Neurological and Head/Eyes/Ears/Nose/Throat Manifestations of COVID-19: A Systematic Review and Meta-Analysis

Abstract

Background/objective: Coronavirus disease 2019 (COVID-19) has been associated with various neurological and atypical head/eyes/ears/nose/throat (HEENT) manifestations. We sought to review the evidence for these manifestations.

Methods: In this systematic review and meta-analysis, we compiled studies published until March 31, 2021 that examined non-respiratory HEENT, central, and peripheral nervous system presentations in COVID-19 patients. We included 477 studies for qualitative synthesis and 59 studies for meta-analyses.

Results: Anosmia, ageusia, and conjunctivitis may precede typical upper/lower respiratory symptoms. Central nervous system (CNS) manifestations include stroke and encephalopathy, potentially with brainstem or cranial nerve involvement. MRI studies support CNS para-/postinfectious etiologies, but direct neuroinvasion seems very rare, with few cases detecting Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in the CNS. Peripheral nervous system (PNS) manifestations include muscle damage, Guillain-Barre syndrome (GBS), and its variants. There was moderate-to-high study heterogeneity and risk of bias. In random-effects meta-analyses, anosmia/ageusia was estimated to occur in 56% of COVID-19 patients (95% CI: 0.41-0.71, I2:99.9%), more commonly than in patients without COVID-19 (OR: 14.28, 95% CI: 8.39-24.29, I2: 49.0%). Neurological symptoms were estimated to occur in 36% of hospitalized patients (95% CI: 0.31-0.42, I2: 99.8%); ischemic stroke in 3% (95% CI: 0.03-0.04, I2: 99.2%), and GBS in 0.04% (0.033%-0.047%), more commonly than in patients without COVID-19 (OR[stroke]: 2.53, 95% CI: 1.16-5.50, I2: 76.4%; OR[GBS]: 3.43,1.15-10.25, I2: 89.1%).

Conclusions: Current evidence is mostly from retrospective cohorts or series, largely in hospitalized or critically ill patients, not representative of typical community-dwelling patients. There remains a paucity of systematically gathered prospective data on neurological manifestations. Nevertheless, these findings support a high index of suspicion to identify HEENT/neurological presentations in patients with known COVID-19, and to test for COVID-19 in patients with such presentations at risk of infection.

Keywords: COVID-19; Guillain–Barre; Neurology – General; Peripheral Neuropathy; Sensory systems; Stroke.

Figure 1:

Summary of postulated mechanisms and consequent neurological and HEENT manifestations for coronavirus infections like COVID-19. The mechanisms summarized in this original figure were adapted from a figure by Wu and colleagues. Note that not all mechanisms feed into all the manifestations illustrated in this figure – for example, hypoxic injury is less likely to be a key mechanism in peripheral nerve disorders.

Figure 2:

PRISMA flow diagram for our systematic review of neurological and HEENT manifestations in patients with COVID-19.

Figure 3.

Number of published papers as of March 31, 2021 on (A) head–eyes–ears–nose–throat (HEENT), (B) central nervous system (CNS), and (C) peripheral nervous system (PNS) manifestations of COVID-19. CVST = Cerebral Venous Sinus Thrombosis, GBS = Guillain–Barre Syndrome, MFS = Miller–Fisher Syndrome, NMJ = Neuromuscular Junction disorders like myasthenia gravis.

Figure 4.

Forest plots from random-effects meta-analyses for studies examining (A) the proportion of patients with COVID-19 who have anosmia and/or dysgeusia (restricted to studies with at least 100 patients) and (B) comparing the occurrence of these symptoms with control groups without COVID-19. The studies are grouped by their design (cross-sectional, case–control, retrospective or prospective cohorts). They included a heterogeneous mix of hospitalized and community-dwelling patients. In Figure 4B, the “Yes” columns indicate the number of patients in a given group (COVID-19 patients or control) who had anosmia and/or ageusia, while “No” indicates the number of patients who did not have this symptom.

Figure 5.

Forest plots from random-effects meta-analyses for studies examining the proportion of patients with COVID-19 who have general neurological symptoms that met inclusion criteria for pooled analysis, grouped by study design. These studies generally only included hospitalized patients.

Figure 6.

Forest plots from random-effects meta-analyses for studies examining (A) the proportion of patients with COVID-19 who have an ischemic stroke and (B) comparing the occurrence of ischemic stroke in COVID-19 with control groups without COVID-19. The studies are grouped by their design. These studies generally only included hospitalized patients. In Figure 6B, the “Yes” columns indicate the number of patients in a given group (COVID-19 patients or control) who had an ischemic stroke, while “No” indicates the number of patients who did not have this symptom.

Figure 7.

Forest plots from random-effects meta-analyses for two retrospective cohort studies examining (A) the proportion of patients with COVID-19 who develop Guillain–Barre Syndrome (GBS) and (B) comparing the occurrence of GBS in COVID-19 with control groups without COVID-19. In Figure 7B, the “Yes” columns indicate the number of patients in a given group (COVID-19 patients or control) who had GBS, while “No” indicates the number of patients who did not have this symptom.