Covid-19 can involve multiple organs including the nervous system. We sought to characterize the neurologic manifestations, their risk factors, and associated outcomes in hospitalized patients with Covid-19.

Methods

We examined neurologic manifestations in 509 consecutive patients admitted with confirmed Covid-19 within a hospital network in Chicago, Illinois. We compared the severity of Covid-19 and outcomes in patients with and without neurologic manifestations. We also identified independent predictors of any neurologic manifestations, encephalopathy, and functional outcome using binary logistic regression.

Results

Neurologic manifestations were present at Covid-19 onset in 215 (42.2%), at hospitalization in 319 (62.7%), and at any time during the disease course in 419 patients (82.3%). The most frequent neurologic manifestations were myalgias (44.8%), headaches (37.7%), encephalopathy (31.8%), dizziness (29.7%), dysgeusia (15.9%), and anosmia (11.4%). Strokes, movement disorders, motor and sensory deficits, ataxia, and seizures were uncommon (0.2 to 1.4% of patients each). Severe respiratory disease requiring mechanical ventilation occurred in 134 patients (26.3%). Independent risk factors for developing any neurologic manifestation were severe Covid-19 (OR 4.02; 95% CI 2.04–8.89; P < 0.001) and younger age (OR 0.982; 95% CI 0.968–0.996; P = 0.014). Of all patients, 362 (71.1%) had a favorable functional outcome at discharge (modified Rankin Scale 0–2). However, encephalopathy was independently associated with worse functional outcome (OR 0.22; 95% CI 0.11–0.42; P < 0.001) and higher mortality within 30 days of hospitalization (35 [21.7%] vs. 11 [3.2%] patients; P < 0.001).

Interpretation

Neurologic manifestations occur in most hospitalized Covid-19 patients. Encephalopathy was associated with increased morbidity and mortality, independent of respiratory disease severity.

As of 8 September 2020, severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has led to over 26.5 million confirmed infections and 875,000 deaths from coronavirus disease-2019 (Covid-19) worldwide.¹

Like most infections caused by members of the coronavirus family, SARS-CoV-2 manifests itself with upper respiratory tract infections and flu-like symptoms of varying severity.² However, Covid-19 is unique in its ability to cause a multi-organ disease, with involvement of the central and peripheral nervous system in some individuals.

Indeed, a wide range of neurologic manifestations of SARS-CoV-2 infection have been recognized, and evidence of their severity and persistence is increasing.^3–10 However, the frequency of those manifestations and associated risk factors remain unclear. We sought to characterize the incidence of neurologic manifestations, in patients with confirmed Covid-19 and identify factors associated with the development of neurologic manifestations in hospitalized patients with both severe and non-severe respiratory disease. Furthermore, neurologic manifestations, especially encephalopathy, have been associated with worse clinical outcomes in other systemic illnesses including sepsis and may even lead to significant disability.^11, 12 Therefore, we sought to identify if encephalopathy was associated with greater morbidity in hospitalized patients with Covid-19.

Discussion

This study highlights the high frequency and range of neurologic manifestations, which occurred in more than four fifths of Covid-19 patients hospitalized in our hospital network system. These results expand findings of neurologic manifestations in 36.4% of hospitalized Covid-19 patients in China and 57.4% in Europe^16, 17, albeit with increased prevalence in our US cohort. Differences in frequencies may be caused by genetic factors including polymorphism in expression of the viral receptor angiotensin-converting enzyme 2 (ACE 2) in the nervous system, and possibly, SARS-CoV-2 strain variations.¹⁸ In addition, our hospital network system was never stressed beyond capacity due to surge preparation and most patients had moderate disease, with only one quarter developing severe respiratory distress requiring mechanical ventilation.¹⁹ This may have allowed for more detailed evaluation and identification of neurologic manifestations.

The fact that any neurologic manifestations as a whole were more likely to occur in younger people is surprising, and could potentially be explained by greater clinical emphasis on the risk of respiratory failure than other symptoms in older patients. Alternatively, early neurologic manifestations such as myalgia, headache, or dizziness may have prompted earlier medical care. In contrast, encephalopathy was more frequent in older patients. Risk factors for encephalopathy also included severe Covid-19 disease and history of any neurological disorder or chronic kidney disease. This is consistent with recent literature identifying higher rates of mortality in Covid-19 patients with pre-existing chronic neurological disorders.²⁰

The increased morbidity and mortality associated with encephalopathy, independent of respiratory severity, parallels previous literature in sepsis-associated encephalopathy and delirium-associated mortality^11, 21 and emphasizes its relevance in Covid-19. We also found that encephalopathy in Covid-19 was associated with triple the hospital length of stay. Broad recognition and screening for encephalopathy as a contributor to disease severity in Covid-19 may have utility in resource allocation and potential to improve patient outcomes. Furthermore, our findings emphasize the broader need to develop interventions that target encephalopathy as a component of multi-organ system medical illness.

The cause of encephalopathy could not be determined with certainty given the lack of extensive diagnostic neurologic testing for most patients in this study due to ongoing pandemic restrictions. However, the most likely etiology of encephalopathy in patients with Covid-19 is multifactorial, including systemic disease and inflammation, coagulopathy, direct neuroinvasion by the virus, endotheliitis and possibly post-infectious auto-immune mechanisms.⁵ Additionally, traditional risk factors associated with intensive care unit delirium and encephalopathy also need to be taken into account, including sedation and analgesia doses, disruption of sleep/wake cycles, and infectious complications.^22, 23 Critical illness encephalopathy, in general, can result from multiple mechanisms or combinations of mechanisms that remain an unresolved area of basic science research.²⁴

Our hospital network system includes an AMC and nine other hospitals. There was no meaningful difference in severity of disease between the AMC and the other hospitals, but patients at the AMC had better functional outcomes and lower 30-day mortality. One potential explanation for this finding may be related to specialty care, access to resources, and lower rates of do not resuscitate/intubate and comfort measures-only orders. Our AMC is also the largest hospital within the NMHC system with the greatest number of ICU beds, which may confer a survival benefit to critically ill patients with Covid-19.²⁵ A similar difference has been observed in patients with sepsis, who had better outcomes and lower mortality when treated by tertiary versus non-tertiary hospitals.²⁶ Early adoption and implementation of uniform treatment protocols across hospital networks driven by AMCs may be a means to improve outcome and lower mortality of Covid-19 patients that deserves further investigations.

Our study has limitations, including its retrospective nature, and the fact that fewer than 6% of patients were evaluated by neurologists or neurosurgeons. Since most patients were admitted to dedicated Covid-19 wards or ICUs with strict infection control precautions in place, access to brain CT or MRI was not as readily available as for other patients with neurologic diseases. This limited a more complete neurologic work up in many Covid-19 patients. Additionally, patients were cared for at 10 different hospitals and there may have been varying rates of local geographic infection severity. However, this provided us with a more generalized view of the neurologic manifestations in Covid-19 patients and could identify opportunities for regionalized resource allocation and preparedness protocols in a large hospital network system.

Only 9 months into the pandemic, the long-term effects of Covid-19 on the nervous system remain uncertain. Our results suggest that, of all neurologic manifestations, encephalopathy is associated with a worse functional outcome in hospitalized patients with Covid-19, and may have lasting effects.¹² Long-term follow-up is necessary to assess the true burden of encephalopathy in these patients. Whether milder forms occur in non-hospitalized individuals with Covid-19 who complain of protracted inability to concentrate or decreased short term memory (referred to as ‘brain fog’) warrants further evaluation.²⁷ Prospective cognitive and neurologic-focused evaluations through specialized clinics dedicated to further diagnostic assessment and tailored rehabilitation needs could play a significant role in recovery from this pandemic.