In this study involving 154,068 people who had COVID-19, 5,638,795 contemporary controls and 5,859,621 historical controls, which altogether correspond to 14,064,985 person-years of follow up, we show that beyond the first 30 days of infection, people with COVID-19 are at increased risk of an array of neurologic disorders spanning several disease categories including stroke (both ischemic and hemorrhagic), cognition and memory disorders, peripheral nervous system disorders, episodic disorders, extrapyramidal and movement disorders, mental health disorders, musculoskeletal disorders, sensory disorders and other disorders including Guillain–Barré syndrome, and encephalitis or encephalopathy. The risks and burdens were evident in subgroups based on age, race, sex, obesity, smoking, ADI, diabetes, chronic kidney disease, hyperlipidemia, hypertension or immune dysfunction. The risks were evident even in people who did not need hospitalization during the acute phase of the infection and increased according to the care setting of the acute phase of the disease from nonhospitalized to hospitalized to admitted to intensive care. The findings were consistent in comparisons involving the contemporary control group and the historical control group. The results were robust to challenge in sensitivity analyses; the application of negative-exposure and negative-outcome controls yielded results consistent with prior expectations. Altogether, our results show that the risks and burdens of neurologic disorders in the COVID-19 group at 12 months are substantial. The long-term consequences of SARS-CoV-2 infection should be taken into account in devising policies for managing the ongoing pandemic, and developing exit strategies for a postpandemic era. Health systems should consider these findings in capacity planning and in designing clinical care pathways to address the care needs of people who survive the acute phase of COVID-19.
More than 2 years into the COVID-19 global pandemic, it is abundantly clear that infection with SARS-CoV-2 may result in a broad array of long-term disorders. Our report adds to this growing body of evidence by providing a comprehensive account of the neurologic consequences of COVID-19 at 12 months. Given the colossal scale of the pandemic, and even though the absolute numbers reported in this work are small, these may translate into a large number of affected individuals around the world—and this will likely contribute to a rise in the burden of neurologic diseases. This places more emphasis on the continued need for multipronged primary prevention strategies through nonpharmaceutical interventions (for example, masking) and vaccines to reduce—to the extent possible—the risk of contracting SARS-CoV-2. There is also an urgent need to develop long-term sustainable strategies to prevent mass infection with SARS-CoV-2 and to determine whether and how these long-term neurologic (and other) complications could be prevented or otherwise mitigated in people who are already infected with SARS-CoV-2.
Governments and health systems should take into account the findings that SARS-CoV-2 leads to long-term neurologic (and other serious) consequences when devising policy for continued management of this pandemic and developing plans for a postpandemic world. Some of the neurologic disorders reported here are serious chronic conditions that will impact some people for a lifetime. These conditions require early identification and care to reduce the risk of further downstream adverse outcomes. The added burden of new (incident) neurologic disease (and other incident long-term disorders) that result as a consequence of infection with SARS-CoV-2 will likely have profound ramifications not only on patients’ quality of life and life expectancy but also on health systems and economic productivity; these also risk widening inequities15. It is imperative that we recognize the enormous challenges posed by Long Covid and all its downstream long-term consequences. Meeting these challenges requires urgent and coordinated—but so far absent—global, national and regional response strategies.
Our estimates of the risk of cerebrovascular disorders are generally consistent with our prior report (which was focused on investigating cardiovascular outcomes and included cerebrovascular disorders); minor differences in estimates of risk and burden are likely due to updated analytic approach and the longer follow up time (generally 60 more days of follow up in this current study).
Our analyses by age as a continuous variable reveal two key findings.
(1) Regardless of age and across the age spectrum, people with COVID-19 had a higher risk of all the neurologic outcomes examined in this analysis.
(2) Our interaction analyses suggest that the effect of COVID-19 on risk of memory and cognitive disorders, sensory disorders and other neurologic disorders (including Guillain–Barré syndrome and encephalitis or encephalopathy) is stronger in younger adults; the effects of these disorders on younger lives are profound and cannot be overstated; urgent attention is needed to better understand these long-term effects and the means to mitigate them. Equally troubling is the stronger effect of COVID-19 on mental health disorders, musculoskeletal disorders and episodic disorders in older adults, highlighting their vulnerability to these disorders following SARS-CoV-2 infection.
Several mechanisms have been proposed to explain the postacute sequelae of COVID-19; these include persistence of the virus, RNA fragments or viral proteins leading to continued activation of the immune system and chronic inflammation; other mechanisms may involve autoimmunity, microbiome dysbiosis and organ injury during the acute phase that may result in postacute manifestations. The neurologic manifestations of Long Covid are hypothesized to be driven by neuro-inflammation with trafficking of immune cells (T cells and natural killer cells), cytokines and antibodies to the brain parenchyma resulting in activation of microglia and astrocytes, disturbances in synaptic signaling of upper-layer excitatory neurons, impaired neurogenesis and neuroblast formation, loss of oligodendrocytes and reduced myelinated axon density. Other mechanisms may involve endothelial cell injury, complement activation and complement-mediated coagulopathy and microangiopathy leading to microbleeds or microclots27,28,29. Evidence from brain lysates of people with COVID-19 (compared with noninfected controls) demonstrates upregulation of transforming-growth-factor-beta signaling, hyperphosphorylation and posttranslational modification of receptor and channel proteins typically linked to Alzheimer’s disease30. Direct invasion of the virus into the central nervous system has also been proposed as a putative hypothetical mechanism of neuronal injury22. Evidence also suggests significant structural brain changes in the postacute phase of COVID-19; analyses of neuro-imaging data pre- and 4 to 5 months postinfection with SARS-CoV-2 reveal significant longitudinal effects—even in mild cases—including reduction in gray-matter thickness, increased activity of markers of tissue damage and reduction in global brain size2. Because of the broad nature of the neurologic sequelae of SARS-CoV-2, various—and not necessarily mutually exclusive—mechanisms may be at play for different neurologic disorders; these mechanisms may accelerate progression of pre-existing subclinical disease or result in de novo disease31.
This study has several strengths. We leveraged the breadth and depth of the national healthcare databases of the US Department of Veterans Affairs to build a large cohort of 154,068 people who had COVID-19 and more than 11 million people in the control group. We investigated a comprehensive list of prespecified neurologic outcomes. We used both predefined (based on established knowledge) and—in recognition of our incomplete and evolving knowledge of COVID-19—an expanded set of 100 algorithmically selected covariates in several data domains including diagnostic codes, prescription records and laboratory test results to balance the exposure groups and estimate the risk and burden of neurologic disorders at 12 months. We examined the associations in clinically important subgroups and across the spectrum of care during the acute phase of COVID-19 (nonhospitalized, hospitalized and admitted to intensive care). We investigated these associations in COVID-19 versus a contemporary cohort exposed to the broader contextual changes brought on by the pandemic, and a historical cohort from an era undisturbed by the pandemic. We subjected our analyses to the scrutiny of multiple sensitivity analyses and successfully demonstrated testing of negative-exposure and outcome controls. Finally, we provide two measures of risk: (1) hazard ratios on the relative scale; and (2) excess burden on absolute scale. The latter also incorporates the contribution of baseline risk and is useful to understand and contextualize the broader impact of the relative risk on the population.
This study has several limitations. The demographic characteristics of the study population (majority White and male) may limit generalizability of findings. Although we adjusted—through weighting—for predefined and algorithmically selected covariates, and although we used validated definitions for outcomes, and our results were robust to challenge in sensitivity analyses and survived the scrutinous application of negative controls, we cannot completely rule out misclassification bias or residual confounding. Our contemporary control included people who had no evidence of SARS-CoV-2 infection; it is possible that some people had an infection but were not tested for it; these people will have been enrolled in the control group; and if present in large numbers, this may bias the results toward the null and lead to underestimation of risk. While results from inverse probability weighting may be sensitive to different specifications of the weighting processes, we triangulated several approaches to model specification in our sensitivity analyses and all yielded consistent results. Because we aimed to examine outcomes at 12 months, our cohorts were enrolled before 15 January 2021 (before SARS-CoV-2 vaccines were widely available in the US), and less than 1% of people in the COVID-19 group and contemporary control group were vaccinated before T0. Our subgroup analyses were designed to estimate the risk of outcomes in each subgroup, the strength of the association for any specific outcome may not be necessarily comparable across subgroups. Finally, the pandemic remains a highly dynamic global event; as new variants of SARS-CoV-2 emerge, as vaccine uptake improves, as therapeutics for acute COVID-19 (monoclonal antibodies, antiviral agents) become more available, it is possible that the epidemiology of the long-term sequelae of SARS-CoV-2 infection (including long-term neurologic sequelae) may also change over time.
In conclusion, our report provides a comprehensive analysis of neurologic outcomes at 12 months. We show increased risk of an array of neurologic disorders spanning several neurologic disease categories including stroke (both ischemic and hemorrhagic), cognition and memory disorders, peripheral nervous system disorders, episodic disorders, extrapyramidal and movement disorders, mental health disorders, musculoskeletal disorders, sensory disorders, and other disorders including Guillain–Barré syndrome, and encephalitis or encephalopathy. The risks were evident in all examined subgroups and were evident even in people who were not hospitalized during the acute phase of the disease. Altogether, the findings call for attention to the long-term neurologic consequences of SARS-CoV-2 infection. Both healthcare system planning, and more broadly, public policy making, should take into account the long-term neurologic (and other) consequences of infection with SARS-CoV-2.
A study published last month in 
