COVID-19 patients with neurological symptoms have 6x higher hospital mortality

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Patients with clinically diagnosed neurological symptoms associated with COVID-19 are six times more likely to die in the hospital than those without the neurological complications, according to an interim analysis from the Global Consortium Study of Neurologic Dysfunction in COVID-19 (GCS-NeuroCOVID).

A study in JAMA Network Open</strong> presents early results of the global effort to gather information about the incidence, severity and outcomes of neurological manifestations of COVID-19 disease.

"Very early on in the pandemic, it became apparent that a good number of people who were sick enough to be hospitalized also develop neurological problems," said lead author Dr Sherry Chou, principal investigator of the consortium and associate professor of critical care medicine, neurology, and neurosurgery at the University of Pittsburgh School of Medicine and UPMC. "A year later, we are still fighting an unknown invisible enemy and, like in any battle, we need intel — we have to learn as much as we can about neurological impacts of COVID-19 in patients who are actively sick and in survivors."

The GCS-NeuroCOVID is the largest cohort study of neurological manifestations of COVID-19 to date, spanning 133 adult patient sites in all continents except Antarctica.

Among one group of 3,744 hospitalized adult patients with COVID-19, 82% had self-reported or clinically captured neurological symptoms. Nearly 4 out of 10 patients reported having headaches, and approximately 3 out of 10 said they lost their sense of smell or taste. Of the clinically diagnosed syndromes — abnormalities that a bedside clinician can observe, regardless of whether the patient is aware of the problem — acute encephalopathy was most common, affecting nearly half of the patients, followed by coma (17%) and strokes (6%).

Despite early concerns about the coronavirus's ability to directly attack the brain and cause brain swelling and inflammation – meningitis and encephalitis – those events were very rare, occurring in less than 1% of hospitalized COVID-19 patients.

"Acute encephalopathy is by far the most common symptom that we see in the clinic," said Chou, also associate director of the Pitt Safar Center for Resuscitation Research. "Those patients may be in an altered sensory state or have impaired consciousness, or they don't feel like themselves and act confused, delirious or agitated."

The researchers analyzed data from three different types of patient cohorts — the "all COVID-19" cohort, which included all 3,055 hospitalized patients with COVID-19, irrespective of their neurological status; the "neurological" cohort, which included 475 hospitalized COVID-19 patients with clinically confirmed neurological symptoms compiled by the GCS-NeuroCOVID Consortium; and the "ENERGY" cohort, or 214 hospitalized COVID-19 patients who required evaluation by a consulting neurologist and provided consent to participate in the European Academy of Neurology Neuro-COVID Registry (ENERGY), a formal partner of the GCS-NeuroCOVID Consortium.

The study found that having a preexisting neurological condition of any kind — from brain, spinal cord and nerve diseases to chronic migraines, dementia or Alzheimer's disease, among others — is the strongest predictor of developing COVID-19-related neurological complications, increasing the risk by two-fold. In addition, having any neurological symptoms related to COVID-19 — from something as seemingly innocuous as the loss of smell to major events like strokes — is associated with a six-fold higher risk of dying.

But even if a patient beats the odds and recovers, their long-term health outlook is still uncertain.

"Even if the pandemic is completely eradicated, we are still talking about millions of survivors who need our help," said Chou. "It is important to find out what symptoms and health problems those patients are facing, and there is still plenty of work for years to come."

Study details

Global Incidence of Neurological Manifestations Among Patients Hospitalized With COVID-19—A Report for the GCS-NeuroCOVID Consortium and the ENERGY Consortium

Authors: Sherry H.-Y. Chou, Ettore Beghi, Raimund Helbok, Elena Moro, Joshua Sampson, Valeria Altamirano, Shraddha Mainali, Claudio Bassetti, Jose I. Suarez, Molly McNett, Lawrence Nolan, Kristi Temro, Anna M. Cervantes-Arslanian, Pria Anand, Shibani Mukerji, Haitham Alabasi, M. Brandon Westover, Tapan Kavi, Sayona John, Ivan Da Silva, Arif Shaik, Aarti Sarwal, Saef Izzy, Eric M. Liotta, Ayush Batra, Aimee Aysenne, Clio Rubinos, Ahmed Y. Azzam, Mohammed A. Azab, Justin Sandall, LeighAnn M. Persondek, Hanno Ulmer, Verena Rass, Bettina Pfausler, Christoph Müller, Simon Jung, Michael Crean, Sara Meoni, Daniel Bereczki, Tibor Kovács, Netta Agajany, Carmel Armon, Sharon Wolfson, Maria Sofia Cotelli, Elisa Bianchi, Anis Riahi, Serefnur Öztürk, Onur Ural, Gryb Viktoriia, Mariana Lesiv, Luis Maia, Vanessa Oliveira, Mafalda Seabra, Vanessa Carvalho, Paul Vespa, Javier Provencio, Daiwai Olson, Claude Hemphill, Chethan P Venkatasubba Rao, Nerissa Ko, Ericka Fink, Courtney Robertson, Michelle Schober, Ali Smith Scott, Michal Hammond, Nicole Paul, Aleksandra Safonova, Lauren Kaplan, Charith Ratnayake, Adytia D Sharma, Abigail Skeel, Carlos Villamizar Rosales, Dominika Dolak, Panayiotis Varelas, Lev Lotman, Lalit Kaltenbach, and Menon David K.

Published in JAMA Network Open, 2021

Key Points
Question What are the incidence of and outcomes associated with neurologic manifestations in patients with COVID-19?

Findings In this cohort study of 3744 patients in 2 large consortia, neurological manifestations were found in approximately 80% of patients hospitalized with COVID-19; the most common self-reported symptoms included headache (37%) and anosmia or ageusia (26%), whereas the most common neurological signs and/or syndromes were acute encephalopathy (49%), coma (17%), and stroke (6%). Presence of clinically captured neurologic signs and/or syndromes was associated with increased risk of in-hospital death.

Meaning These findings suggest that neurological manifestations are prevalent among patients hospitalized with COVID-19 and are associated with higher in-hospital mortality.


The COVID-19 pandemic continues to affect millions of people globally, with increasing reports of neurological manifestations but limited data on their incidence and associations with outcome.

To determine the neurological phenotypes, incidence, and outcomes among adults hospitalized with COVID-19.

Design, Setting, and Participants
This cohort study included patients with clinically diagnosed or laboratory-confirmed COVID-19 at 28 centers, representing 13 countries and 4 continents. The study was performed by the Global Consortium Study of Neurologic Dysfunction in COVID-19 (GCS-NeuroCOVID) from March 1 to September 30, 2020, and the European Academy of Neurology (EAN) Neuro-COVID Registry (ENERGY) from March to October 2020. Three cohorts were included: (1) the GCS-NeuroCOVID all COVID-19 cohort (n = 3055), which included consecutive hospitalized patients with COVID-19 with and without neurological manifestations; (2) the GCS-NeuroCOVID COVID-19 neurological cohort (n = 475), which comprised consecutive patients hospitalized with COVID-19 who had confirmed neurological manifestations; and (3) the ENERGY cohort (n = 214), which included patients with COVID-19 who received formal neurological consultation.

Clinically diagnosed or laboratory-confirmed COVID-19.

Main Outcomes and Measures
Neurological phenotypes were classified as self-reported symptoms or neurological signs and/or syndromes assessed by clinical evaluation. Composite incidence was reported for groups with at least 1 neurological manifestation. The main outcome measure was in-hospital mortality.

Of the 3055 patients in the all COVID-19 cohort, 1742 (57%) were men, and the mean age was 59.9 years (95% CI, 59.3-60.6 years). Of the 475 patients in the COVID-19 neurological cohort, 262 (55%) were men, and the mean age was 62.6 years (95% CI, 61.1-64.1 years). Of the 214 patients in the ENERGY cohort, 133 (62%) were men, and the mean age was 67 years (95% CI, 52-78 years). A total of 3083 of 3743 patients (82%) across cohorts had any neurological manifestation (self-reported neurological symptoms and/or clinically captured neurological sign and/or syndrome). The most common self-reported symptoms included headache (1385 of 3732 patients [37%]) and anosmia or ageusia (977 of 3700 patients [26%]). The most prevalent neurological signs and/or syndromes were acute encephalopathy (1845 of 3740 patients [49%]), coma (649 of 3737 patients [17%]), and stroke (222 of 3737 patients [6%]), while meningitis and/or encephalitis were rare (19 of 3741 patients [0.5%]). Presence of clinically captured neurologic signs and/or syndromes was associated with increased risk of in-hospital death (adjusted odds ratio [aOR], 5.99; 95% CI, 4.33-8.28) after adjusting for study site, age, sex, race, and ethnicity. Presence of preexisting neurological disorders (aOR, 2.23; 95% CI, 1.80-2.75) was associated with increased risk of developing neurological signs and/or syndromes with COVID-19.

Conclusions and Relevance
In this multicohort study, neurological manifestations were prevalent among patients hospitalized with COVID-19 and were associated with higher in-hospital mortality. Preexisting neurological disorders were associated with increased risk of developing neurological signs and/or syndromes in COVID-19.


Full report (Open access)

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