Abstract
Objective The emergence of coronavirus disease 2019 (COVID-19) presents a challenge for neurologists caring for patients with preexisting neurologic conditions hospitalized for COVID-19 or for evaluation of patients who have neurologic complications during COVID-19 infection. We conducted a scoping review of the available literature on COVID-19 to assess the potential effect on neurologists in terms of prevalent comorbidities and incidence of new neurologic events in patients hospitalized with COVID-19.
Methods We searched MEDLINE/PubMed, CINAHL (EBSCO), and Scopus databases for adult patients with preexisting neurologic disease who were diagnosed and hospitalized for COVID-19 or reported incidence of secondary neurologic events following diagnosis of COVID-19. Pooled descriptive statistics of clinical data and comorbidities were examined.
Results Among screened articles, 322 of 4,014 (8.0%) of hospitalized patients diagnosed and treated for COVID-19 had a preexisting neurologic illness. Four retrospective studies demonstrated an increased risk of secondary neurologic complications in hospitalized patients with COVID-19 (incidence of 6%, 20%, and 36.4%, respectively). Inconsistent reporting and limited statistical analysis among these studies did not allow for assessment of comparative outcomes.
Conclusion Emerging literature suggests a daunting clinical relationship between COVID-19 and neurologic illness. Neurologists need to be prepared to reorganize their consultative practices to serve the neurologic needs of patients during this pandemic.
Glossary
- COVID-19=
- coronavirus disease 2019;
- ICU=
- intensive care unit;
- PPE=
- personal protective equipment
The recent outbreak of SARS-CoV-2, designated “coronavirus disease 2019 (COVID-19)” by the World Health Organization (WHO), was officially declared a pandemic on March 11, 2020, and is expected to continue to spread globally.1,2 The disease spectrum ranges from largely asymptomatic infections with or without mild pneumonia to severe hypoxic respiratory failure with multiorgan dysfunction and/or shock.2 COVID-19 is spread through droplets with a highly variable incubation period (5–14 days) with a case fatality rate of 1.8%–3.4%.3 The highly transmissible nature, asymptomatic carriage, and the wide spectrum of illness make this disease challenging for health care systems. Neurologists face the daunting task of caring for patients with preexisting neurologic disease who contract the virus, infected individuals who present with neurologic emergencies requiring neurologic consultation, and patients with COVID-19 who develop secondary neurologic complications such as ischemic stroke, seizures, or encephalopathy during the course of their illness.4,–,6 This necessitates personal protective equipment (PPE) for emergent neurologic consultations as well as consideration of telehealth alternatives to reduce physical exposure for neurologists. A recent meta-analysis examining the prevalence of comorbidities in COVID-19 infections surprisingly reported no neurologic comorbidities and risk stratification scores that qualify patients for therapies like chloroquine have not yet incorporated neurologic illness.7,8 Hence, we conducted a scoping review of the available literature on COVID-19 to assess the prevalence of patients with preexisting neurologic disease and the incidence of neurologic complications following COVID-19 diagnosis.
Methods
The authorship team designed a primary literature search to understand the incidence of patients with preexisting neurologic disease who were diagnosed with and hospitalized for COVID-19 or had reported incidence of secondary neurologic events following diagnosis of COVID-19.
Eligibility criteria
Research studies were selected for inclusion if they met the following criteria: (1) adult patients (aged ≥18 years); (2) diagnosed and received inpatient treatment for COVID-19; and (3) reported data on preexisting neurologic comorbidities or neurologic events occurring during the course of the illness. Additional articles were included through a gray search via Google search engine and manual review of references listed articles to find relevant articles. Studies were not restricted according to design and had to be available in the English language. Because of the rapidly evolving state of the COVID-19 pandemic, non–peer-reviewed articles available via pre-acceptance open access were included. We did not find any pediatric literature relevant to this review.
Information sources and search strategy
We searched electronic databases: MEDLINE/PubMed, CINAHL (EBSCO), and Scopus from January 1, 2020, to April 15, 2020. We summarize the comprehensive search strategies with Boolean operators in table 1.
Electronic database search strategy
Study selection and data collection
At least 2 independent reviewers independently screened all publications, including title and abstract, to determine whether studies met the inclusion criteria. After agreement on included articles, 1 reviewer independently retrieved comorbidity and clinical variables from the selected articles.
Statistical analysis
Pooled descriptive statistics of clinical data and comorbidities were examined.9 The primary goal of this scoping review was to report on the incidence of neurologic comorbidities and occurrence of secondary neurologic events; as such, meta-analysis was not performed.
Results
Preexisting neurologic disease and COVID-19 diagnosis
Articles were screened by title and abstract. Twenty-two studies met the inclusion criteria (figure). Twenty retrospective studies,6,10,–,28 1 prospective observational trial,29 and 1 randomized controlled trial30 were included. Twenty studies were conducted in China, 1 in Italy, and 1 in France. In total, 4,014 patients were included, with a mean age of 55.6 ± 8.4 years and 57% male predominance. The pooled percentage for having a preexisting neurologic disease was 8.0% (n = 322/4,014, range of 0%–40% for individual studies; table 2). The presence of preexisting neurologic disease was frequently not specified and grouped only as cerebrovascular disease, nervous system disease, or history of prior stroke. In addition, 5 studies grouped cerebrovascular disease and cardiovascular disease together, potentially inflating the incidence.17,19,–,21
Prevalence of preexisting neurologic diseases for patients hospitalized for COVID-19
We found headache to be a commonly reported symptom at presentation as it was mentioned in 22 articles. However, headache was not reported as a comorbidity and hence not included. Other neurologic comorbidities rarely mentioned in screened articles included dementia and Parkinson disease (table 1). We did not find a mention of anosmia in any searched scientific literature. We attempted but were unable to assess comparative outcomes from COVID-19 in patients with preexisting neurologic disease due to inconsistency in reporting, potential overlap in multiple studies reporting similar patients, and limited statistical analysis of the included studies. However, a few studies assessed the risk of worse patient outcomes and considered demographic and clinical variables including comorbidities as predictors in the analysis.
Among all patients with COVID-19, those requiring treatment in an intensive care unit (ICU) were more likely to be older, male sex, and have an underlying comorbidity, specifically cerebrovascular disease (16.7% vs 1.0%).12 Similarly, patients who did not have clinical improvement or remission of symptoms within the first 10 days of hospitalization had higher incidence of preexisting cerebrovascular disease (8.2% vs 0%).11 Patients with COVID-19 and underlying cerebrovascular disease were also more likely to develop acute respiratory distress syndrome (11% vs 0%) in a cohort of 109 patients in Wuhan.18 Univariate analysis in a prospective cohort of 179 patients with COVID-19 pneumonia showed that preexisting cardiovascular or cerebrovascular disease was predictive of mortality (odds ratio = 11.059, 95% confidence interval = 4–30).29 We also observed a reported coincidence of Parkinson disease in COVID-19 similar to previously reported with SARS-CoV.15,31 This correlation has been previously explored in several publications.32
Incidence of secondary neurologic disease after COVID-19
We found 10 publications reporting secondary neurologic events in patients diagnosed with COVID-19 (table 3). Four retrospective studies demonstrated a relationship between secondary neurologic events and treatment of COVID-19. One study demonstrated that 36% of 214 patients hospitalized for COVID-19 developed neurologic symptoms or secondary cerebral events.20 Another study demonstrated that 6% of 221 patients hospitalized for COVID-19 had an acute cerebrovascular event (ischemic stroke, cerebral thrombosis, and/or cerebral hemorrhage) while undergoing treatment.21 Hypoxic ischemic encephalopathy was reported in 20% of patients in another case series.24 A French study reported confusion in 65% patients and diffuse corticospinal signs in 67% patients during hospitalization. This study also reported dysexecutive syndrome in 33% of patients at discharge. Among 13 patients undergoing brain MRI in this study, 3 had acute/subacute ischemic strokes, 11 had bilateral frontotemporal hypoperfusion, and 8 had leptomeningeal enhancement with negative CSF RT-PCR.28 Older age, more severe illness, and underlying cardiovascular or cerebrovascular disease were risk factors for secondary cerebrovascular events.20,21 Further case reports have described various neurologic illnesses including acute necrotizing encephalopathy, ischemic strokes, seizures, intracranial hemorrhage, Guillain-Barre syndrome, and meningoencephalitis.22,33,–,37
Incidence and risk of secondary neurologic events during respiratory coronavirus infections
Discussion
These data suggest that patients with underlying neurologic impairment are vulnerable to more severe illness when infected with COVID-19. We saw a trend toward patients with preexisting cerebrovascular disease having higher risk of ICU admission as well as overall mortality. In addition, patients hospitalized with COVID-19 showed a 6%–36% incidence of neurologic events during the course of their illness.
Whether the trend toward worse outcomes is related to vulnerability from neurologic disorders or the presence of other cardiovascular comorbidities leading to neurologic complications in these patients is difficult to discern without further data. The neurotropism of the coronavirus itself is being investigated as a possible mechanism behind the higher incidence of brainstem-mediated cardiopulmonary complications in patients who have more severe disease.38,39
Experimental data including autopsy samples of human brain tissue suggest a neuroinvasive potential of respiratory pathogens including coronaviruses in patients with and without preexisting neurologic disease.40,–,42 Published case series of other corona respiratory viruses like Middle East respiratory syndrome-related coronavirus (MERS-CoV) and severe acute respiratory syndrome-related coronavirus (SARS-CoV) in prior years have listed similar neurologic complications including intracranial hemorrhage, ischemic stroke, polyneuropathy, Bickerstaff encephalitis, and Guillain-Barre syndrome.43
Further data on the vulnerability of patients with neurologic illness may be impactful in targeting this population for proactive viral screening. Risk stratification scores that identify patients at high risk of deterioration or that qualify patients for empiric therapies like hydroxychloroquine also need to reconsider adding patients with cerebrovascular disease.8
The burden of neurologic events occurring in hospitalized patients demonstrates the need for appropriate infrastructure to facilitate neurologic assessments in this population that may be deterred by the cumbersome nature of protection required for clinical assessments. This infrastructure may include a robust supply of PPE for neurologists to assess patients, telemedicine alternatives for remote assessment of bedside examination, and protocols for transporting these patients for neuroimaging including emergent evaluation for cerebrovascular disease.
This scoping review has several limitations. Our analyses are limited by small sample sizes, even smaller incidences of neurologic comorbidities, lack of long-term follow-up, and the possibility of overlap in populations described in reviewed articles potentially biasing the results. The studies included in this scoping review also have inherent bias based on the study designs. The retrospective nature of most of the included studies potentially presents selection and presentation bias. Retrospective studies are subject to misclassification bias with limited ability to control for all potential confounders. In addition, retrospective studies require large sample sizes to generate statistical power to determine different in-study end points. We did not specifically perform a risk of bias assessment in this scoping review, but instead choose to focus on the overall prevalence. Lack of neurologic history reported in medical records by an overstretched health care system, lack of exhaustive reporting of neurologic comorbidities in acutely reported publications, and challenges of neurologic assessments or neuroimaging in patients with COVID-19 may have contributed to the lower reported incidence of neurologic comorbidities or secondary neurologic events in hospitalized patients. Two meta-analyses reporting comorbidities in COVID-19 and MERS-CoV failed to report neurologic comorbidities, highlighting challenges of collecting such data.7,44 We were unable to perform meta-analysis or predict worse outcomes based on comorbidity status.
Conclusions
The culmination of studies indicates a daunting clinical relationship between COVID-19 and secondary neurologic complications and needs a concerted effort by neurologists to reorganize consultative practices to serve the neurologic needs of patients during this pandemic. More sensitive data extraction measures and comprehensive clinical documentation are required to better understand the prevalence of neurologic comorbidities and preexisting neurologic disorders in patients with COVID-19.
Study funding
No targeted funding reported.
Disclosure
The authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.
Appendix Authors
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
- Received March 25, 2020.
- Accepted in final form April 22, 2020.
- © 2020 American Academy of Neurology
References
Letters: Rapid online correspondence
- Reader response: Scoping review of prevalence of neurologic comorbidities in patients hospitalized for COVID-19
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