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Researchers explore neurological manifestations among long COVID patients

In a recent study published in Nature Medicine, researchers assessed the long-term neurological sequelae in the post-acute phase of coronavirus disease 2019 (COVID-19) or long COVD.

Study: Long-term neurologic outcomes of COVID-19. Image Credit: Starocean/Shutterstock

Long COVID refers to the spectrum of post-acute COVID-19 sequelae involving several extrapulmonary manifestations, including neurological abnormalities. Most studies investigating long COVID-associated neurological disorders have been restricted to patients hospitalized during acute SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infections, followed up for <6 months for a small range of neurological outcomes.

A comprehensive assessment of neurological long COVID outcomes after a year of acute COVID-19 is required, evaluating neurological outcomes across different care settings in the acute COVID-19 phase, including those who were non-hospitalized, hospitalized, and intensive care unit (ICU-admitted).

About the study

In the present study, researchers assessed neurological sequelae among long COVID patients.

Data were obtained from national healthcare databases of the United States (US) Veterans Affairs department for 154,068 individuals who lived beyond the initial month of SARS-CoV-2 infections and two groups of control individuals: the contemporary control group comprising 5,638,795 US VHA (veterans’ healthcare system department) users lacking SARS-CoV-2 exposure, and the historical control group comprising 5,859,621 US VHA users who predated the SARS-CoV-2 pandemic (2017).

Inverse probability weighting was used for balancing the COVID-19 and contemporary control groups, hazard ratios (HRs) were calculated, and the burdens and risks of prespecified neurological disorders after a year of acute COVID-19 were estimated. Further, the team assessed incident neurological disorders among the SARS-CoV-2 infection group based on acute COVID-19 care settings (hospitalized, hospitalized and ICU-admitted comprising 131,915, 16,764, and 5,389 patients, respectively).  

Furthermore, two sensitivity analyses were performed; one involved prespecified covariates only, and the other involved applying covariate adjustments and weighting. To verify the reproducibility of the study approach, fatigue was assessed as a positive outcome control and the receipt of influenza vaccinations between March 1, 2020, and January 15, 2021, on even and odd calendar days among 571,291 and 605,453 individuals, respectively, as negative exposure controls.


Individuals who lived beyond the initial month of SARS-CoV-2 infections showed an elevated risk of developing cerebral venous thrombosis (CVT, HR 2.7; burden 0.1), hemorrhagic stroke (HR 2.2; burden 0.2), and ischemic stroke [HR 1.5; burden 3.4 for every 1,000 individuals at one-year, transient ischemic attacks (HR 1.6; burden 2.0)]. The burden and risk of the composite cerebrovascular outcome were 4.9 and 1.6, respectively.

Elevated risks were noted for Alzheimer’s disease (AD, HR 2.0, burden 1.7) and memory issues (HR 1.8; burden 10) with the memory and cognition outcome composite burden and risk being 10 and 1.8, respectively. The risks and burdens for peripheral neuropathic illness (HR 1.3, burden 5.6), paraesthesia (HR 1.3, burden 2.9), Bell’s palsy (HR 1.5, burden 0.3), and dysautonomia (HR 1.3, burden 1.6) with the peripheral nerve disorder outcome composite burden and risk being 8.6 and 1.3, respectively.

Episodic disorder outcomes included seizures and epilepsy (HR 1.8; burden 2.0), headache-associated illnesses (HR 1.4, burden 1.5), and migraine (HR 1.2, burden 2.0), with the composite burden and risk for the episodic disorder outcome being 4.8 and 1.3, respectively. Movement and extrapyramidal disorders included involuntary movement abnormalities (HR 1.4, burden 2.9), tremors (HR 1.4, burden 1.1), Parkinson-like illness (HR 1.5, burden 0.9), myoclonus (HR 1.4, burden 0.1), and dystonia (HR 1.6, burden 0.4) with the composite burden and risk for the movement and extrapyramidal disorder outcome being 4.0 and 1.4, respectively.

Mental health illnesses included prime depressive illnesses (HR 1.4, burden 17), adjustment and stress illnesses (HR 1.4, burden 14.3), anxiety (HR 1.4, burden 12.4) and psychotic illnesses (HR 1.5, burden 1.0). The composite burden and risk for mental health issues were 25 and 1.4, respectively. Musculoskeletal diseases included arthralgia (HR 1.3, burden 28), myopathic illness (HR 2.8, burden 0.7), and myalgia (HR 1.8, burden 16), with the composite burden and risk of the musculoskeletal disorder outcome being 40 and 1.5, respectively.

Sensory disorder outcomes included tinnitus or hearing abnormalities (HR 1.2, burden 11.9), vision dysfunction (HR 1.3, burden 5.6), smell loss (HR 4.1, burden 1.1) and taste loss (HR 2.3, burden 0.1), with the composite burden and risk for the sensory disorder outcome being 17 and 1.3, respectively. Other neurological or associated disorder outcomes included somnolence (HR 1.7, burden 0.6), dizziness (HR 1.4, burden 6.7), Guillain–Barré syndrome (HR 2.2, burden 0.1), transverse myelitis (HR 1.5, burden 0.03), and encephalopathy or encephalitis (HR 1.8, burden 0.1) and the composite burden and risk for the other neurological or associated disorder outcome were 7.4 and 1.5, respectively.

The overall burden and risk of any prespecified neurological sequela were estimated as 71 and 1.4 per 1,000 persons at one-year post-acute COVID-19, respectively, compared to contemporary controls. The risks and burdens among COVID-19 patients (vs. contemporary controls) were elevated even among patients not requiring hospital admissions in acute COVID-19, based on COVID-19 severity.

The risks for developing episodic disorders, mental health disorders, musculoskeletal disorders, and any neurologic disorder increased with age. In contrast, those of cognition and memory disorders, sensory disorders, and other neurological or associated disorders decreased with age. Similar findings were obtained in the sensitivity analyses, and COVID-19 was associated with elevated fatigue risks compared to contemporary controls but had no significant association with influenza vaccinations.

Overall, the study findings highlighted the neurologic sequelae of long COVID, which would help guide policy-making and healthcare planning for long COVID patient care.

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