Long-term neurologic outcomes of COVID-19

Abstract

The neurologic manifestations of acute COVID-19 are well characterized, but a comprehensive evaluation of postacute neurologic sequelae at 1 year has not been undertaken. Here we use the national healthcare databases of the US Department of Veterans Affairs to build a cohort of 154,068 individuals with COVID-19, 5,638,795 contemporary controls and 5,859,621 historical controls; we use inverse probability weighting to balance the cohorts, and estimate risks and burdens of incident neurologic disorders at 12 months following acute SARS-CoV-2 infection. Our results show that in the postacute phase of COVID-19, there was increased risk of an array of incident neurologic sequelae including ischemic and hemorrhagic stroke, cognition and memory disorders, peripheral nervous system disorders, episodic disorders (for example, migraine and seizures), extrapyramidal and movement disorders, mental health disorders, musculoskeletal disorders, sensory disorders, Guillain-Barré syndrome, and encephalitis or encephalopathy. We estimated that the hazard ratio of any neurologic sequela was 1.42 (95% confidence intervals 1.38, 1.47) and burden 70.69 (95% confidence intervals 63.54, 78.01) per 1,000 persons at 12 months. The risks and burdens were elevated even in people who did not require hospitalization during acute COVID-19. Limitations include a cohort comprising mostly White males. Taken together, our results provide evidence of increased risk of long-term neurologic disorders in people who had COVID-19.

Fig. 1. Cohort construction flowchart.

Cohort construction for COVID-19 group (blue), contemporary control group (orange) and historical control group (pink). Comparisons between groups are presented in green.

Fig. 2. Risks and 12-month burdens of incident postacute COVID-19 neurologic outcomes compared with the contemporary control cohort.

Outcomes were ascertained 30 days after the COVID-19-positive test until the end of follow up. COVID-19 cohort (n = 154,068) and contemporary control cohort (n = 5,638,795). Adjusted HRs (dots) and 95% (error bars) CIs are presented, as are estimated excess burdens (bars) and 95% CIs (error bars). Burdens are presented per 1,000 persons at 12 months of follow up. The dashed line marks a HR of 1.00; lower limits of 95% CIs with values greater than 1.00 indicate significantly increased risk.

Fig. 3. Risks and 12-month burdens of incident postacute COVID-19 composite neurologic outcomes compared with the contemporary control cohort.

Composite outcomes consisted of cerebrovascular disorders (ischemic stroke, TIA, hemorrhagic stroke and cerebral venous thrombosis), cognition and memory (memory problems and Alzheimer’s disease), disorders of the peripheral nerves (peripheral neuropathy, paresthesia, dysautonomia and Bell’s palsy), episodic disorders (migraine, epilepsy and seizures and headache disorders), extrapyramidal and movement disorders (abnormal involuntary movements, tremor, Parkinson-like disease, dystonia, myoclonus), mental health disorders (major depressive disorders, stress and adjustment disorders, anxiety disorders, and psychotic disorders), musculoskeletal disorders (joint pain, myalgia and myopathy), sensory disorders (hearing abnormalities or tinnitus, vision abnormalities, loss of smell and loss of taste), other neurologic or related disorders (dizziness, somnolence, Guillain–Barré syndrome, encephalitis or encephalopathy and transverse myelitis) and any neurologic outcome (incident occurrence of any neurologic outcome studied). Outcomes were ascertained 30 days after the COVID-19-positive test until the end of follow up. The COVID-19 cohort had n = 154,068 and the contemporary control cohort had n = 5,638,795. Adjusted HRs (dots) and 95% (error bars) CIs are presented, as are estimated excess burdens (bars) and 95% CIs (error bars). Burdens are presented per 1,000 persons at 12 months of follow up. The dashed line marks a HR of 1.00; lower limits of 95% CIs with values greater than 1.00 indicate significantly increased risk.

Fig. 4. Subgroup analyses of the risks of incident postacute COVID-19 composite neurologic outcomes compared with the contemporary control cohort.

Composite outcomes consisted of cerebrovascular disorders (ischemic stroke, TIA, hemorrhagic stroke and cerebral venous thrombosis), cognition and memory (memory problems and Alzheimer’s disease) disorders, disorders of the peripheral nerves (peripheral neuropathy, paresthesia, dysautonomia and Bell’s palsy), episodic disorders (migraine, epilepsy and seizures, and headache disorders), extrapyramidal and movement disorders (abnormal involuntary movements, tremor, Parkinson-like disease, dystonia, myoclonus), mental health disorders (major depressive disorders, stress and adjustment disorders, anxiety disorders, and psychotic disorders), musculoskeletal disorders (joint pain, myalgia and myopathy), sensory disorders (hearing abnormalities or tinnitus, vision abnormalities, loss of smell and loss of taste), other neurologic or related disorders (dizziness, somnolence, Guillain–Barré syndrome, encephalitis or encephalopathy and transverse myelitis) and any neurologic outcome (incident occurrence of any neurologic outcome studied). Outcomes were ascertained 30 days after the COVID-19-positive test until the end of follow up. COVID-19 cohort (n = 154,068) and contemporary control cohort (n = 5,638,795). Adjusted HRs (dots) and 95% (error bars) CIs are presented. The dashed line marks a HR of 1.00; lower limits of 95% CIs with values greater than 1.00 indicate significantly increased risk.

Fig. 5. Risks and 12-month burdens of incident postacute COVID-19 neurologic outcomes compared with the contemporary control cohort by care setting of the acute infection.

Risks and burdens were assessed at 12 months in mutually exclusive groups comprising nonhospitalized individuals with COVID-19 (green), individuals hospitalized for COVID-19 (orange) and individuals admitted to intensive care for COVID-19 during the acute phase (first 30 days) of COVID-19 (purple). Outcomes were ascertained 30 days after the COVID-19-positive test until the end of follow up. The contemporary control cohort served as the referent category. Within the COVID-19 cohort, nonhospitalized (n = 131,915), hospitalized (n = 16,764), admitted to intensive care (n = 5,389) and contemporary control cohort (n = 5,606,761). Adjusted HRs (dots) and 95% (error bars) CIs are presented, as are estimated excess burdens (bars) and 95% CIs (error bars). Burdens are presented per 1,000 persons at 12 months of follow up. ICU, intensive care unit. The dashed line marks a HR of 1.00; lower limits of 95% CIs with values greater than 1.00 indicate significantly increased risk.

Fig. 6. Risks and 12-month burdens of incident postacute COVID-19 composite neurologic outcomes compared with the contemporary control cohort by care setting of the acute infection.

Risks and burdens were assessed at 12 months in mutually exclusive groups comprising nonhospitalized individuals with COVID-19 (green), individuals hospitalized for COVID-19 (orange) and individuals admitted to intensive care for COVID-19 during the acute phase (first 30 days) of COVID-19 (purple). Composite outcomes consisted of cerebrovascular disorders (ischemic stroke, TIA, hemorrhagic stroke and cerebral venous thrombosis), cognition and memory disorders (memory problems and Alzheimer’s disease), disorders of the peripheral nerves (peripheral neuropathy, paresthesia, dysautonomia and Bell’s palsy), episodic disorders (migraine, epilepsy and seizures, and headache disorders), extrapyramidal and movement disorders (abnormal involuntary movements, tremor, Parkinson-like disease, dystonia, myoclonus), mental health disorders (major depressive disorders, stress and adjustment disorders, anxiety disorders, and psychotic disorders), musculoskeletal disorders (joint pain, myalgia and myopathy), sensory disorders (hearing abnormalities or tinnitus, vision abnormalities, loss of smell and loss of taste), other neurologic or related disorders (dizziness, somnolence, Guillain–Barré syndrome, encephalitis or encephalopathy and transverse myelitis) and any neurologic outcome (incident occurrence of any neurologic outcome studied). Outcomes were ascertained 30 days after the COVID-19-positive test until the end of follow up. The contemporary control cohort served as the referent category. Within the COVID-19 cohort were the nonhospitalized (n = 131,915), hospitalized (n = 16,764), those admitted to intensive care (n = 5,389) and contemporary control cohort (n = 5,606,761). Adjusted HRs (dots) and 95% (error bars) CIs are presented, as are estimated excess burdens (bars) and 95% CIs (error bars). Burdens are presented per 1,000 persons at 12 months of follow up. The dashed line marks a HR of 1.00; lower limits of 95% CIs with values greater than 1.00 indicate significantly increased risk.

Extended Data Fig. 1. Standardized mean difference of predefined and algorithmically selected high-dimensional variables.

Standardized mean difference between COVID-19 and contemporary control.

Extended Data Fig. 2. The risks of incident postacute COVID-19 composite neurologic outcomes across age compared with the contemporary control cohort.

Composite outcomes consisted of cerebrovascular disorders (ischemic stroke, TIA, hemorrhagic stroke, and cerebral venous thrombosis), cognition and memory (memory problems and Alzheimer’s disease), disorders of the peripheral nerves (peripheral neuropathy, paresthesia, dysautonomia, and Bell’s palsy), episodic disorders (migraine, epilepsy and seizures, and headache disorders), extrapyramidal and movement disorders (abnormal involuntary movements, tremor, Parkinson-like disease, dystonia, myoclonus), mental health disorders (major depressive disorders, stress and adjustment disorders, anxiety disorders, and psychotic disorders), musculoskeletal disorders (joint pain, myalgia, and myopathy), sensory disorders (Hearing abnormalities or tinnitus, vision abnormalities, loss of smell, and loss of taste), other neurologic or related disorders (dizziness, somnolence, Guillain-Barré syndrome, encephalitis or encephalopathy and transverse myelitis), and any neurologic outcome (incident occurrence of any neurologic outcome studied). Outcomes were ascertained 30d after the COVID-19-positive test until the end of follow up. COVID-19 cohort (n = 154,068) and contemporary control cohort (n = 5,638,795). Age was transformed into restricted cubic spline function for the analyses. P value was based on 2-sided Wald Chi-Squared test on interaction between age and exposure, without multiple comparisons adjustment. A P value of <0.05 suggests that age modifies the association between COVID-19 and the neurologic outcome. The P value for cerebrovascular disorders=0.38, cognition and memory disorders=0.001, disorders of the peripheral nerves=0.15, episodic disorders<0.001, extrapyramidal and movement disorders=0.88, mental health disorders<0.001, musculoskeletal disorders<0.001, sensory disorders<0.001, other neurologic or related disorders<0.001, and any neurologic disorder=0.003.

Extended Data Fig. 3. Standardized mean difference of predefined and algorithmically selected high-dimensional variables.

(a) by care setting of the acute infection between COVID-19 and contemporary control; (b) between COVID-19 and historical control; (c) by care setting of the acute infection between COVID-19 and historical control.

Extended Data Fig. 4. Risks and 12-month burdens of incident postacute COVID-19 neurologic outcomes compared with the historical control cohort.

Outcomes were ascertained 30 d after the COVID-19-positive test until the end of follow-up. COVID-19 cohort (n = 154,068) and historical control cohort (n = 5,859,621). Adjusted HRs (dots) and 95% (error bars) CIs are presented, as are estimated excess burdens (bars) and 95% confidence intervals (error bars). Burdens are presented per 1000 persons at 12 months of follow up. The dashed line marks a HR of 1.00; lower limits of 95% CIs with values greater than 1.00 indicate significantly increased risk.

Extended Data Fig. 5. Risks and 12-month burdens of incident postacute COVID-19 composite neurologic outcomes compared with the historical control cohort.

Composite outcomes consisted of cerebrovascular disorders (ischemic stroke, TIA, hemorrhagic stroke, and cerebral venous thrombosis), cognition and memory (memory problems and Alzheimer’s disease), disorders of the peripheral nerves (peripheral neuropathy, paresthesia, dysautonomia, and Bell’s palsy), episodic disorders (migraine, epilepsy and seizures, and headache disorders), extrapyramidal and movement disorders (abnormal involuntary movements, tremor, Parkinson-like disease, dystonia, myoclonus), mental health disorders (major depressive disorders, stress and adjustment disorders, anxiety disorders, and psychotic disorders), musculoskeletal disorders (joint pain, myalgia, and myopathy), sensory disorders (Hearing abnormalities or tinnitus, vision abnormalities, loss of smell, and loss of taste), other neurologic or related disorders (dizziness, somnolence, Guillain-Barré syndrome, encephalitis or encephalopathy and transverse myelitis), and any neurologic outcome (incident occurrence of any neurologic outcome studied). Outcomes were ascertained 30d after the COVID-19-positive test until the end of follow up. COVID-19 cohort (n = 154,068) and historical control cohort (n = 5,859,621). Adjusted HRs (dots) and 95% (error bars) CIs are presented, as are estimated excess burdens (bars) and 95% confidence intervals (error bars). Burdens are presented per 1000 persons at 12 months of follow up. The dashed line marks a HR of 1.00; lower limits of 95% CIs with values greater than 1.00 indicate significantly increased risk.

Extended Data Fig. 6. Subgroup analyses of the risks of incident postacute COVID-19 composite neurologic outcomes compared with the historical control cohort.

Composite outcomes consisted of cerebrovascular disorders (ischemic stroke, TIA, hemorrhagic stroke, and cerebral venous thrombosis), cognition and memory (memory problems and Alzheimer’s disease), disorders of the peripheral nerves (peripheral neuropathy, paresthesia, dysautonomia, and Bell’s palsy), episodic disorders (migraine, epilepsy and seizures, and headache disorders), extrapyramidal and movement disorders (abnormal involuntary movements, tremor, Parkinson-like disease, dystonia, myoclonus), mental health disorders (major depressive disorders, stress and adjustment disorders, anxiety disorders, and psychotic disorders), musculoskeletal disorders (joint pain, myalgia, and myopathy), sensory disorders (Hearing abnormalities or tinnitus, vision abnormalities, loss of smell, and loss of taste), other neurologic or related disorders (dizziness, somnolence, Guillain-Barré syndrome, encephalitis or encephalopathy and transverse myelitis), and any neurologic outcome (incident occurrence of any neurologic outcome studied). Outcomes were ascertained 30d after the COVID-19-positive test until the end of follow up. COVID-19 cohort (n = 154,068) and historical control cohort (n = 5,859,621). Adjusted HRs (dots) and 95% (error bars) CIs are presented. The dashed line marks a HR of 1.00; lower limits of 95% CIs with values greater than 1.00 indicate significantly increased risk.

Extended Data Fig. 7. The risks of incident postacute COVID-19 composite neurologic outcomes across age compared with the historical control cohort.

Composite outcomes consisted of cerebrovascular disorders (ischemic stroke, TIA, hemorrhagic stroke, and cerebral venous thrombosis), cognition and memory (memory problems and Alzheimer’s disease), disorders of the peripheral nerves (peripheral neuropathy, paresthesia, dysautonomia, and bell’s palsy), episodic disorders (migraine, epilepsy and seizures, and headache disorders), extrapyramidal and movement disorders (abnormal involuntary movements, tremor, Parkinson-like disease, dystonia, myoclonus), mental health disorders (major depressive disorders, stress and adjustment disorders, anxiety disorders, and psychotic disorders), musculoskeletal disorders (joint pain, myalgia, and myopathy), sensory disorders (Hearing abnormalities or tinnitus, vision abnormalities, loss of smell, and loss of taste), other neurologic or related disorders (dizziness, somnolence, Guillain-Barré syndrome, encephalitis or encephalopathy and transverse myelitis), and any neurologic outcome (incident occurrence of any neurologic outcome studied). Outcomes were ascertained 30d after the COVID-19-positive test until the end of follow up. COVID-19 cohort (n = 154,068) and historical control cohort (n = 5,859,621). Age was transformed into restricted cubic spline function for the analyses. P value was based on 2 sided Wald Chi-Squared test on interaction between age and exposure, without multiple comparisons adjustment. A P value of <0.05 suggests that age modifies the association between COVID-19 and the neurologic outcome. The P value for cerebrovascular disorders=0.57, cognition and memory disorders=0.009, disorders of the peripheral nerves=0.04, episodic disorders<0.001, extrapyramidal and movement disorders=0.05, mental health disorders<0.001, musculoskeletal disorders<0.001, sensory disorders<0.001, other neurologic or related disorders=0.002, and any neurologic disorder<0.001.

Extended Data Fig. 8. Risks and 12-month burdens of incident postacute COVID-19 neurologic outcomes by care setting of the acute infection compared with the historical control cohort.

Risks and burdens were assessed at 12 months in mutually exclusive groups comprising nonhospitalized individuals with COVID-19 (green), individuals hospitalized for COVID-19 (orange) and individuals admitted to intensive care for COVID-19 during the acute phase (first 30 d) of COVID-19 (purple). Outcomes were ascertained 30 d after the COVID-19-positive test until the end of follow up. The historical control cohort served as the referent category. Within the COVID-19 cohort, nonhospitalized (n = 131,915), hospitalized (n = 16,764), admitted to intensive care (n = 5,389) and historical control cohort (n = 5,809,908). Adjusted HRs (dots) and 95% (error bars) CIs are presented, as are estimated excess burdens (bars) and 95% confidence intervals (error bars). Burdens are presented per 1000 persons at 12 months of follow up. The dashed line marks a HR of 1.00; lower limits of 95% CIs with values greater than 1.00 indicate significantly increased risk.

Extended Data Fig. 9. Risks and 12-month burdens of incident postacute COVID-19 composite neurologic outcomes by care setting of the acute infection compared with the historical control cohort.

Risks and burdens were assessed at 12 months in mutually exclusive groups comprising nonhospitalized individuals with COVID-19 (green), individuals hospitalized for COVID-19 (orange) and individuals admitted to intensive care for COVID-19 during the acute phase (first 30 d) of COVID-19 (purple). Composite outcomes consisted of cerebrovascular disorders (ischemic stroke, TIA, hemorrhagic stroke, and cerebral venous thrombosis), cognition and memory (memory problems and Alzheimer’s disease), disorders of the peripheral nerves (peripheral neuropathy, paresthesia, dysautonomia, and Bell’s palsy), episodic disorders (migraine, epilepsy and seizures, and headache disorders), extrapyramidal and movement disorders (abnormal involuntary movements, tremor, Parkinson-like disease, dystonia, myoclonus), mental health disorders (major depressive disorders, stress and adjustment disorders, anxiety disorders, and psychotic disorders), musculoskeletal disorders (joint pain, myalgia, and myopathy), sensory disorders (Hearing abnormalities or tinnitus, vision abnormalities, loss of smell, and loss of taste), other neurologic or related disorders (dizziness, somnolence, Guillain-Barré syndrome, encephalitis or encephalopathy and transverse myelitis), and any neurologic outcome (incident occurrence of any neurologic outcome studied). Outcomes were ascertained 30 d after the COVID-19-positive test until the end of follow up. The historical control cohort served as the referent category. Within the COVID-19 cohort, nonhospitalized (n = 131,915), hospitalized (n = 16,764), admitted to intensive care (n = 5,389) and historical control cohort (n = 5,809,908). Adjusted HRs (dots) and 95% (error bars) CIs are presented, as are estimated excess burdens (bars) and 95% confidence intervals (error bars). Burdens are presented per 1000 persons at 12 months of follow up. The dashed line marks a HR of 1.00; lower limits of 95% CIs with values greater than 1.00 indicate significantly increased risk.