Neurologic Manifestations & Associations of COVID-19
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
NEUROCRITICAL CARE
& COVID-19
Neurologic Manifestations &
Associations of COVID-19
High-quality epidemiologic data is still urgently needed to better understand
neurologic effects of COVID-19.
By Shraddha Mainali, MD and Marin Darsie, MD
Severe acute respiratory syn- Moreover, given the ubiquity of the virus, it is challenging to
drome coronavirus 2 (SARS- parse COVID-19–related complications from coexisting condi-
CoV-2) infection continues to tions. There is an urgent need for high-quality epidemiologic
prevail as a deadly pandemic data reflecting COVID-19 prevalence by age, sex, race, and eth-
and unparalleled global crisis. nicity on a local, state, national, and international level.
More than 74 million people
have been infected globally, and over 1.6 million have died as Neurologic and Neuropsychiatric Manifestations
of mid-December 2020. The virus transmits mainly through of COVID-19
close contacts and respiratory droplets.1 Although the mean Prevalence estimates of acute neurologic dysfunctions
incubation period is 3 to 9 days (range, 0-24 days), transmission caused by COVID-19 are widely variable, with reports ranging
may occur prior to symptom onset, and about 18% of cases from 3.5% to 36.4%.6 A recent study from Chicago showed
remain asymptomatic.2 The highest rates of coronavirus dis- that in those with COVID-19 who develop neurologic com-
ease 2019 (COVID-19) in the US have been reported in adults plications, 42% had neurologic complaints at disease onset,
age 18 to 29 and 50 to 64 years, representing 23.8% and 20.5% 63% had them during hospitalization, and 82% experienced
of cases, respectively.3 Although adults age 65 and older make them during the course of illness.7 Considering the widespread
up only 14.6% of total cases in the US, they account for the nature of the pandemic, with millions infected globally, neu-
vast majority of deaths (79.9%).3 Similarly, men appear to be rologic complications of COVID-19 could lead to a significant
more vulnerable to the disease, accounting for 69% of intensive increase in morbidity, mortality, and economic burden.
care unit (ICU) admissions and 58% of deaths despite nearly People over age 50 with comorbidities (eg, hypertension,
equal disease prevalence between men and women.4 In terms diabetes, and cardiovascular disease) are prone to neurologic
of ethnicity, Black Americans account for 15.6% of COVID‑19 complications.2,8 Common nonspecific symptoms include
infections and 19.7% of related deaths, whereas Hispanic/Latinx headache, fatigue, malaise, myalgia, nausea, vomiting, confu-
Americans account for 26.3% of COVID-19 infections and sion, anorexia, and dizziness. COVID-19 is known character-
15.7% of COVID-19 deaths, despite these groups comprising istically to affect taste (dysgeusia) and smell (anosmia) in the
13.4% and 16.7% of the US population, respectively.3,5 absence of coryza with variable prevalence estimates rang-
The most commonly reported symptoms are fever, dry ing from 5% to 85%.9 Since the first report on hospitalized
cough, fatigue, dyspnea, and anorexia.2 Numerous studies have individuals in Wuhan, China, numerous other reports have
also reported a spectrum of neurologic dysfunctions, includ- indicated a spectrum of mild-to-severe neurologic complica-
ing mild symptoms (eg, headache, anosmia, and dysgeusia) to tions, including cerebrovascular events, seizures, demyelinating
severe complications (eg, stroke and encephalitis). Despite the disease, and encephalitis.8,10-13 As a result of fragmented data
prolific reports of neurologic associations and complications from across the world with diverse neurologic manifestations
of COVID-19 in the face of a raging pandemic with limited and multiple potential mechanisms of injury, the classification
resources, there is a significant lack of control for important of neurologic dysfunctions in COVID-19 is complex and varies
confounders including the severity of systemic disease, exac- across the literature. Here we present 2 pragmatic classification
erbation or recrudescence of preexisting neurologic disease, approaches based on 1) type and site of neurologic manifesta-
iatrogenic complications, and hospital-acquired conditions. tions (Table 1A) and 2) disease categories (Table 1B).
42 PRACTICAL NEUROLOGY JANUARY 2021
NEUROCRITICAL CARE
& COVID-19
Table 1A. Classification of Neurologic Table 1B. Classification of Neurologic
Dysfunctions Due to COVID-19 by Type and Site Dysfunctions and Associations of COVID-19
Type/location Neurologic dysfunctions Disease categories Examples
Nonspecific Headache, confusion, dizziness, fatigue, Nonspecific Agitation, acute confusional state,
symptoms anorexia, syncope, myalgia, nausea, vomiting
encephalopathy dysexecutive syndrome
Neuro- Anxiety, depression, psychosis
psychiatric Posttraumatic stress disorder Neuropsychiatric disorders Anxiety, psychosis, PTSD, insomnia
Central Encephalo- Acute encephalopathy/con- CNS infections Meningitis, meningoencephalitis
nervous pathy, fusional state/dysexecutive Cerebrovascular disease Ischemic stroke, hemorrhagic
system (CNS) encephalitis, syndrome stroke, venous sinus thrombosis,
and cranial impaired Leukoencephalopathy PRES, microvascular thrombosis
nerves consciousness Acute necrotizing encephalo-
pathy Seizures Focal seizures, NCSE, convulsive
status epilepticus
Encephalitis/rhombenencephalitis
Meningoencephalitis Neuroinflammatory and ANHE, ADEM, GBS, vasculitis
PRES immunologic conditions
Postinfectious encephalopathy Neurologic complications Hypoxic brain injury, toxic-
Hypoxic brain injury of systemic disease metabolic encephalopathy
Cerebro- Acute ischemic stroke Exacerbation/recrudes- Myasthenia gravis exacerbation,
vascular Intracranial hemorrhage (IPH/ cence of preexisting recrudescence of old stroke
disease IVH/SAH) conditions
CVST Iatrogenic and other Anticoagulation-related ICH,
Cerebral microhemorrhage hospital-acquired steroid-induced myopathy, critical
Cerebral vasculitis conditions illness myopathy/polyneuropathy,
Seizure/status epilepticus deconditioning
Acute ADEM
Miscellaneous Movement disorders, myositis/rhab-
demyelin- Acute myelitis
ation domyolysis, coexisting conditions
Optic neuritis
ADEM, acute disseminated encephalomyelitis; ANHE, acute
Acute encephalomyelitis
necrotizing hemorrhagic encephalopathy; COVID-19, corona-
CLOCC
virus disease 2019; GBS, Guillain-Barré syndrome; ICH, intra-
Movement Myoclonus cranial hemorrhage; NCSE, nonconvulsive status epilepticus;
disorders Hypokinetic-rigid syndrome PRES, posterior reversible encephalopathy syndrome; PTSD,
Myelopathy Acute myelitis/transverse posttraumatic stress disorder.
myelitis
Cranial neu- Cranial nerve palsies Pathophysiology
ropathy Trigeminal neuropathy The virus that causes COVID-19, SARS-CoV-2, is a positive-
Glossopharyngeal neuralgia sense, single-stranded RNA virus with a bilayered lipid enve-
Anosmia/dysgeusia lope that can fuse with the host cell membrane via protein
Peripheral Guillain-Barré syndrome and variants binding with subsequent release of RNA into the host cell
nervous Plexopathy cytoplasm.2 The RNA translates into viral proteins, and
system (PNS) Numbness/paresthesias the newly replicated RNA genome and these viral proteins
assemble into new viruses that eventually burst from the cell.2
Autonomic Dysautonomia/POTS
SARS-CoV-2 utilizes the angiotensin-converting enzyme 2
Musculo- Myalgias, myopthy, myositis, rhabdomyolysis,
(ACE2) receptors for entry into host cells and the transmem-
skeletal myasthenia gravis exacerbation
brane protease serine 2 (TMPRSS2) for S protein priming.14
ADEM, acute disseminated encephalomyelitis; CLOCC, cyto-
ACE2 receptors are expressed in various organs including lung,
toxic lesions of the corpus callosum; COVID-19, coronavirus
disease 2019; CVST, cerebral venous sinus thrombosis; IPH: heart, kidney, testicles, and brain.15 These receptors are also
intraparenchymal hemorrhage; IVH, intraventricular hemor- found on the neurons and glial cells in multiple regions of the
rhage; POTS, postural orthostatic tachycardia syndrome; SAH, brain, including the cerebral cortex, the striatum, the posterior
subarachnoid hemorrhage. hypothalamic area, the substantia nigra, and the brain stem.16
JANUARY 2021 PRACTICAL NEUROLOGY 43NEUROCRITICAL CARE
& COVID-19
There are multiple hypotheses surrounding mechanisms systematic and experimental studies regarding the neuro-
of COVID-19–related nervous system injury. Frequently dis- tropism of SARS-CoV-2 are lacking, several plausible routes
cussed mechanisms of commonly associated neurologic dys- of viral entry to the brain have been proposed, including
functions are discussed below and summarized in Table 2. transcribial, transneuronal (ie, retrograde axonal transport
and transsynaptic dissemination), hematogenous, and lym-
Direct Viral Invasion phatic routes.16 Anosmia, dysgeusia, hypoxia (through respi-
An exploration of the possibility of direct central nervous ratory center involvement), and neuropsychiatric conditions
system (CNS) involvement of SARS-CoV-2 in physiologically may be manifestations of this mode of injury.
relevant models noted that TMPRSS2, cathepsin L, and furin,
all of which are important for SARS-CoV-2 infection, are Immune-mediated Injury
readily found in human neural progenitor cells.17 Although Exaggerated systemic immune response with focal paren-
chymal infiltrate of T lymphocytes or the upregulation of
Table 2. Pathophysiologic Classification of interferon-g, granulocyte-monocyte colony-stimulating
Neurologic Manifestations of COVID-19 factor, interleukin (IL)-2, IL-7, monocyte chemoattractant
protein-1, macrophage inflammatory protein-1α, and tumor
Mechanisms Potential neurologic manifestations
necrosis factor-α, have been reported with hypercytokinemia-
Direct viral invasion Transneuronal (e.g., retrograde resembling hemophagocytic lymphohistiocytosis.16,18 Cases of
axonal transport and transsynaptic acute necrotizing hemorrhagic encephalopathy (ANHE) have
dissemination) also been noted with COVID-19, which could be a result of
Hematogenous spread hyperinflammation or cytokine storm induced by the virus.13
Transcribial Additional immune-mediated conditions may include acute
psychosis, seizures, encephalitis, and multiorgan dysfunction.19
Lymphatic spread
Immune-mediated Dysregulated immunomodulation Hypoxic Neuronal Injury
injury (eg, cytokine storm, SIRS, leaky BBB, COVID-19 related lung injury or pneumonia can lead
impaired neurotransmission) to severe acute respiratory distress syndrome (ARDS) in
Immune cell transmigration to CNS a subset of patients with resultant hypoxemia, which, if
(eg, microglial activation, latent viral severe, can cause hypoxic-ischemic encephalopathy (HIE).19
existence in neural and glial cells, Furthermore, cerebral hypoperfusion due to systemic hypo-
neural inflammation) tension or intracranial hypertension (eg, as a result of a pri-
Autoimmunity (eg, vasculitis, post- mary brain injury like intracranial hemorrhage) can also lead
infectious conditions) to secondary hypoxic brain injury. Those infected with SARS-
COV-2 may manifest various symptoms, including headache,
Hypoxic injury Systemic hypoxia
somnolence, encephalopathy, seizures, and coma.
Systemic hypotension
Intracranial hypertension/ICP crisis Injury Related to Endothelial Dysfunction/Blood-Brain
Brain edema Barrier Disruption
Postmortem evidence has suggested the presence of SARS-
Seizures/fever (neurovascular
CoV-2 in the neural and capillary endothelial cells of the frontal
uncoupling)
lobes.20 Additionally, endothelial cells contain abundant ACE2
Thrombotic com- Arterial thrombosis receptors, TMPRSS2, sialic acid receptors, and extracellular
plications related to Venous thrombosis matrix metalloproteinase inducer (CD147), all of which are
hypercoagulability necessary to facilitate viral entry to the host cells.21 COVID‑19–
Microvascular thrombosis/micro-
angiopathy mediated endothelial injury may precipitate intravascular
thrombosis and microangiopathy. Moreover, disruption of the
Injury related to Vasculitis
blood-brain barrier can facilitate immune cell transmigration
endothelial dysfunc- Thrombosis
to the CNS with neuronal inflammation and microglial activa-
tion/BBB breakdown
Stroke tion, leading to further injury.19
Abbreviations: BBB, blood-brain barrier; CNS, central nervous
system; COVID‑19, coronavirus disease 2019; ICP, intracranial
Thrombotic Complications of Systemic Hypercoagulability
pressure; SIRS, systemic inflammatory response syndrome.
COVID‐19 infection is associated with a thromboinflamma-
tory response with characteristic increases in IL-6, D-dimer, and
44 PRACTICAL NEUROLOGY JANUARY 2021NEUROCRITICAL CARE
& COVID-19
fibrinogen.22 Risk of intravascular thrombosis is comparatively mediated therapies are thought to have the most significant
high in COVID-19 and can manifest as acute ischemic stroke, impact just before or soon after symptom onset. In contrast,
venous sinus thrombosis, and cerebral microvascular throm- anti-inflammatory medications and immunomodulators have
bosis. In addition, systemic thrombosis—including pulmonary a larger role once the disease is well established. Treatment rec-
embolism with hypoxemia and cardiac emboli—further con- ommendations for COVID-19, which reflect expert consensus
tributes to neurologic morbidity and mortality. as of early November 2020, are summarized in Table 3.23,25,29
Among the antiviral therapies studied on a large scale (eg,
Overview of COVID-19 Treatment remdesivir, hydroxychloroquine, chloroquine, azithromy-
The majority of patients with COVID-19 require hospitaliza- cin, and lopinavir/ritonavir), remdesivir is the only antiviral
tion owing to the pulmonary manifestations of the disease. To agent to have received Food and Drug Administration (FDA)
date, most clinical trials have been primarily designed with end approval for hospitalized adults and children with COVID‑19.23
points related to pulmonary outcomes, time to clinical recov- Remdesivir has been shown to improve time to clinical recov-
ery, and mortality. Aside from supportive care with supple- ery with a trend towards improved mortality.25 Remdesivir
mental oxygen, optimized nutrition, and venous thromboem- inhibits viral replication by binding to the viral RNA-dependent
bolism prophylaxis, COVID-19 treatments fall into 3 main cat- RNA polymerase, which results in premature termination of
egories: antiviral, anti-inflammatory and immunomodulators, RNA transcription.23 The use of chloroquine or hydroxychloro-
and adjunctive therapies.23,24 Current treatment frameworks quine with or without azithromycin is not recommended after
are based on the assumption that the early phase of COVID-19 several randomized trials failed to demonstrate any benefit in
is characterized by particularly active viral replication, whereas patients with COVID-19. Furthermore, lopinavir/ritonavir are
a hyperinflammatory state and hypercoagulopathy define not recommended for the treatment of COVID-19 except in
the later stages of the disease.24 Thus, antiviral and antibody- the context of a clinical trial.23
Table 3. Treatment Recommendations for Patients with COVID-19 Based on Disease Severity
Disease severity Antiviral and anti-inflammatory therapy Other treatment considerations
recommendations
Not hospitalizeda No recommended treatments Continue chronic anticoagulant or antiplate-
let agents; VTE prophylaxis not recommended
Hospital- Not on supple- Remdesivirb 200 mg IV x 1 day, followed by 100 mg IV Standard dose VTE prophylaxisc
ized mental oxygena daily x 4 days or until hospital discharge (DC)
On supple- Remdesivir 200 mg IV x 1 day, followed by 100 mg IV Standard dose VTE prophylaxisc
mental oxygen daily x 4 days or until DC
or
Remdesivir (dose and duration as above) plus dexametha-
sone 6 mg IV or oral daily for up to 10 days or until DC
or
Dexamethasone monotherapy if remdesivir cannot be used
Requiring Dexamethasone plus remdesivir at the doses and dura- Standard dose VTE prophylaxisc
HFNC or tions discussed above
NIPPV or
Dexamethasone monotherapy
Requiring Dexamethasone at the dose and duration as above Standard dose VTE prophylaxisc,d
mechanical or or
ventilation or Dexamethasone plus remdesivir for recently intubated Consider empiric therapeutic AC if too
ECMO patients at the doses and durations discussed above unstable for VTE testing
AC, anticoagulation; COVID-19, coronavirus disease 2019; ECMO, extracorporeal membrane oxygenation; HFNC, high-flow nasal cannula;
IV, intravenously; NIPPV, noninvasive positive-pressure ventilation; VTE, venous thromboembolism. aThe National Institutes of Health (NIH)
COVID-19 Treatment Guidelines Panel recommends against dexamethasone use due to the suggestion of harm within these patient popu-
lations in the RECOVERY trial. bAn individualized risk-benefit analysis should be conducted before the use of remdesivir in each patient
with moderate COVID-19. cUnfractionated heparin or low-molecular-weight heparin (preferred agent); consider at 50% increase in dose for
patients with obesity. dIntermediate-dose low-molecular-weight heparin is a reasonable consideration in these high-risk patients..
JANUARY 2021 PRACTICAL NEUROLOGY 45NEUROCRITICAL CARE
& COVID-19
Agents that modulate the immune response to SARS-CoV-2 typical fashion to account for extremes of weight, severe
continue to be explored through randomized clinical trials and thrombocytopenia, and impaired renal function.29
include human-blood derived products, monoclonal antibod- The International Society on Thrombosis and Haemostasis
ies, anti-inflammatory medications, and immunomodulators. (ISTH) consensus statement imparts that bleeding risks out-
Numerous studies have evaluated the use of convalescent weigh the possible benefits of empiric initiation of therapeu-
plasma without clear cut benefit. However, there appears to be tic anticoagulation; however, standard therapeutic anti-
a trend of improved mortality with the use of plasma contain- coagulation should be initiated in the setting of venous
ing a high titer of antibody compared with a low titer of anti- thromboembolism.29 Individual risk-benefit analyses are
body and the administration of convalescent plasma within 3 required when treating critically ill individuals who have
days of COVID-19 diagnosis.26 The Infectious Disease Society COVID-19 and are too unstable for formal diagnostic testing
of America (IDSA) recommends restricting use of COVID-19 to confirm the presence of venous thromboembolism.29
convalescent plasma to clinical trials.25 In late October 2020, Some mainstays of immunomodulatory therapy for
the FDA granted an emergency use authorization for treat- neurologic emergencies, such as intravenous immunoglob-
ment with bamlanivimab, a neutralizing IgG1 monoclonal anti- ulin (IVIG) and plasmapheresis, are currently being studied
body that binds to the spike protein of SARS-CoV-2, for the for the treatment of severe COVID-19 pneumonia (See
treatment of mild or moderate COVID-19 in people who do Neuroimmunomodulation and COVID-19 in this issue).30,31
not require hospitalization.27 National guidelines have not yet However, clinical trials focused on therapeutic efficacy for
incorporated monoclonal antibody therapies. individual neurologic manifestations of COVID-19 seem unlike-
Corticosteroids, such as hydrocortisone, have been widely ly given the relatively low prevalence of cases. A pragmatic
studied for their ability to modulate the hyperinflammatory approach dictates the use of available therapies traditionally
response that can lead to lung injury and multiorgan dysfunc- embraced for the treatment of neurologic manifestations of
tion in sepsis and ARDS. The RECOVERY trial helped establish other viruses and their postinfectious sequelae (eg, IVIG or
glucocorticoids as a standard of care for the treatment of plasmapheresis to treat Guillain-Barré syndrome (GBS), treat-
COVID-19 in hospitalized patients requiring supplemental ment of cerebral venous sinus thrombosis with anticoagula-
oxygen after demonstrating a mortality benefit.28 The IDSA tion, and consideration of steroids for viral encephalitis).32
and the National Institutes of Health (NIH) recommend
using dexamethasone (or an equivalent total daily dose of an Discussion
alternative glucocorticoid) for hospitalized individuals who The COVID-19 pandemic continues to surge relentlessly.
require supplemental oxygen.23,25 Glucocorticoids are not Efforts to collect robust COVID-19 epidemiologic data and
recommended for those who do not require hospitalization therapeutics have been hampered globally by insufficient
or supplemental oxygen.23,25 Other immunomodulators, such testing supplies, bureaucratic inertia, and inadequate pub-
as interferon-b or IL-6 inhibitors (eg, tocilizumab), are not cur- lic health funding. Nonetheless, the National Institute of
rently recommended for the treatment of COVID-19 except Health’s COVID-19 Prevention Trials Network (COVPN)
in the context of a clinical trial.23,25 and efforts form numerous nongovernmental organizations
Antithrombotic agents are a crucial adjunctive therapy including the World Health Organization (WHO) COVID‑19
in the treatment of moderate and severe COVID-19, con- situation dashboard, the Johns Hopkins Coronavirus
sidering the propensity for an associated coagulopathy Resource Center have risen to fill the void.33,34
and an increased incidence of thromboembolism.23 The Infection is more prevalent in adults age 18 to 29 and 50 to
prothrombotic nature of this disease is thought to account 64 years but tends to severely affect adults over age 65.3,4
for the serious cerebrovascular complications such as acute Neurologic manifestations are reportedly more common in
ischemic stroke and cerebral venous sinus thrombosis (See individuals over age 65 and those with medical comorbidities
Stroke and COVID-19 in this issue). Several registries (eg, and severe systemic disease.8 In the US, COVID-19 shows a
RIETE, CORONA-VTE, and CORE-19) are capturing data to predilection for certain groups, particularly Black and Hispanic/
inform thromboprophylaxis and anticoagulation recom- Latinx Americans.3 Social determinants of health and structural
mendations for COVID-19.29 Expert opinion recommends racism may contribute to such disparities. Although a wide
continuing chronic anticoagulation and antiplatelet thera- variety of neurologic manifestations have been reported, these
pies after COVID-19 diagnosis unless there is a compelling complications are reminiscent of those described in the other
reason to interrupt their use.23 All hospitalized patients with coronavirus epidemics (eg, the SARS epidemic in 2003 and the
COVID-19 should receive thromboprophylaxis with stan- Middle East Respiratory Syndrome [MERS] outbreak in 2012)
dard-dose unfractionated heparin or low-molecular-weight and span a spectrum of neurologic conditions from encepha-
heparin (preferred agent) unless there is an unacceptable lopathy, stroke, and encephalitis to sepsis, hypercoagulability,
bleeding risk.23,29 Standard dosing should be adjusted in the vasculitis, and GBS.13
46 PRACTICAL NEUROLOGY JANUARY 2021NEUROCRITICAL CARE
& COVID-19
11. Iadecola C, Anrather J, Kamel H. Effects of COVID-19 on the nervous system. Cell. 2020;183(1):16-27.e1. doi:10.1016/j.
Among the unique challenges posed by the COVID-19 cell.2020.08.028
pandemic is the propensity for local healthcare systems to be 12. Sharifian-Dorche M, Huot P, Osherov M, et al. Neurological complications of coronavirus infection; a comparative review
and lessons learned during the COVID-19 pandemic. J Neurol Sci. 2020;417:117085. doi:10.1016/j.jns.2020.117085
periodically overwhelmed by COVID-19–related admissions. 13. Paterson RW, Brown RL, Benjamin L, et al. The emerging spectrum of COVID-19 neurology: clinical, radiological and
The management and care provided are thus dictated by the laboratory findings. Brain. 2020;143(10):3104-3120.
14. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by
availability of resources at any given time point. Strict infection a clinically proven protease inhibitor. Cell. 2020;181(2):271-280.e8. doi:10.1016/j.cell.2020.02.052
control protocols, the need to preserve PPE, and the clinical 15. Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus
interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci. 2020;11(7):995-998.
instability of critically ill individuals may dictate the timing 16. Chen X, Laurent S, Onur OA, et al. A systematic review of neurological symptoms and complications of COVID-19. J Neurol.
and variety of diagnostic test options available. The diagnostic 2020;1-11. doi:10.1007/s00415-020-10067-3
17. Zhang BZ, Chu H, Han S, et al. SARS-CoV-2 infects human neural progenitor cells and brain organoids. Cell Res.
evaluation of those with suspected neurologic dysfunctions of 2020;30(10):928-931.
COVID-19 should proceed as in any person with new neuro- 18. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and
immunosuppression. Lancet. 2020;395(10229):1033-1034.
logic signs or symptoms. Clinicians need to maintain a high 19. Banerjee D, Viswanath B. Neuropsychiatric manifestations of COVID-19 and possible pathogenic mechanisms: insights from
index of suspicion as ongoing shortages of testing supplies other coronaviruses. Asian J Psychiatr. 2020;54:102350. doi:10.1016/j.ajp.2020.102350
20. Paniz-Mondolfi A, Bryce C, Grimes Z, et al. Central nervous system involvement by severe acute respiratory syndrome
may preclude SARS-COV-2 testing in otherwise asymptomatic coronavirus-2 (SARS-CoV-2). J Med Virol. 2020;92(7):699-702.
individuals. Similarly, patients with postinfectious neurologic 21. Sardu C, Gambardella J, Morelli MB, Wang X, Marfella, Santulli G. Hypertension, thrombosis, kidney failure, and diabetes: is
covid-19 an endothelial disease? A comprehensive evaluation of clinical and basic evidence. J Clin Med. 202;9:1417.
sequelae of COVID-19 may test negative for the SARS-CoV-2 22. Connors JM, Levy JH. Thromboinflammation and the hypercoagulability of COVID-19. J Thromb Haemost.
virus, because the viral RNA may be undetectable in the naso- 2020;18(7):1559-1561.
23. National Institutes of Health. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Published online 2020. Accessed
pharynx by the time of presentation.32 Because the mechanisms November 5, 2020. https://covid19treatmentguidelines.nih.gov/
related to neurologic complications of COVID-19 are not well 24. Gandhi RT, Lynch JB, del Rio C. Mild or moderate Covid-19. N Engl J Med. 2020;383(18):1757-1766.
25. Cheng VC, Edwards KM, Gandhi R, Gallagher J. Infectious Diseases Society of America Guidelines on the Treatment and
established, it is vital to maintain a broad differential diagnosis Management of Patients with COVID-19. Published April 11, 2020. Updated September 25, 2020. Accessed November 17,
while evaluating these neurologic sequelae that may be the 2020. https://www.idsociety.org/COVID19guidelines
26. Joyner MJ, Senefeld JW, Klassen SA, et al. Effect of convalescent plasma on mortality among hospitalized patients with
result of the SARS-CoV-2 virus itself, result from a coincidental COVID-19: initial three-month experience. [Preprint] medRxiv Prepr Serv Heal Sci. Published online prior to peer review
infection, reflect side effects of disease treatment, or represent August 12, 2020. Accessed November 17, 2020. https://doi.org/10.1101/2020.08.12.20169359
27. Hinton, DM. Bamlanivimab emergency use authorization letter. US Food and Drug Administration, Published November 10,
the manifestation of critical illness.32 Concerted global efforts 2020. Accessed November 17, 2020. https://www.fda.gov/media/143602/download
with a systematic approach are needed to understand the true 28. Prescott HC, Rice TW. Corticosteroids in COVID-19 ARDS: evidence and hope during the pandemic. JAMA.
2020;324(13):1292-1295.
complications and mechanisms of neurologic dysfunctions of 29. Spyropoulos AC, Levy JH, Ageno W, et al. Scientific and Standardization Committee communication: clinical guidance on
COVID-19. Multiple national and international collaborative the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19. J Thromb
Haemost. 2020;18(8):1859-1865.
efforts, such as the GCS-NeuroCOVID consortium, are currently 30. Khamis F, Al-Zakwani I, Al Hashmi S, et al. Therapeutic plasma exchange in adults with severe COVID-19 infection. Int J
underway to address some of these critical concerns.35 Infect Dis. 2020;99:214-218.
31. Shao Z, Feng Y, Zhong L, et al. Clinical efficacy of intravenous immunoglobulin therapy in critical ill patients with COVID-19:
a multicenter retrospective cohort study. Clin Transl Immunol. 2020;9(10):e1192. doi:10.1002/cti2.1192
Conclusions 32. Ellul MA, Benjamin L, Singh B, et al. Neurological associations of COVID-19. Lancet Neurol. 2020;19(9):767-783.
33. Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. [published correction
In summary, COVID-19 is associated with neurologic dys- appears in Lancet Infect Dis. 2020 Sep;20(9):e215]. Lancet Infect Dis. 2020;20(5):533-534. doi:10.1016/S1473-
functions in up to one-third of the infected population and 3099(20)30120-1[
34. Thorlund K, Dron L, Park J, Hsu G, Forrest JI, Mills EJ. A real-time dashboard of clinical trials for COVID-19. Lancet Digit Heal.
has varied presentations and severity. Neurologic manifesta- 2020;2(6):e286-e287. doi:10.1016/S2589-7500(20)30086-8
tions are diverse and more common in patients with severe 35. Frontera J, Mainali S, Fink EL, et al. Global consortium study of neurological dysfunction in COVID-19 (GCS-NeuroCOVID):
study design and rationale. Neurocrit Care. 2020;33(1):25-34.
systemic disease and those with medical comorbidities.
Coordinated global efforts are required to understand the
true prevalence, mechanisms, disease course, and outcomes Shraddha Mainali, MD
of neurologic dysfunctions associated with COVID-19. n Assistant Professor of Neurology
The Ohio State University Wexner Medical Center
1. Jin Y, Yang H, Ji W, et al. Virology, epidemiology, pathogenesis, and control of covid-19. Viruses. 2020;12(4):372.
2. Siordia JA. Epidemiology and clinical features of COVID-19: a review of current literature. J Clin Virol. 2020;127:104357. Columbus, OH
doi:10.1016/j.jcv.2020.104357
3. Centers for Disease Control and Prevention. COVID-19 Case Surveillance Public Use Data. Published May 15, 2020.
Updated November 3, 2020. Accessed November 17, 2020. https://data.cdc.gov/Case-Surveillance/COVID-19-Case- Marin Darsie, MD
Surveillance-Public-Use-Data/vbim-akqf Assistant Professor of Emergency Medicine and
4. Global Health 50/50. COVID-19: data disaggregated by age and sex. Published online 2020. Accessed November 15, 2020.
https://globalhealth5050.org/the-sex-gender-and-covid-19-project/ Neurological Surgery
5. US Census Bureau. QuickFacts US Population, V2019. Accessed November 15, 2020. https://www.census.gov/quickfacts/ University of Wisconsin Hospitals and Clinics
fact/table/US/PST045219
6. Herman C, Mayer K, Sarwal A. Scoping review of prevalence of neurologic comorbidities in patients hospitalized for Madison, WI
COVID-19. Neurology. 2020;95(2):77-84.
7. Liotta EM, Batra A, Clark JR, et al. Frequent neurologic manifestations and encephalopathy‐associated morbidity in
Covid‐19 patients. Ann Clin Transl Neurol. 2020;7(11):2221-2230. Both authors contributed equally to this work
8. Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in
Wuhan, China. JAMA Neurol. 2020;77(6):683-690.
9. Parma V, Ohla K, Veldhuizen MG, et al. More than smell-COVID-19 is associated with severe impairment of smell, taste, Disclosures
and chemesthesis. Chem Senses. 2020;45(7):609-622. SM and MD report no disclosures related to this content
10. DeKosky ST, Kochanek PM, Valadka A, et al. Blood biomarkers for detection of brain injury in COVID-19 patients. J
Neurotrauma. 2020;43:1-43. doi:10.1089/neu.2020.7332
JANUARY 2021 PRACTICAL NEUROLOGY 47You can also read
