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.

Neuropathology and virus in brain of SARS-CoV-2 infected non-human primates

“…Additional life-saving efforts were not made for animals that developed serious disease (e.g., ARDS), as would be done with humans, and were quickly euthanized to minimize pain and suffering of the animal. It is worth noting that autopsy reports of significant lymphocyte infiltration into the CNS or COVID-associated encephalitis are relatively few and may be a less common complication of disease 8 .…”

“…Among the more urgent COVID-19-associated neurological presentations, stroke, meningoencephalitis, and hemorrhagic necrotizing encephalopathies have been associated with more severe disease 2 , 4 – 6 ; however, even comparatively mild neurological symptoms, such as dizziness or unresolving headache 4 , 7 , may be indicative of neuropathological processes in the context of infection and disease. Notably, individuals across the lifespan, with and without significant comorbidities, and with all disease severities, including asymptomatic patients, have suffered the variety of reported neurological manifestations 8 .…”

Brain MRI and neuropsychological findings at long-term follow-up after COVID-19 hospitalisation: an observational cohort study

“…However, a meta-analysis of neurological complications associated with COVID-19 also found that cerebrovascular disease was the most common neurological injury in individuals aged >50 years, occurring in more than 50% of individuals, and could not be explained by increasing age. 26 This suggests that there seems to be an age-associated vulnerability for cerebrovascular disease as a complication of COVID-19 infection. Furthermore, all the patients who underwent MRI during the acute phase of COVID-19 had acquired multiple new white matter lesions when examined at follow-up.…”

Adulthood systemic inflammation accelerates the trajectory of age-related cognitive decline

“…In addition, severe acute systemic inflammation can result in long-lasting cognitive impairments, including increased susceptibility to neurodegeneration after resolution of the infection [ 12 – 14 ]. Concern about the history of inflammation has increased due to the COVID-19 pandemic and neurological features of the disease, which suggest possible long-term effects [ 15 – 19 ]. The results from studies in humans suggest that in order to understand the relationship between severe infections that arise in adulthood and cognitive impairment with advanced age, it is important to distinguish between changes in baseline verses a difference in the trajectory of cognitive decline [ 10 , 11 , 20 – 26 ].…”