BMC Neurology: Long-term Neurological and Cognitive Impact of COVID-19: A Systematic Review and Meta-analysis in over 4 Million Patients

#18,759

In the opening months of the COVID pandemic we looked at a study (see JAMA: Neurologic Manifestations Of Patients With Severe Coronavirus Disease) which reported more than 1/3rd of a study group (n=214) hospitalized in Wuhan, China showed signs of neurological involvement.

Neurological manifestations ranged from relatively mild (headaches, dizziness, anosmia, mild confusion, etc.) to more profound (seizures, stupor, loss of consciousness, etc.) to potentially fatal (ischemic stroke, cerebral hemorrhage, muscle injury (rhabdomyolysis), etc.). 

While this early report from Wuhan indicated an unusually high percentage of patients with neurological symptoms, it isn't unheard of that a severe respiratory infection can cause neurological complications. 

Two years previously, in Neuroinfluenza: A Review Of Recently Published Studies, we had looked at rare instances of neurological manifestations associated with with seasonal (and avian) influenza infection.

Credit CDC 2018 COCA Call On Severe Influenza

Over that first summer we saw a number of studies on neurological manifestations in COVID patients - with some warning of potential long-term sequelae - including an enhanced risk of Parkinson's disease.

• In mid-June, in The Lancet: COVID-19: Can We Learn From Encephalitis Lethargica?, we revisited the mysterious neurological epidemic that began around the time of the 1918 pandemic, and continued on for a decade.
• A couple of weeks later, in The Lancet: Yet Another Study On Neurological Manifestations In Severe COVID-19 Patients, we looked at report published in The Lancet Psychiatry, that described 153 COVID-19 cases treated in UK hospitals which found a wide range of neurological and psychiatric complications affecting both younger and elderly patients.
• In July I blogged on a 63-page report from the Journal Brain called The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings.
• In August, in J. Neurology: COVID-19 As A Potential Risk Factor For Chronic Neurological. Disorders, we revisited the growing concerns over the long-term neurological impacts of COVID-19 infection.
• And late last month (see Parkinsonism as a Third Wave of the COVID-19 Pandemic?) we looked at a Review Article, published in the Journal of Parkinson's Disease, that examined the parallels between COVID-19 and epidemics of the past, and the potential for seeing a new wave of neurological disorders.

By November of 2020 it had become apparent that COVID caused more than just a nasty respiratory infection; that it could affect many other parts of the body, and sometimes leave behind a wide range of post-covid symptoms (see CDC: Late Sequelae of COVID-19 (Long COVID).

Although the degree of impairment can vary widely, and many of these impacts may lessen or resolve over time, we've seen studies suggesting that as many as 1 in 5 adults (20%) experience some type of `Long-COVID' sequelae.

Studies suggest that Post-COVID sequelae also includes increased cardiac risks, increased new onset hypertension, an increased risk of developing diabetes, strokes, and kidney disease/injury. 

None of this information was exactly welcomed by governments eager to `move past' the pandemic - and a public desperate for a return to `normalcy' - so much of the research over the past 4 years has been dismissed or ignored.

Despite the accumulating evidence to the contrary - to most people - COVID is now regarded as little more than a `bad cold'.

COVID vaccine uptake has plummeted, despite research showing it can provide significant protection against both severe outcomes and `Long COVID' (see ECDC Rapid Review: Does COVID-19 Vaccination Reduce the Risk and Duration of Post COVID-19 Condition?).

While I could wax apoplectic for hours on this topic, today we've an impressive Systematic Review & Meta-analysis based on more that 4 million patients, which finds that neurological symptoms are both common and persistent in COVID-19 survivors.

This is, as you might imagine, an extensive review and its 16-page PDF deserves careful reading. But briefly, they report fatigue affecting over 40% of patients and memory disorders affecting nearly 30%, at least 6 months post infection. 

There is obviously a great deal to take in, so follow the link to read this review in its entirety.  I'll have a brief postscript when you return. 

Long-term neurological and cognitive impact of COVID-19: a systematic review and meta-analysis in over 4 million patients
Toka Elboraay, Mahmoud A. Ebada, Maged Elsayed, Heba Ahmed Aboeldahab, Hazem Mohamed Salamah, Omar Rageh, Mohamed Elmallahy, Hadeer Elsaeed AboElfarh, Lena Said Mansour, Yehia Nabil, Ahmed Khaled Abd Eltawab, Hany Atwan & Souad Alkanj

BMC Neurology volume 25, Article number: 250 (2025) Cite this article

Abstract

Background

Neuropsychiatric symptoms emerged early in the COVID-19 pandemic as a key feature of the virus, with research confirming a range of neuropsychiatric manifestations linked to acute SARS-CoV-2 infection. However, the persistence of neurological symptoms in the post-acute and chronic phases remains unclear. This meta-analysis assesses the long-term neurological effects of COVID-19 in recovered patients, providing insights for mental health service planning.

Methods

A comprehensive literature search was conducted across five electronic databases: PubMed, Scopus, Web of Science, EBSCO, and CENTRAL, up to March 22, 2024. Studies evaluating the prevalence of long-term neurological symptoms in COVID-19 survivors with at least six months of follow-up were included. Pooled prevalence estimates, subgroup analyses, and meta-regression were performed, and publication bias was assessed.

Results

The prevalence rates for the different symptoms were as follows: fatigue 43.3% (95% CI [36.1-50.9%]), memory disorders 27.8% (95% CI [20.1-37.1%]), cognitive impairment 27.1% (95% CI [20.4-34.9%]), sleep disorders 24.4% (95% CI [18.1-32.1%]), concentration impairment 23.8% (95% CI [17.2-31.9%]), headache 20.3% (95% CI [15-26.9%]), dizziness 16% (95% CI [9.5-25.7%]), stress 15.9% (95% CI [10.2-24%]), depression 14.0% (95% CI [10.1-19.2%]), anxiety 13.2% (95% CI [9.6-17.9%]), and migraine 13% (95% CI [2.2-49.8%]). Significant heterogeneity was observed across all symptoms. Meta-regression analysis showed higher stress, fatigue, and headache in females, and increased stress and concentration impairment with higher BMI.

Conclusions

Neurological symptoms are common and persistent in COVID-19 survivors. This meta-analysis highlights the significant burden these symptoms place on individuals, emphasizing the need for well-resourced multidisciplinary healthcare services to support post-COVID recovery.

Registration and protocol

This meta-analysis was registered in PROSPERO with registration number CRD42024576237.

       (SNIP)

Conclusion

In conclusion, this meta-analysis highlights the significant prevalence of long-term neuropsychiatric symptoms associated with COVID-19, including fatigue, depression, anxiety, cognitive impairment, sleep disturbances, and headaches.

These persistent issues underscore the need for healthcare systems to prioritize mental health and cognitive care for post-COVID-19 patients. Comprehensive, multidisciplinary strategies that address both physical and mental health are essential to improve patient outcomes and quality of life. Such efforts will support the development of targeted treatments, mitigating the pandemic’s enduring impact on mental health and enhancing overall wellbeing.

        (Continue . . . )

Although this review focuses on observed (or reported) post-COVID neurological manifestations, the authors do discuss the potential for seeing neurodegenerative diseases develop over a longer time period.

Our findings indicated that 27.8% of 1,299,214 patients experienced memory problems, a prevalence significantly higher than the 17.5% reported by Zeng et al. (2023) among 7,322 patients. This elevated prevalence may stem from multiple interconnected mechanisms, including neuroinflammation, disrupted neurotransmitter activity, and irregular sleep patterns, all known to impair hippocampal function. The hippocampus is vital for memory consolidation, learning, and neurogenesis, specifically through the production of neural stem cells in the dentate gyrus.

However, this brain region is particularly vulnerable to neurodegenerative processes and psychiatric disorders, which may be amplified by SARS-CoV-2 infection. Evidence suggests that the hippocampus is a primary target of the virus’s effects, contributing to post-infection memory loss through mechanisms such as oxidative stress, cytokine-driven inflammation, and vascular damage [160, 165, 180].

Two years ago we looked at a study (see Neuron: Virus Exposure and Neurodegenerative Disease Risk Across National Biobanks), which found statistical linkage between viral illnesses and developing neurodegenerative diseases in the future.

Even if these worst-case neurodegenerative impacts from COVID never materialize, there are other viruses with pandemic potential - including H5N1 - which have been repeatedly linked to neurological impacts (see here, here, here, and here).

Making it imperative that we take the lessons from COVID seriously, else we risk far more damage from the next global health crisis.