key: cord-0946169-sfur3vkn
authors: Krupp, Karl; Madhivanan, Purnima; Killgore, William D. “Scott”; Ruiz, John M.; Carvajal, Scott; Coull, Bruce M.; Grandner, Michael A.
title: Neurological Manifestations in COVID-19: An Unrecognized Crisis in Our Elderly?
date: 2021-06-16
journal: Adv Geriatr Med Res
DOI: 10.20900/agmr20210013
sha: abe2df7ed0e20d44d050d2ad641c416f1d073d11
doc_id: 946169
cord_uid: sfur3vkn

As of December 2020, there were more than 900,000 COVID-19 hospitalizations in the US with about 414,000 among individuals aged 65 years and older. Recent evidence suggests a growing number of older patients continue to suffer serious neurological comorbidities including polyneuropathy, cerebrovascular disease, central nervous system infection, cognitive deficits, and fatigue following discharge. Studies suggest that complaints manifest late in disease and persist beyond resolution of acute COVID-19 symptoms. Recent research reports that neurocognitive symptoms are correlated with severe disease, older age, male gender, and comorbidities including hypertension, renal failure, and neoplastic disease. The underlying causes are unclear, but current hypotheses include hypoxic-ischemic brain injury, immunopathological mechanisms, and neurotropism of SARS-CoV-2 infection. There is a pressing need for more research into the underlying mechanisms of post-COVID-19 neurological sequela, particularly in the elderly, a population already burdened with neurocognitive disorders.

beyond hospital discharge and are often accompanied by nonspecific complaints of fatigue, nonrestorative sleep, and attention problems [3, 5] . A recent study of Italian COVID-19 patients found they were independently correlated with severe disease, older age, male gender, and non-COVID-19 comorbidities including hypertension, renal failure, and neoplastic disease [6] . Since SARS-CoV-2 is a novel virus, the outlook for these patients is unknown.

A recent study by the Imperial College London analyzing data from 84,285 recovered COVID-19 patients, found "significant cognitive deficits after controlling for age, gender, education level, income, racial-ethnic group, and pre-existing medical disorders" [7] . Patients on mechanical ventilation suffered the worst effects with a 0.57 standard deviation (SD) global composite score reduction equivalent to an average 10-year decline in global performance compared to controls. Standardized differences were larger than the mean deficit for people reporting previous strokes (−0.40 SDs) or learning disabilities (−0.49 SDs). While caution is warranted in interpreting these findings, they are consistent with other research reporting cognitive impairment following COVID-19 disease. Studies from China found that recovered COVID-19 patients exhibited cognitive dysfunction in the sustained attention domain as revealed by Continuous Performance Testing [8] . Data from previous coronavirus epidemics also suggests a potential for long term COVID-19 neurological impairment among vulnerable seniors [9, 10] .

Hypothesized mechanisms for COVID-19 neurocognitive symptoms include hypoxicischemic injury resulting from severe lung damage, immunopathological mechanisms, and neurotropism of SARS-CoV-2 infection [11, 12] . Ample evidence from other age-related hypoxic conditions supports a role for oxygen deprivation in COVID-19-related neuropathology [13] . Less data, however, supports other suggested mechanisms. A recent study did note a disease-associated increase in brain microthrombi and cerebral microstructural alterations in the hippocampus and other brain areas that appeared to be linked to immunopathological causes [14] . Studies using animal models of coronavirus infection have also reported immune-mediated, chronic demyelinating disease similar to multiple sclerosis in humans [15, 16] . Other research using mouse-adapted strains of SARS-CoV, found widespread neuronal infection following virus entry via an olfactory route [17] . Post-mortem studies of COVID-19 patients also found demyelinating lesions in the brain and spine, and detected the SARS-CoV-2 virus in the central nervous system (CNS), suggesting the brain and CNS may be extra-pulmonary targets of COVID-19 disease [17] [18] [19] [20] [21] .

There is a pressing need for longitudinal research among recovered COVID-19 patients to assess the prevalence and persistence of post-COVID-19 neurological symptoms. Studies have yet to explore the relationship between pre-existing neurocognitive disorders and post-COVID-19-related neurological complaints. There is also little data on how long symptoms persist, or if they negatively impact cognitive trajectories in patients with dementia or other neurocognitive disorders. Neurological and cognitive impairments are associated with reduced quality of life, increased caregiver burden, and ultimately, loss of independent living. There is therefore a public health need for a more systematic assessment of cognitive function in patients recovering from COVID-19. The field is currently challenged however, by a lack of precision in case definitions, and poor consensus around the best methods for measuring specific COVID-19 deficits [22] .

What do we need in a neurocognitive research agenda for COVID-19? Clearly, the gaps in our understanding of the disease extend well beyond basic pathophysiology and clinical management. We are entering a period where large numbers of elderly COVID-19 patients are being discharged into the community following extended hospitalizations. The US CDC reports that as many as 9% of those patients are readmitted within two months of treatment [23] . Among first-time readmissions, 3.2% are for CNS, mental, behavioral or neurodevelopmental complaints; and that rises to 4.6% in second readmissions [24] . Given the already overwhelming pandemic-related stress on hospital systems, the prospect of a large and growing number of elderly COVID-19 patients having multiple readmissions, should give us all concern. Following the SARS-CoV-1 epidemic of the 2000's, it was estimated that approximately 3% of survivors required inpatient rehabilitation, and 46% needed some type of outpatient rehabilitative services [25] . Understanding how we can manage this daunting challenge should be a priority question for healthcare systems researchers. Studies assessing the post-pandemic impact of COVID-19 cognitive and neurological disorders on caregiver stress, chronic disease self-management, and the mitigation of accidents and injuries in seniors, is also needed. While we are presently in the middle of one of the most serious healthcare crises in recent memory, the time for planning for post-pandemic challenges is short. Setting an agenda for addressing the needs of seniors suffering the lingering effects of COVID-19 should be a pressing public health priority. 

17-department-of-health-services-medicalmarijuana-program/article-3-dispensaries-and-dispensary-agents/section-r9-17-317-productlabeling

World Health Organization. WHO Coronavirus Disease (COVID-19) Dashboard

Neurological associations of COVID-19

Neurological manifestations of COVID-19: a systematic review and meta-analysis of proportions

Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent Symptoms in Patients After Acute COVID-19

Neurological comorbidity and severity of COVID-19

Cognitive deficits in people who have recovered from COVID-19 relative to controls: An N=84,285 online study

Usefulness and Validity of Continuous Performance Tests in the Diagnosis of Attention-Deficit Hyperactivity Disorder Children

Cognition and chronic hypoxia in pulmonary diseases

Potential neurological impact of coronaviruses: implications for the novel SARS-CoV-2

SARS-CoV-2 and the Nervous System: From Clinical Features to Molecular Mechanisms

Neurological Manifestations of COVID-19 (SARS-CoV-2): A Review

The role of inflammation in age-related disease

Cerebral Micro-Structural Changes in COVID-19 Patients-An MRI-based 3-month Follow-up Study

The pathogenesis of murine coronavirus infection of the central nervous system

Role of the inflammasome-related cytokines Il-1 and Il-18 during infection with murine coronavirus

Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2

Neuroinvasion of SARS-CoV-2 in human and mouse brain. bioRxiv: 169946

SARS-CoV-2 infects human neural progenitor cells and brain organoids

Neuropathology of COVID-19: a spectrum of vascular and acute disseminated encephalomyelitis (ADEM)-like pathology

SARS-CoV-2 can induce brain and spine demyelinating lesions

The measurement of everyday cognition (ECog): scale development and psychometric properties

Characteristics of Hospitalized COVID-19 Patients Discharged and Experiencing Same-Hospital Readmission-United States

MMWR Supplementary Table for

How Will We Care For Coronavirus Patients After They Leave The Hospital? By Building Postacute Care Surge Capacity