Neurologic manifestations of COVID-19 in critically ill patients: results of the prospective multicenter registry PANDEMIC
Authors: Dimitriadis Konstantinos , Meis Jan , Neugebauer Hermann , Barlinn Kristian , Neumann Bernhard , Gahn Georg , Lochner Piergiorgio , Knier Benjamin , Lindemann Sarah , Sühs Kurt Wolfram , Szabo Kristina , Pfefferkorn Thomas , Schirotzek Ingo , Freilinger Tobias , Burc Bassa , Günther Albrecht , Wittstock Matthias , Schramm Patrick , Reimann Gernot , Godau Jana , Nagy Gabor , Koenig Fatima B. , Essig Fabian , Klinker Hartwig , Hartmann Christian , Schmidbauer Moritz L. , Steinberg Tim , Lefterova Lora , Klose Christina , Bösel Julian ,   for the IGNITE study group
Published: July 2022

Abstract
Background
Neurologic manifestations are increasingly reported in patients with coronavirus disease 2019 (COVID-19). Yet, data on prevalence, predictors and relevance for outcome of neurological manifestations in patients requiring intensive care are scarce. We aimed to characterize prevalence, risk factors and impact on outcome of neurologic manifestations in critically ill COVID-19 patients.

Methods
In the prospective, multicenter, observational registry study PANDEMIC (Pooled Analysis of Neurologic DisordErs Manifesting in Intensive care of COVID-19), we enrolled COVID-19 patients with neurologic manifestations admitted to 19 German intensive care units (ICU) between April 2020 and September 2021. We performed descriptive and explorative statistical analyses. Multivariable models were used to investigate factors associated with disorder categories and their underlying diagnoses as well as to identify predictors of outcome.

Results
Of the 392 patients included in the analysis, 70.7% (277/392) were male and the mean age was 65.3 (SD ± 3.1) years. During the study period, a total of 2681 patients with COVID-19 were treated at the ICUs of 15 participating centers. New neurologic disorders were identified in 350 patients, reported by these centers, suggesting a prevalence of COVID-19-associated neurologic disorders of 12.7% among COVID-19 ICU patients. Encephalopathy (46.2%; 181/392), cerebrovascular (41.0%; 161/392) and neuromuscular disorders (20.4%; 80/392) were the most frequent categories identified. Out of 35 cerebrospinal fluid analyses with reverse transcriptase PCR for SARS-COV-2, only 3 were positive. In-hospital mortality was 36.0% (140/389), and functional outcome (mRS 3 to 5) of surviving patients was poor at hospital discharge in 70.9% (161/227). Intracerebral hemorrhage (OR 6.2, 95% CI 2.5–14.9, p < 0.001) and acute ischemic stroke (OR 3.9, 95% CI 1.9–8.2, p < 0.001) were the strongest predictors of poor outcome among the included patients.

Conclusions
Based on this well-characterized COVID-19 ICU cohort, that comprised 12.7% of all severe ill COVID-19 patients, neurologic manifestations increase mortality and morbidity. Since no reliable evidence of direct viral affection of the nervous system by COVID-19 could be found, these neurologic manifestations may for a great part be indirect para- or postinfectious sequelae of the infection or severe critical illness. Neurologic ICU complications should be actively searched for and treated.