed in 85% of studies; studies with higher risk of bias yielded higher prevalence estimates. Stroke was the most common neurologic diagnosis (pooled prevalence 2%). In patients with COVID-19 ≥60 years of age, the pooled prevalence of acute confusion/delirium was 34%, and the presence of any neurologic manifestations in this age group was associated with mortality (OR 1.80, 95% CI 1.11-2.91).

DISCUSSION: Up to one-third of patients with COVID-19 analyzed in this review experienced at least 1 neurologic manifestation. One in 50 patients experienced stroke. In those >60 years of age, more than one-third had acute confusion/delirium; the presence of neurologic manifestations in this group was associated with nearly a doubling of mortality. Results must be interpreted with the limitations of observational studies and associated bias in mind.

DATA SOURCES: MEDLINE, EMBASE and CENTRAL were systematically searched from their inception until December 2018.

REVIEW METHODS: All randomised clinical trials were included.

RESULTS: Sixteen trials (1634 patients) were included in this meta-analysis. Incidence of delirium was not significantly lower in patients who received melatonin, with an odd ratio, OR (95%Cl) of 0.55 (0.24-1.26); ρ = 0.16, certainty of evidence = low, trial sequential analysis = inconclusive. However, patients who randomised to melatonin had a significantly shorter length of stay in intensive care units, with a mean difference, MD (95%CI) of -1.84 days (-2.46, -1.21); ρ delirium of hospitalised patients. We identified high heterogeneity across all the included trials and low certainty of evidence with potential type II error. Future multi-centre, adequately powered randomised controlled trials are warranted to provide more certainty on the use of melatonin for the prevention of delirium.