Abstract
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. 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. 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%). 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.
Highlights
There is a growing appreciation that various manifestations affecting the head/eyes/ears/nose/throat, (HEENT) central and peripheral nervous systems (CNS and Peripheral nervous system (PNS)) may be seen in patients with coronavirus disease 2019 (COVID-19), the pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).[1]Prior outbreaks of the Severe Acute Respiratory Syndrome caused by SARS-CoV-1 and of the Middle East Respiratory Syndrome caused by MERS-CoV implicated coronaviruses in various neurological presentations, but mostly in small case reports or series
Whereas the focus of our review was on the association of COVID-19 with HEENT/ neurological symptoms, we went back as far as the index dates in PubMed and Embase to help contextualize our findings within the framework of what we know from prior coronavirus outbreaks like SARS and MERS
We found a wealth of literature that has emerged over just this past year on neurological and HEENT manifestations of COVID-19
Summary
There is a growing appreciation that various manifestations affecting the head/eyes/ears/nose/throat, (HEENT) central and peripheral nervous systems (CNS and PNS) may be seen in patients with coronavirus disease 2019 (COVID-19), the pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).[1]Prior outbreaks of the Severe Acute Respiratory Syndrome caused by SARS-CoV-1 and of the Middle East Respiratory Syndrome caused by MERS-CoV implicated coronaviruses in various neurological presentations, but mostly in small case reports or series. Muscle symptoms were especially common with SARS; approximately one-third of patients manifested myalgias, elevated creatine kinase (CK),[2,3] and rhabdomyolysis in some series.[4,5] In parallel with these clinical reports, basic and translational science studies have indicated how coronaviruses like SARS-CoV-1, MERS-CoV, and the new SARS-CoV-2 may damage the HEENT and nervous systems (Figure 1).[6] These include direct infection via the circulation or through a neuronal pathway (such as olfactory nerve/bulb invasion), hypoxic injury, modulation of angiotensinconverting enzyme type 2 (ACE2) receptors,[7,8] and immunemediated injury.[9] with prior outbreaks, there was little evidence that these viruses are neuroinvasive, with just one report of SARS-CoV-1 detected in the brain tissue of a patient with neurological symptoms.[10] The eyes may be another route of entry; coronaviruses can cause conjunctivitis, anterior uveitis, retinitis, and even optic neuritis in feline and murine models.[11] The systemic inflammatory response syndrome (SIRS) precipitated by coronaviruses may drive neurological/ HEENT symptoms through the action of tumor necrosis factor α12 and nitric oxide, which may induce apoptotic responses, local demyelination, and axonal degeneration.[13]
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