Neurologic Manifestations & Associations of COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to prevail as a deadly pandemic and unparalleled global crisis. More than 74 million people have been infected globally, and over 1.6 million have died as of mid-December 2020. The virus transmits mainly through close contacts and respiratory droplets.¹ Although the mean incubation period is 3 to 9 days (range, 0-24 days), transmission may occur prior to symptom onset, and about 18% of cases remain asymptomatic.² The highest rates of coronavirus disease 2019 (COVID-19) in the US have been reported in adults age 18 to 29 and 50 to 64 years, representing 23.8% and 20.5% of cases, respectively.³ Although adults age 65 and older make up only 14.6% of total cases in the US, they account for the vast majority of deaths (79.9%).³ Similarly, men appear to be more vulnerable to the disease, accounting for 69% of intensive care unit (ICU) admissions and 58% of deaths despite nearly equal disease prevalence between men and women.⁴ In terms of ethnicity, Black Americans account for 15.6% of COVID-19 infections and 19.7% of related deaths, whereas Hispanic/Latinx Americans account for 26.3% of COVID-19 infections and 15.7% of COVID-19 deaths, despite these groups comprising 13.4% and 16.7% of the US population, respectively.^3,5

The most commonly reported symptoms are fever, dry cough, fatigue, dyspnea, and anorexia.² Numerous studies have also reported a spectrum of neurologic dysfunctions, including mild symptoms (eg, headache, anosmia, and dysgeusia) to severe complications (eg, stroke and encephalitis). Despite the prolific reports of neurologic associations and complications of COVID-19 in the face of a raging pandemic with limited resources, there is a significant lack of control for important confounders including the severity of systemic disease, exacerbation or recrudescence of preexisting neurologic disease, iatrogenic complications, and hospital-acquired conditions. Moreover, given the ubiquity of the virus, it is challenging to parse COVID-19–related complications from coexisting conditions. There is an urgent need for high-quality epidemiologic data reflecting COVID-19 prevalence by age, sex, race, and ethnicity on a local, state, national, and international level.

Neurologic and Neuropsychiatric Manifestations of COVID-19

Prevalence estimates of acute neurologic dysfunctions caused by COVID-19 are widely variable, with reports ranging from 3.5% to 36.4%.⁶ A recent study from Chicago showed that in those with COVID-19 who develop neurologic complications, 42% had neurologic complaints at disease onset, 63% had them during hospitalization, and 82% experienced them during the course of illness.⁷ Considering the widespread nature of the pandemic, with millions infected globally, neurologic complications of COVID-19 could lead to a significant increase in morbidity, mortality, and economic burden.

People over age 50 with comorbidities (eg, hypertension, diabetes, and cardiovascular disease) are prone to neurologic complications.^2,8 Common nonspecific symptoms include headache, fatigue, malaise, myalgia, nausea, vomiting, confusion, anorexia, and dizziness. COVID-19 is known characteristically to affect taste (dysgeusia) and smell (anosmia) in the absence of coryza with variable prevalence estimates ranging from 5% to 85%.⁹ Since the first report on hospitalized individuals in Wuhan, China, numerous other reports have indicated a spectrum of mild-to-severe neurologic complications, including cerebrovascular events, seizures, demyelinating disease, and encephalitis.^8,10-13 As a result of fragmented data from across the world with diverse neurologic manifestations and multiple potential mechanisms of injury, the classification of neurologic dysfunctions in COVID-19 is complex and varies across the literature. Here we present 2 pragmatic classification approaches based on 1) type and site of neurologic manifestations (Table 1A) and 2) disease categories (Table 1B).

Pathophysiology

The virus that causes COVID-19, SARS-CoV-2, is a positive-sense, single-stranded RNA virus with a bilayered lipid envelope that can fuse with the host cell membrane via protein binding with subsequent release of RNA into the host cell cytoplasm.² The RNA translates into viral proteins, and the newly replicated RNA genome and these viral proteins assemble into new viruses that eventually burst from the cell.² SARS-CoV-2 utilizes the angiotensin-converting enzyme 2 (ACE2) receptors for entry into host cells and the transmembrane protease serine 2 (TMPRSS2) for S protein priming.¹⁴ ACE2 receptors are expressed in various organs including lung, heart, kidney, testicles, and brain.¹⁵ These receptors are also found on the neurons and glial cells in multiple regions of the brain, including the cerebral cortex, the striatum, the posterior hypothalamic area, the substantia nigra, and the brain stem.¹⁶

There are multiple hypotheses surrounding mechanisms of COVID-19–related nervous system injury. Frequently discussed mechanisms of commonly associated neurologic dysfunctions are discussed below and summarized in Table 2.

Direct Viral Invasion

An exploration of the possibility of direct central nervous system (CNS) involvement of SARS-CoV-2 in physiologically relevant models noted that TMPRSS2, cathepsin L, and furin, all of which are important for SARS-CoV-2 infection, are readily found in human neural progenitor cells.¹⁷ Although systematic and experimental studies regarding the neuro-tropism of SARS-CoV-2 are lacking, several plausible routes of viral entry to the brain have been proposed, including transcribial, transneuronal (ie, retrograde axonal transport and transsynaptic dissemination), hematogenous, and lymphatic routes.¹⁶ Anosmia, dysgeusia, hypoxia (through respiratory center involvement), and neuropsychiatric conditions may be manifestations of this mode of injury.

Immune-mediated Injury

Exaggerated systemic immune response with focal parenchymal infiltrate of T lymphocytes or the upregulation of interferon-γ, granulocyte-monocyte colony-stimulating factor, interleukin (IL)-2, IL-7, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and tumor necrosis factor-α, have been reported with hypercytokinemia-resembling hemophagocytic lymphohistiocytosis.^16,18 Cases of acute necrotizing hemorrhagic encephalopathy (ANHE) have also been noted with COVID-19, which could be a result of hyperinflammation or cytokine storm induced by the virus.¹³ Additional immune-mediated conditions may include acute psychosis, seizures, encephalitis, and multiorgan dysfunction.¹⁹

Hypoxic Neuronal Injury

COVID-19 related lung injury or pneumonia can lead to severe acute respiratory distress syndrome (ARDS) in a subset of patients with resultant hypoxemia, which, if severe, can cause hypoxic-ischemic encephalopathy (HIE).¹⁹ Furthermore, cerebral hypoperfusion due to systemic hypotension or intracranial hypertension (eg, as a result of a primary brain injury like intracranial hemorrhage) can also lead to secondary hypoxic brain injury. Those infected with SARS-COV-2 may manifest various symptoms, including headache, somnolence, encephalopathy, seizures, and coma.

Injury Related to Endothelial Dysfunction/Blood-Brain Barrier Disruption

Postmortem evidence has suggested the presence of SARS-CoV-2 in the neural and capillary endothelial cells of the frontal lobes.²⁰ Additionally, endothelial cells contain abundant ACE2 receptors, TMPRSS2, sialic acid receptors, and extracellular matrix metalloproteinase inducer (CD147), all of which are necessary to facilitate viral entry to the host cells.²¹ COVID-19–mediated endothelial injury may precipitate intravascular thrombosis and microangiopathy. Moreover, disruption of the blood-brain barrier can facilitate immune cell transmigration to the CNS with neuronal inflammation and microglial activation, leading to further injury.¹⁹

Thrombotic Complications of Systemic Hypercoagulability

COVID‐19 infection is associated with a thromboinflammatory response with characteristic increases in IL-6, D-dimer, and fibrinogen.²² Risk of intravascular thrombosis is comparatively high in COVID-19 and can manifest as acute ischemic stroke, venous sinus thrombosis, and cerebral microvascular thrombosis. In addition, systemic thrombosis—including pulmonary embolism with hypoxemia and cardiac emboli—further contributes to neurologic morbidity and mortality.

Overview of COVID-19 Treatment

The majority of patients with COVID-19 require hospitalization owing to the pulmonary manifestations of the disease. To date, most clinical trials have been primarily designed with end points related to pulmonary outcomes, time to clinical recovery, and mortality. Aside from supportive care with supplemental oxygen, optimized nutrition, and venous thromboembolism prophylaxis, COVID-19 treatments fall into 3 main categories: antiviral, anti-inflammatory and immunomodulators, and adjunctive therapies.^23,24 Current treatment frameworks are based on the assumption that the early phase of COVID-19 is characterized by particularly active viral replication, whereas a hyperinflammatory state and hypercoagulopathy define the later stages of the disease.²⁴ Thus, antiviral and antibody-mediated therapies are thought to have the most significant impact just before or soon after symptom onset. In contrast, anti-inflammatory medications and immunomodulators have a larger role once the disease is well established. Treatment recommendations for COVID-19, which reflect expert consensus as of early November 2020, are summarized in Table 3.^23,25,29

Among the antiviral therapies studied on a large scale (eg, remdesivir, hydroxychloroquine, chloroquine, azithromycin, and lopinavir/ritonavir), remdesivir is the only antiviral agent to have received Food and Drug Administration (FDA) approval for hospitalized adults and children with COVID-19.²³ Remdesivir has been shown to improve time to clinical recovery with a trend towards improved mortality.²⁵ Remdesivir inhibits viral replication by binding to the viral RNA-dependent RNA polymerase, which results in premature termination of RNA transcription.²³ The use of chloroquine or hydroxychloroquine with or without azithromycin is not recommended after several randomized trials failed to demonstrate any benefit in patients with COVID-19. Furthermore, lopinavir/ritonavir are not recommended for the treatment of COVID-19 except in the context of a clinical trial.²³

Agents that modulate the immune response to SARS-CoV-2 continue to be explored through randomized clinical trials and include human-blood derived products, monoclonal antibodies, anti-inflammatory medications, and immunomodulators. Numerous studies have evaluated the use of convalescent plasma without clear cut benefit. However, there appears to be a trend of improved mortality with the use of plasma containing a high titer of antibody compared with a low titer of antibody and the administration of convalescent plasma within 3 days of COVID-19 diagnosis.²⁶ The Infectious Disease Society of America (IDSA) recommends restricting use of COVID-19 convalescent plasma to clinical trials.²⁵ In late October 2020, the FDA granted an emergency use authorization for treatment with bamlanivimab, a neutralizing IgG1 monoclonal antibody that binds to the spike protein of SARS-CoV-2, for the treatment of mild or moderate COVID-19 in people who do not require hospitalization.²⁷ National guidelines have not yet incorporated monoclonal antibody therapies.

Corticosteroids, such as hydrocortisone, have been widely studied for their ability to modulate the hyperinflammatory response that can lead to lung injury and multiorgan dysfunction in sepsis and ARDS. The RECOVERY trial helped establish glucocorticoids as a standard of care for the treatment of COVID-19 in hospitalized patients requiring supplemental oxygen after demonstrating a mortality benefit.²⁸ The IDSA and the National Institutes of Health (NIH) recommend using dexamethasone (or an equivalent total daily dose of an alternative glucocorticoid) for hospitalized individuals who require supplemental oxygen.^23,25 Glucocorticoids are not recommended for those who do not require hospitalization or supplemental oxygen.^23,25 Other immunomodulators, such as interferon-β or IL-6 inhibitors (eg, tocilizumab), are not currently recommended for the treatment of COVID-19 except in the context of a clinical trial.^23,25

Antithrombotic agents are a crucial adjunctive therapy in the treatment of moderate and severe COVID-19, considering the propensity for an associated coagulopathy and an increased incidence of thromboembolism.²³ The prothrombotic nature of this disease is thought to account for the serious cerebrovascular complications such as acute ischemic stroke and cerebral venous sinus thrombosis (See Stroke and COVID-19 in this issue). Several registries (eg, RIETE, CORONA-VTE, and CORE-19) are capturing data to inform thromboprophylaxis and anticoagulation recommendations for COVID-19.²⁹ Expert opinion recommends continuing chronic anticoagulation and antiplatelet therapies after COVID-19 diagnosis unless there is a compelling reason to interrupt their use.²³ All hospitalized patients with COVID-19 should receive thromboprophylaxis with standard-dose unfractionated heparin or low-molecular-weight heparin (preferred agent) unless there is an unacceptable bleeding risk.^23,29 Standard dosing should be adjusted in the typical fashion to account for extremes of weight, severe thrombocytopenia, and impaired renal function.²⁹

The International Society on Thrombosis and Haemostasis (ISTH) consensus statement imparts that bleeding risks outweigh the possible benefits of empiric initiation of therapeutic anticoagulation; however, standard therapeutic anti-coagulation should be initiated in the setting of venous thromboembolism.²⁹ Individual risk-benefit analyses are required when treating critically ill individuals who have COVID-19 and are too unstable for formal diagnostic testing to confirm the presence of venous thromboembolism.²⁹

Some mainstays of immunomodulatory therapy for neurologic emergencies, such as intravenous immunoglob-ulin (IVIG) and plasmapheresis, are currently being studied for the treatment of severe COVID-19 pneumonia (See Neuroimmunomodulation and COVID-19 in this issue).^30,31 However, clinical trials focused on therapeutic efficacy for individual neurologic manifestations of COVID-19 seem unlikely given the relatively low prevalence of cases. A pragmatic approach dictates the use of available therapies traditionally embraced for the treatment of neurologic manifestations of other viruses and their postinfectious sequelae (eg, IVIG or plasmapheresis to treat Guillain-Barré syndrome (GBS), treatment of cerebral venous sinus thrombosis with anticoagulation, and consideration of steroids for viral encephalitis).³²

Discussion

The COVID-19 pandemic continues to surge relentlessly. Efforts to collect robust COVID-19 epidemiologic data and therapeutics have been hampered globally by insufficient testing supplies, bureaucratic inertia, and inadequate public health funding. Nonetheless, the National Institute of Health’s COVID-19 Prevention Trials Network (COVPN) and efforts form numerous nongovernmental organizations including the World Health Organization (WHO) COVID-19 situation dashboard, the Johns Hopkins Coronavirus Resource Center have risen to fill the void.^33,34

Infection is more prevalent in adults age 18 to 29 and 50 to 64 years but tends to severely affect adults over age 65.^3,4 Neurologic manifestations are reportedly more common in individuals over age 65 and those with medical comorbidities and severe systemic disease.⁸ In the US, COVID-19 shows a predilection for certain groups, particularly Black and Hispanic/Latinx Americans.³ Social determinants of health and structural racism may contribute to such disparities. Although a wide variety of neurologic manifestations have been reported, these complications are reminiscent of those described in the other coronavirus epidemics (eg, the SARS epidemic in 2003 and the Middle East Respiratory Syndrome [MERS] outbreak in 2012) and span a spectrum of neurologic conditions from encephalopathy, stroke, and encephalitis to sepsis, hypercoagulability, vasculitis, and GBS.¹³

Among the unique challenges posed by the COVID-19 pandemic is the propensity for local healthcare systems to be periodically overwhelmed by COVID-19–related admissions. The management and care provided are thus dictated by the availability of resources at any given time point. Strict infection control protocols, the need to preserve PPE, and the clinical instability of critically ill individuals may dictate the timing and variety of diagnostic test options available. The diagnostic evaluation of those with suspected neurologic dysfunctions of COVID-19 should proceed as in any person with new neuro-logic signs or symptoms. Clinicians need to maintain a high index of suspicion as ongoing shortages of testing supplies may preclude SARS-COV-2 testing in otherwise asymptomatic individuals. Similarly, patients with postinfectious neurologic sequelae of COVID-19 may test negative for the SARS-CoV-2 virus, because the viral RNA may be undetectable in the nasopharynx by the time of presentation.³² Because the mechanisms related to neurologic complications of COVID-19 are not well established, it is vital to maintain a broad differential diagnosis while evaluating these neurologic sequelae that may be the result of the SARS-CoV-2 virus itself, result from a coincidental infection, reflect side effects of disease treatment, or represent the manifestation of critical illness.³² Concerted global efforts with a systematic approach are needed to understand the true complications and mechanisms of neurologic dysfunctions of COVID-19. Multiple national and international collaborative efforts, such as the GCS-NeuroCOVID consortium, are currently underway to address some of these critical concerns.³⁵

Conclusions

In summary, COVID-19 is associated with neurologic dysfunctions in up to one-third of the infected population and has varied presentations and severity. Neurologic manifestations are diverse and more common in patients with severe systemic disease and those with medical comorbidities. Coordinated global efforts are required to understand the true prevalence, mechanisms, disease course, and outcomes of neurologic dysfunctions associated with COVID-19.