COVID-19 and Risk for Mental Disorders Among Adults in Denmark.

Importance: Psychiatric outcomes after COVID-19 have been of high concern during the pandemic; however, studies on a nationwide level are lacking. Objective: To estimate the risk of mental disorders and use of psychotropic medication among individuals with COVID-19 compared with individuals not tested, individuals with SARS-CoV-2-negative test results, and those hospitalized for non-COVID-19 infections. Design, Setting, and Participants: This nationwide cohort study used Danish registries to identify all individuals who were alive, 18 years or older, and residing in Denmark between January 1 and March 1, 2020 (N = 4 152 792), excluding individuals with a mental disorder history (n = 616 546), with follow-up until December 31, 2021. Exposures: Results of SARS-CoV-2 polymerase chain reaction (PCR) testing (negative, positive, and never tested) and COVID-19 hospitalization. Main Outcomes and Measures: Risk of new-onset mental disorders (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes F00-F99) and redeemed psychotropic medication (Anatomical Therapeutic Chemical classification codes N05-N06) was estimated through survival analysis using a Cox proportional hazards model, with a hierarchical time-varying exposure, reporting hazard rate ratios (HRR) with 95% CIs. All outcomes were adjusted for age, sex, parental history of mental illness, Charlson Comorbidity Index, educational level, income, and job status. Results: A total of 526 749 individuals had positive test results for SARS-CoV-2 (50.2% men; mean [SD] age, 41.18 [17.06] years), while 3 124 933 had negative test results (50.6% women; mean [SD] age, 49.36 [19.00] years), and 501 110 had no tests performed (54.6% men; mean [SD] age, 60.71 [19.78] years). Follow-up time was 1.83 years for 93.4% of the population. The risk of mental disorders was increased in individuals with positive (HRR, 1.24 [95% CI, 1.17-1.31]) and negative (HRR, 1.42 [95% CI, 1.38-1.46]) test results for SARS-CoV-2 compared with those never tested. Compared with individuals with negative test results, the risk of new-onset mental disorders in SARS-CoV-2-positive individuals was lower in the group aged 18 to 29 years (HRR, 0.75 [95% CI, 0.69-0.81]), whereas individuals 70 years or older had an increased risk (HRR, 1.25 [95% CI, 1.05-1.50]). A similar pattern was seen regarding psychotropic medication use, with a decreased risk in the group aged 18 to 29 years (HRR, 0.81 [95% CI, 0.76-0.85]) and elevated risk in those 70 years or older (HRR, 1.57 [95% CI, 1.45-1.70]). The risk for new-onset mental disorders was substantially elevated in hospitalized patients with COVID-19 compared with the general population (HRR, 2.54 [95% CI, 2.06-3.14]); however, no significant difference in risk was seen when compared with hospitalization for non-COVID-19 respiratory tract infections (HRR, 1.03 [95% CI, 0.82-1.29]). Conclusion and Relevance: In this Danish nationwide cohort study, overall risk of new-onset mental disorders in SARS-CoV-2-positive individuals did not exceed the risk among individuals with negative test results (except for those aged ≥70 years). However, when hospitalized, patients with COVID-19 had markedly increased risk compared with the general population, but comparable to risk among patients hospitalized for non-COVID-19 infections. Future studies should include even longer follow-up time and preferentially include immunological biomarkers to further investigate the impact of infection severity on postinfectious mental disorder sequelae.

COVID-19 and the subsequent risk of mental disorders: A nationwide study of all SARS-CoV-2 PCR test results in Denmark

Importance Psychiatric outcomes after COVID-19 have been of high concern during the pandemic, however, studies on a nation-wide level are lacking. Objective To examine the risk of mental disorders and use of psychotropic medication among individuals with COVID-19 compared to individuals not tested, individuals tested SARS-CoV-2 negative and those hospitalized for non-COVID infections. Design, setting and participants Nation-wide cohort study using Danish registries to identify all individuals alive, ≥18 years and resident in Denmark between January-March-2020 (N=4,152,792), excluding everyone with a previous history of a mental disorder (N=616,546). Exposures SARS-CoV-2 PCR testing (negative, positive, and never tested) and COVID-19 hospitalization. Main outcomes and measures Risk of new-onset mental disorders and redeemed psychotropic medication was estimated through survival analysis using a Cox proportional hazard model reporting hazard rate ratios (HRR) with 95% confidence intervals (CI) as measures of relative risk. All outcomes were adjusted for age, sex, parental history of mental illness, Charlson-Comorbidity-Index, education-level, income, and job-status. Results A total of 526,749 individuals tested positive for SARS-CoV-2, while 3,124,933 tested negative and 501,110 had no tests performed. The risk of mental disorders was increased in individuals tested positive, respectively, negative for SARS-CoV-2 (HRR, 1.24;95%CI, 1.17-1.31, respectively, HRR, 1.42;95%CI, 1.38-1.46), compared to those never tested. Compared to individuals tested negative, the risk of new-onset mental disorders in SARS-CoV-2 positive individuals was lower in the 18-29yrs age-group (HRR, 0.75;95%CI, 0.69-0.81), whereas individuals >70-years had increased risk (HRR, 1.25;95%CI, 1.05-1.50). A similar pattern was seen regarding psychotropic medication use with a decreased risk in the 18-29 years age-group (HRR, 0.81;95%CI, 10.76-0.85) and elevated risk in those >70yrs (HRR, 1.57;95%CI, 1.45-1.70). The risk for new-onset mental disorders were substantially elevated in hospitalized COVID-19 patients compared to the general population (HRR, 2.52;95%CI, 2.34-2.72);however, no difference in risk was seen when compared to hospitalization for non-COVID respiratory infections (HRR, 1.03;95%CI, 0.82-1.29). Conclusion and relevance In this nation-wide cohort study, overall risk of new-onset mental disorders in SARS-CoV-2 positive did not exceed the risk among individuals tested negative (except for those >70yrs). However, when hospitalized, COVID-19 patients had markedly increased risk compared to the general population, but comparable to those hospitalized for non-COVID infections.

Duration of Device-Based Fever Prevention after Cardiac Arrest.

BACKGROUND: Guidelines recommend active fever prevention for 72 hours after cardiac arrest. Data from randomized clinical trials of this intervention have been lacking. METHODS: We randomly assigned comatose patients who had been resuscitated after an out-of-hospital cardiac arrest of presumed cardiac cause to device-based temperature control targeting 36°C for 24 hours followed by targeting of 37°C for either 12 or 48 hours (for total intervention times of 36 and 72 hours, respectively) or until the patient regained consciousness. The primary outcome was a composite of death from any cause or hospital discharge with a Cerebral Performance Category of 3 or 4 (range, 1 to 5, with higher scores indicating more severe disability; a category of 3 or 4 indicates severe cerebral disability or coma) within 90 days after randomization. Secondary outcomes included death from any cause and the Montreal Cognitive Assessment score (range, 0 to 30, with higher scores indicating better cognitive ability) at 3 months. RESULTS: A total of 393 patients were randomly assigned to temperature control for 36 hours, and 396 patients were assigned to temperature control for 72 hours. At 90 days after randomization, a primary end-point event had occurred in 127 of 393 patients (32.3%) in the 36-hour group and in 133 of 396 patients (33.6%) in the 72-hour group (hazard ratio, 0.99; 95% confidence interval, 0.77 to 1.26; P = 0.70) and mortality was 29.5% in the 36-hour group and 30.3% in the 72-hour group. At 3 months, the median Montreal Cognitive Assessment score was 26 (interquartile range, 24 to 29) and 27 (interquartile range, 24 to 28), respectively. There was no significant between-group difference in the incidence of adverse events. CONCLUSIONS: Active device-based fever prevention for 36 or 72 hours after cardiac arrest did not result in significantly different percentages of patients dying or having severe disability or coma. (Funded by the Novo Nordisk Foundation; BOX ClinicalTrials.gov number, NCT03141099.).

Incidence and prevalence of coma in the UK and the USA.

The epidemiology of coma is unknown because case ascertainment with traditional methods is difficult. Here, we used crowdsourcing methodology to estimate the incidence and prevalence of coma in the UK and the USA. We recruited UK and US laypeople (aged ≥18 years) who were nationally representative (i.e. matched for age, gender and ethnicity according to census data) of the UK and the USA, respectively, utilizing a crowdsourcing platform. We provided a description of coma and asked survey participants if they-'right now' or 'within the last year'-had a family member in coma. These participants (UK n = 994, USA n = 977) provided data on 30 387 family members (UK n = 14 124, USA n = 16 263). We found more coma cases in the USA (n = 47) than in the UK (n = 20; P = 0.009). We identified one coma case in the UK (0.007%, 95% confidence interval 0.00-0.04%) on the day of the survey and 19 new coma cases (0.13%, 95% confidence interval 0.08-0.21%) within the preceding year, resulting in an annual incidence of 135/100 000 (95% confidence interval 81-210) and a point prevalence of 7 cases per 100 000 population (95% confidence interval 0.18-39.44) in the UK. We identified five cases in the USA (0.031%, 95% confidence interval 0.01-0.07%) on the day of the survey and 42 new cases (0.26%, 95% confidence interval 0.19-0.35%) within the preceding year, resulting in an annual incidence of 258/100 000 (95% confidence interval 186-349) and a point prevalence of 31 cases per 100 000 population (95% confidence interval 9.98-71.73) in the USA. The five most common causes were stroke, medically induced coma, COVID-19, traumatic brain injury and cardiac arrest. To summarize, for the first time, we report incidence and prevalence estimates for coma across diagnosis types and settings in the UK and the USA using crowdsourcing methods. Coma may be more prevalent in the USA than in the UK, which requires further investigation. These data are urgently needed to expand the public health perspective on coma and disorders of consciousness.

Frequency of Neurological Diseases After COVID-19, Influenza A/B and Bacterial Pneumonia.

Introduction: COVID-19 might affect the incidence of specific neurological diseases, but it is unknown if this differs from the risk following other infections. Here, we characterized the frequency of neurodegenerative, cerebrovascular, and immune-mediated neurological diseases after COVID-19 compared to individuals without COVID-19 and those with other respiratory tract infections. Methods: This population-based cohort study utilized electronic health records covering ~50% of Denmark's population (n = 2,972,192). Between 02/2020 and 11/2021, we included individuals tested for COVID-19 or diagnosed with community-acquired bacterial pneumonia in hospital-based facilities. Additionally, we included individuals tested for influenza in the corresponding pre-pandemic period between 02/ 2018 and 11/2019. We stratified cohorts for in- and outpatient status, age, sex, and comorbidities. Results: In total, 919,731 individuals were tested for COVID-19, of whom 43,375 tested positive (35,362 outpatients, 8,013 inpatients). Compared to COVID-negative outpatients, COVID-19 positive outpatients had an increased RR of Alzheimer's disease (RR = 3.5; 95%CI: 2.2-5.5) and Parkinson's disease (RR = 2.6; 95%CI: 1.7-4.0), ischemic stroke (RR = 2.7; 95%CI: 2.3-3.2) and intracerebral hemorrhage (RR = 4.8; 95%CI: 1.8-12.9). However, when comparing to other respiratory tract infections, only the RR for ischemic stroke was increased among inpatients with COVID-19 when comparing to inpatients with influenza (RR = 1.7; 95%CI: 1.2-2.4) and only for those >80 years of age when comparing to inpatients with bacterial pneumonia (RR = 2.7; 95%CI: 1.2-6.2). Frequencies of multiple sclerosis, myasthenia gravis, Guillain-Barré syndrome and narcolepsy did not differ after COVID-19, influenza and bacterial pneumonia. Conclusion: The risk of neurodegenerative and cerebrovascular, but not neuroimmune, disorders was increased among COVID-19 positive outpatients compared to COVID-negative outpatients. However, except for ischemic stroke, most neurological disorders were not more frequent after COVID-19 than after other respiratory infections.

Neuropsychiatric and Cognitive Outcomes in Patients 6 Months After COVID-19 Requiring Hospitalization Compared With Matched Control Patients Hospitalized for Non-COVID-19 Illness.

Importance: Prolonged neuropsychiatric and cognitive symptoms are increasingly reported in patients after COVID-19, but studies with well-matched controls are lacking. Objective: To investigate cognitive impairment, neuropsychiatric diagnoses, and symptoms in survivors of COVID-19 compared with patients hospitalized for non-COVID-19 illness. Design, Setting, and Participants: This prospective case-control study from a tertiary referral hospital in Copenhagen, Denmark, conducted between July 2020 and July 2021, followed up hospitalized COVID-19 survivors and control patients hospitalized for non-COVID-19 illness, matched for age, sex, and intensive care unit (ICU) status 6 months after symptom onset. Exposures: Hospitalization for COVID-19. Main Outcomes and Measures: Participants were investigated with the Mini-International Neuropsychiatric Interview, the Montreal Cognitive Assessment (MoCA), neurologic examination, and a semi-structured interview for subjective symptoms. Primary outcomes were total MoCA score and new onset of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) psychiatric diagnoses. Secondary outcomes included specific psychiatric diagnoses, subjective symptoms, and neurologic examination results. All outcomes were adjusted for age, sex, ICU admission, admission length, and days of follow-up. Secondary outcomes were adjusted for multiple testing. Results: A total of 85 COVID-19 survivors (36 [42%] women; mean [SD] age 56.8 [14] years) after hospitalization and 61 matched control patients with non-COVID-19 illness (27 [44%] women, mean age 59.4 years [SD, 13]) were enrolled. Cognitive status measured by total geometric mean MoCA scores at 6-month follow-up was lower (P = .01) among COVID-19 survivors (26.7; 95% CI, 26.2-27.1) than control patients (27.5; 95% CI, 27.0-27.9). The cognitive status improved substantially (P = .004), from 19.2 (95% CI, 15.2-23.2) at discharge to 26.1 (95% CI, 23.1-29.1) for 15 patients with COVID-19 with MoCA evaluations from hospital discharge. A total of 16 of 85 patients with COVID-19 (19%) and 12 of 61 control patients (20%) had a new-onset psychiatric diagnosis at 6-month follow-up, which was not significantly different (odds ratio, 0.93; 95% CI, 0.39-2.27; P = .87). In fully adjusted models, secondary outcomes were not significantly different, except anosmia, which was more common after COVID-19 (odds ratio, 4.56; 95% CI, 1.52-17.42; P = .006); but no longer when adjusting for multiple testing. Conclusions and Relevance: In this prospective case-control study, cognitive status at 6 months was worse among survivors of COVID-19, but the overall burden of neuropsychiatric and neurologic signs and symptoms among survivors of COVID-19 requiring hospitalization was comparable with the burden observed among matched survivors hospitalized for non-COVID-19 causes.

Prevalence and Predictors of Prolonged Cognitive and Psychological Symptoms Following COVID-19 in the United States.

BACKGROUND/OBJECTIVES: Little is known regarding the prevalence and predictors of prolonged cognitive and psychological symptoms of COVID-19 among community-dwellers. We aimed to quantitatively measure self-reported metrics of fatigue, cognitive dysfunction, anxiety, depression, and sleep and identify factors associated with these metrics among United States residents with or without COVID-19. METHODS: We solicited 1000 adult United States residents for an online survey conducted February 3-5, 2021 utilizing a commercial crowdsourcing community research platform. The platform curates eligible participants to approximate United States demographics by age, sex, and race proportions. COVID-19 was diagnosed by laboratory testing and/or by exposure to a known positive contact with subsequent typical symptoms. Prolonged COVID-19 was self-reported and coded for those with symptoms ≥ 1 month following initial diagnosis. The primary outcomes were NIH PROMIS/Neuro-QoL short-form T-scores for fatigue, cognitive dysfunction, anxiety, depression, and sleep compared among those with prolonged COVID-19 symptoms, COVID-19 without prolonged symptoms and COVID-19 negative subjects. Multivariable backwards step-wise logistic regression models were constructed to predict abnormal Neuro-QoL metrics. RESULTS: Among 999 respondents, the average age was 45 years (range 18-84), 49% were male, 76 (7.6%) had a history of COVID-19 and 19/76 (25%) COVID-19 positive participants reported prolonged symptoms lasting a median of 4 months (range 1-13). Prolonged COVID-19 participants were more often younger, female, Hispanic, and had a history of depression/mood/thought disorder (all P < 0.05). They experienced significantly higher rates of unemployment and financial insecurity, and their symptoms created greater interference with work and household activities compared to other COVID-19 status groups (all P < 0.05). After adjusting for demographics, past medical history and stressor covariates in multivariable logistic regression analysis, COVID-19 status was independently predictive of worse Neuro-QoL cognitive dysfunction scores (adjusted OR 11.52, 95% CI 1.01-2.28, P = 0.047), but there were no significant differences in quantitative measures of anxiety, depression, fatigue, or sleep. CONCLUSION: Prolonged symptoms occurred in 25% of COVID-19 positive participants, and NeuroQoL cognitive dysfunction scores were significantly worse among COVID-19 positive subjects, even after accounting for demographic and stressor covariates. Fatigue, anxiety, depression, and sleep scores did not differ between COVID-19 positive and negative respondents.

Central and peripheral nervous system complications of COVID-19: a prospective tertiary center cohort with 3-month follow-up.

OBJECTIVE: To systematically describe central (CNS) and peripheral (PNS) nervous system complications in hospitalized COVID-19 patients. METHODS: We conducted a prospective, consecutive, observational study of adult patients from a tertiary referral center with confirmed COVID-19. All patients were screened daily for neurological and neuropsychiatric symptoms during admission and discharge. Three-month follow-up data were collected using electronic health records. We classified complications as caused by SARS-CoV-2 neurotropism, immune-mediated or critical illness-related. RESULTS: From April to September 2020, we enrolled 61 consecutively admitted COVID-19 patients, 35 (57%) of whom required intensive care (ICU) management for respiratory failure. Forty-one CNS/PNS complications were identified in 28 of 61 (45.9%) patients and were more frequent in ICU compared to non-ICU patients. The most common CNS complication was encephalopathy (n = 19, 31.1%), which was severe in 13 patients (GCS ≤ 12), including 8 with akinetic mutism. Length of ICU admission was independently associated with encephalopathy (OR = 1.22). Other CNS complications included ischemic stroke, a biopsy-proven acute necrotizing encephalitis, and transverse myelitis. The most common PNS complication was critical illness polyneuromyopathy (13.1%), with prolonged ICU stay as independent predictor (OR = 1.14). Treatment-related PNS complications included meralgia paresthetica. Of 41 complications in total, 3 were para/post-infectious, 34 were secondary to critical illness or other causes, and 4 remained unresolved. Cerebrospinal fluid was negative for SARS-CoV-2 RNA in all 5 patients investigated. CONCLUSION: CNS and PNS complications were common in hospitalized COVID-19 patients, particularly in the ICU, and often attributable to critical illness. When COVID-19 was the primary cause for neurological disease, no signs of viral neurotropism were detected, but laboratory changes suggested autoimmune-mediated mechanisms.

Thirty-Day Mortality and Morbidity in COVID-19 Positive vs. COVID-19 Negative Individuals and vs. Individuals Tested for Influenza A/B: A Population-Based Study.

Background: As of October 2020, COVID-19 has caused 1,000,000 deaths worldwide. However, large-scale studies of COVID-19 mortality and new-onset comorbidity compared to individuals tested negative for COVID-19 and individuals tested for influenza A/B are lacking. We investigated COVID-19 30-day mortality and new-onset comorbidity compared to individuals with negative COVID-19 test results and individuals tested for influenza A/B. Methods and findings: This population-based cohort study utilized electronic health records covering roughly half (n = 2,647,229) of Denmark's population, with nationwide linkage of microbiology test results and death records. All individuals ≥18 years tested for COVID-19 and individuals tested for influenza A/B were followed from 11/2017 to 06/2020. Main outcome was 30-day mortality after a test for either COVID-19 or influenza. Secondary outcomes were major comorbidity diagnoses 30-days after the test for either COVID-19 or influenza A/B. In total, 224,639 individuals were tested for COVID-19. To enhance comparability, we stratified the population for in- and outpatient status at the time of testing. Among inpatients positive for COVID-19, 356 of 1,657 (21%) died within 30 days, which was a 3.0 to 3.1-fold increased 30-day mortality rate, when compared to influenza and COVID-19-negative inpatients (all p < 0.001). For outpatients, 128 of 6,263 (2%) COVID-19-positive patients died within 30 days, which was a 5.5 to 6.9-fold increased mortality rate compared to individuals tested negative for COVID-19 or individuals tested positive or negative for influenza, respectively (all p < 0.001). Compared to hospitalized patients with influenza A/B, new-onset ischemic stroke, diabetes and nephropathy occurred more frequently in inpatients with COVID-19 (all p < 0.05). Conclusions: In this population-based study comparing COVID-19 positive with COVID-19 negative individuals and individuals tested for influenza, COVID-19 was associated with increased rates of major systemic and vascular comorbidity and substantially higher mortality. Results should be interpreted with caution because of differences in test strategies for COVID-19 and influenza, use of aggregated data, the limited 30-day follow-up and the possibility for changing mortality rates as the pandemic unfolds. However, the true COVID-19 mortality may even be higher than the stated 3.0 to 5.5-fold increase, owing to more extensive testing for COVID-19.

The Neurology of Death and the Dying Brain: A Pictorial Essay.

As neurologists earn their living with the preservation and restoration of brain function, they are also well-positioned to address the science behind the transition from life to death. This essay in pictures highlights areas of neurological expertise needed for brain death determination; shows pitfalls to avoid during the clinical examination and interpretation of confirmatory laboratory tests in brain death protocols; illustrates the great variability of brain death legislations around the world; discusses arguments for the implementation of donation after circulatory death (DCD); points to unresolved questions related to DCD and the time between cardiac standstill and organ procurement ("hands-off period"); provides an overview of the epidemiology and semiology of near-death experiences, including their importance for religion, literature, and the visual arts; suggests biological mechanisms for near-death experiences such as dysfunction of temporoparietal cortex, N-methyl-D-aspartate receptor antagonism, migraine aura, and rapid eye movement sleep; hypothesizes that thanatosis (aka. death-feigning, a common behavioral trait in the animal kingdom) represents the evolutionary origin of near-death experiences; and speculates about the future implications of recent attempts of brain resuscitation in an animal model. The aim is to provide the reader with a thorough understanding that the boundaries within the neurology of death and the dying brain are being pushed just like everywhere else in the clinical neurosciences.

Bioenergy Crisis in Coronavirus Diseases?

Coronavirus disease (COVID-19) has been declared as a pandemic by the World Health Organization (WHO).[...].