Age-Associated Neurological Complications of COVID-19: A Systematic Review and Meta-Analysis

Abstract

The outbreak of the novel and highly infectious severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in hundreds of millions of infections and millions of deaths globally. Infected individuals that progress to coronavirus disease-19 (COVID-19) experience upper and lower respiratory complications that range in severity and may lead to wide-spread inflammation and generalized hypoxia or hypoxemia that impacts multiple organ systems, including the central and peripheral nervous systems. Since the SARS-CoV-2 outbreak, multiple reports continue to emerge that detail neurological symptoms, ranging from relatively mild (e.g., impaired taste and/or smell) to severe (e.g., stroke), suggesting SARS-CoV-2 may be neurotropic and/or contribute to nervous system injury through direct and/or indirect mechanisms. To gain insight into the types of neurological complications associated with SARS-CoV-2 infection and their possible relationship with age, sex, COVID-19 severity, and comorbidities, we performed a systematic review of case reports and series published in 2020 - April 4, 2021 of infected patients with neurological manifestations. Meta-analyses were conducted using individual patient data from reports where these data could be extracted. Here, we report neurological injury occurs across the lifespan in the context of infection, with and without known comorbidities, and with all disease severities, including asymptomatic patients. Older individuals, however, are more susceptible to developing life-threatening COVID-19 and cerebrovascular disease (CVD), such as stroke. A mild but inverse correlation with age was seen with CNS inflammatory diseases, such as encephalitis, as well as taste and/or smell disorders. When reported, increased age was also associated with comorbid cardiovascular risk factors, including hypertension, diabetes mellitus, and lipid disorders, but not with obesity. Obesity did correlate with development of critical COVID-19. Discussion into potential pathophysiological mechanisms by which neurological symptoms arise and long-term consequences of infection to the nervous system is also provided.

Keywords: COVID-19; SARS-CoV-2; aging brain; brain; cerebrovascular events; encephalopathy.

FIGURE 1

PRISMA flow diagram of systematic literature search and screening for studies of COVID-19 patients with neurological conditions.

FIGURE 2

Total number (A) and percent of (B) reported neurological conditions occurring in patients, regardless of demographics (total n = 2,390). Individual diagnoses have been categorized as cerebrovascular diseases (n = 592), peripheral neuropathies (n = 75), encephalopathies (n = 175), demyelinating diseases (n = 23), smell and/or taste disorders (n = 1,303), CNS inflammatory diseases (n = 45), and other (neurological symptoms that cannot be attributed to a specific neurological condition, such as headache, seizure, ataxia, aphasia) (n = 177).

FIGURE 3

Percent of total neurological conditions (n = 1,360) occurring in (A) children (<19 years), (B) young adults (19–50 years), and (C) older adults (>50 years) diagnosed with COVID-19.

FIGURE 4

Total number (n = 584) of reported neurological manifestations occurring in patients with COVID-19 per decade ranging from ≤9 to ≥80 years of age.

FIGURE 5

Simple linear regressions demonstrating the effect of age on (A) cerebrovascular disease, (B) encephalopathy, (C) peripheral neuropathy, (D) CNS inflammatory disease, (E) demyelinating disease, (F) taste and/or smell disorders, and (G) other non-specific neurological symptoms and their relationships with age (years) for patients with COVID-19 (n = 510).

FIGURE 6

Pearson’s correlation matrices and heat maps for (A) age and neurological disease (n = 510), (B) age and COVID-19 symptom severity (n = 495), and (C) age and comorbidities (n = 363) of patients with COVID-19 and diagnosed with a neurological condition(s). Pearson’s correlation coefficients are displayed and assigned color based on the distance from zero, with blue representing positive and red representing negative correlations. CVD, Cerebrovascular disease; Enceph, Encephalopathy; CNS inflamm, Central nervous system inflammatory disease; PN, Peripheral neuropathy; Asympt, Asymptomatic; HTN, Hypertension; DM, Diabetes mellitus.

FIGURE 7

Pearson correlation matrix for age, neurological disease, COVID-19 symptom severity, and comorbidities of COVID-19 patients diagnosed with a neurological condition(s) (n = 303). Pearson’s correlation coefficients are displayed and assigned color based on the distance from zero, with blue representing positive and red representing negative correlations. CVD, Cerebrovascular disease; Enceph, Encephalopathy; CNS inflamm, Central nervous system inflammatory disease; PN, Peripheral neuropathy; Asympt, Asymptomatic; HTN, Hypertension; DM, Diabetes mellitus.

FIGURE 8

ANOVA of COVID-19 severity or comorbidities score by neurological disease category (n = 350). Significant differences in mean COVID-19 severity (A) were seen among all neurological disease categories. Demyelinating disease had the highest mean, with CVD and encephalopathy second and third. Similarly, demyelinating disease had the highest mean comorbidities score, with CVD and encephalopathy second and third (B). Loss of taste/smell had the lowest mean COVID-19 severity and comorbidities score. Data were derived from the same subjects. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.

FIGURE 9

COVID-19 pathology in the CNS: primary impacts and potential mechanisms. Infection by SARS-CoV-2 primarily impacts the lungs, often leading to a hypoxic state and resulting in a robust increase in proinflammatory cytokine production. This may ultimately cause a “cytokine storm” and/or activate glia in the brain. Should such events occur, there is potential for hypoxemia or hypoxia, exacerbated “cytokine storm,” and/or infiltration of peripheral immune cells through endothelial cell infection to occur within the brain; any of which can result in significant brain injury to the infected patient. Although currently unclear, if SARS-CoV-2 can establish a productive or even non-productive infection within the CNS compartment, persistent inflammation and/or impaired cell function may result, increasing the potential for serious injury of the brain and/or pathological brain aging. Created with BioRender.com.