Neurological Manifestations

Last reviewed: February 22, 2022 

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• Overview
• Key Literature 
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The following is a curated review of key information and literature about this topic. It is not comprehensive of all data related to this subject. 

Overview 

Neurologic complications are common in hospitalized patients with COVID-19. Reported neurological manifestations include but are not limited to: headache, impaired consciousness, stroke, seizure, meningitis, encephalitis, necrotizing encephalopathy, Guillain-Barré syndrome and acute demyelinating encephalomyelitis (Koralnik, June 2020; Mao, June 2020; Moriguchi, May 2020; Poyiadji, March 2020).

It is not clear if neurological manifestations in patients with COVID-19 occur due to direct SARS-CoV-2 infection of the peripheral or the central nervous system, inflammation of the nervous system and/or its vasculature, or a systemic response (Ellul, July 2020). Similar neurological manifestations have been noted in other respiratory viruses, including other coronaviruses such as SARS and MERS (Desforges, December 2019; Giannis, June 2020; Ellul, July 2020).

In one autopsy study of 18 patients who died with COVID-19, histopathological examination of brain specimens showed only hypoxic changes and no changes directly attributable to SARS-CoV-2 (Solomon, September 2020). There was no cytoplasmic viral staining on immunohistochemistry; SARS-CoV-2 was detected at low levels in the brains of five patients, but this may have been due to either in situ virions or viremia.

Olfactory dysfunction: The majority of our current understanding of the neurologic manifestations of COVID-19 is derived from studies in hospitalized patients rather than outpatients. One exception is that of new-onset olfactory dysfunction, which appears to be a common symptom in patients with COVID-19 in the outpatient setting. In one review, the incidence of olfactory dysfunction ranged from 33.9-68%. However, many of the studies included in the review were limited by a lack of standard assessment of olfactory dysfunction or a lack of control for nasal congestion (Meng, September 2020). Olfactory dysfunction may be the first and also the only symptom of COVID-19 (Lechien, April 2). ). ).

Encephalopathy: Based on larger cohort studies of hospitalized patients with COVID-19, it appears encephalopathy is one of the most common neurologic symptoms, although the incidence reported in studies is variable. In one study of 841 patients in a Spanish hospital admitted with COVID-19, 19.6% had an altered level of consciousness, while in a study of 917 patients admitted to three hospitals in China, 2.7% had decreased level of consciousness (Romero-Sánchez, August 2020; Xiong, September 2020).

Cerebrovascular accidents: Ischemic stroke appears to be rare in patients with COVID-19. In one study of 3,556 patients hospitalized with COVID-19 in a New York City health system, 0.9% had a proven ischemic stroke (Yaghi, May 2020). In another study comparing patients who presented to an emergency department or were hospitalized with COVID-19 (1,916 patients) or influenza (1,486 patients), the incidence of ischemic stroke in patients was 1.6% and 0.2%, respectively (Merkler, July 2020). 

Meningoencephalitis: Meningoencephalitis (viral and autoimmune) is rare in patients with COVID-19 (Paterson, October 2020).  COVID-19-associated meningoencephalitis can present with diverse clinical neurological manifestations, altered mental status being most common. (Mondal, December 2020). Cerebrospinal fluid pleocytosis is common, but SARS-COV-2 is not always detected in the  cerebrospinal fluid. Brain imaging can show hyperintense signal changes in the white matter and enhancement of meninges (Lv, April 2021).

Multisystem inflammatory syndrome: Some adults and children with COVID-19 develop a multisystem inflammatory syndrome with neurocognitive symptoms, which we have described elsewhere: MIS-A, MIS-C.

Critical illness neuropathy and myopathy: Critical illness myopathy and critical illness polyneuropathy, present alone or in combination, are the most common cause of neuromuscular weakness in the intensive care unit and have been described in post-COVID conditions.

Other neurologic signs/syndromes: Rare cases of seizures, posterior reversible encephalopathy syndrome, Guillain-Barré syndrome and myositis have been reported in patients with COVID-19 (Romero-Sanchez, August 2020; Helms, June 2020; Lin, November 2020). In one study of 19 patients who underwent early postmortem structural brain MRI 24 hours or less after dying with COVID-19, two patients had micro or macro bleeds, one had posterior reversible encephalopathy syndrome, and one had nonspecific white matter changes (Coolen, June 2020). Asymmetric olfactory bulbs were noted in four patients.

Here we review select key epidemiologic literature evaluating the neurological manifestations and complications of patients with COVID-19. The frequency with which other specific neurological complications of SARS-CoV-2 infection occur is not clear; current data predominantly consist of case reports/case series or single-center studies with small numbers of patients. Here we have focused on the studies with the highest level of evidence, with the most generalizable results.

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Key Literature 

Global Incidence of Neurological Manifestations Among Patients Hospitalized With COVID-19 (Chou, May 2021).

Overall, in this cohort study, neurological manifestations were found in approximately 80% of patients hospitalized with COVID-19 and were associated with higher in-hospital mortality.

Study population:

• The study population included patients with clinically diagnosed or laboratory-confirmed COVID-19 from 28 centers in 13 countries and included three cohorts:
  • The ENERGY registry (214 patients, 13 sites) included patients with COVID-19 and neurological manifestations.
  • The GCS-NeuroCOVID COVID-19 neurological cohort (475 patients, nine sites) included patients hospitalized with COVID-19 and neurological manifestations.
  • The GCS-NeuroCOVID all COVID-19 cohort (3,055 patients, six sites) included patients hospitalized with COVID-19 with and without neurological manifestations.
• Mean ages in the ENERGY registry, GCS-NeuroCOVID COVID-19 neurological cohort and GCS-NeuroCOVID all-COVID-19 cohort were 67 years, 62.6 years and 59.9 years, respectively.

Primary endpoint:

• To investigate self-reported symptoms or neurological signs and/or syndromes assessed by clinical evaluation.
• The main outcome measure was in-hospital mortality.

Key findings:

• 3,083 of 3,743 patients (82%) across all cohorts had any neurological manifestation.
• The most common self-reported symptoms included headache (37%) and anosmia or ageusia (26%).
• Clinically captured neurologic signs and/or syndromes were associated with higher risk of in-hospital mortality (adjusted odds ratio, 5.99; 95% CI, 4.33-8.28) on adjusting analysis.
• Preexisting neurological disorders were associated with double the odds of developing neurological signs and/or syndromes in COVID-19.

Limitations:

• This was not a formal population-based study.
• There were no a priori sample size and power calculations.
• Ascertainment bias could have occurred due to prospective and retrospective data collection.
• There were variations in care and resource availability across sites, and possible lack of inter-rater reliability.

Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study (Varatharaj, October 2020). 

Overall, in this retrospective study of patients with moderate-severe COVID-19, cerebrovascular events were common, as was altered mental status. The median age of the cohort was older and may have influenced the results. 

Study population:

• 125 patients with complete clinical datasets available and that met clinical case definitions associated with COVID-19, including:
• Cerebrovascular event (defined as an acute ischemic, hemorrhagic or thrombotic vascular event involving the brain parenchyma or subarachnoid space);
• Altered mental status (defined as an acute alteration in personality, behavior, cognition or consciousness); 
• Peripheral neurology (defined as involving nerve roots, peripheral nerves, neuromuscular junction or muscle);
• Other neurological symptoms (with free text boxes for those not meeting these syndromic presentations). 

Primary endpoint: 

• To investigate the neurological complications in patients with COVID-19 via an online network of secure rapid-response case report notification portals across several UK neuroscience bodies.  

Key findings: 

• Median patient age was 71 years (range 23–94; IQR 58–79). 
• 77 of 125 patients (62%) presented with a cerebrovascular event, of whom 57 had an ischemic stroke (74%), 9 had an intracerebral hemorrhage (12%) and 1 had Central Nervous System (CNS) vasculitis. 
• 39 of 125 patients (31%) presented with altered mental status, comprising 9 patients with unspecified encephalopathy (23%) and 7 patients with encephalitis (18%). 
• The remaining 23 (59%) patients with altered mental status fulfilled the clinical case definitions for psychiatric diagnoses as classified by the notifying psychiatrist or neuropsychiatrist, and 21 (92%) of these were new diagnoses. 
• 10 of 23 patients with neuropsychiatric disorders had new-onset psychosis (43%), 6 had a neurocognitive (dementia-like) syndrome (26%) and 4 had an affective disorder (17%). 
• 18 of 37 patients with altered mental status were <60 years (49%) and 19 were >60 years (51%), whereas 13 of 74 patients with cerebrovascular events were <60 years (18%) versus 61 who were >60 years (82%). 

Limitations:

• There is a potential for reporting bias due to the online system requirement. 
• The median patient age was 71, which may limit the applicability of the results to younger age groups, particularly given older age may have predisposed patients to neurological complications. 
• Since this study specifically focused on patients with moderate to severe complications of COVID-19, the cohort might underrepresent patients with milder outpatient symptoms, such as reduced taste or smell. 
  

 

Loss of smell in COVID-19 patients: MRI data reveals a transient edema of the olfactory clefts (Eliezer, September 2020). 

Overall, in this small study of patients with patients with COVID-19, patients with olfactory dysfunction were noted to have edematous obstruction of the olfactory cortex on MRI.

Study population:

• Prospective case-controlled study of 20 SARS-CoV-2-infected patients with olfactory function loss compared to 20 age-matched control healthy subjects. 
• All infected patients underwent olfactory function assessment and 3T MRI, performed both at the early stage of the disease and at one-month follow-up. 

Primary endpoint: 

• To assess the physiopathology of olfactory function loss in COVID-19 patients. 

Key findings: 

• At early stages of SARS-CoV-2 infection, patients had a mean olfactory score of 2.8 +/- 2.7 (range 0–8), and MRI displayed a complete obstruction of the olfactory cortex in 19 out of 20 individuals. 
• Controls had normal olfactory scores and no obstruction of the olfactory cortex  on MRI. 
• At one-month follow-up, the olfactory score had improved to 8.3 +/- 1.9 (range 4–10) in SARS-CoV-2-infected patients, and only 7 out of 20 patients still had an obstruction of the olfactory cortex. 
• There was a correlation between olfactory score and obstruction of the olfactory cortex (p=0.004). 

Limitations:

• Small sample size. 

New-Onset Neurological Events in People with COVID-19 in 3 Regions in China (Ziong, September 2020). 

Overall, in this large retrospective cohort study of hospitalized patients with COVID-19 in China, the incidence of new neurological events was low. 

Study population:

• Retrospective multicenter cohort study of 917 symptomatic patients hospitalized with confirmed COVID-19 in China. 
• The mean age was 48.7 ± 17.1 years (IQR 3 months-91 years). 
• 44% had non-neurologic comorbidities, and 3% had neurologic comorbidities. 
• 55% were male. 
• Patients who had nonspecific symptoms that could be attributed to other causes were excluded. 

Primary endpoint:

• To identify new-onset neurologic events during the acute phase of COVID-19. 

Key findings: 

• New-onset critical neurologic events occurred in 32 out of 917 patients (3.5%).
• Critical events included disorders of consciousness, cerebrovascular accidents, CNS infection, seizures and status epilepticus. 
• New-onset critical neurological events occurred in 9.4% of patients with severe-to-critical disease (30 out of 319). 
• These events included impaired consciousness (25 patients) and stroke (10 patients). 
• Noncritical neurologic events occurred in <1% of patients, and included muscle cramps, headache, occipital neuralgia, tic and tremor. No seizures were noted. 
• In multivariate analysis, being older than 60 years of age was associated with new onset critical neurologic events (p=0.000). 

Limitations:

• This was a retrospective study and could be subject to associated bias. 
• The study only included hospitalized patients, which limits the applicability of the findings to outpatients. 
• 145 patients (approximately 16% of the cohort) were still hospitalized when the study ended, which could have led to an underestimation of the incidence of new neurologic events. 
• The incidence of specific comorbidities was not discussed; these conditions could have contributed to the development of neurologic symptoms. 

Smell and Taste Dysfunction in Patients With COVID-19: A Systematic Review and Meta-analysis (Agyeman, August 2020). 

Overall, in this systematic review and meta-analysis, new-onset olfactory dysfunction in patients with confirmed COVID-19 was high; however, there was significant heterogeneity among the included studies, and many studies did not use objective assessment methods.

Study population:

• 24 studies including 8,438 patients from 13 countries with confirmed COVID-19. 

Primary endpoint:

• To estimate the prevalence of olfactory and gustatory dysfunctions in patients with COVID-19.

Key findings: 

• The pooled proportions of olfactory and gustatory dysfunction were 41.0% (95% CI, 28.5% to 53.9%) and 38.2% (95% CI, 24.0% to 53.6%), respectively. 
• Increasing mean age was correlated with a lower prevalence of olfactory (coefficient = -0.076; p = .02) and gustatory (coefficient = -0.073; p=.03) dysfunctions. 
• There was a higher prevalence of olfactory dysfunctions when objective measurements were used, as opposed to self-reports (coefficient = 2.33; P = .01). 
• No differences by sex were noted.
• An I2 of >50% was considered to represent substantial heterogeneity. For olfactory dysfunction, the I2 was I2 = 99.1% and for gustatory dysfunction it was 98.8%. 

Limitations:

• High statistical heterogeneity was largely attributable to the observational nature of the studies and not explained by differences in patients' age, gender, region or olfactory and gustatory dysfunction assessment methods. This limits the applicability of the overall findings. 
• Most studies were in Europe, which may affect the generalizability of the results. 
• Few studies used objective assessment methods for establishing the presence of olfactory and gustatory dysfunction; most relied on self-reports.  
  

 

Neurologic manifestations in hospitalized patients with COVID-19: The ALBACOVID registry (Romero-Sánchez, August 2020). 

Overall, in this large retrospective cohort study of hospitalized patients with COVID-19 in Spain, the incidence of new neurological events was high, but the authors did not account for alternative explanations for symptoms, and the use of therapies that could also cause neurologic symptoms was high. 

Study population:

• Retrospective single center cohort study of 841 hospitalized symptomatic patients in Spain with confirmed COVID-19. 
• Average age was 66.4 years; 56.2% were male. 
• The most common systemic comorbidities included hypertension (55.2%), obesity (44.5%), dyslipidemia (43.3%), tobacco smoking (36%), diabetes mellitus (25.1%) and heart disease (18.8%). 
• Numerous therapies, including lopinavir/ritonavir, pulse-dose steroids, hydroxychloroquine and immune modulators, were used. 
• 35.3% received full dose anticoagulation. 

Primary endpoint:

• To determine whether neurologic manifestations are common in hospitalized patients with COVID-19 and to describe their main characteristics. 

Key findings: 

• 329 patients (39.1%) had severe COVID-19, 77 (9.16%) were admitted to the intensive care unit and 197 (23.4%) died during the course of their hospital admission. 
• Of the 841 patients, 57.4% developed a neurologic symptom. 
• Early in infection, myalgias (17.2%), headache (14.1%) and dizziness (6.1%) occurred. 
• Anosmia (4.9%) and dysgeusia (6.2%) tended to occur early as well (60% as the first clinical manifestation) — more frequently in less severe cases. 
• Disorders of consciousness were common (19.6%) and primarily occurred in older patients and in severe and advanced COVID-19 stages. 
• Myopathy (3.1%), dysautonomia (2.5%), cerebrovascular diseases (1.7%), seizures (0.7%), movement disorders (0.7%), encephalitis (n=1), Guillain-Barré syndrome (n=1) and optic neuritis (n=1) were also reported. 
• Neurologic complications were the main cause of death in 4.1% of all deceased study participants. 

Limitations:

• Alternative causes of symptoms were not assessed. 
• The rate of comorbidities which could have contributed to neurological syndromes was high. 
• Many patients received therapies that could cause several of the symptoms reported in the cohort, including headache, dizziness, changes in consciousness, etc. 
• One third of the cohort received full-dose anticoagulation, which could have affected the incidence of stroke. 
• This was a retrospective study and could be subject to associated bias. 
• The study only included hospitalized patients, which limits the applicability of the findings to outpatients. 

Neurologic Features in Severe SARS-CoV-2 Infection (Helms, June 2020). 

Overall, in this small retrospective study of patients with acute respiratory distress syndrome related to COVID-19, neurologic symptoms were common. Whether the symptoms were due to SARS-CoV-2 infection alone, as opposed to being critically ill, is not clear. 

Study population:

• 58 patients in France admitted to the hospital because of acute respiratory distress syndrome due to COVID-19. 

Primary endpoint:

• To report the neurological features in patients with COVID-19. 

Key findings: 

• Neurologic findings were recorded in 8 of the 58 patients (14%) on admission to the ICU (before treatment) and in 39 patients (67%) when sedation and a neuromuscular blocker were withheld. 
• The median patient age was 63 years. 
• The median Simplified Acute Physiology Score II at the time of neurologic examination was 52 (IQR 37 to 65, on a scale ranging from 0 to 163, with higher scores indicating greater severity of illness). 
• 7 patients had prior neurologic disorders, including transient ischemic attack, partial epilepsy and mild cognitive impairment. 
• Agitation was present in 40 patients (69%) when neuromuscular blockade was discontinued. 
• 26 of 40 patients had confusion according to the Confusion Assessment Method for the ICU. 
• Diffuse corticospinal tract signs with enhanced tendon reflexes, ankle clonus and bilateral extensor plantar reflexes were present in 39 patients (67%). 
• Magnetic resonance imaging of the brain was performed in 13 patients due to unexplained encephalopathic features. 
• Enhancement in leptomeningeal spaces was noted in 8 patients, and bilateral frontotemporal hypoperfusion was noted in all 11 patients who underwent perfusion imaging. 
• 2 asymptomatic patients each had a small acute ischemic stroke. 
• In the 8 patients who underwent electroencephalography, only nonspecific changes were detected; 1 of the 8 patients had diffuse bifrontal slowing consistent with encephalopathy. 
• Cerebrospinal fluid samples from 7 patients showed no cells; in 2 patients, oligoclonal bands were present with an identical electrophoretic pattern in serum, and protein and IgG levels were elevated in 1 patient. 

Limitations:

• Small sample size. 
• Data is lacking to determine which neurological findings were due to critical illness. 

Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China (Mao, April 2020). 

Overall, in this retrospective EHR-based study of patients hospitalized with COVID-19, one-third of patients developed neurologic manifestations. 

Study population:

• Retrospective observational study of 214 patients hospitalized with laboratory-confirmed diagnosis of COVID-19 in China. 

Primary endpoint: 

• To study the neurologic manifestations of patients with COVID-19. 

Key findings: 

• The mean (SD) age was 52.7 (15.5) years and 87 patients (40.7%) were men.
• Of 214 patients with COVID-19, 126 had non-severe infection (58.9%) and 88 had severe infection (41.1%) according to respiratory status. 
• 78 of the 214 patients (36.4%) had neurologic manifestations. 
• Compared with patients with non-severe infection, patients with severe infection were older, had more underlying disorders, especially hypertension, and showed fewer typical symptoms of COVID-19, such as fever and cough. 
• Patients with more severe infection vs. non-severe infection experienced neurologic manifestations such as acute cerebrovascular diseases (5 [5.7%] vs. 1 [0.8%]), impaired consciousness (13 [14.8%] vs. 3 [2.4%]) and skeletal muscle injury (17 [19.3%] vs. 6 [4.8%]). 
• Aside from cerebrovascular disease and impaired consciousness, most neurologic manifestations occurred early in the illness (median time 1-2 days). 

Limitations:

• Single-center study, limiting generalizability to other settings. 
• All data were abstracted from the electronic medical records; certain patients with neurologic symptoms might not be captured if their neurologic manifestations were mild, such as with taste and smell impairment. 

Additional Literature

Neuropathology of Patients with COVID-19 in Germany: A Post-Mortem Case Series (Matschke, October 2020). Researchers examined neuropathological features in the brains of 43 patients (median age 76 years [IQR 70–86]) who died between March 13 and April 24, 2020, in Hamburg, Germany. Of these, 37 patients (86%) had astrogliosis in all assessed regions. Activation of microglia and infiltration by cytotoxic T lymphocytes was most pronounced in the brainstem and cerebellum. Meningeal cytotoxic T lymphocyte infiltration was seen in 34 patients (79%). Samples from 40 patients (93%) underwent immunohistochemical staining for SARS-CoV-2 spike and nucleocapsid proteins, with SARS-CoV-2 detected in the brains of 21 of these 40 patients  (53%) and SARS-CoV-2 viral proteins found in cranial nerves originating from the lower brainstem and in isolated cells of the brainstem.

A Prospective Study of Neurologic Disorders in Hospitalized COVID-19 Patients in New York City (Frontera, October 2020). A prospective, multi-center, observational study of 4,491 consecutive hospitalized adults in New York City with laboratory-confirmed SARS-CoV-2 infection. Of these, 606 patients (13.5%) developed a new neurologic disorder in a median of 2 days from COVID-19 symptom onset. The most common diagnoses were: toxic/metabolic encephalopathy (6.8%), seizure (1.6%), stroke (1.9%) and hypoxic/ischemic injury (1.4%). COVID-19 patients with neurologic disorders had increased risk of in-hospital mortality (HR 1.38, 95% CI 1.17-1.62, p<0.001) and decreased likelihood of discharge home (HR 0.72, 95% CI 0.63-0.85, p<0.001).

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