Is the Frontal Lobe the Primary Target of SARS-CoV-2?

Acute delirium and other neuropsychiatric symptoms have frequently been reported in COVID-19 patients and are variably referred to as acute encephalopathy, COVID-19 encephalopathy, SARS-CoV-2 encephalitis, or steroid-responsive encephalitis. COVID-19 specific biomarkers of cognitive impairment are currently lacking, but there is some evidence that SARS-CoV-2 could preferentially and directly target the frontal lobes, as suggested by behavioral and dysexecutive symptoms, fronto-temporal hypoperfusion on MRI, EEG slowing in frontal regions, and frontal hypometabolism on 18F-FDG-PET imaging. We suggest that an inflammatory parainfectious process targeting preferentially the frontal lobes (and/or frontal networks) could be the underlying cause of these shared clinical, neurophysiological, and imaging findings in COVID-19 patients. We explore the biological mechanisms and the clinical biomarkers that might underlie such disruption of frontal circuits and highlight the need of standardized diagnostic procedures to be applied when investigating patients with these clinical findings. We also suggest the use of a unique label, to increase comparability across studies.

Neurologic Syndromes Predict Higher In-Hospital Mortality in COVID-19.

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is protean in its manifestations, affecting nearly every organ system. However, nervous system involvement and its effect on disease outcome are poorly characterized. The objective of this study was to determine whether neurologic syndromes are associated with increased risk of inpatient mortality. METHODS: A total of 581 hospitalized patients with confirmed SARS-CoV-2 infection, neurologic involvement, and brain imaging were compared to hospitalized non-neurologic patients with coronavirus disease 2019 (COVID-19). Four patterns of neurologic manifestations were identified: acute stroke, new or recrudescent seizures, altered mentation with normal imaging, and neuro-COVID-19 complex. Factors present on admission were analyzed as potential predictors of in-hospital mortality, including sociodemographic variables, preexisting comorbidities, vital signs, laboratory values, and pattern of neurologic manifestations. Significant predictors were incorporated into a disease severity score. Patients with neurologic manifestations were matched with patients of the same age and disease severity to assess the risk of death. RESULTS: A total of 4,711 patients with confirmed SARS-CoV-2 infection were admitted to one medical system in New York City during a 6-week period. Of these, 581 (12%) had neurologic issues of sufficient concern to warrant neuroimaging. These patients were compared to 1,743 non-neurologic patients with COVID-19 matched for age and disease severity admitted during the same period. Patients with altered mentation (n = 258, p = 0.04, odds ratio [OR] 1.39, confidence interval [CI] 1.04-1.86) or radiologically confirmed stroke (n = 55, p = 0.001, OR 3.1, CI 1.65-5.92) had a higher risk of mortality than age- and severity-matched controls. CONCLUSIONS: The incidence of altered mentation or stroke on admission predicts a modest but significantly higher risk of in-hospital mortality independent of disease severity. While other biomarker factors also predict mortality, measures to identify and treat such patients may be important in reducing overall mortality of COVID-19.

Delirium in Older Patients With COVID-19 Presenting to the Emergency Department.

Importance: Delirium is common among older emergency department (ED) patients, is associated with high morbidity and mortality, and frequently goes unrecognized. Anecdotal evidence has described atypical presentations of coronavirus disease 2019 (COVID-19) in older adults; however, the frequency of and outcomes associated with delirium in older ED patients with COVID-19 infection have not been well described. Objective: To determine how frequently older adults with COVID-19 present to the ED with delirium and their associated hospital outcomes. Design, Setting, and Participants: This multicenter cohort study was conducted at 7 sites in the US. Participants included consecutive older adults with COVID-19 presenting to the ED on or after March 13, 2020. Exposure: COVID-19 was diagnosed by positive nasal swab for severe acute respiratory syndrome coronavirus 2 (99% of cases) or classic radiological findings (1% of cases). Main Outcomes and Measures: The primary outcome was delirium as identified from the medical record according to a validated record review approach. Results: A total of 817 older patients with COVID-19 were included, of whom 386 (47%) were male, 493 (62%) were White, 215 (27%) were Black, and 54 (7%) were Hispanic or Latinx. The mean (SD) age of patients was 77.7 (8.2) years. Of included patients, 226 (28%) had delirium at presentation, and delirium was the sixth most common of all presenting symptoms and signs. Among the patients with delirium, 37 (16%) had delirium as a primary symptom and 84 (37%) had no typical COVID-19 symptoms or signs, such as fever or shortness of breath. Factors associated with delirium were age older than 75 years (adjusted relative risk [aRR], 1.51; 95% CI, 1.17-1.95), living in a nursing home or assisted living (aRR, 1.23; 95% CI, 0.98-1.55), prior use of psychoactive medication (aRR, 1.42; 95% CI, 1.11-1.81), vision impairment (aRR, 1.98; 95% CI, 1.54-2.54), hearing impairment (aRR, 1.10; 95% CI 0.78-1.55), stroke (aRR, 1.47; 95% CI, 1.15-1.88), and Parkinson disease (aRR, 1.88; 95% CI, 1.30-2.58). Delirium was associated with intensive care unit stay (aRR, 1.67; 95% CI, 1.30-2.15) and death (aRR, 1.24; 95% CI, 1.00-1.55). Conclusions and Relevance: In this cohort study of 817 older adults with COVID-19 presenting to US emergency departments, delirium was common and often was seen without other typical symptoms or signs. In addition, delirium was associated with poor hospital outcomes and death. These findings suggest the clinical importance of including delirium on checklists of presenting signs and symptoms of COVID-19 that guide screening, testing, and evaluation.

Neurocovid: Pharmacological Recommendations for Delirium Associated With COVID-19.

BACKGROUND: The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as one of the biggest health threats of our generation. A significant portion of patients are presenting with delirium and neuropsychiatric sequelae of the disease. Unique examination findings and responses to treatment have been identified. OBJECTIVE: In this article, we seek to provide pharmacologic and treatment recommendations specific to delirium in patients with COVID-19. METHODS: We performed a literature search reviewing the neuropsychiatric complications and treatments in prior coronavirus epidemics including Middle Eastern respiratory syndrome and severe acute respiratory syndrome coronaviruses, as well as the emerging literature regarding COVID-19. We also convened a work group of consultation-liaison psychiatrists actively managing patients with COVID-19 in our hospital. Finally, we synthesized these findings to provide preliminary pharmacologic recommendations for treating delirium in these patients. RESULTS: Delirium is frequently found in patients who test positive for COVID-19, even in the absence of respiratory symptoms. There appears to be a higher rate of agitation, myoclonus, abulia, and alogia. No data are currently available on the treatment of delirium in patients with COVID-19. Extrapolating from general delirium treatment, Middle Eastern respiratory syndrome/severe acute respiratory syndrome case reports, and our experience, preliminary recommendations for pharmacologic management have been assembled. CONCLUSIONS: COVID-19 is associated with neuropsychiatric symptoms. Low-potency neuroleptics and alpha-2 adrenergic agents may be especially useful in this setting. Further research into the pathophysiology of COVID-19 will be key in developing more targeted treatment guidelines.

Functional and cognitive outcomes after COVID-19 delirium.

PURPOSE: To ascertain delirium prevalence and outcomes in COVID-19. METHODS: We conducted a point-prevalence study in a cohort of COVID-19 inpatients at University College Hospital. Delirium was defined by DSM-IV criteria. The primary outcome was all-cause mortality at 4 weeks; secondary outcomes were physical and cognitive function. RESULTS: In 71 patients (mean age 61, 75% men), 31 (42%) had delirium, of which only 12 (39%) had been recognised by the clinical team. At 4 weeks, 20 (28%) had died, 26 (36%) were interviewed by telephone and 21 (30%) remained as inpatients. Physical function was substantially worse in people after delirium - 50 out of 166 points (95% CI - 83 to - 17, p = 0.01). Mean cognitive scores at follow-up were similar and delirium was not associated with mortality in this sample. CONCLUSIONS: Our findings indicate that delirium is common, yet under-recognised. Delirium is associated with functional impairments in the medium term.

Spectrum of Neurological Manifestations in Covid-19: A Review.

COVID-19, in most patients, presents with mild flu-like illness. Elderly patients with comorbidities, like hypertension, diabetes, or lung and cardiac disease, are more likely to have severe disease and deaths. Neurological complications are frequently reported in severely or critically ill patients with comorbidities. In COVID-19, both central and peripheral nervous systems can be affected. The SARS-CoV-2 virus causes the disease COVID-19 and has the potential to invade the brain. The SARS-CoV-2 virus enters the brain either via a hematogenous route or olfactory system. Angiotensin-converting enzyme two receptors, present on endothelial cells of cerebral vessels, are a possible viral entry point. The most severe neurological manifestations, altered sensorium (agitation, delirium, and coma), are because of hypoxic and metabolic abnormalities. Characteristic cytokine storm incites severe metabolic changes and multiple organ failure. Profound coagulopathies may manifest with ischemic or hemorrhagic stroke. Rarely, SARS-CoV-2 virus encephalitis or pictures like acute disseminated encephalomyelitis or acute necrotizing encephalopathy have been reported. Nonspecific headache is a commonly experienced neurological symptom. A new type of headache "personal protection equipment-related headache" has been described. Complete or partial anosmia and ageusia are common peripheral nervous system manifestations. Recently, many cases of Guillain-Barré syndrome in COVID-19 patients have been observed, and a postinfectious immune-mediated inflammatory process was held responsible for this. Guillain-Barré syndrome does respond to intravenous immunoglobulin. Myalgia/fatigue is also common, and elevated creatine kinase levels indicate muscle injury. Most of the reports about neurological complications are currently from China. COVID-19 pandemic is spreading to other parts of the world; the spectrum of neurological complications is likely to widen further.